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Greenspun BC, Foshag A, Tumati A, Marshall T, Xue D, Yang L, Chen S, Zarnegar R, Fahey TJ, Finnerty BM. DAXX is associated with early recurrence of pancreatic neuroendocrine tumors after R0 resection. Surgery 2025; 177:108824. [PMID: 39366850 DOI: 10.1016/j.surg.2024.06.064] [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: 02/11/2024] [Revised: 06/12/2024] [Accepted: 06/18/2024] [Indexed: 10/06/2024]
Abstract
INTRODUCTION ATRX, DAXX, MEN1, and PTEN mutations are proposed drivers of pancreatic neuroendocrine tumor tumorigenesis and independent prognostic factors for metastasis and mortality. However, their implications after R0 resection remain debated. Thus, we sought to identify genomic signatures of pancreatic neuroendocrine tumor disease-specific mortality and recurrence after surgery for curative intent. METHODS Pancreatic neuroendocrine tumor patients who underwent whole exome sequencing with available survival data were identified using cBioPortal. Clinicopathologic variables, genomics, and outcomes were analyzed. RESULTS Seventy patients who underwent R0 resection were identified. Forty-five of 70 patients were disease free at last follow-up, whereas 25 of 70 patients had disease-specific mortality or recurrent disease and therefore were categorized as part of the recurrent cohort. There were no significant differences in age (P = .245), sex (P = .201), or median follow-up (38.9 vs 33.7 months, P = .122) between groups. Clinicopathologically, the recurrent cohort had significantly greater tumor size (median 5.0 cm vs 3.2 cm, P = .012) and were more likely to have vascular invasion (88% vs 40%, P = .000), positive lymph nodes (68.0% vs 35.6%, P = .013), and metastatic disease (44% vs 4.4%, P < .000). For both cohorts, most tumors were well or moderately differentiated. Tumor mutation burden was greater in the recurrent cohort (median 0.77 vs 0.43 mutations/Mb, P = .004). DAXX mutations were more frequent in the recurrent cohort (36% vs 11%, P = .026) and in those with vascular invasion (51% vs 92%, P = .010). CONCLUSION Our analysis demonstrated the prognostic significance of DAXX mutations after curative-intent surgery. Future studies investigating DAXX mutations as a biomarker for aggressive features to guide treatment are warranted.
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Affiliation(s)
- Benjamin C Greenspun
- Department of Surgery, Weill Cornell Medicine, New York, NY; Center for Genomic Health, Weill Cornell Medicine, New York, NY.
| | - Amanda Foshag
- Department of Surgery, Weill Cornell Medicine, New York, NY
| | - Abhinay Tumati
- Department of Surgery, Weill Cornell Medicine, New York, NY
| | | | - Dongxiang Xue
- Department of Surgery, Weill Cornell Medicine, New York, NY; Center for Genomic Health, Weill Cornell Medicine, New York, NY
| | - Liuliu Yang
- Department of Surgery, Weill Cornell Medicine, New York, NY; Center for Genomic Health, Weill Cornell Medicine, New York, NY
| | - Shuibing Chen
- Department of Surgery, Weill Cornell Medicine, New York, NY; Center for Genomic Health, Weill Cornell Medicine, New York, NY
| | - Rasa Zarnegar
- Department of Surgery, Weill Cornell Medicine, New York, NY
| | - Thomas J Fahey
- Department of Surgery, Weill Cornell Medicine, New York, NY
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Greenberg JA, Shah Y, Ivanov NA, Marshall T, Kulm S, Williams J, Tran C, Scognamiglio T, Heymann JJ, Lee-Saxton YJ, Egan C, Majumdar S, Min IM, Zarnegar R, Howe J, Keutgen XM, Fahey TJ, Elemento O, Finnerty BM. Developing a Predictive Model for Metastatic Potential in Pancreatic Neuroendocrine Tumor. J Clin Endocrinol Metab 2024; 110:263-274. [PMID: 38817124 PMCID: PMC11651689 DOI: 10.1210/clinem/dgae380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 05/29/2024] [Accepted: 05/29/2024] [Indexed: 06/01/2024]
Abstract
CONTEXT Pancreatic neuroendocrine tumors (PNETs) exhibit a wide range of behavior from localized disease to aggressive metastasis. A comprehensive transcriptomic profile capable of differentiating between these phenotypes remains elusive. OBJECTIVE Use machine learning to develop predictive models of PNET metastatic potential dependent upon transcriptomic signature. METHODS RNA-sequencing data were analyzed from 95 surgically resected primary PNETs in an international cohort. Two cohorts were generated with equally balanced metastatic PNET composition. Machine learning was used to create predictive models distinguishing between localized and metastatic tumors. Models were validated on an independent cohort of 29 formalin-fixed, paraffin-embedded samples using NanoString nCounter®, a clinically available mRNA quantification platform. RESULTS Gene expression analysis identified concordant differentially expressed genes between the 2 cohorts. Gene set enrichment analysis identified additional genes that contributed to enriched biologic