|
1
|
Yuan H, Zhang Y, Liu F, Wu Y, Huang X, Liu X, Jiang L, Xiao B, Zhu Y, Chen Q, Wu P, Jiang K. Exploring the biological mechanism and clinical value of perineural invasion in pancreatic cancer. Cancer Lett 2025; 613:217515. [PMID: 39892698 DOI: 10.1016/j.canlet.2025.217515] [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: 10/28/2024] [Revised: 01/30/2025] [Accepted: 01/30/2025] [Indexed: 02/04/2025]
Abstract
Pancreatic cancer (PC) is an extremely aggressive malignancy, with a 5-year survival rate of only 13 %. Perineural invasion (PNI) is a hallmark pathological feature of PC and is observed in almost all cases. Accordingly, PC ranks highly among solid tumors in terms of PNI incidence. The interaction between PC and the nervous system plays a pivotal role in tumor growth and metastasis. In PC, PNI is a key driver of local tumor progression, distant metastasis, and poor prognosis. Clarification of tumor-nerve crosstalk and the underlying molecular mechanisms is needed to facilitate the development of new therapeutic strategies to slow PC progression and alleviate PNI-associated symptoms. In this review, we present a comprehensive overview of the manifestations and characteristics of PNI in PC, summarize the molecular networks that regulate PNI, examine the relationship between PNI and the tumor microenvironment, and discuss the current research challenges and future directions in this critical area.
Collapse
Affiliation(s)
- Hao Yuan
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yufeng Zhang
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Fengyuan Liu
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yang Wu
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Xumin Huang
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Xinjian Liu
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, China
| | - Luyang Jiang
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Bin Xiao
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yi Zhu
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China; Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
| | - Qun Chen
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China.
| | - Pengfei Wu
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China.
| | - Kuirong Jiang
- Pancreas Centre, First Affiliated Hospital, Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China.
| |
Collapse
|
|
2
|
Sanford NN, Narang AK, Aguilera TA, Bassetti MF, Chuong MD, Erickson BA, Goodman KA, Herman JM, Intven M, Kilcoyne A, Kim H, Paulson E, Reyngold M, Tsai S, Tchelebi LT, Tuli R, Versteijne E, Wei AC, Wo JY, Zhang Y, Hong TS, Hall WA. NRG Oncology International Consensus Contouring Atlas on Target Volumes and Dosing Strategies for Dose-Escalated Pancreatic Cancer Radiation Therapy. Int J Radiat Oncol Biol Phys 2025; 121:918-929. [PMID: 39510320 DOI: 10.1016/j.ijrobp.2024.10.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/09/2024] [Accepted: 10/11/2024] [Indexed: 11/15/2024]
Abstract
PURPOSE Dose-escalated radiation therapy is increasingly used in the treatment of pancreatic cancer; however, approaches to target delineation vary widely. We present the first North American cooperative group consensus contouring atlas for dose-escalated pancreatic cancer radiation therapy. METHODS AND MATERIALS An expert international panel comprising 15 radiation oncologists, 2 surgeons, and 1 radiologist was recruited. Participants used MimCloud software to contour high- and low-risk clinical target volumes (CTVs) on 3 pancreatic cancer cases: a borderline resectable head tumor, a locally advanced head tumor, and a medically inoperable tail tumor. Simultaneous Truth and Performance Level Estimation volumes were created, and contours were analyzed using Dice similarity coefficients. RESULTS The contoured gross tumor volume for the borderline head, locally advanced head, and unresectable tail tumor cases were 156.7, 58.2, and 9.0 cc, respectively, and the Dice similarity coefficients (SD) for the high- and low-risk CTV ranged from 0.45 to 0.82. Consensus volumes were agreed upon by authors. High-risk CTVs comprised the tumor plus abutting vessels. Low-risk CTVs started superiorly at (tail and distal body tumors) or 1 cm above (head, neck and proximal body tumors) the celiac takeoff and extended inferiorly to the superior mesenteric artery at the level of the first jejunal takeoff. For head, neck, and proximal body tumors, the lateral volume encompassed the entire pancreas head and 5 to 10 mm around the celiac, superior mesenteric artery, superior mesenteric vein, including the common hepatic artery and medial portal vein, consistent with a "Triangle" volume-based approach. For distal body and tail tumors, the entire tail was included, along with the splenic vessels and the takeoffs of celiac artery. CONCLUSIONS Through multidisciplinary collaboration, we created consensus contouring guidelines for dose-escalated pancreatic cancer radiation therapy. These volumes include not only gross disease, but also routine elective coverage, and can be used to standardize practice for future trials seeking to define the role of dose-escalated radiation therapy in pancreatic cancer.
Collapse
Affiliation(s)
- Nina N Sanford
- Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas.
| | - Amol K Narang
- Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Todd A Aguilera
- Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Michael F Bassetti
- Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, Wisconsin
| | - Michael D Chuong
- Department of Radiation Oncology, Miami Cancer Institute, Miami, Florida
| | - Beth A Erickson
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Karyn A Goodman
- Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Joseph M Herman
- Northwell Health Cancer Institute, Department of Radiation Medicine, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY; Histosonics, Plymouth, Minnesota
| | - Martijn Intven
- Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Aoife Kilcoyne
- Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts
| | - Hyun Kim
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri
| | - Eric Paulson
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Marsha Reyngold
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Susan Tsai
- Department of Surgical Oncology, Ohio State University, Columbus, Ohio
| | - Leila T Tchelebi
- Northwell Health Cancer Institute, Department of Radiation Medicine, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY
| | - Richard Tuli
- Department of Radiation Oncology, University of South Florida, Morsani College of Medicine, Florida
| | - Eva Versteijne
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Alice C Wei
- Department of Radiation Oncology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Jennifer Y Wo
- Department of Surgical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ying Zhang
- Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Theodore S Hong
- Department of Surgical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - William A Hall
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| |
Collapse
|
|
3
|
Rutkowski K, Gola M, Godlewski J, Starzyńska A, Marvaso G, Mastroleo F, Giulia Vincini M, Porazzi A, Zaffaroni M, Jereczek-Fossa BA. Understanding the role of nerves in head and neck cancers - a review. Oncol Rev 2025; 18:1514004. [PMID: 39906323 PMCID: PMC11791411 DOI: 10.3389/or.2024.1514004] [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: 10/19/2024] [Accepted: 12/03/2024] [Indexed: 02/06/2025] Open
Abstract
Worldwide, head and neck cancers (HNCs) account for approximately 900,000 cases and 500,000 deaths annually, with their incidence continuing to rise. Carcinogenesis is a complex, multidimensional molecular process leading to cancer development, and in recent years, the role of nerves in the pathogenesis of various malignancies has been increasingly recognized. Thanks to the abundant innervation of the head and neck region, peripheral nervous system has gained considerable interest for its possible role in the development and progression of HNCs. Intratumoral parasympathetic, sympathetic, and sensory nerve fibers are emerging as key players and potential targets for novel anti-cancer and pain-relieving medications in different tumors, including HNCs. This review explores nerve-cancer interactions, including perineural invasion (PNI), cancer-related axonogenesis, neurogenesis, and nerve reprogramming, with an emphasis on their molecular mechanisms, mediators and clinical implications. PNI, an adverse histopathologic feature, has been widely investigated in HNCs. However, its prognostic value remains debated due to inconsistent results when classified dichotomously (present/absent). Emerging evidence suggests that quantitative and qualitative descriptions of PNI may better reflect its clinical usefulness. The review also examines therapies targeting nerve-cancer crosstalk and highlights the influence of HPV status on tumor innervation. By synthesizing current knowledge, challenges, and future perspectives, this review offers insights into the molecular basis of nerve involvement in HNCs and the potential for novel therapeutic approaches.
Collapse
Affiliation(s)
- Krzysztof Rutkowski
- Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Michał Gola
- Department of Human Histology and Embryology, Collegium Medicum, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland
- Department of Oncology and Immuno-Oncology, Clinical Hospital of the Ministry of Internal Affairs and Administration with the Warmia-Mazury Oncology Centre, Olsztyn, Poland
| | - Janusz Godlewski
- Department of Human Histology and Embryology, Collegium Medicum, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland
- Department of Surgical Oncology, Clinical Hospital of the Ministry of Internal Affairs and Administration with the Warmia-Mazury Oncology Centre, Olsztyn, Poland
| | - Anna Starzyńska
- Department of Oral Surgery, Medical University of Gdańsk, Gdańsk, Poland
- Department of Otolaryngology, Phoniatrics and Audiology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Giulia Marvaso
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Federico Mastroleo
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Maria Giulia Vincini
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Alice Porazzi
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | - Mattia Zaffaroni
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | - Barbara Alicja Jereczek-Fossa
- Division of Radiation Oncology, European Institute of Oncology (IEO), Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| |
Collapse
|
|
4
|
Trentini F, Agnetti V, Manini M, Giovannetti E, Garajová I. NGF-mediated crosstalk: unraveling the influence of metabolic deregulation on the interplay between neural and pancreatic cancer cells and its impact on patient outcomes. Front Pharmacol 2024; 15:1499414. [PMID: 39723256 PMCID: PMC11668609 DOI: 10.3389/fphar.2024.1499414] [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: 09/20/2024] [Accepted: 11/21/2024] [Indexed: 12/28/2024] Open
Abstract
Neural invasion is one of the most common routes of invasion in pancreatic cancer and it is responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Several molecules implicated in neural invasion are also responsible for pain onset including NGF belonging to the family of neutrophins. NGF released by cancer cells can sensitize sensory nerves which in turn results in severe pain. NGF receptors, TrkA and P75NTR, are expressed on both PDAC cells and nerves, strongly suggesting their role in neural invasion. The crosstalk between the nervous system and cancer cells has emerged as an important regulator of pancreatic cancer and its microenvironment. Nerve cells influence the pancreatic tumor microenvironment and these interactions are important for cancer metabolism reprogramming and tumor progression. In this review, we summarized the current knowledge on the interaction between nerves and pancreatic cancer cells and its impact on cancer metabolism.
Collapse
Affiliation(s)
| | - Virginia Agnetti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Martina Manini
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, Lab of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, Netherlands
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Pisa, Italy
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, Cancer Pharmacology Iacome Department, San Giuliano Terme, Italy
| | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| |
Collapse
|
|
5
|
Fan H, Liang X, Tang Y. Neuroscience in peripheral cancers: tumors hijacking nerves and neuroimmune crosstalk. MedComm (Beijing) 2024; 5:e784. [PMID: 39492832 PMCID: PMC11527832 DOI: 10.1002/mco2.784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/25/2024] [Accepted: 09/25/2024] [Indexed: 11/05/2024] Open
Abstract
Cancer neuroscience is an emerging field that investigates the intricate relationship between the nervous system and cancer, gaining increasing recognition for its importance. The central nervous system governs the development of the nervous system and directly affects brain tumors, and the peripheral nervous system (PNS) shapes the tumor microenvironment (TME) of peripheral tumors. Both systems are crucial in cancer initiation and progression, with recent studies revealing a more intricate role of the PNS within the TME. Tumors not only invade nerves but also persuade them through remodeling to further promote malignancy, creating a bidirectional interaction between nerves and cancers. Notably, immune cells also contribute to this communication, forming a triangular relationship that influences protumor inflammation and the effectiveness of immunotherapy. This review delves into the intricate mechanisms connecting the PNS and tumors, focusing on how various immune cell types influence nerve‒tumor interactions, emphasizing the clinical relevance of nerve‒tumor and nerve‒immune dynamics. By deepening our understanding of the interplay between nerves, cancer, and immune cells, this review has the potential to reshape tumor biology insights, inspire innovative therapies, and improve clinical outcomes for cancer patients.
Collapse
Affiliation(s)
- Hua‐Yang Fan
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial SurgeryWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Xin‐Hua Liang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial SurgeryWest China Hospital of StomatologySichuan UniversityChengduChina
| | - Ya‐Ling Tang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Oral PathologyWest China Hospital of StomatologySichuan UniversityChengduChina
| |
Collapse
|
|
6
|
Uemura M, Sugiura T, Ashida R, Ohgi K, Yamada M, Otsuka S, Aramaki T, Notsu A, Uesaka K. Predictive factors of actual 5-y recurrence-free survival after upfront surgery for resectable pancreatic cancer: Exploration of patients who did not require neoadjuvant treatment. Ann Gastroenterol Surg 2024; 8:1126-1136. [PMID: 39502725 PMCID: PMC11533024 DOI: 10.1002/ags3.12834] [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: 02/27/2024] [Revised: 05/02/2024] [Accepted: 05/21/2024] [Indexed: 11/08/2024] Open
Abstract
Aim The present study investigated the prognostic factors associated with actual 5-y recurrence-free survival (RFS) after upfront surgery for resectable pancreatic cancer (R-PC) in patients who were deemed not to require neoadjuvant treatment. Methods Between 2007 and 2016, 316 patients who underwent pancreatectomy for radiologically R-PC were retrospectively reviewed to evaluate the predictors of actual 5-y RFS. Predictors were identified using logistic regression analysis of preoperative evaluable factors. The cutoff values for continuous variables were determined based on a minimum p-value approach (model 1) or the value that maximized the rate of 5-y RFS survivors (model 2). Results Fifty-one patients (16.1%) achieved a 5-y RFS. A tumor size ≤23 mm, the absence of serosal invasion on computed tomography (CT), and Neutrophil-to-Lymphocyte Ratio <1.0, were significantly associated with the 5-y RFS in model 1. A Prognostic Nutritional Index ≥58 and the absence of serosal invasion and extrapancreatic nerve plexus invasion on CT were significantly associated with 5-y RFS in model 2. Only six (11.8%, model 1) and four (7.8%, model 2) patients had all three prognostic factors, and their 5-y RFS rates were 83.3% and 100%, respectively. Conclusions A modest number of patients who underwent upfront surgery achieved 5-y RFS, but only ~10% of them could be identified preoperatively. Based on these results, almost all R-PC patients are forced to undergo neoadjuvant treatment in daily practice.