pathways in metastatic PNETs. Expression values for these genes were combined with an additional 7 genes known to contribute to PNET oncogenesis and prognosis, including ARX and PDX1. Eight specific genes (AURKA, CDCA8, CPB2, MYT1L, NDC80, PAPPA2, SFMBT1, ZPLD1) were identified as sufficient to classify the metastatic status with high sensitivity (87.5-93.8%) and specificity (78.1-96.9%). These models remained predictive of the metastatic phenotype using NanoString nCounter® on the independent validation cohort, achieving a median area under the receiving operating characteristic curve of 0.886. CONCLUSION We identified and validated an 8-gene panel predictive of the metastatic phenotype in PNETs, which can be detected using the clinically available NanoString nCounter® system. This panel should be studied prospectively to determine its utility in guiding operative vs nonoperative management.
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Affiliation(s)
| | - Yajas Shah
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA
| | - Nikolay A Ivanov
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - Teagan Marshall
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - Scott Kulm
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA
| | - Jelani Williams
- Department of Surgery, University of Chicago Medicine, Chicago, IL 60637, USA
| | - Catherine Tran
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Theresa Scognamiglio
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Jonas J Heymann
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yeon J Lee-Saxton
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - Caitlin Egan
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - Sonali Majumdar
- Genomics Facility, The Wistar Institute, Philadelphia, PA 19104, USA
| | - Irene M Min
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - Rasa Zarnegar
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - James Howe
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Xavier M Keutgen
- Department of Surgery, University of Chicago Medicine, Chicago, IL 60637, USA
| | - Thomas J Fahey
- Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
| | - Olivier Elemento
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA
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Liao T, Su T, Lu Y, Huang L, Wei WY, Feng LH. Random survival forest algorithm for risk stratification and survival prediction in gastric neuroendocrine neoplasms. Sci Rep 2024; 14:26969. [PMID: 39506090 PMCID: PMC11541730 DOI: 10.1038/s41598-024-77988-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 10/28/2024] [Indexed: 11/08/2024] Open
Abstract
This study aimed to construct and assess a machine-learning algorithm designed to forecast survival rates and risk stratification for patients with gastric neuroendocrine neoplasms (gNENs) after diagnosis. Data on patients with gNENs were extracted and randomly divided into training and validation sets using the Surveillance, Epidemiology, and End Results database. We developed a prediction model using 10 machine learning algorithms across 101 combinations to forecast cancer-related mortality in patients with gNENs, selecting the best model using the highest mean over a sequence of time-dependent area under the receiver operating characteristic (ROC) curve (AUC). The performance of the final model was assessed through time-dependent ROC curves for discrimination and calibration curves for calibration. The maximum selection rank method was used to determine the best prognostic risk score threshold for classifying patients into high- and low-risk groups. Afterward, Kaplan-Meier analysis and log-rank test were used to compare survival rates among these groups. Our study examined 775 patients with gNENs, dividing them into training and validation sets. A training set comprised 543 patients, with a median follow-up of 42 months and cumulative mortality rates of 40.0% at 1 year, 48.6% at 3 years, and 54.0% at 5 years. A validation set comprised 232 patients, with cumulative mortality rates of 29.1% at 1 year, 43.5% at 3 years, and 53.2% at 5 years. The optimal random survival forest (RSF) model (mtry = 4, node size = 5) achieved an AUC of 0.839 for survival prediction in the training set. Comprising 11 variables such as demographics, treatment details, tumor characteristics, T staging, N staging, and M staging, the RSF model revealed high predictive accuracy with AUCs of 0.92, 0.96, and 0.96 for 1-, 3-, and 5-year survival, respectively, which was consistently reflected in the validation set with AUCs of 0.88, 0.92, and 0.89, respectively. Moreover, patients were risk-stratified. Although our RSF model effectively stratified patients into different prognostic groups, it needs external validation to confirm its utility for noninvasive prognostic prediction and risk stratification in gNENs. Further research is required to verify its broader clinical applicability.
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Affiliation(s)
- Tianbao Liao
- Department of President's Office, Youjiang Medical University for Nationalities, Baise, China
| | - Tingting Su
- Department of ECG Diagnostics, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yang Lu
- Department of International Medical, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Lina Huang
- Department of Endocrinology and Metabolism Nephrology, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Wei-Yuan Wei
- Department of Gastric and Abdominal Tumor Surgery, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China.
| | - Lu-Huai Feng
- Department of Endocrinology and Metabolism Nephrology, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China.
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Zhou H, Zhu Y, Qin B, Liu Y, Wang Z, Guo C, Wang J, Chen X. The association between non-HDL cholesterol and high-grade pancreatic neuroendocrine neoplasms. Endocrine 2024; 86:584-591. [PMID: 38844608 DOI: 10.1007/s12020-024-03910-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 06/01/2024] [Indexed: 10/19/2024]
Abstract
PURPOSE High-density lipoprotein cholesterol (HDL-c) plays an important role in tumorigenesis in several endocrine-related cancers. Few studies have shown the effect of non-HDL-c in malignant tumors. The present study aimed to identify the association between non-HDL-c and high-grade pancreatic neuroendocrine neoplasms (PNENs). METHODS A total of 197 PNEN patients who underwent surgery were analyzed retrospectively. Clinical and histopathological features, such as patients' age and sex, tumor location and size, tumor grade, the level of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and fasting plasma-glucose levels were obtained. Non-HDL-c was calculated as total cholesterol - HDL-c. The relationships between those features and high-grade PNENs were identified using logistic regression analysis. RESULTS Among the 197 patients with PNENs, a lower HDL-c level was more common seen in patients with poorly differentiated PNENs than in those with well-differentiated PNENs (P < 0.05). The non-HDL-c/HDL-c ratio was greater in patients with poorly differentiated PNENs than in those with well-differentiated PNENs (P < 0.01). Similarly, a greater proportion of patients with a non-HDL-c/HDL-c ratio larger than 5 was found in patients with poorly differentiated PNENs than in those with well-differentiation PNENs (P < 0.01). Multivariate logistic analysis showed that the non-HDL-c/HDL-c ratio was positively associated with poorly differentiated PNENs (odds ratio (OR) = 1.45, 95% conference interval (CI):1.13-1.87). Similarly, the risk of poorly differentiated PNENs increased significantly in patients with a non-HDL-c/HDL-c greater than 5 (OR = 14.13, 95%CI: 2.98-66.89). The risk of high-grade PNENs increased in patients with a high non-HDL-c/HDL-c ratio (OR = 1.27, 95% CI: 1.04-1.55), and the risk also increased markedly when the ratio was greater than 5 (OR = 5.00, 95%CI: 1.28-19.49). CONCLUSIONS A high ratio of non-HDL-c/HDL-c was associated with high-grade PNENs or poorly differentiated PNENs.