Collapse
Affiliation(s)
- Masao Uemura
- Division of Hepato‐Biliary‐Pancreatic SurgeryShizuoka Cancer CenterShizuokaJapan
| | - Teiichi Sugiura
- Division of Hepato‐Biliary‐Pancreatic SurgeryShizuoka Cancer CenterShizuokaJapan
| | - Ryo Ashida
- Division of Hepato‐Biliary‐Pancreatic SurgeryShizuoka Cancer CenterShizuokaJapan
| | - Katsuhisa Ohgi
- Division of Hepato‐Biliary‐Pancreatic SurgeryShizuoka Cancer CenterShizuokaJapan
| | - Mihoko Yamada
- Division of Hepato‐Biliary‐Pancreatic SurgeryShizuoka Cancer CenterShizuokaJapan
| | - Shimpei Otsuka
- Division of Hepato‐Biliary‐Pancreatic SurgeryShizuoka Cancer CenterShizuokaJapan
| | - Takeshi Aramaki
- Division of Diagnostic RadiologyShizuoka Cancer CenterShizuokaJapan
| | - Akifumi Notsu
- Clinical Research CenterShizuoka Cancer CenterShizuokaJapan
| | - Katsuhiko Uesaka
- Division of Hepato‐Biliary‐Pancreatic SurgeryShizuoka Cancer CenterShizuokaJapan
| |
Collapse
|
|
7
|
Wang J, Yang J, Narang A, He J, Wolfgang C, Li K, Zheng L. Consensus, debate, and prospective on pancreatic cancer treatments. J Hematol Oncol 2024; 17:92. [PMID: 39390609 PMCID: PMC11468220 DOI: 10.1186/s13045-024-01613-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 09/25/2024] [Indexed: 10/12/2024] Open
Abstract
Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite the improvement of multi-modality treatment strategies, the prognosis of pancreatic cancer was not improved dramatically. For resectable or borderline resectable patients, the surgical strategy centered on improving R0 resection rate is consensus; however, the role of neoadjuvant therapy in resectable patients and the optimal neoadjuvant therapy of chemotherapy with or without radiotherapy in borderline resectable patients were debated. Postoperative adjuvant chemotherapy of gemcitabine/capecitabine or mFOLFIRINOX is recommended regardless of the margin status. Chemotherapy as the first-line treatment strategy for advanced or metastatic patients included FOLFIRINOX, gemcitabine/nab-paclitaxel, or NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan was the only standard of care second-line therapy. Immunotherapy is an innovative therapy although anti-PD-1 antibody is currently the only agent approved by for MSI-H, dMMR, or TMB-high solid tumors, which represent a very small subset of pancreatic cancers. Combination strategies to increase the immunogenicity and to overcome the immunosuppressive tumor microenvironment may sensitize pancreatic cancer to immunotherapy. Targeted therapies represented by PARP and KRAS inhibitors are also under investigation, showing benefits in improving progression-free survival and objective response rate. This review discusses the current treatment modalities and highlights innovative therapies for pancreatic cancer.
Collapse
Affiliation(s)
- Junke Wang
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Jie Yang
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041, Sichuan, China
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Amol Narang
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Jin He
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Christopher Wolfgang
- Department of Surgery, New York University School of Medicine and NYU-Langone Medical Center, New York, NY, USA
| | - Keyu Li
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, 37 Guoxue Alley, Chengdu, 610041, Sichuan, China.
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA.
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA.
- The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- The Multidisciplinary Gastrointestinal Cancer Laboratories Program, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
| |
Collapse
|
|
8
|
Seufferlein T, Mayerle J, Boeck S, Brunner T, Ettrich TJ, Grenacher L, Gress TM, Hackert T, Heinemann V, Kestler A, Sinn M, Tannapfel A, Wedding U, Uhl W. S3-Leitlinie Exokrines Pankreaskarzinom – Version 3.1. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1724-1785. [PMID: 39389105 DOI: 10.1055/a-2338-3716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Affiliation(s)
| | | | | | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz, Austria
| | | | | | - Thomas Mathias Gress
- Gastroenterologie und Endokrinologie Universitätsklinikum Gießen und Marburg, Germany
| | - Thilo Hackert
- Klinik und Poliklinik für Allgemein-, Viszeral- und Thoraxchirurgie, Universitätsklinikum Hamburg-Eppendorf, Germany
| | - Volker Heinemann
- Medizinische Klinik und Poliklinik III, Klinikum der Universität München-Campus Grosshadern, München, Germany
| | | | - Marianne Sinn
- Medizinische Klinik und Poliklinik II Onkologie und Hämatologie, Universitätsklinikum Hamburg-Eppendorf, Germany
| | | | | | - Waldemar Uhl
- Allgemein- und Viszeralchirurgie, St Josef-Hospital, Bochum, Germany
| |
Collapse
|
|
9
|
Seufferlein T, Mayerle J, Boeck S, Brunner T, Ettrich TJ, Grenacher L, Gress TM, Hackert T, Heinemann V, Kestler A, Sinn M, Tannapfel A, Wedding U, Uhl W. S3-Leitlinie Exokrines Pankreaskarzinom – Version 3.1. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:e874-e995. [PMID: 39389103 DOI: 10.1055/a-2338-3533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Affiliation(s)
| | | | | | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz, Austria
| | | | | | - Thomas Mathias Gress
- Gastroenterologie und Endokrinologie Universitätsklinikum Gießen und Marburg, Germany
| | - Thilo Hackert
- Klinik und Poliklinik für Allgemein-, Viszeral- und Thoraxchirurgie, Universitätsklinikum Hamburg-Eppendorf, Germany
| | - Volker Heinemann
- Medizinische Klinik und Poliklinik III, Klinikum der Universität München-Campus Grosshadern, München, Germany
| | | | - Marianne Sinn
- Medizinische Klinik und Poliklinik II Onkologie und Hämatologie, Universitätsklinikum Hamburg-Eppendorf, Germany
| | | | | | - Waldemar Uhl
- Allgemein- und Viszeralchirurgie, St Josef-Hospital, Bochum, Germany
| |
Collapse
|
|
10
|
Nozzoli F, Catalano M, Messerini L, Cianchi F, Nassini R, De Logu F, Iannone LF, Ugolini F, Simi S, Massi D, Geppetti P, Roviello G. Perineural invasion score system and clinical outcomes in resected pancreatic cancer patients. Pancreatology 2024; 24:553-561. [PMID: 38514359 DOI: 10.1016/j.pan.2024.03.004] [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: 01/10/2024] [Revised: 02/21/2024] [Accepted: 03/06/2024] [Indexed: 03/23/2024]
Abstract
BACKGROUND/OBJECTIVES Perineural invasion (PNI), classified according to its presence or absence in tumor specimens, is recognized as a poor prognostic factor in pancreatic ductal adenocarcinoma (PDAC) patients. Herein, we identified five histological features of PNI and investigated their impact on survival outcomes of PDAC resected patients. METHODS Five histopathological features of PNI (diameter, number, site, sheath involvement, and mitotic figures within perineural invasion) were combined in an additional final score (ranging from 0 to 8), and clinical data of PDAC patients were retrospectively analyzed. PNI + patients were stratified in two categories according to the median score value (<6 and ≥ 6, respectively). Impact of PNI on disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS Forty-five patients were enrolled, of whom 34 with PNI (PNI+) and 11 without PNI (PNI-). The DFS was 11 months vs. not reached (NR) (p = 0.258), while the OS was 19 months vs. NR (p = 0.040) in PNI+ and PNI- patients, respectively. A ≥6 PNI was identified as an independent predictor of worse OS vs. <6 PNI + patients (29 vs. 11 months, p < 0.001) and <6 PNI+ and PNI- patients (43 vs. 11 months, p < 0.001). PNI ≥6 was an independent negative prognostic factor of DFS vs. <6 PNI+ and PNI- patients (13 vs. 6 months, p = 0.022). CONCLUSIONS We report a PNI scoring system that stratifies surgically-treated PDAC patients in a graded manner that correlates with patient prognosis better than the current dichotomous (presence/absence) definition. However, further and larger studies are needed to support this PNI scoring system.
Collapse
Affiliation(s)
- Filippo Nozzoli
- Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy.
| | - Martina Catalano
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Luca Messerini
- Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Fabio Cianchi
- Section of Surgery, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Romina Nassini
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Francesco De Logu
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Luigi Francesco Iannone
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Filippo Ugolini
- Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Sara Simi
- Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Daniela Massi
- Section of Anatomic Pathology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Pierangelo Geppetti
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Giandomenico Roviello
- Section of Clinical Pharmacology & Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| |
Collapse
|
|
11
|
Lan Y, Zou S, Wang W, Chen Q, Zhu Y. Progress in cancer neuroscience. MedComm (Beijing) 2023; 4:e431. [PMID: 38020711 PMCID: PMC10665600 DOI: 10.1002/mco2.431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 12/01/2023] Open
Abstract
Cancer of the central nervous system (CNS) can crosstalk systemically and locally in the tumor microenvironment and has become a topic of attention for tumor initiation and advancement. Recently studied neuronal and cancer interaction fundamentally altered the knowledge about glioma and metastases, indicating how cancers invade complex neuronal networks. This review systematically discussed the interactions between neurons and cancers and elucidates new therapeutic avenues. We have overviewed the current understanding of direct or indirect communications of neuronal cells with cancer and the mechanisms associated with cancer invasion. Besides, tumor-associated neuronal dysfunction and the influence of cancer therapies on the CNS are highlighted. Furthermore, interactions between peripheral nervous system and various cancers have also been discussed separately. Intriguingly and importantly, it cannot be ignored that exosomes could mediate the "wireless communications" between nervous system and cancer. Finally, promising future strategies targeting neuronal-brain tumor interactions were reviewed. A great deal of work remains to be done to elucidate the neuroscience of cancer, and future more research should be directed toward clarifying the precise mechanisms of cancer neuroscience, which hold enormous promise to improve outcomes for a wide range of malignancies.
Collapse
Affiliation(s)
- Yu‐Long Lan
- Department of NeurosurgerySecond Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangChina
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological DiseasesHangzhouZhejiangChina
- Clinical Research Center for Neurological Diseases of Zhejiang ProvinceHangzhouChina
| | - Shuang Zou
- Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical ScienceZhejiang Chinese Medical UniversityHangzhouChina
| | - Wen Wang
- Department of NeurosurgeryBeijing Tiantan Hospital, Capital Medical UniversityBeijingChina
| | - Qi Chen
- Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical ScienceZhejiang Chinese Medical UniversityHangzhouChina
| | - Yongjian Zhu
- Department of NeurosurgerySecond Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangChina
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological DiseasesHangzhouZhejiangChina
- Clinical Research Center for Neurological Diseases of Zhejiang ProvinceHangzhouChina
| |
Collapse
|
|
12
|
Lee M, Thomas AS, Lee SY, Cho YJ, Jung HS, Yun WG, Han Y, Jang JY, Kluger MD, Kwon W. Reconsidering the absence of extrapancreatic extension in T staging for pancreatic adenocarcinoma in the AJCC (8 th ed) Staging Manual using the National Cancer Database. J Gastrointest Surg 2023; 27:2484-2492. [PMID: 37848688 DOI: 10.1007/s11605-023-05850-2] [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: 06/07/2023] [Accepted: 09/16/2023] [Indexed: 10/19/2023]
Abstract
PURPOSE Although the concept of extrapancreatic extension (EPEx) was removed in the eighth edition of the American Joint Committee on Cancer pancreatic cancer staging system, several studies have supported the prognostic significance of EPEx. This study aimed to investigate the significance of EPEx in pancreatic ductal adenocarcinoma (PDAC) using the National Cancer Database (NCDB). METHODS Data of patients who underwent resection for PDAC between 2006 and 2016 were extracted and analyzed from the NCDB. Cases arising from premalignant lesions, those with metastases, and those treated with neoadjuvant therapy were excluded. RESULTS Among 37,634 patients, the median overall survival was 23 months and the 5-year survival rate was 22.7%. The EPEx prevalence was the lowest for T1 stage (63.2%) and increased with each T-stage (T2:83.4%, T3:85.8%). The overall survival was better in EPEx-negative patients than in EPEx-positive patients (median 33.7 vs. 21.5 months; p<0.001). When the T-stages were stratified by EPEx, EPEx-positive patients showed worse survival in all T-stages than EPEx-negative patients. Survival was comparable between T1 EPEx-positive and T2 or T3 EPEx-negative patients (p=0.088 and p=0.178, respectively). Furthermore, T2 and T3 EPEx-negative patients had similar survival to each other (p=0.877), and distinctly superior survival compared to T2 and T3 EPEx-positive patients (p<0.001). CONCLUSIONS EPEx was an important prognostic factor in the overall cohort and in differentiating between T stages. This study strongly suggests that staging systems should reinstate EPEx and apply it to all T-stages, especially in T1, where EPEx was absent in 36% of patients.