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Affiliation(s)
- Hao Zhou
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Yong Zhu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Bin Qin
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Yongkang Liu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Zhongqiu Wang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Chuangen Guo
- Department of Radiology, the First Affiliated Hospital of Zhejiang University School of Medicine, Haznghozu, 310003, China
| | - Jianhua Wang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
| | - Xiao Chen
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
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Pandrowala SA, Kapoor D, Kunte A, Chopde A, Puranik A, Dev ID, Parghane R, Basu S, Ramaswamy A, Ostwal V, Chaudhari VA, Bhandare MS, Shrikhande SV. Factors Predicting Prognosis in Metastatic Grade 1 Gastro-entero-pancreatic Neuroendocrine Tumors. J Gastrointest Cancer 2024; 55:1220-1228. [PMID: 38874852 PMCID: PMC11347461 DOI: 10.1007/s12029-024-01077-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/04/2024] [Indexed: 06/15/2024]
Abstract
INTRODUCTION The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) has steadily increased. These tumors are considered relatively indolent even when metastatic. What determines survival outcomes in such situations is understudied. MATERIALS AND METHODS Retrospective analysis of a prospectively maintained NET clinic database, to include patients of metastatic grade 1 GEP-NET, from January 2018 to December 2021, to assess factors affecting progression-free survival (PFS). RESULTS Of the 589 patients of GEP-NET treated during the study period, 100 were grade 1, with radiological evidence of distant metastasis. The median age was 50 years, with 67% being men. Of these, 15 patients were observed, while 85 patients received treatment in the form of surgery (n = 32), peptide receptor radionuclide therapy (n = 50), octreotide LAR (n = 22), and/or chemotherapy (n = 4), either as a single modality or multi-modality treatment. The median (PFS) was 54.5 months. The estimated 3-year PFS and 3-year overall survival rates were 72.3% (SE 0.048) and 93.4% (SE 0.026), respectively. On Cox regression, a high liver tumor burden was the only independent predictor of PFS (OR 3.443, p = 0.014). The 5-year OS of patients with concomitant extra-hepatic disease was significantly lower than that of patients with liver-limited disease (70.7% vs. 100%, p = 0.017). CONCLUSION A higher burden of liver disease is associated with shorter PFS in patients with metastatic grade I GEP-NETs. The OS is significantly lower in patients with associated extrahepatic involvement. These parameters may justify a more aggressive treatment approach in metastatic grade 1 GEP-NETs.
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Affiliation(s)
- Saneya A Pandrowala
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, 400012, India
| | - Deeksha Kapoor
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, 400012, India
| | - Aditya Kunte
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, 400012, India
| | - Amit Chopde
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, 400012, India
| | - Ameya Puranik
- Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, 400012, India
| | - Indraja Devidas Dev
- Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, 400012, India
| | - Rahul Parghane
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Mumbai, Maharashtra, 400012, India
| | - Sandip Basu
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Mumbai, Maharashtra, 400012, India
| | - Anant Ramaswamy
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, 400012, India
| | - Vikas Ostwal
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, 400012, India
| | - Vikram A Chaudhari
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, 400012, India
| | - Manish S Bhandare
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, 400012, India.
| | - Shailesh V Shrikhande
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, 400012, India
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Maharati A, Moghbeli M. Role of microRNA-505 during tumor progression and metastasis. Pathol Res Pract 2024; 258:155344. [PMID: 38744001 DOI: 10.1016/j.prp.2024.155344] [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: 12/23/2023] [Revised: 04/23/2024] [Accepted: 05/09/2024] [Indexed: 05/16/2024]
Abstract
Late diagnosis of cancer in advanced stages due to the lack of screening methods is considered as the main cause of poor prognosis and high mortality rate among these patients. Therefore, it is necessary to investigate the molecular tumor biology in order to introduce biomarkers that can be used in cancer screening programs and early diagnosis. MicroRNAs (miRNAs) have key roles in regulation of the cellular pathophysiological processes. Due to the high stability of miRNAs in body fluids, they are widely used as the non-invasive tumor markers. According to the numerous reports about miR-505 deregulation in a wide range of cancers, we investigated the role of miR-505 during tumor progression. It was shown that miR-505 mainly has the tumor suppressor functions through the regulation of signaling pathways, chromatin remodeling, and cellular metabolism. This review has an effective role in introducing miR-505 as a suitable marker for the early cancer diagnosis.
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Affiliation(s)
- Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Komiyama S, Okusaka T, Maruki Y, Ohba A, Nagashio Y, Kondo S, Hijioka S, Morizane C, Ueno H, Sukeda A, Mizui T, Takamoto T, Nara S, Ban D, Esaki M, Hiraoka N, Shimada K. Clinicopathological Findings and Treatment Outcomes of Patients with Primary Hepatobiliary Neuroendocrine Neoplasms: A Retrospective Single-institution Analysis. Intern Med 2024; 63:891-901. [PMID: 37612088 PMCID: PMC11045373 DOI: 10.2169/internalmedicine.2016-23] [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: 03/31/2023] [Accepted: 07/11/2023] [Indexed: 08/25/2023] Open
Abstract
Objective Primary hepatobiliary neuroendocrine neoplasms (NENs) are rare tumors exhibiting several morphological and behavioral characteristics. Considering the lack of relevant data on this topic, we evaluated the clinicopathological features and treatment outcomes of patients with primary hepatobiliary NENs. Methods/Patients We examined 43 consecutive patients treated at the National Cancer Center Hospital with pathological diagnoses of primary hepatobiliary NEN between 1980 and 2016. Results Nine patients were diagnosed with neuroendocrine tumor (NET) G1, 9 with NET G2, and 25 with neuroendocrine carcinoma (NEC) based on the World Health Organization 2019 classification. Patients with NEC had primary sites across the hepatobiliary organs, although sites in patients with NET G1 and NET G2 only included the liver and ampulla of Vater. Patients with primary extrahepatic bile duct or ampulla of Vater NENs tended to be diagnosed earlier than patients with primary gallbladder NENs. The median survival times in the NET G1, NET G2, and NEC groups were 167.9, 97.4, and 11.1 months, respectively. A good performance status, absence of distant metastases, and low tumor grade were identified as independent predictors of a favorable prognosis. Conclusion The NET-to-NEC ratio and tumor stage distribution at the diagnosis differed depending on the primary site. Patients with G1 and G2 NETs who underwent surgical resection had good prognoses, whereas those with NEC exhibited more advanced disease and poorer prognoses. The performance status, staging classification, and tumor grade are important factors to consider when devising an appropriate treatment strategy and predicting the prognoses of patients with primary hepatobiliary NEN.
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Affiliation(s)
- Satoshi Komiyama
- Chemotherapy Department, Yokohama City University Medical Center, Japan
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Yuta Maruki
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Akihiro Ohba
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Yoshikuni Nagashio
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Shunsuke Kondo
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Susumu Hijioka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Hideki Ueno
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Japan
| | - Aoi Sukeda
- Pathology and Clinical Laboratories, National Cancer Center Hospital, Japan
- Department of Anatomic Pathology, Tokyo Medical University, Japan
| | - Takahiro Mizui
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Takeshi Takamoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Satoshi Nara
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Daisuke Ban
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Minoru Esaki
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
| | - Nobuyoshi Hiraoka
- Pathology and Clinical Laboratories, National Cancer Center Hospital, Japan
| | - Kazuaki Shimada
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Japan
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Chen G, Liu L, Tan C, Tan Q, Chen Y, An X, Liu X, Wang X. Prognostic significance of systemic immune-inflammation index in patients with nonfunction pancreatic neuroendocrine tumor undergoing surgical resection. Cancer Med 2024; 13:e7114. [PMID: 38553949 PMCID: PMC10980930 DOI: 10.1002/cam4.7114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 10/12/2023] [Accepted: 03/04/2024] [Indexed: 04/02/2024] Open
Abstract
PURPOSE The purpose of our study was to investigate the clinical significance and prognostic role of the systemic immune-inflammation index (SII) in patients who underwent surgical resection for nonfunctioning pancreatic neuroendocrine tumors (pNETs). METHODS We conducted a retrospective analysis of 364 patients with nonfunctioning pNETs. The association between the SII level and clinical parameters was investigated. The receiver operating characteristic (ROC) curve was used to calculate the optimal SII value. Cox proportional hazard analysis was performed to evaluate the prognostic factors. RESULTS Our study included 364 patients with nonfunctioning pNETs who underwent surgery. The median age was 51.0 (43.0, 59.3), and 164 (45.1%) were male. The optimal threshold of SII determined by ROC analysis was 523.95. Higher SII levels were significantly associated with older age (p = 0.001), sex (p = 0.011), tumor size (p = 0.032), and tumor grade (p = 0.002). Recurrence was observed in 70 (19.2%) patients following a median follow-up of 98 months. Univariate analysis showed that higher SII (p < 0.0001), tumor size >4 cm (p = 0.015), and G2/G3 grade (p = 0.002) were significantly associated with disease-free survival (DFS). Multivariate analysis revealed that higher SII (HR: 7.35; 95% CI: 3.44, 15.70; p < 0.0001) and G2/G3 grade (HR: 3.11; 95% CI: 1.42, 6.82; p = 0.005) remained significantly associated with tumor recurrence. Furthermore, 46 (12.6%) patients died during the follow-up. Higher SII (HR: 8.43; 95% CI: 3.19, 22.72; p < 0.0001) and G2/G3 grade (HR: 3.16; 95% CI: 1.01, 9.86; p = 0.048) were independent predictors of overall survival (OS) by multivariate analysis. CONCLUSION In conclusion, our study revealed that a higher SII level was associated with tumor-related features (larger tumor size and advanced grade) and subsequent shorter DFS and OS in patients with nonfunctioning pNETs. These results indicated that the SII could serve as an efficient prognostic biomarker for nonfunctioning pNETs.