Collapse
Affiliation(s)
- Mirang Lee
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Chongno-gu, Seoul, 03080, South Korea
| | - Alexander S Thomas
- Division of GI/Endocrine Surgery, Department of Surgery, Columbia University Vagelos College of Physicians and Surgeons, New York, USA
| | - Seung Yeoun Lee
- Department of Mathematics and Statistics, Sejong University College of Natural Sciences, Seoul, Republic of Korea
| | - Young Jae Cho
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Chongno-gu, Seoul, 03080, South Korea
| | - Hye-Sol Jung
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Chongno-gu, Seoul, 03080, South Korea
| | - Won-Gun Yun
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Chongno-gu, Seoul, 03080, South Korea
| | - Youngmin Han
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Chongno-gu, Seoul, 03080, South Korea
| | - Jin-Young Jang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Chongno-gu, Seoul, 03080, South Korea
| | - Michael D Kluger
- Division of GI/Endocrine Surgery, Department of Surgery, Columbia University Vagelos College of Physicians and Surgeons, New York, USA
| | - Wooil Kwon
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Chongno-gu, Seoul, 03080, South Korea.
| |
Collapse
|
|
13
|
Bahmad HF, Gogola S, Rejzer M, Stoyanov K, Gomez AS, Valencia AK, Cummings A, Skerry T, Alloush F, Aljamal AA, Deb A, Alghamdi S, Poppiti R. Unraveling the Mysteries of Perineural Invasion in Benign and Malignant Conditions. Curr Oncol 2023; 30:8948-8972. [PMID: 37887547 PMCID: PMC10605475 DOI: 10.3390/curroncol30100647] [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: 09/08/2023] [Revised: 09/27/2023] [Accepted: 09/29/2023] [Indexed: 10/28/2023] Open
Abstract
Perineural invasion (PNI) is defined as the dissemination of neoplastic cells within the perineural space. PNI can be a strong indicator of malignancy and is linked to poor prognosis and adverse outcomes in various malignant neoplasms; nevertheless, it can also be seen in benign pathologic conditions. In this review article, we discuss various signaling pathways and neurotrophic factors implicated in the development and progression of PNI. We also describe the methodology, benefits, and limitations of different in vitro, ex vivo, and in vivo models of PNI. The spectrum of presentation for PNI can range from diffuse spread within large nerves ("named" nerves) all the way through localized spread into unnamed microscopic nerves. Therefore, the clinical significance of PNI is related to its extent rather than its mere presence or absence. In this article, we discuss the guidelines for the identification and quantification of PNI in different malignant neoplasms based on the College of American Pathologists (CAP) and World Health Organization (WHO) recommendations. We also describe benign pathologic conditions and neoplasms demonstrating PNI and potential mimics of PNI. Finally, we explore avenues for the future development of targeted therapy options via modulation of signaling pathways involved in PNI.
Collapse
Affiliation(s)
- Hisham F. Bahmad
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA; (F.A.); (A.D.); (S.A.); (R.P.)
| | - Samantha Gogola
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (S.G.); (M.R.); (K.S.); (A.S.G.); (A.-K.V.); (A.C.); (T.S.)
| | - Michael Rejzer
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (S.G.); (M.R.); (K.S.); (A.S.G.); (A.-K.V.); (A.C.); (T.S.)
| | - Kalin Stoyanov
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (S.G.); (M.R.); (K.S.); (A.S.G.); (A.-K.V.); (A.C.); (T.S.)
| | - Aaron S. Gomez
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (S.G.); (M.R.); (K.S.); (A.S.G.); (A.-K.V.); (A.C.); (T.S.)
| | - Ann-Katrin Valencia
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (S.G.); (M.R.); (K.S.); (A.S.G.); (A.-K.V.); (A.C.); (T.S.)
| | - Adonicah Cummings
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (S.G.); (M.R.); (K.S.); (A.S.G.); (A.-K.V.); (A.C.); (T.S.)
| | - Timothy Skerry
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA; (S.G.); (M.R.); (K.S.); (A.S.G.); (A.-K.V.); (A.C.); (T.S.)
| | - Ferial Alloush
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA; (F.A.); (A.D.); (S.A.); (R.P.)
| | - Abed A. Aljamal
- Department of Medicine, Division of Hematology Oncology, Medical University of South Carolina, Charleston, SC 29425, USA;
| | - Arunima Deb
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA; (F.A.); (A.D.); (S.A.); (R.P.)
| | - Sarah Alghamdi
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA; (F.A.); (A.D.); (S.A.); (R.P.)
- Department of Pathology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Robert Poppiti
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA; (F.A.); (A.D.); (S.A.); (R.P.)
- Department of Pathology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| |
Collapse
|
|
14
|
Schiavo Lena M, Gasparini G, Crippa S, Belfiori G, Aleotti F, Di Salvo F, Redegalli M, Cangi MG, Taveggia C, Falconi M, Doglioni C. Quantification of perineural invasion in pancreatic ductal adenocarcinoma: proposal of a severity score system. Virchows Arch 2023; 483:225-235. [PMID: 37291275 DOI: 10.1007/s00428-023-03574-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 05/02/2023] [Accepted: 05/27/2023] [Indexed: 06/10/2023]
Abstract
Perineural invasion (PNI) is a common feature in pancreatic ductal adenocarcinoma (PDAC) and correlates with an aggressive tumor behavior already at early stages of disease. PNI is currently considered as a "present vs. absent" feature, and a severity score system has not yet been established. The aim of the present study was thus to develop and validate a score system for PNI and to correlate it with other prognostic features. In this monocentric retrospective study, 356 consecutive PDAC patients (61.8% upfront surgery patients, 38.2% received neoadjuvant therapy) were analyzed. PNI was scored as follows: 0: absent; 1: the presence of neoplasia along nerves < 3 mm in caliber; and 2: neoplastic infiltration of nerve fibers ≥ 3 mm and/or massive perineural infiltration and/or the presence of necrosis of the infiltrated nerve bundle. For every PNI grade, the correlation with other pathological features, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed. Uni- and multivariate analysis for DFS and DSS were also performed. PNI was found in 72.5% of the patients. Relevant trends between PNI score and tumor differentiation grade, lymph node metastases, vascular invasion, and surgical margins status were found. The latter was the only parameter statistically correlated with the proposed score. The agreement between pathologists was substantial (Cohen's K 0.61). PNI severity score significantly correlated also with decreased DFS and DSS at univariate analysis (p < 0.001). At multivariate analysis, only the presence of lymph node metastases was an independent predictor of DFS (HR 2.235 p < 0.001). Lymph node metastases (HR 2.902, p < 0.001) and tumor differentiation grade (HR 1.677, p = 0.002) were independent predictors of DSS. Our newly developed PNI score correlates with other features of PDAC aggressiveness and proved to have a prognostic role though less robust than lymph nodes metastases and tumor differentiation grade. A prospective validation is needed.
Collapse
Affiliation(s)
- Marco Schiavo Lena
- Pathology Unit, Pancreas Translational and Clinical Research Center, San Raffaele Research Hospital, 20132, Milan, Italy.
| | - Giulia Gasparini
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Research Hospital, Milan, Italy
| | - Stefano Crippa
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Research Hospital, Milan, Italy
| | - Giulio Belfiori
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Research Hospital, Milan, Italy
| | - Francesca Aleotti
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Research Hospital, Milan, Italy
| | - Francesca Di Salvo
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Research Hospital, Milan, Italy
| | - Miriam Redegalli
- Pathology Unit, Pancreas Translational and Clinical Research Center, San Raffaele Research Hospital, 20132, Milan, Italy
| | - Maria Giulia Cangi
- Pathology Unit, Pancreas Translational and Clinical Research Center, San Raffaele Research Hospital, 20132, Milan, Italy
| | - Carla Taveggia
- Axo-Glial Interaction Unit, Division of Neuroscience, San Raffaele Research Hospital, Milan, Italy
| | - Massimo Falconi
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Research Hospital, Milan, Italy
| | - Claudio Doglioni
- Pathology Unit, Pancreas Translational and Clinical Research Center, San Raffaele Research Hospital, 20132, Milan, Italy
| |
Collapse
|
|
15
|
Tu W, Gottumukkala RV, Schieda N, Lavallée L, Adam BA, Silverman SG. Perineural Invasion and Spread in Common Abdominopelvic Diseases: Imaging Diagnosis and Clinical Significance. Radiographics 2023; 43:e220148. [PMID: 37319024 DOI: 10.1148/rg.220148] [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: 06/17/2023]
Abstract
Malignancies and other diseases may spread by multiple pathways, including direct extension, hematogenous spread, or via lymphatic vessels. A less-well-understood route is the peripheral nervous system, which is known as perineural spread (PNS). In addition to accounting for pain and other neurologic symptoms, PNS affects both disease prognosis and management. Although PNS is commonly discussed in relation to head and neck tumors, there is emerging data regarding PNS in abdominopelvic malignancies and other conditions such as endometriosis. Due to improved contrast and spatial resolution, perineural invasion, a finding heretofore diagnosed only at pathologic examination, can be detected at CT, MRI, and PET/CT. PNS most commonly manifests as abnormal soft-tissue attenuation extending along neural structures, and diagnosis of it is aided by optimizing imaging parameters, understanding pertinent anatomy, and becoming familiar with the typical neural pathways of spread that largely depend on the disease type and location. In the abdomen, the celiac plexus is a central structure that innervates the major abdominal organs and is the principal route of PNS in patients with pancreatic and biliary carcinomas. In the pelvis, the lumbosacral plexus and inferior hypogastric plexus are the central structures and principal routes of PNS in patients with pelvic malignancies. Although the imaging findings of PNS may be subtle, a radiologic diagnosis can have a substantial effect on patient care. Knowledge of anatomy and known routes of PNS and optimizing imaging parameters is of utmost importance in providing key information for prognosis and treatment planning. © RSNA, 2023 Supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article. Quiz questions for this article are available through the Online Learning Center.
Collapse
Affiliation(s)
- Wendy Tu
- From the Department of Radiology and Diagnostic Imaging (W.T.) and Department of Laboratory Medicine and Pathology (B.A.A.), University of Alberta, 116 St & 85 Ave, Edmonton, AB, Canada T6G 2R3; Department of Radiology, Brigham and Women's Hospital, Harvard University, Boston, Mass (R.V.G., S.G.S.); and Departments of Radiology (N.S.) and Urology (L.L.), University of Ottawa, Ottawa, Ontario, Canada
| | - Ravi V Gottumukkala
- From the Department of Radiology and Diagnostic Imaging (W.T.) and Department of Laboratory Medicine and Pathology (B.A.A.), University of Alberta, 116 St & 85 Ave, Edmonton, AB, Canada T6G 2R3; Department of Radiology, Brigham and Women's Hospital, Harvard University, Boston, Mass (R.V.G., S.G.S.); and Departments of Radiology (N.S.) and Urology (L.L.), University of Ottawa, Ottawa, Ontario, Canada
| | - Nicola Schieda
- From the Department of Radiology and Diagnostic Imaging (W.T.) and Department of Laboratory Medicine and Pathology (B.A.A.), University of Alberta, 116 St & 85 Ave, Edmonton, AB, Canada T6G 2R3; Department of Radiology, Brigham and Women's Hospital, Harvard University, Boston, Mass (R.V.G., S.G.S.); and Departments of Radiology (N.S.) and Urology (L.L.), University of Ottawa, Ottawa, Ontario, Canada
| | - Luke Lavallée
- From the Department of Radiology and Diagnostic Imaging (W.T.) and Department of Laboratory Medicine and Pathology (B.A.A.), University of Alberta, 116 St & 85 Ave, Edmonton, AB, Canada T6G 2R3; Department of Radiology, Brigham and Women's Hospital, Harvard University, Boston, Mass (R.V.G., S.G.S.); and Departments of Radiology (N.S.) and Urology (L.L.), University of Ottawa, Ottawa, Ontario, Canada
| | - Benjamin A Adam
- From the Department of Radiology and Diagnostic Imaging (W.T.) and Department of Laboratory Medicine and Pathology (B.A.A.), University of Alberta, 116 St & 85 Ave, Edmonton, AB, Canada T6G 2R3; Department of Radiology, Brigham and Women's Hospital, Harvard University, Boston, Mass (R.V.G., S.G.S.); and Departments of Radiology (N.S.) and Urology (L.L.), University of Ottawa, Ottawa, Ontario, Canada
| | - Stuart G Silverman
- From the Department of Radiology and Diagnostic Imaging (W.T.) and Department of Laboratory Medicine and Pathology (B.A.A.), University of Alberta, 116 St & 85 Ave, Edmonton, AB, Canada T6G 2R3; Department of Radiology, Brigham and Women's Hospital, Harvard University, Boston, Mass (R.V.G., S.G.S.); and Departments of Radiology (N.S.) and Urology (L.L.), University of Ottawa, Ottawa, Ontario, Canada
| |
Collapse
|
|
16
|
Abstract
The nervous system regulates tissue stem and precursor populations throughout life. Parallel to roles in development, the nervous system is emerging as a critical regulator of cancer, from oncogenesis to malignant growth and metastatic spread. Various preclinical models in a range of malignancies have demonstrated that nervous system activity can control cancer initiation and powerfully influence cancer progression and metastasis. Just as the nervous system can regulate cancer progression, cancer also remodels and hijacks nervous system structure and function. Interactions between the nervous system and cancer occur both in the local tumour microenvironment and systemically. Neurons and glial cells communicate directly with malignant cells in the tumour microenvironment through paracrine factors and, in some cases, through neuron-to-cancer cell synapses. Additionally, indirect interactions occur at a distance through circulating signals and through influences on immune cell trafficking and function. Such cross-talk among the nervous system, immune system and cancer-both systemically and in the local tumour microenvironment-regulates pro-tumour inflammation and anti-cancer immunity. Elucidating the neuroscience of cancer, which calls for interdisciplinary collaboration among the fields of neuroscience, developmental biology, immunology and cancer biology, may advance effective therapies for many of the most difficult to treat malignancies.