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Affiliation(s)
- Guanhua Chen
- Division of Pancreatic Surgery, Department of General Surgery, West China HospitalSichuan UniversityChengduSichuanChina
| | - Li Liu
- Division of Pancreatic Surgery, Department of General Surgery, West China HospitalSichuan UniversityChengduSichuanChina
| | - Chunlu Tan
- Division of Pancreatic Surgery, Department of General Surgery, West China HospitalSichuan UniversityChengduSichuanChina
| | - Qingquan Tan
- Division of Pancreatic Surgery, Department of General Surgery, West China HospitalSichuan UniversityChengduSichuanChina
| | - Yonghua Chen
- Division of Pancreatic Surgery, Department of General Surgery, West China HospitalSichuan UniversityChengduSichuanChina
| | - Xiangrong An
- Department of PediatricsSouthwest Medical UniversityLuzhouSichuanChina
| | - Xubao Liu
- Division of Pancreatic Surgery, Department of General Surgery, West China HospitalSichuan UniversityChengduSichuanChina
| | - Xing Wang
- Division of Pancreatic Surgery, Department of General Surgery, West China HospitalSichuan UniversityChengduSichuanChina
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Ma J, Wang X, Tang M, Zhang C. Preoperative prediction of pancreatic neuroendocrine tumor grade based on 68Ga-DOTATATE PET/CT. Endocrine 2024; 83:502-510. [PMID: 37715934 PMCID: PMC10850018 DOI: 10.1007/s12020-023-03515-3] [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: 07/08/2023] [Accepted: 08/29/2023] [Indexed: 09/18/2023]
Abstract
OBJECTIVE To establish a prediction model for preoperatively predicting grade 1 and grade 2/3 tumors in patients with pancreatic neuroendocrine tumors (PNETs) based on 68Ga-DOTATATE PET/CT. METHODS Clinical data of 41 patients with PNETs were included in this study. According to the pathological results, they were divided into grade 1 and grade 2/3. 68Ga-DOTATATE PET/CT images were collected within one month before surgery. The clinical risk factors and significant radiological features were filtered, and a clinical predictive model based on these clinical and radiological features was established. 3D slicer was used to extracted 107 radiomic features from the region of interest (ROI) of 68Ga-dotata PET/CT images. The Pearson correlation coefficient (PCC), recursive feature elimination (REF) based five-fold cross validation were adopted for the radiomic feature selection, and a radiomic score was computed subsequently. The comprehensive model combining the clinical risk factors and the rad-score was established as well as the nomogram. The performance of above clinical model and comprehensive model were evaluated and compared. RESULTS Adjacent organ invasion, N staging, and M staging were the risk factors for PNET grading (p < 0.05). 12 optimal radiomic features (3 PET radiomic features, 9 CT radiomic features) were screen out. The clinical predictive model achieved an area under the curve (AUC) of 0.785. The comprehensive model has better predictive performance (AUC = 0.953). CONCLUSION We proposed a comprehensive nomogram model based on 68Ga-DOTATATE PET/CT to predict grade 1 and grade 2/3 of PNETs and assist personalized clinical diagnosis and treatment plans for patients with PNETs.
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Affiliation(s)
- Jiao Ma
- Department of Nuclear Medicine, The Affilliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, PR China
| | - Xiaoyong Wang
- Department of Radiology, The Affilliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, PR China
| | - Mingsong Tang
- Department of Radiology, The Affilliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, PR China
| | - Chunyin Zhang
- Department of Nuclear Medicine, The Affilliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, PR China.
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, 646000, Sichuan, PR China.
- Academician (expert) Workstation of Sichuan Province, Luzhou, 646000, Sichuan, PR China.
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Park YM, Seo HI, Noh BG, Kim S, Hong SB, Lee NK, Kim DU, Han SY. Clinicopathological characteristics of extrahepatic biliary neuroendocrine neoplasms in the gallbladder, extrahepatic biliary tract, and ampulla of Vater: A single-center cross-sectional study. Ann Hepatobiliary Pancreat Surg 2023; 27:380-387. [PMID: 37840317 PMCID: PMC10700941 DOI: 10.14701/ahbps.23-045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 10/17/2023] Open
Abstract
Backgrounds/Aims In 2019, the grading and staging system for neuroendocrine neoplasms (NENs) was significantly changed. In this study, we report the clinicopathological characteristics and surgical outcomes of patients with extrahepatic biliary NENs who underwent curative resection with or without adjuvant treatment. Methods We retrospectively reviewed a database of 16 patients who developed NENs, neuroendocrine carcinoma (NEC), and mixed endocrine non-endocrine neoplasms (MiNENs) after curative resection. Among them, eight patients had ampulla of Vater (AoV) tumors, and eight patients had non-AoV tumors. Results G1 and G2 were more frequently observed in the AoV group than in the non-AoV group (12.5% and 62.5%, respectively). In contrast, NEC and MiNEN were more common in the non-AoV group (50.0%). High Ki-67 index (> 20%) and perineural invasion (PNI) were more frequently observed in the non-AoV group. Advanced age (> 65 years), mitotic count > 20 per 2 mm2, and Ki-67 index > 20% were strongly correlated with patient survival (p = 0.018, 0.009, and 0.044, respectively). Advanced age (> 65 years) and mitotic count > 20 per 2 mm2 were significantly correlated with disease recurrence (p = 0.033 and 0.010, respectively). Conclusions AoV and non-AoV tumors had significant differences in the histologic grade, Ki67, and PNI. Patients with non-AoV tumors had an increased risk for survival and recurrence than those in the AoV group. For extrahepatic biliary NENs, early detection of tumors, adequate surgery, and aggressive adjuvant treatment for high-risk patients are important to achieve long-term survival and prevent disease recurrence.
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Affiliation(s)
- Young Mok Park
- Department of Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Hyung Il Seo
- Department of Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Byeong Gwan Noh
- Department of Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Suk Kim
- Department of Radiology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Seung Baek Hong
- Department of Radiology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Nam Kyung Lee
- Department of Radiology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Dong Uk Kim
- Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Sung Yong Han
- Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
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11
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Xu X, Ji H, Guo Z, Lu X. Elevated serum MMP-1 associated with advanced disease stage and lymph node metastasis in patients with pancreatic carcinoma. Am J Cancer Res 2023; 13:5405-5417. [PMID: 38058827 PMCID: PMC10695808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/08/2023] [Indexed: 12/08/2023] Open
Abstract
Pancreatic cancer is a malignancy with extremely poor prognosis. This study aimed to investigate the application value of tumour markers and matrix metalloproteinase-1 (MMP-1) in predicting clinical staging and lymph node metastasis of pancreatic cancer. Totally, 130 pancreatic cancer patients and 40 healthy controls admitted to Haian Hospital Affiliated to Nantong University from January 2018 to January 2022 were collected. The expression of MMP-1, carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), and carbohydrate antigen 125 (CA125) were detected in their serum. MMP-1 was highly expressed in pancreatic cancer tissue, and MMP-1, CA199, CA125, and CEA could serve as diagnostic markers for pancreatic cancer. MMP-1 and CA199 had higher diagnostic value for early pancreatic cancer. Additionally, MMP-1 also demonstrated high predictive value for lymph node metastasis. Multivariate Cox regression analysis identified TNM staging, differentiation, MMP-1, and CA199 as independent risk factors affecting the overall survival of pancreatic cancer patients. The risk score model constructed based on Cox regression coefficients could better predict the prognosis of pancreatic cancer patients. MMP-1 demonstrates promising application value in determining clinical staging and lymph node metastasis of pancreatic cancer.