Collapse
Affiliation(s)
- Rebecca Mancusi
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
- Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
| |
Collapse
|
|
17
|
Kiemen AL, Damanakis AI, Braxton AM, He J, Laheru D, Fishman EK, Chames P, Pérez CA, Wu PH, Wirtz D, Wood LD, Hruban RH. Tissue clearing and 3D reconstruction of digitized, serially sectioned slides provide novel insights into pancreatic cancer. MED 2023; 4:75-91. [PMID: 36773599 PMCID: PMC9922376 DOI: 10.1016/j.medj.2022.11.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 10/06/2022] [Accepted: 11/23/2022] [Indexed: 01/26/2023]
Abstract
Pancreatic cancer is currently the third leading cause of cancer death in the United States. The clinical hallmarks of this disease include abdominal pain that radiates to the back, the presence of a hypoenhancing intrapancreatic lesion on imaging, and widespread liver metastases. Technologies such as tissue clearing and three-dimensional (3D) reconstruction of digitized serially sectioned hematoxylin and eosin-stained slides can be used to visualize large (up to 2- to 3-centimeter cube) tissues at cellular resolution. When applied to human pancreatic cancers, these 3D visualization techniques have provided novel insights into the basis of a number of the clinical characteristics of this disease. Here, we describe the clinical features of pancreatic cancer, review techniques for clearing and the 3D reconstruction of digitized microscope slides, and provide examples that illustrate how 3D visualization of human pancreatic cancer at the microscopic level has revealed features not apparent in 2D microscopy and, in so doing, has closed the gap between bench and bedside. Compared with animal models and 2D microscopy, studies of human tissues in 3D can reveal the difference between what can happen and what does happen in human cancers.
Collapse
Affiliation(s)
- Ashley L Kiemen
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Chemical & Biomolecular Engineering, The Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA
| | - Alexander Ioannis Damanakis
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany
| | - Alicia M Braxton
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jin He
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Daniel Laheru
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Elliot K Fishman
- Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Patrick Chames
- Antibody Therapeutics and Immunotargeting Team, Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France
| | - Cristina Almagro Pérez
- Department of Chemical & Biomolecular Engineering, The Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA
| | - Pei-Hsun Wu
- Department of Chemical & Biomolecular Engineering, The Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA
| | - Denis Wirtz
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Chemical & Biomolecular Engineering, The Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA
| | - Laura D Wood
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
| | - Ralph H Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
| |
Collapse
|
|
18
|
Sung MK, Park H, Park G, Park SY, Lee W, Song KB, Lee JH, Kim SC, Hwang DW, Hong SM. Extranodal extension influences prognosis in pancreatic head cancer: A retrospective cohort study. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2023; 30:240-251. [PMID: 35687075 DOI: 10.1002/jhbp.1199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/08/2022] [Accepted: 05/11/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND Extranodal extension (ENE) is an established prognostic factor in several gastrointestinal cancers. However, the prognostic impact remains unclear. Here, we investigated the prognostic implications of ENE in patients with surgically resected pancreatic cancer. METHODS We retrospectively reviewed 476 surgically resected pancreatic head cancer patients who consecutively underwent upfront pancreaticoduodenectomy for pathologically confirmed pancreatic ductal adenocarcinoma between January 2009 and December 2013. We compared the disease-free survival (DFS) rates of the patients according to ENE status. RESULTS Among the 476 patients, patients with ENE had lower DFS rates than those without ENE (N0, 13 months; LN+/ENE-, 7 months; LN+/ENE+, 6 months; P < .001). In addition, even in the same N stage, patients with ENE had lower DFS rates than those without ENE (N0, 13 months; N1/ENE- 8 months; N1/ENE+, 7 months; N2/ENE-, 7 months; N2/ENE+, 4 months, P < .001). However, there was no significant difference in survival rates between patients in the N1/ENE+ group and those in the N2/ENE- group. Additionally, ENE was an independent prognostic factor for pancreatic cancer. CONCLUSIONS Extranodal extension significantly predicted a poor prognosis among patients with pancreatic head cancer, especially those with nodal metastasis. Therefore, ENE should be considered a prognostic factor in future editions of the staging system.
Collapse
Affiliation(s)
- Min Kyu Sung
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hosub Park
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Guisuk Park
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seo Young Park
- Department of Statistics and Data Science, Korea National Open University, Seoul, Korea
| | - Woohyung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ki Byung Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Hoon Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Song Cheol Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dae Wook Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seung Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| |
Collapse
|
|
19
|
Suzuki H, Mitsunaga S, Ikeda M, Aoyama T, Yoshizawa K, Yamaguchi M, Suzuki M, Narita M, Kawasaki T, Ochiai A. Interleukin 6/gp130 axis promotes neural invasion in pancreatic cancer. Cancer Med 2022; 11:5001-5012. [PMID: 35578571 PMCID: PMC9761092 DOI: 10.1002/cam4.4823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 08/14/2021] [Accepted: 08/24/2021] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Nerve invasion (N-inv) is an important prognostic factor in pancreatic ductal adenocarcinoma (PDAC). Elucidation of circulating N-inv stimulators could provide deeper insights and novel perspectives for PDAC therapy. The interleukin (IL)-6/gp130 axis was evaluated in this study as a candidate N-inv stimulator. METHODS A human pancreatic cancer (PC) cell, Capan-1, was confirmed to have the stimulant activity of IL-6/gp130 axis through the evaluation of mRNA, cell surface protein and intracellular protein levels and chemotaxis and wound healing assay. The upregulation of IL-6/gp130 axis was evaluated using tumor-derived IL-6 level and intratumoral pSTAT3 expression in N-inv of murine sciatic nerves by intraneural injection of Capan-1 cell (N-inv model) and using resected pancreatic cancer tissue and clinical data from 46 PDAC patients. RESULTS mRNA and protein expressions of IL-6 and IL-6 receptor were found in whole cell lysate and condition medium from PC cell. Cell surface protein expression of gp130 were clearly detected on PC cell. IL-6 promoted migration and chemotaxis of PC cell. Serum IL-6 and tumoral IL-6 mRNA levels in N-inv model mice were significantly higher than those in subcutaneous tumor mice (p = 0.004 and p = 0.002, respectively). Silencing of IL-6 and gp130 on PC cell and administration of an anti-IL-6 receptor antibody, tocilizumab, suppressed N-inv, compared to each control (p = 0.070, p = 0.118 and p = 0.122, respectively). In PDAC patients, the high-N-inv group showed poor prognosis (p =0.059) and elevated serum levels of IL-6 and C-reactive protein, synthesis of which is promoted by IL-6, compared to those in the low-N-inv group (p = 0.006 and p = 0.075, respectively). Tumoral gp130 expression at N-inv was higher than that in the primary pancreatic tumor (p = 0.026). CONCLUSION Biological activity of IL-6/gp130 axis promoted N-inv in murine model and was upregulated in PDAC patients with severe N-inv. This study is the first evidence that the IL-6/gp130 axis offers a potential therapeutic target in PDAC with N-inv.
Collapse
Affiliation(s)
- Hidetaka Suzuki
- Division of Biomarker DiscoveryExploratory Oncology Research & Clinical Trial Center, National Cancer CenterKashiwaJapan
- Laboratory of PharmacotherapeuticsFaculty of Pharmaceutical Science, Tokyo University of ScienceTokyoJapan
- Department of PharmacyNational Cancer Center Hospital EastKashiwaJapan
| | - Shuichi Mitsunaga
- Division of Biomarker DiscoveryExploratory Oncology Research & Clinical Trial Center, National Cancer CenterKashiwaJapan
- Department of Hepatobiliary and Pancreatic OncologyNational Cancer Center Hospital EastKashiwaJapan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic OncologyNational Cancer Center Hospital EastKashiwaJapan
| | - Takao Aoyama
- Laboratory of PharmacotherapeuticsFaculty of Pharmaceutical Science, Tokyo University of ScienceTokyoJapan
| | - Kazumi Yoshizawa
- Laboratory of Pharmacology and TherapeuticsFaculty of Pharmaceutical Science, Tokyo University of ScienceTokyoJapan
| | - Masayuki Yamaguchi
- Division of Functional ImagingExploratory Oncology Research & Clinical Trial Center, National Cancer CenterKashiwaJapan
| | - Masami Suzuki
- Division of Cancer Genome Informatics MedicineGraduate School of Medicine, Osaka UniversityOsakaJapan
| | - Minoru Narita
- School of Pharmacy and Pharmaceutical SciencesHoshi UniversityTokyoJapan
| | | | - Atsushi Ochiai
- Division of Biomarker DiscoveryExploratory Oncology Research & Clinical Trial Center, National Cancer CenterKashiwaJapan
| |
Collapse
|
|
20
|
Seufferlein T, Mayerle J, Böck S, Brunner T, Ettrich TJ, Grenacher L, Gress TM, Hackert T, Heinemann V, Kestler A, Sinn M, Tannapfel A, Wedding U, Uhl W. S3-Leitlinie zum exokrinen Pankreaskarzinom – Langversion 2.0 – Dezember 2021 – AWMF-Registernummer: 032/010OL. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:e812-e909. [PMID: 36368658 DOI: 10.1055/a-1856-7346] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
| | | | - Stefan Böck
- Medizinische Klinik und Poliklinik III, Universitätsklinikum München, Germany
| | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz, Austria
| | | | | | - Thomas Mathias Gress
- Klinik für Gastroenterologie und Endokrinologie, Universitätsklinikum Gießen und Marburg, Germany
| | - Thilo Hackert
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie Universitätsklinikum, Heidelberg, Germany
| | - Volker Heinemann
- Medizinische Klinik und Poliklinik III, Klinikum der Universität München-Campus Grosshadern, München, Germany
| | | | - Marianne Sinn
- Universitätsklinikum Hamburg-Eppendorf Medizinische Klinik und Poliklinik II Onkologie Hämatologie, Hamburg, Germany
| | | | | | - Waldemar Uhl
- Allgemein- und Viszeralchirurgie, St Josef-Hospital, Bochum, Germany
| |
Collapse
|
|
21
|
Seufferlein T, Mayerle J, Böck S, Brunner T, Ettrich TJ, Grenacher L, Gress TM, Hackert T, Heinemann V, Kestler A, Sinn M, Tannapfel A, Wedding U, Uhl W. S3-Leitlinie zum exokrinen Pankreaskarzinom – Kurzversion 2.0 – Dezember 2021, AWMF-Registernummer: 032/010OL. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:991-1037. [PMID: 35671996 DOI: 10.1055/a-1771-6811] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
| | | | - Stefan Böck
- Medizinische Klinik und Poliklinik III, Universitätsklinikum München, Germany
| | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz, Austria
| | | | | | - Thomas Mathias Gress
- Klinik für Gastroenterologie und Endokrinologie, Universitätsklinikum Gießen und Marburg, Germany
| | - Thilo Hackert
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie Universitätsklinikum, Heidelberg, Germany
| | - Volker Heinemann
- Medizinische Klinik und Poliklinik III, Klinikum der Universität München-Campus Grosshadern, München, Germany
| | | | - Marianne Sinn
- Universitätsklinikum Hamburg-Eppendorf Medizinische Klinik und Poliklinik II Onkologie Hämatologie, Hamburg, Germany
| | | | | | - Waldemar Uhl
- Allgemein- und Viszeralchirurgie, St Josef-Hospital, Bochum, Germany
| |
Collapse
|
|
22
|
Erin N, Shurin GV, Baraldi JH, Shurin MR. Regulation of Carcinogenesis by Sensory Neurons and Neuromediators. Cancers (Basel) 2022; 14:2333. [PMID: 35565462 PMCID: PMC9102554 DOI: 10.3390/cancers14092333] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/26/2022] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate in carcinogenesis and metastasis. Nerve endings have been identified within solid tumors in humans and experimental animals. Although the involvement of the efferent sympathetic and parasympathetic innervation in carcinogenesis has been extensively investigated, the role of the afferent sensory neurons and the neuropeptides in tumor development, growth, and progression is recently appreciated. Similarly, current findings point to the significant role of Schwann cells as part of neuro-immune interactions. Hence, in this review, we mainly focus on local and systemic effects of sensory nerve activity as well as Schwann cells in carcinogenesis and metastasis. Specific denervation of vagal sensory nerve fibers, or vagotomy, in animal models, has been reported to markedly increase lung metastases of breast carcinoma as well as pancreatic and gastric tumor growth, with the formation of liver metastases demonstrating the protective role of vagal sensory fibers against cancer. Clinical studies have revealed that patients with gastric ulcers who have undergone a vagotomy have a greater risk of stomach, colorectal, biliary tract, and lung cancers. Protective effects of vagal activity have also been documented by epidemiological studies demonstrating that high vagal activity predicts longer survival rates in patients with colon, non-small cell lung, prostate, and breast cancers. However, several studies have reported that inhibition of sensory neuronal activity reduces the development of solid tumors, including prostate, gastric, pancreatic, head and neck, cervical, ovarian, and skin cancers. These contradictory findings are likely to be due to the post-nerve injury-induced activation of systemic sensory fibers, the level of aggressiveness of the tumor model used, and the local heterogeneity of sensory fibers. As the aggressiveness of the tumor model and the level of the inflammatory response increase, the protective role of sensory nerve fibers is apparent and might be mostly due to systemic alterations in the neuro-immune response. Hence, more insights into inductive and permissive mechanisms, such as systemic, cellular neuro-immunological mechanisms of carcinogenesis and metastasis formation, are needed to understand the role of sensory neurons in tumor growth and spread.
Collapse
Affiliation(s)
- Nuray Erin
- Department of Medical Pharmacology, Immunopharmacology, and Immuno-Oncology Unit, School of Medicine, Akdeniz University, 07070 Antalya, Turkey
| | - Galina V. Shurin
- Department of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA; (G.V.S.); (M.R.S.)
| | - James H. Baraldi
- Department of Neuroscience, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA;
| | - Michael R. Shurin
- Department of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA; (G.V.S.); (M.R.S.)
- Department of Immunology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA
| |
Collapse
|
|
23
|
Hill CS, Fu W, Hu C, Sehgal S, Reddy AV, He J, Herman JM, Meyer JJ, Zaheer A, Narang AK. Location, Location, Location: What Should be Targeted Beyond Gross Disease for Localized Pancreatic Ductal Adenocarcinoma? Proposal of a Standardized Clinical Tumor Volume for Pancreatic Ductal Adenocarcinoma of the Head: The "Triangle Volume". Pract Radiat Oncol 2022; 12:215-225. [PMID: 35144016 DOI: 10.1016/j.prro.2022.01.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/28/2021] [Accepted: 01/18/2022] [Indexed: 10/19/2022]
Abstract
PURPOSE In patients with borderline resectable or locally advanced pancreatic adenocarcinoma (BRPC/LAPC), local failure rates after resection remain significant, even in the setting of neoadjuvant chemotherapy and radiation. Suboptimal local control may relate to variable radiation target delineation, as no consensus exists around clinical tumor volume (CTV) design in this context. In the surgical literature, recent attention has been given to the "triangle" volume (TV) as a source of subclinical, residual disease. To understand whether the TV can inform optimal CTV design, we mapped locoregional failures after resection in a large cohort of patients with BRPC/LAPC and compared locations of failure to the TV. METHODS AND MATERIALS Patients with BRPC/LAPC of the head or neck diagnosed between 2016 AND 2019 who developed locoregional failure after surgery, neoadjuvant chemotherapy, and radiation were identified. Descriptive statistics were generated to report the frequency of locoregional failures located within the TV and the frequency of new vascular involvement at time of failure, compared with vascular involvement at diagnosis. Additionally, dosimetric coverage of the TV with the preoperative radiation plan that had been used was assessed. RESULTS In 31 patients who experienced locoregional failure, the centroid of failure was located within the TV in 28 cases (90%). Extent of vascular involvement at time of locoregional failure included vasculature that had not been involved at diagnosis in 13 cases (42%). The preoperative radiation plan that had been used provided a median V33 Gy and V25 Gy of the TV of only 53% (interquartile range, 34%-72%) and 70% (IQR, 48%-85%), respectively. CONCLUSIONS The TV encompassed the vast majority of locoregional failures, but dosimetric coverage of the TV was poor when only targeting gross disease and the full circumference of involved vasculature. As such, the TV may better serve as a basis for CTV design in patients with BRPC/LAPC undergoing neoadjuvant radiation.
Collapse
Affiliation(s)
- Colin S Hill
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Wei Fu
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Chen Hu
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Shuchi Sehgal
- Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania
| | - Abhinav V Reddy
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jin He
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Joseph M Herman
- Department of Radiation Medicine, Northwell Health Cancer Institute, New Hyde Park, New York
| | - Jeffrey J Meyer
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Atif Zaheer
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Amol K Narang
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
24
|
Xuan L, Yuan J, Zhang H, Zhang Y, Liu H. Dominant cell type analysis predicts head and neck adenoid cystic carcinoma outcomes. Ann Diagn Pathol 2021; 56:151867. [PMID: 34826781 DOI: 10.1016/j.anndiagpath.2021.151867] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 11/11/2021] [Indexed: 11/01/2022]
Abstract
Traditional histological grading for predicting adenoid cystic carcinoma (ACC) outcomes is challenging and unreliable. We explored the relationship between dominant cell type (DCT) and outcomes for ACC of the head and neck to develop a new approach to predicting prognosis. Clinicopathological data were obtained from a retrospective cohort of 167 patients with primary ACC of the head and neck. Using immunohistochemistry markers to determine DCT, tumors were subclassified into three distinct subtypes, epithelial-predominant (E-ACC), myoepithelial-predominant (M-ACC), and conventional (C-ACC). Differences in clinicopathological parameters and clinical outcomes among these subtypes were then analyzed. Compared to that of M-ACC and C-ACC, E-ACC exhibited more aggressive clinicopathological features with predominantly solid components, high-grade transformation, lymphovascular invasion, tumor necrosis (TN), Ki-67 ≥ 30%, and advanced stage of disease. Both E-ACC and M-ACC could present as solid morphological forms, but E-ACC had a significantly worse prognosis than M-ACC. DCT, TN, and disease stage were independent predictors of recurrence-free survival. DCT, TN, age ≥ 50 years, and disease stage were independent predictors for overall survival. In conclusion, DCT was an independent prognostic indicator for both recurrence-free and overall survival for ACC. Our results provide a new approach to predicting prognosis in ACC and a strong pathological basis for clinically optimizing treatment.
Collapse
Affiliation(s)
- Lanlan Xuan
- Department of Pathology, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology, NO. 1, Dongjiaominxiang Street, Beijing 100730, China; Department of Pathology, Anqing Hospital, Anhui Medical University, Anqing Municipal Hospital, NO. 87, Tianzhushandong Street, Anqing 246003, China
| | - Jianwei Yuan
- Department of Oncology Surgery, Anqing Hospital, Anhui Medical University, Anqing Municipal Hospital, NO. 87, Tianzhushandong Street, Anqing 246003, China
| | - Hong Zhang
- Department of Pathology, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology, NO. 1, Dongjiaominxiang Street, Beijing 100730, China
| | - Ying Zhang
- Department of Pathology, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology, NO. 1, Dongjiaominxiang Street, Beijing 100730, China
| | - Honggang Liu
- Department of Pathology, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Head and Neck Molecular Diagnostic Pathology, NO. 1, Dongjiaominxiang Street, Beijing 100730, China.
| |
Collapse
|
|
25
|
Li J, Kang R, Tang D. Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma. Cancer Commun (Lond) 2021; 41:642-660. [PMID: 34264020 PMCID: PMC8360640 DOI: 10.1002/cac2.12188] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/11/2021] [Accepted: 06/18/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a unique tumor microenvironment surrounded by an interlaced network of cancer and noncancerous cells. Recent works have revealed that the dynamic interaction between cancer cells and neuronal cells leads to perineural invasion (PNI), a clinical pathological feature of PDAC. The formation and function of PNI are dually regulated by molecular (e.g., involving neurotrophins, cytokines, chemokines, and neurotransmitters), metabolic (e.g., serine metabolism), and cellular mechanisms (e.g., involving Schwann cells, stromal cells, T cells, and macrophages). Such integrated mechanisms of PNI not only support tumor development, growth, invasion, and metastasis but also mediate the formation of pain, all of which are closely related to poor disease prognosis in PDAC. This review details the modulation, signaling pathways, detection, and clinical relevance of PNI and highlights the opportunities for further exploration that may benefit PDAC patients.
Collapse
Affiliation(s)
- Jingbo Li
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, 75390, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, 75390, USA
| |
Collapse
|
|
26
|
Gao Y, Zheng L, Zhang JG, Liu SM, Zhang JY, Dong S. Surgery combined with iodine-125 interstitial brachytherapy for treatment of parotid adenoid cystic carcinoma: A single-institution experience. Brachytherapy 2020; 20:383-392. [PMID: 33309285 DOI: 10.1016/j.brachy.2020.09.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 07/31/2020] [Accepted: 09/30/2020] [Indexed: 10/22/2022]
Abstract
PURPOSE The purpose of this study was to analyze the effectiveness and safety of the combination of surgery plus postoperative iodine-125 interstitial brachytherapy for treatment of adenoid cystic carcinoma (ACC) of the parotid. METHODS AND MATERIALS This study included a retrospective analysis of the data of patients who underwent postoperative iodine-125 interstitial brachytherapy for histology-confirmed ACC of the parotid between January 2002 and November 2018 in Peking University Hospital of Stomatology. Acute and long-term radiation-related toxicities were assessed by the criteria of the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer. Multivariate analysis was used to identify the factors affecting overall survival, disease-free survival (DFS), and distant metastasis-free survival (DMFS). RESULTS A total of 86 patients (53 women; median age 50 years, SD = 13.1) were included. Median followup was for 45.5 months. About half the patients (44/86, 51.3%) had clinical stage IV disease. Local recurrence occurred in 11 of 86 (12.8%) patients. No patient had nodal metastases in the followup period. The five- and 10-year DFS rates were 74.8% and 66.6%, respectively. The mean DMFS was 60.6 months. On multivariate analysis, preoperative facial palsy, type of surgery, perineural spread (PNS), and distant metastases were independent prognostic factors for DFS; preoperative facial palsy, nodal metastases, and PNS were independent prognostic factors for overall survival; and preoperative facial palsy, type of surgery, PNS, and pathological type were independent prognostic factor for DMFS. CONCLUSIONS The combination of surgery and iodine-125 interstitial brachytherapy appears to be an effective and safe treatment for primary ACC of the parotid.
Collapse
Affiliation(s)
- Ya Gao
- Department of Oral and Maxillofacial Surgery, Peking University School of Stomatology, Beijing, China
| | - Lei Zheng
- Department of Oral and Maxillofacial Surgery, Peking University School of Stomatology, Beijing, China.
| | - Jian-Guo Zhang
- Department of Oral and Maxillofacial Surgery, Peking University School of Stomatology, Beijing, China
| | - Shu-Ming Liu
- Department of Oral and Maxillofacial Surgery, Peking University School of Stomatology, Beijing, China
| | - Jian-Yun Zhang
- Department of Pathology, Peking University School of Stomatology, Beijing, China
| | - Shuang Dong
- Department of Oral and Maxillofacial Surgery, Peking University School of Stomatology, Beijing, China
| |
Collapse
|
|
27
|
Important CT and histopathological findings for recurrence and overall survival in patients with pancreatic ductal adenocarcinoma who underwent surgery after neoadjuvant FOLFIRINOX. Eur Radiol 2020; 31:3616-3626. [PMID: 33201279 DOI: 10.1007/s00330-020-07489-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/10/2020] [Accepted: 11/06/2020] [Indexed: 10/23/2022]
Abstract
OBJECTIVES To investigate important factors for recurrence-free survival (RFS) and overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDA) who underwent surgery after neoadjuvant FOLFIRINOX using CT and histopathological findings. MATERIALS AND METHODS Sixty-nine patients with PDA who underwent surgery after neoadjuvant FOLFIRINOX were retrospectively included. All patients underwent baseline and first follow-up CT. Two reviewers assessed the CT findings and resectability based on the NCCN guideline. They graded extrapancreatic perineural invasion (EPNI) using a 3-point scale focused on 5 routes. Clinical and histopathological results, such as T- and N-stage, tumor regression grade (TRG) using the College of American Pathology (CAP) grading system, and resection status, were also investigated. Kaplan-Meier methods were used for RFS and OS. The Cox proportional hazard model and logistic regression model were used to identify significant predictive factors. RESULTS There were 57 patients (82.6%) without residual tumors (R0) and 12 patients (17.4%) with residual tumors (R1 or R2). The median RFS was 13 months (range 0~22 months). For RFS, EPNI on baseline CT (hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.116-5.733, p = 0.026) and TRG (HR 1.76, 95% CI 1.000-3.076, p = 0.046) were important predictors of early recurrence. The mean OS was 48 months (range 11~35 months). For OS, TRG (HR 1.05, 95% CI 1.251-6.559, p = 0.013) was a significant factor. However, there were no independent predictors for residual tumors according to the CT findings. CONCLUSION EPNI on baseline CT and TRG were important prognostic factors for tumor recurrence. In addition, TRG was also an important prognostic factor for OS. KEY POINTS • CT and histopathological findings are helpful for predicting early recurrence and poor survival. • EPNI on baseline CT (HR 2.53, p = 0.026) is an important predictor of early recurrence. • The TRG is an important prognostic factor for early recurrence (HR 1.76, p = 0.046) and poor survival (HR 1.05, p = 0.013).
Collapse
|
|
28
|
Kawai M, Hirono S, Okada KI, Miyazawa M, Kitahata Y, Kobayashi R, Ueno M, Hayami S, Yamaue H. Radiographic Splenic Artery Involvement Is a Poor Prognostic Factor in Upfront Surgery for Patients with Resectable Pancreatic Body and Tail Cancer. Ann Surg Oncol 2020; 28:1521-1532. [PMID: 32705517 DOI: 10.1245/s10434-020-08922-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 07/07/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE The prognostic impact of radiographic splenic vessel involvement in pancreatic cancer remains unclear. We evaluate its oncological significance in resectable pancreatic body/tail cancer. PATIENTS AND METHODS We retrospectively review 102 cases of resectable pancreatic cancer and 51 of borderline resectable pancreatic cancer (BRPC) who underwent pancreatectomy for pancreatic body/tail cancer. Resectable pancreatic body/tail cancer was classified into one of three categories based on radiographic splenic vessel involvement. RESULTS Among 102 cases of resectable pancreatic cancer, 37 (36.3%), 35 (34.3%), and 30 cases (29.4%) were classified as no splenic vessel involvement (Rnone), splenic vein involvement (RV), and splenic artery involvement (RA), respectively. Disease-free survival (DFS) among patients with Rnone, RV, RA, and BRPC was 58.5, 18.4, 10.8, and 9.2 months, respectively. Patients with RV and RA had significantly poorer DFS than patients with Rnone (P = 0.010, P < 0.001, respectively). Median survival among Rnone, RV, RA, and BRPC was 80.6, 23.4, 15.1, and 21.3 months, respectively. Patients with RV and RA had significantly poorer survival than patients with Rnone (P = 0.001, P < 0.001, respectively) and had short survival similar to that of those with BRPC. Multivariate Cox proportional hazard analysis detected preoperative CA19-9 ≥ 37 IU/L, radiologic splenic vein involvement, radiologic splenic artery involvement, intraoperative bleeding ≥ 500 ml, transfusion, positive washing cytology, and noncompletion of adjuvant therapy as independent prognostic factors. CONCLUSIONS Radiographic splenic artery involvement is a poor prognostic factor in resectable pancreatic body/tail cancer and may have a role in stratification of treatment strategy.
Collapse
Affiliation(s)
- Manabu Kawai
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Seiko Hirono
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Ken-Ichi Okada
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Motoki Miyazawa
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Yuji Kitahata
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Ryohei Kobayashi
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Masaki Ueno
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Shinya Hayami
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan
| | - Hiroki Yamaue
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan.
| |
Collapse
|
|
29
|
Cao Y, Deng S, Yan L, Gu J, Li J, Wu K, Cai K. Perineural invasion is associated with poor prognosis of colorectal cancer: a retrospective cohort study. Int J Colorectal Dis 2020; 35:1067-1075. [PMID: 32179991 DOI: 10.1007/s00384-020-03566-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/06/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE Perineural invasion (PNI) is associated with poor prognosis in a variety of cancers. Our aim was to determine the clinicopathological factors associated with PNI in colorectal cancer (CRC) and its impact on patient survival. MATERIAL AND METHODS The clinical data of 1412 patients diagnosed with CRC from July 2013 to July 2016 were retrospectively collected. PNI was determined based on hematoxylin-eosin staining. The relationships of PNI with various clinicopathological factors and prognosis were analyzed. RESULTS The incidence of PNI in the entire cohort was 21.5%. PNI was significantly more common in patients with lower tumor differentiation, higher tumor stage, vascular invasion, TNM stage, tumor diameter, MMR/KRAS/NRAS/BRAF mutation, and more positive lymph nodes. Logistic regression analysis showed that T stage, vascular invasion, tumor diameter, and MMR were the main influencing factors of PNI. Cox regression analysis showed that poor tumor differentiation, N stage, TNM stage, PNI, and BRAF status were independent prognostic factors for OS. The OS, CSS, and PFS rate of the PNI (-) group was higher than that of the PNI (+) group, and the difference was statistically significant (P < 0.001). CONCLUSION PNI in patients with colorectal cancer is significantly associated with T stage, TNM stage, vessel invasion, tumor diameter, MMR status, and BRAF mutation. PNI status is an independent prognostic factor for CRC. Assessing the postoperative PNI status may help predict prognosis and determine further treatment options for these patients.
Collapse
Affiliation(s)
- Yinghao Cao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, Hubei, China
| | - Shenghe Deng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, Hubei, China
| | - Lizhao Yan
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, Hubei, China
| | - Junnan Gu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, Hubei, China
| | - Jiang Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, Hubei, China
| | - Ke Wu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, Hubei, China.
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, Hubei, China.
| |
Collapse
|
|
30
|
Umezawa R, Ito Y, Wakita A, Nakamura S, Okamoto H, Takahashi K, Inaba K, Murakami N, Igaki H, Jingu K, Itami J. How Much Was the Elective Lymph Node Region Covered in Involved-Field Radiation Therapy for Locally Advanced Pancreatic Cancer? Evaluation of Overlap Between Gross Target Volume and Celiac Artery-Superior Mesenteric Artery Lymph Node Regions. Adv Radiat Oncol 2020; 5:377-387. [PMID: 32529131 PMCID: PMC7278027 DOI: 10.1016/j.adro.2019.08.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 08/24/2019] [Accepted: 08/27/2019] [Indexed: 12/26/2022] Open
Abstract
Purpose The purpose of this study was to investigate the overlaps between gross target volume (GTV) and the celiac artery (CA) and superior mesenteric artery (SMA) lymph node regions and to examine the dose incidentally irradiated to the CA and SMA lymph node regions by involved-field radiation therapy (IFRT) for locally advanced pancreatic cancer (LAPC). Methods and Materials Fifty-nine patients who had LAPC without distant metastasis were included. They received IFRT at 50.4 Gy in 28 fractions with 3-dimensional conformal radiation therapy. We calculated the percentages of overlap of GTV in the CA and SMA lymph node regions and examined what cases tend to have an overlap. We also investigated the dose metrics of CA and SMA lymph node regions by IFRT and the frequency of CA or SMA lymph node metastasis after IFRT. Results The median GTV volume was 52.2 mL. Median overlap percentages in the CA and SMA lymph node regions were 39.2% and 28.6%, respectively. There was a significant correlation between GTV volume and SMA overlap percentage (P < .001). Although the SMA overlap percentage was higher in the pancreas head (P = .028), the CA overlap percentage was higher in the pancreas body or tail (P = .002). Median mean dose, D95, and minimum dose in the CA lymph node region were 50.1 Gy, 48.7 Gy, and 45.9 Gy, respectively, and those in the SMA lymph node region 49.9 Gy, 47.3 Gy, and 39.2 Gy, respectively. CA lymph node metastases after IFRT were detected in 4 patients (6.8%). Conclusions An overlap between GTV and CA-SMA lymph node regions was detected in many patients, and the CA and SMA lymph node regions were irradiated incidentally even by IFRT. Prophylactic lymph node regions might not be necessary in radiation therapy planning of LAPC.
Collapse
Affiliation(s)
- Rei Umezawa
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan.,Department of Radiation Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshinori Ito
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan.,Department of Radiation Oncology, Showa University School of Medicine, Tokyo, Japan
| | - Akihisa Wakita
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Satoshi Nakamura
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroyuki Okamoto
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kana Takahashi
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Koji Inaba
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Naoya Murakami
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroshi Igaki
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Keiichi Jingu
- Department of Radiation Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Jun Itami
- Department of Radiation Oncology, National Cancer Center Hospital, Tokyo, Japan
| |
Collapse
|
|
31
|
Extrapancreatic Nerve Plexus Invasion on Imaging Predicts Poor Survival After Upfront Surgery for Anatomically Resectable Pancreatic Cancer. Pancreas 2020; 49:675-682. [PMID: 32433406 DOI: 10.1097/mpa.0000000000001547] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES This study aimed to analyze the risk factors for poor survival of the patients with anatomically resectable pancreatic ductal adenocarcinoma (PDAC), focusing on detailed computed tomography (CT) findings of tumor extent to the peripancreatic tissue. METHODS The study included 192 patients who underwent upfront pancreaticoduodenectomy for anatomically resectable PDAC. Preoperative CT images were rereviewed by an experienced radiologist for the pattern of tumor extension to the surrounding tissue: biliary, duodenal, serosal, retroperitoneal, portal venous, arterial, extrapancreatic nerve plexus, and other-organ invasion. Imaging findings and other clinical data that could be obtained before surgery were evaluated for their association with a shorter disease-specific survival (DSS) and recurrence-free survival (RFS). RESULTS Of the 192 anatomically resectable PDAC patients, extrapancreatic nerve plexus invasion was observed on CT in 38 patients (20%), and this finding was independently associated with a shorter DSS (hazard ratio, 2.258; P < 0.001) and RFS (hazard ratio, 2.665; P < 0.001). The median survival of patients with and without extrapancreatic nerve plexus invasion on CT was 19.7 versus 38.5 months (P < 0.001). CONCLUSIONS Extrapancreatic nerve plexus invasion was shown as an only CT finding associated with a shorter DSS and RFS after upfront surgery for the patients with anatomically resectable PDAC.
Collapse
|
|
32
|
Midkine activation of CD8 + T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth. Nat Commun 2020; 11:2177. [PMID: 32358581 PMCID: PMC7195398 DOI: 10.1038/s41467-020-15770-3] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 03/26/2020] [Indexed: 12/17/2022] Open
Abstract
Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naïve CD8+ T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting. The role of neurons and T cells in glioma progression remains poorly understood. Here the authors show that midkine-dependent activation of a neuron-T cell-microglia axis promotes the growth of optic pathway gliomas.
Collapse
|
|
33
|
Clinical Utility of Histological and Radiological Evaluations of Tumor Necrosis for Predicting Prognosis in Pancreatic Cancer. Pancreas 2020; 49:634-641. [PMID: 32433400 DOI: 10.1097/mpa.0000000000001539] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVES Tumor necrosis is often found in pancreatic ductal adenocarcinoma (PDAC). Objective histological assessment and adequate radiological detection of necrosis could be used as biomarkers for therapeutic decision. However, standardized clinical utility of necrosis remains unknown. Here, we aimed to determine the prognostic potential of histological and radiological evaluations of necrosis. METHODS We investigated histological necrosis in 221 patients, who underwent surgery for PDAC, and classified its size as small (≤5 mm) or large (>5 mm). We also evaluated poorly enhanced areas on preoperative computed tomography to assess their ability for predicting histological necrosis and postoperative prognosis. RESULTS Tumor necrosis was found in 115 patients (52%) and was related to tumor area, lymph node metastasis, and lymphovascular invasion. Size of necrosis was significantly associated with tumor area, perimeter of necrosis, circularity of necrosis, number of ruptured cancer glands, and presence of collagen bundle (P < 0.05 for all). Both presence of necrosis and their size were strongly correlated to postoperative prognosis. Patients with poorly enhanced areas showed worse prognosis (P < 0.01). CONCLUSIONS Our findings underline the capacity of histological and radiological assessment of tumor necrosis for prognosis prediction in PDAC.
Collapse
|
|
34
|
Cao Y, Yang M, Yan L, Deng S, Gu J, Mao F, Wu K, Liu L, Cai K. Colon metal stents as a bridge to surgery had no significant effects on the perineural invasion: a retrospective study. World J Surg Oncol 2020; 18:77. [PMID: 32321517 PMCID: PMC7178988 DOI: 10.1186/s12957-020-01845-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Accepted: 03/25/2020] [Indexed: 02/08/2023] Open
Abstract
PURPOSE The long-term oncological effects of self-expandable metallic stent (SEMS) as a "bridge to surgery" are contradictory, and perineural invasion was supposed to be enhanced by the stenting. In this retrospective study, we compared the perineural invasion and the oncological outcomes between the stent as a bridge to surgery (SBTS)- and emergency surgery (ES)-treated patients to evaluate the results of stenting on the perineural invasion. METHODS The clinical data of patients with acute intestinal obstruction caused by colorectal cancer from January 2013 to January 2017 were retrospectively collected. Forty-three patients underwent semi-elective curative resection after endoscopic SEMS insertion, and sixty-three underwent ES. The adverse events and long-term follow-up outcomes were assessed. The clinicopathological characteristics, perineural invasion rates, and survival rates were compared between the two patient groups. RESULTS Stent insertion resulted in significantly lower stoma rate (32.6% vs 46%; P = 0.03), post-operative overall complication rate (11.6% vs 28.6%, P = 0.038), and total hospital stay (17.07 ± 5.544 days vs 20.48 ± 7.372 days, P = 0.042). Compared with the ES group, there was no significant increase in the incidence of peripheral invasion in the SBTS group (39.5% vs 47.6%, P = 0.411). No significant difference was noted in the survival rate and long-term prognosis between the SEMS and ES groups (P = 0.964). The technical success rate was 95.6%, and the clinical success rate was 97.7%. CONCLUSIONS Preoperative colon stenting was an effective transitional method for colorectal cancer patients with complete obstruction. Short-term stent implantation had no significant effect on perineural invasion in patients with CRC.
Collapse
Affiliation(s)
- Yinghao Cao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Ming Yang
- Department of Pathology, Union Hospital, Tongji Medical, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Lizhao Yan
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Shenghe Deng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Junnan Gu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Fuwei Mao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Ke Wu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, The Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China.
| |
Collapse
|
|
35
|
Abstract
The nervous system is intimately involved in physiological processes from development and growth to tissue homeostasis and repair throughout the body. It logically follows that the nervous system has the potential to play analogous roles in the context of cancer. Progress toward understanding the crucial role of the nervous system in cancer has accelerated in recent years, but much remains to be learned. Here, we highlight rapidly evolving concepts in this burgeoning research space and consider next steps toward understanding and therapeutically targeting the neural regulation of cancer.
Collapse
Affiliation(s)
- Shawn Gillespie
- Cancer Biology Graduate Program, Stanford University, Stanford, California 94305, USA
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA
| |
Collapse
|
|
36
|
Lu M, Xiu DR, Guo LM, Yuan CH, Zhang LF, Tao LY. Extrapancreatic Neuropathy Correlates with Early Liver Metastasis in Pancreatic Head Adenocarcinoma. Onco Targets Ther 2019; 12:11083-11095. [PMID: 31908477 PMCID: PMC6924582 DOI: 10.2147/ott.s221844] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 11/07/2019] [Indexed: 01/18/2023] Open
Abstract
Background Pancreatic ductal adenocarcinoma has a devastatingly poor prognosis, and most prognostic factors reflected the tumor stage more than the tumors' biology. The peripheral nerve plexus is densely distributed in the tumor micro-environment, and there are interactions between tumor cells and these nerves. Perineural invasion is an important risk factor for tumor recurrence and metastasis in pancreatic head adenocarcinoma, but the concrete types of extrapancreatic neuropathy and its role in predicting prognosis are still not clear. Objective To clarify the role of extrapancreatic neuropathy in the early postoperative liver metastasis and tumor-related mortality in pancreatic head adenocarcinoma and to study the mechanism of tumor recurrence and liver metastasis in pancreatic head adenocarcinoma. Methods We reported a retrospective study of 60 patients with resectable pancreatic head adenocarcinoma, all of whom accepted radical pancreaticoduodenectomy. Plexus pancreaticus capitalis II (PLX-II) was the representation of extrapancreatic plexus in our study, and all of these plexus had immunohistochemical staining. We defined the postoperative tumor recurrence and tumor-related mortality within 6 months as the early prognostic indicators and analyzed the pathological alterations in PLX-II among different prognosis groups. Results There were 18 patients suffering early postoperative liver metastasis; these two groups differed significantly in the average number of nerve trunks (P<0.001), the proportion of neuritis (P=0.003), the content of sympathetic nerve fibers (P=0.004) and parasympathetic nerve fibers (P<0.001) per unit area of PLX-II. There were 15 patients suffering early postoperative mortality, and there were significant differences between these two groups in the average number of nerve trunks (P<0.001), the proportion of neuritis (P=0.009), the content of sympathetic nerve fibers (P=0.023) and parasympathetic nerve fibers (P<0.001) per unit area of PLX-II. Conclusion The patterns of extrapancreatic neuropathy could reflect the biological behavior of resectable pancreatic head adenocarcinoma, and the pathological features of PLX-II were closely related to early liver metastasis and mortality.
Collapse
Affiliation(s)
- Meng Lu
- Department of Pulmonary Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, People's Republic of China
| | - Dian-Rong Xiu
- Department of General Surgery, Peking University Third Hospital, Beijing, People's Republic of China
| | - Li-Mei Guo
- Department of Pathology, Peking University Third Hospital, Beijing, People's Republic of China
| | - Chun-Hui Yuan
- Department of General Surgery, Peking University Third Hospital, Beijing, People's Republic of China
| | - Ling-Fu Zhang
- Department of General Surgery, Peking University Third Hospital, Beijing, People's Republic of China
| | - Lian-Yuan Tao
- Department of General Surgery, Peking University Third Hospital, Beijing, People's Republic of China
| |
Collapse
|
|
37
|
Pathological analysis of the superior mesenteric artery boundary in preoperative computed tomography of resectable pancreatic head adenocarcinoma. Oncol Lett 2019; 17:5711-5720. [PMID: 31186797 DOI: 10.3892/ol.2019.10269] [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: 05/13/2018] [Accepted: 03/26/2019] [Indexed: 11/09/2022] Open
Abstract
The aim of the present study was to evaluate the biological and prognostic implications of the superior mesenteric artery (SMA) boundary on preoperative abdominal contrast-enhanced computed tomography (CE-CT) for resectable adenocarcinoma of the pancreatic head. A total of 121 patients treated over a 6-year period at Peking University Third Hospital (Beijing, China) were included in the present study. The pattern of the SMA boundary was investigated on preoperative CE-CT and detailed pathological analysis of the extrapancreatic plexus [the pancreatic head plexus II (PLX-II) located on the right edge of the SMA] was performed. The results revealed that the radiological SMA boundary was associated with the grade of parasympathetic neurogenesis (P=0.014) in PLX-II, and was predictive of postoperative disease-free survival (P=0.014) and liver metastasis (P=0.013). Therefore, it was proposed that extrapancreatic parasympathetic neurogenesis may account for the different patterns of the SMA boundary on preoperative abdominal CE-CT, and affect the prognosis, particularly for liver metastasis in resectable pancreatic head adenocarcinoma.
Collapse
|
|
38
|
Kovač JD, Mayer P, Hackert T, Klauss M. The Time to and Type of Pancreatic Cancer Recurrence after Surgical Resection: Is Prediction Possible? Acad Radiol 2019; 26:775-781. [PMID: 30254003 DOI: 10.1016/j.acra.2018.07.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 07/29/2018] [Accepted: 07/30/2018] [Indexed: 12/14/2022]
Abstract
RATIONALE AND OBJECTIVES To evaluate factors predicting pancreatic cancer recurrence, and to determine the most common appearance of tumor relapse. MATERIALS AND METHODS Ninety patients with recurrent pancreatic cancer were retrospectively included in the study. 74.4% had pancreatic head tumors (group 1) and 25.6% pancreatic body and/or tail tumor (group 2). The tumor localization, operative technique, TNM stage, the R-status, tumor grade, lymphovascular, and perineural invasion were recorded. Location of local tumor recurrence, lymph node recurrence, or organ metastases were analyzed on the basis of follow-up CT imaging. RESULTS Mean recurrence time was 17.4 ± 13.2 months. The most common recurrence type was local recurrence (84.4%), followed by lymph node (15.5%), liver (14.4%), and lung metastasis (6.7%). The predominant site of local recurrence in pancreatic head tumors was close to superior mesenteric artery, common hepatic artery, and/or celiac artery (57.4%), followed by area defined by portal vein, inferior vena cava, CA or superior mesenteric artery (31.2%). Patients with pancreatic body and/or tail carcinoma had higher incidence (p = 0.003) of metastatic disease comparing to pancreatic head tumors, while resection margin was the most common type of local tumor recurrence, seen in 46.7% cases versus 8.2% of patients with pancreatic head tumors (p < 0.001). CONCLUSION The most common recurrence type in patients with resected pancreatic carcinoma was local recurrence along cardinal arteries. The localization of primary tumor influences the type of tumor relapse and site of local recurrence.
Collapse
Affiliation(s)
- Jelena Djokić Kovač
- Center for Radiology and Magnetic Resonance Imaging, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Pasterova 2, 11000, Belgrade, Serbia.
| | - Philipp Mayer
- Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Thilo Hackert
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Miriam Klauss
- Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
39
|
Abstract
Pancreatic ductal adenocarcinoma continues to be a highly lethal disease, despite advances in modern medicine. Curative surgical options continue to carry significant morbidity and offer little improvement in overall 5-year survival. Currently, imaging plays an essential role in the pre-operative evaluation of patients who are undergoing evaluation for resection. However, some pancreatic cancers have particularly aggressive biology, despite appearing resectable by conventional imaging criteria. Imaging biomarkers that serve as surrogates for tumors with such aggressive phenotype have been recently described, namely duodenal invasion and extrapancreatic perineural invasion. In this pictorial review, we will summarize key concepts of extrapancreatic perineural invasion, describe its association with a poor prognosis, and highlight the role of imaging in its detection.
Collapse
Affiliation(s)
- Bhavik N Patel
- Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr., H1307, Stanford, CA, 94305, USA.
| | - Eric Olcott
- Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr., H1307, Stanford, CA, 94305, USA
- Department of Radiology, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA, 94304, USA
| | - R Brooke Jeffrey
- Department of Radiology, Stanford University School of Medicine, 300 Pasteur Dr., H1307, Stanford, CA, 94305, USA
| |
Collapse
|
|
40
|
Montejo Gañán I, Ángel Ríos L, Sarría Octavio de Toledo L, Martínez Mombila M, Ros Mendoza L. Staging pancreatic carcinoma by computed tomography. RADIOLOGIA 2018. [DOI: 10.1016/j.rxeng.2017.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
|
|
41
|
Montejo Gañán I, Ángel Ríos LF, Sarría Octavio de Toledo L, Martínez Mombila ME, Ros Mendoza LH. Staging pancreatic carcinoma by computed tomography. RADIOLOGIA 2018; 60:10-23. [PMID: 29078990 DOI: 10.1016/j.rx.2017.08.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 08/10/2017] [Accepted: 08/11/2017] [Indexed: 02/08/2023]
Abstract
Pancreatic carcinoma is becoming more common in our environment; the mortality rate for this tumor has barely changed over the last 20 years. Early diagnosis and accurate staging are crucial to ensure an appropriate therapeutic approach, which should aim to improve survival in patients in whom complete resection is possible and to minimize surgical morbidity and mortality in those with a high risk of residual disease after the intervention. Various imaging techniques are used for tumor staging: multidetector computed tomography (CT), magnetic resonance imaging, positron emission tomography (PET)-CT, endoscopic ultrasound, and diagnostic laparoscopy. Currently, multidetector CT is the technique of choice for the study of pancreatic tumors; thus, this article aims to review the state of the art in staging adenocarcinoma of the pancreas, focusing mainly on the applications and limitations of this technique.
Collapse
Affiliation(s)
- I Montejo Gañán
- Servicio de Radiodiagnóstico, Hospital Universitario Miguel Servet, Zaragoza, España.
| | - L F Ángel Ríos
- Servicio de Radiodiagnóstico, Hospital Universitario Miguel Servet, Zaragoza, España
| | | | - M E Martínez Mombila
- Servicio de Radiodiagnóstico, Hospital Universitario Miguel Servet, Zaragoza, España
| | - L H Ros Mendoza
- Servicio de Radiodiagnóstico, Hospital Universitario Miguel Servet, Zaragoza, España
| |
Collapse
|
|
42
|
Carr RA, Roch AM, Zhong X, Ceppa EP, Zyromski NJ, Nakeeb A, Schmidt CM, House MG. Prospective Evaluation of Associations between Cancer-Related Pain and Perineural Invasion in Patients with Resectable Pancreatic Adenocarcinoma. J Gastrointest Surg 2017; 21:1658-1665. [PMID: 28785934 DOI: 10.1007/s11605-017-3513-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 07/19/2017] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Perineural invasion is a unique characteristic of pancreatic adenocarcinoma biology and is present in the majority of resected pathologic specimens. The purpose of this study was to understand the relationships between preoperative pain and perineural invasion in patients with pancreatic adenocarcinoma. METHODS Fifty-two chemotherapy naive patients undergoing resection for pancreatic adenocarcinoma from 2012 to 2014 completed a previously validated Brief Pain Inventory survey for preoperative clinical pain scoring. Preoperative pain was correlated with multiple clinicopathologic features. RESULTS Preoperative pain was not associated with pathologic cancer stage, lymph node status, lymph node positivity ratio, resection margin status, or tumor location within the pancreas. In the subgroup of pancreatic head cancers, pain interference with affect was associated with the absence of perineural invasion (p = 0.02). Patients with stage I cancer had higher pain interference scores than those with stage II cancer (p = 0.02). CONCLUSIONS Preoperative pain does not predict the presence of perineural invasion or other pathologic prognostic factors in patients with resectable pancreatic adenocarcinoma. Higher pain scores in pancreatic head cancers correlated with absence of perineural invasion and early cancer stage. The effects of preoperative pain on quality and interference of daily life deserve further investigation in larger prospective studies involving patients with pancreatic cancer.
Collapse
Affiliation(s)
- Rosalie A Carr
- Department of General Surgery, Indiana University School of Medicine, 515 Barnhill Drive, Indianapolis, IN, 46202, USA
| | - Alexandra M Roch
- Department of General Surgery, Indiana University School of Medicine, 515 Barnhill Drive, Indianapolis, IN, 46202, USA
| | - Xin Zhong
- Department of General Surgery, Indiana University School of Medicine, 515 Barnhill Drive, Indianapolis, IN, 46202, USA
| | - Eugene P Ceppa
- Department of General Surgery, Indiana University School of Medicine, 515 Barnhill Drive, Indianapolis, IN, 46202, USA
| | - Nicholas J Zyromski
- Department of General Surgery, Indiana University School of Medicine, 515 Barnhill Drive, Indianapolis, IN, 46202, USA
| | - Attila Nakeeb
- Department of General Surgery, Indiana University School of Medicine, 515 Barnhill Drive, Indianapolis, IN, 46202, USA
| | - C Max Schmidt
- Department of General Surgery, Indiana University School of Medicine, 515 Barnhill Drive, Indianapolis, IN, 46202, USA
| | - Michael G House
- Department of General Surgery, Indiana University School of Medicine, 515 Barnhill Drive, Indianapolis, IN, 46202, USA.
| |
Collapse
|
|
43
|
Abstract
Recent studies have demonstrated a critical role for nerves in enabling tumor progression. The association of nerves with cancer cells is well established for a variety of malignant tumors, including pancreatic, prostate and the head and neck cancers. This association is often correlated with poor prognosis. A strong partnership between cancer cells and nerve cells leads to both cancer progression and expansion of the nerve network. This relationship is supported by molecular pathways related to nerve growth and repair. Peripheral nerves form complex tumor microenvironments, which are made of several cell types including Schwann cells. Recent studies have revealed that Schwann cells enable cancer progression by adopting a de-differentiated phenotype, similar to the Schwann cell response to nerve trauma. A detailed understanding of the molecular and cellular mechanisms involved in the regulation of cancer progression by the nerves is essential to design strategies to inhibit tumor progression.
Collapse
|
|
44
|
Yao J, Zhang LL, Huang XM, Li WY, Gao SG. Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer. World J Gastroenterol 2017; 23:3907-3914. [PMID: 28638231 PMCID: PMC5467077 DOI: 10.3748/wjg.v23.i21.3907] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 10/27/2016] [Accepted: 12/08/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To detect the expression of pleiotrophin (PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion (PNI).
METHODS An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis.
RESULTS The expression rates of PTN and N-syndecan proteins were 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI (P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites (P = 0.009), liver metastasis (P = 0.035), and decreased survival time (P = 0.022). N-syndecan expression was significantly associated with tumor size (P = 0.025), but not with survival time (P = 0.539).
CONCLUSION High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer.
Collapse
|
|
45
|
Venkatesh H, Monje M. Neuronal Activity in Ontogeny and Oncology. Trends Cancer 2017; 3:89-112. [PMID: 28718448 DOI: 10.1016/j.trecan.2016.12.008] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 12/29/2016] [Accepted: 12/30/2016] [Indexed: 01/06/2023]
Abstract
The nervous system plays a central role in regulating the stem cell niche in many organs, and thereby pivotally modulates development, homeostasis, and plasticity. A similarly powerful role for neural regulation of the cancer microenvironment is emerging. Neurons promote the growth of cancers of the brain, skin, prostate, pancreas, and stomach. Parallel mechanisms shared in development and cancer suggest that neural modulation of the tumor microenvironment may prove a universal theme, although the mechanistic details of such modulation remain to be discovered for many malignancies. We review here what is known about the influences of active neurons on stem cell and cancer microenvironments across a broad range of tissues, and we discuss emerging principles of neural regulation of development and cancer.
Collapse
Affiliation(s)
- Humsa Venkatesh
- Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Biology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Michelle Monje
- Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
| |
Collapse
|
|
46
|
Bapat AA, Munoz RM, Von Hoff DD, Han H. Blocking Nerve Growth Factor Signaling Reduces the Neural Invasion Potential of Pancreatic Cancer Cells. PLoS One 2016; 11:e0165586. [PMID: 27792755 PMCID: PMC5085053 DOI: 10.1371/journal.pone.0165586] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 10/16/2016] [Indexed: 01/01/2023] Open
Abstract
Perineural invasion (PNI) is thought to be one of the factors responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Signaling via the nerve growth factor (NGF) pathway between pancreatic cancer cells and the surrounding nerves has been implicated in PNI, and increased levels of these proteins have been correlated to poor prognosis. In this study, we examine the molecular mechanism of the NGF signaling pathway in PNI in pancreatic cancer. We show that knocking down NGF or its receptors, TRKA and p75NTR, or treatment with GW441756, a TRKA kinase inhibitor, reduces the proliferation and migration of pancreatic cancer cells in vitro. Furthermore, pancreatic cancer cells migrate towards dorsal root ganglia (DRG) in a co-culture assay, indicating a paracrine NGF signaling between the DRGs and pancreatic cancer cells. Knocking down the expression of NGF pathway proteins or inhibiting the activity of TRKA by GW441756 reduced the migratory ability of Mia PaCa2 towards the DRGs. Finally, blocking NGF signaling by NGF neutralizing antibodies or GW441756 inhibited the neurite formation in PC-12 cells in response to conditioned media from pancreatic cancer cells, indicating a reciprocal signaling pathway between the pancreatic cancer cells and nerves. Our results indicate that NGF signaling pathway provides a potential target for developing molecularly targeted therapies to decrease PNI and reduce pain generation. Since there are several TRKA antagonists currently in early clinical trials they could now be tested in the clinical situation of pancreatic cancer induced pain.
Collapse
Affiliation(s)
- Aditi A. Bapat
- Clinical Translational Research Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Ruben M. Munoz
- Clinical Translational Research Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Daniel D. Von Hoff
- Clinical Translational Research Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Haiyong Han
- Clinical Translational Research Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America
- * E-mail:
| |
Collapse
|
|
47
|
Liu C, Tian X, Xie X, Gao H, Zhuang Y, Yang Y. Comparison of Uncinate Process Cancer and Non-Uncinate Process Pancreatic Head Cancer. J Cancer 2016; 7:1242-9. [PMID: 27390599 PMCID: PMC4934032 DOI: 10.7150/jca.15062] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 05/01/2016] [Indexed: 12/20/2022] Open
Abstract
The special anatomical position accounts for unusual clinicopathological features of uncinate process cancer. This study aimed to compare clinicopathological features of patients with uncinate process cancer to patients with non-uncinate process pancreatic head cancer. Total 160 patients with pancreatic head cancer were enrolled and classified into two groups: uncinate process cancer and non-uncinate process pancreatic head cancer. We found that the ratio of vascular invasion was significantly higher in patients with uncinate process cancer than in patients with non-uncinate process pancreatic head cancer. In addition, the rate of R1 resection was significantly higher in patients with uncinate process cancer. Furthermore, the median disease-free survival (11 months vs. 15 months, p=0.043) and overall survival (15 months vs. 19 months, p=0.036) after R0 resection were lower for uncinate process cancer. Locoregional recurrence was more frequent (p=0.017) and earlier (12 months vs. 36 months; p=0.002) in patients with uncinate process cancer than in patients with non-uncinate process pancreatic head cancer. In conclusion, uncinate process cancer is more likely to invade blood vessel and has worse prognosis due to the earlier and more frequent locoregional recurrence.
Collapse
Affiliation(s)
- Chang Liu
- Department of General Surgery, Peking University First hospital, 8th Xishiku Street, Beijing 100034, People's Republic of China
| | - Xiaodong Tian
- Department of General Surgery, Peking University First hospital, 8th Xishiku Street, Beijing 100034, People's Republic of China
| | - Xuehai Xie
- Department of General Surgery, Peking University First hospital, 8th Xishiku Street, Beijing 100034, People's Republic of China
| | - Hongqiao Gao
- Department of General Surgery, Peking University First hospital, 8th Xishiku Street, Beijing 100034, People's Republic of China
| | - Yan Zhuang
- Department of General Surgery, Peking University First hospital, 8th Xishiku Street, Beijing 100034, People's Republic of China
| | - Yinmo Yang
- Department of General Surgery, Peking University First hospital, 8th Xishiku Street, Beijing 100034, People's Republic of China
| |
Collapse
|
|
48
|
Amit M, Eran A, Billan S, Fridman E, Na'ara S, Charas T, Gil Z. Perineural Spread in Noncutaneous Head and Neck Cancer: New Insights into an Old Problem. J Neurol Surg B Skull Base 2016; 77:86-95. [PMID: 27123384 PMCID: PMC4846400 DOI: 10.1055/s-0036-1571834] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Head and neck malignancies have the propensity to invade nerves. Perineural tumor invasion is common, with some series reporting rates of 30 to 100%. Squamous cell carcinoma and adenoid cystic carcinoma are the most commonly involved tumors. The most commonly involved nerves are the trigeminal (cranial nerve [CN] V) and facial (CN VII) and their branches. Neural spread away from a tumor is encountered less often and usually causes specific symptoms such as pain, muscle weakness, and atrophy, depending on the involved nerves. While clinical symptoms and physical examination may suggest the presence of neural invasion, specific imaging modalities such as fat-suppressed T1-weighted magnetic resonance images, should be utilized to identify perineural tumor spread in its early phases. Perineural tumor spread should be considered and addressed in the treatment planning of patients with head and neck or skull base cancers as it can influence the extent of surgery, and the dosage and fields of radiation therapy. In the current review, we discuss the clinical course of perineural tumor spread and its therapeutic implications.
Collapse
Affiliation(s)
- Moran Amit
- The Laboratory for Applied Cancer Research, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel
- The Head and Neck Center, Department of Otolaryngology-Head and Neck Surgery, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel
| | - Ayelet Eran
- Department of Radiology, Rambam Healthcare Campus, Israel Institute of Technology, Haifa, Israel
| | - Salem Billan
- Department of Oncology, Rambam Healthcare Campus, Israel Institute of Technology, Haifa, Israel
| | - Eran Fridman
- The Laboratory for Applied Cancer Research, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel
- The Head and Neck Center, Department of Otolaryngology-Head and Neck Surgery, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel
| | - Shorook Na'ara
- The Laboratory for Applied Cancer Research, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel
- The Head and Neck Center, Department of Otolaryngology-Head and Neck Surgery, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel
| | - Tomer Charas
- Department of Oncology, Rambam Healthcare Campus, Israel Institute of Technology, Haifa, Israel
| | - Ziv Gil
- The Laboratory for Applied Cancer Research, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel
- The Head and Neck Center, Department of Otolaryngology-Head and Neck Surgery, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion, Israel Institute of Technology, Haifa, Israel
| |
Collapse
|
|
49
|
Kondo N, Murakami Y, Uemura K, Hashimoto Y, Nakagawa N, Sasaki H, Sueda T. An Increased Number of Perineural Invasions Is Independently Associated With Poor Survival of Patients With Resectable Pancreatic Ductal Adenocarcinoma. Pancreas 2015; 44:1345-51. [PMID: 26465957 DOI: 10.1097/mpa.0000000000000413] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES The aim of this study was to investigate the impact of the number of perineural invasions (PNIs) in resected specimens on the survival of patients with pancreatic ductal adenocarcinoma (PDAC). METHODS A retrospective cohort study of 209 patients underwent surgical resection for PDAC between 1999 and 2013 was performed. The severity of PNI was evaluated by counting the number of PNIs in all sections with PDAC. The relationships of the number of PNIs with disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS At least 1 PNI was observed in 197 (94%) of 209 patients. Significant differences in DFS and OS were found between groups when analyzed by the median number of PNIs (≥25 vs <25) (DFS: P < 0.0001; OS: P < 0.0001) and among tertiles greater than 40 versus 40 to 14 versus less than 14 (DFS: P < 0.0001, OS: P < 0.0001). By multivariate analysis, an increased number of PNIs (>40 vs 40-14 vs <14) was identified as an independent risk factor for poor DFS (P < 0.0001) and OS (P < 0.0001). CONCLUSIONS The severity of PNI evaluated by counting the number of PNIs in resected specimens was useful for predicting the prognosis of patients with resectable PDAC.
Collapse
Affiliation(s)
- Naru Kondo
- From the Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | | | | | | | | | | | | |
Collapse
|
|
50
|
Li J, Ma J, Han L, Xu Q, Lei J, Duan W, Li W, Wang F, Wu E, Ma Q, Huo X. Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer. Cancer Biol Ther 2015; 16:912-21. [PMID: 25946624 DOI: 10.1080/15384047.2015.1040952] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Glucose intolerance and frank diabetes mellitus (DM) can increase the risk of cancer death for pancreatic cancer (PanCa). However, the mechanism by which these factors influence cancer deaths is not clear. In this study, we established a model system to mimic the pancreatic tumor microenvironment in patients with DM to examine the biological behavior of PanCa cells and nerves in cell culture and in animals. Our in vitro studies demonstrated that hyperglycemia promoted the proliferation and invasion of PanCa cell lines and upregulated the expression of nerve growth factor in these cells. Also, the migration of Schwann cells (SCs) was inhibited by hyperglycemia and neurites exerted pathological regeneration. Furthermore, the interaction between the PanCa cells and nerves was enhanced in the tumor microenvironment. We further showed that hyperglycemia promoted the perineural invasion (PNI) of PanCa in vivo. These data suggest that DM worsens the prognosis of PanCa because of aggravated PNI. Thus, our study illustrates a novel mechanism by which hyperglycemia decreases survival in patients with PanCa.
Collapse
Affiliation(s)
- Junhui Li
- a Department of Hepatobiliary Surgery ; First Affiliated Hospital of Medical College; Xi'an Jiaotong University ; Xi'an , China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|