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Affiliation(s)
- Xiaoqing Xu
- Department of Oncology Pain, The Haian Hospital Affiliated to Nantong UniversityHaian 226600, Jiangsu, China
| | - Hualiang Ji
- Department of Gastroenterology, The Haian Hospital Affiliated to Nantong UniversityHaian 226600, Jiangsu, China
| | - Zongfeng Guo
- Department of Anesthesiology, The Haian Hospital Affiliated to Nantong UniversityHaian 226600, Jiangsu, China
| | - Xiaomin Lu
- Department of Oncology, The Haian Hospital Affiliated to Nantong UniversityHaian 226600, Jiangsu, China
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12
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Park YJ, Park YS, Kim ST, Hyun SH. A Machine Learning Approach Using [ 18F]FDG PET-Based Radiomics for Prediction of Tumor Grade and Prognosis in Pancreatic Neuroendocrine Tumor. Mol Imaging Biol 2023; 25:897-910. [PMID: 37395887 DOI: 10.1007/s11307-023-01832-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 05/30/2023] [Accepted: 06/19/2023] [Indexed: 07/04/2023]
Abstract
PURPOSE We sought to develop and validate machine learning (ML) models for predicting tumor grade and prognosis using 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography (PET)-based radiomics and clinical features in patients with pancreatic neuroendocrine tumors (PNETs). PROCEDURES A total of 58 patients with PNETs who underwent pretherapeutic [18F]FDG PET/computed tomography (CT) were retrospectively enrolled. PET-based radiomics extracted from segmented tumor and clinical features were selected to develop prediction models by the least absolute shrinkage and selection operator feature selection method. The predictive performances of ML models using neural network (NN) and random forest algorithms were compared by the areas under the receiver operating characteristic curves (AUROCs) and validated by stratified five-fold cross validation. RESULTS We developed two separate ML models for predicting high-grade tumors (Grade 3) and tumors with poor prognosis (disease progression within two years). The integrated models consisting of clinical and radiomic features with NN algorithm showed the best performances than the other models (stand-alone clinical or radiomics models). The performance metrics of the integrated model by NN algorithm were AUROC of 0.864 in the tumor grade prediction model and AUROC of 0.830 in the prognosis prediction model. In addition, AUROC of the integrated clinico-radiomics model with NN was significantly higher than that of tumor maximum standardized uptake model in predicting prognosis (P < 0.001). CONCLUSIONS Integration of clinical features and [18F]FDG PET-based radiomics using ML algorithms improved the prediction of high-grade PNET and poor prognosis in a non-invasive manner.
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Affiliation(s)
- Yong-Jin Park
- Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
- Department of Nuclear Medicine, Ajou University Medical Center, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon, 16499, South Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, South Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, South Korea
| | - Seung Hyup Hyun
- Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.
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13
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Magi L, Marasco M, Rinzivillo M, Faggiano A, Panzuto F. Management of Functional Pancreatic Neuroendocrine Neoplasms. Curr Treat Options Oncol 2023; 24:725-741. [PMID: 37103745 PMCID: PMC10272249 DOI: 10.1007/s11864-023-01085-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2023] [Indexed: 04/28/2023]
Abstract
OPINION STATEMENT Functional pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous diseases in terms of both clinical and pathological aspects. These tumors secrete hormones or peptides, which may cause a wide variety of symptoms related to a clinical syndrome. The management of functional pNENs is still challenging for clinicians due to the need to control both tumor growth and specific symptoms. Surgery remains the cornerstone in the management of local disease because it can definitively cure the patient. However, when the disease is not resectable, a broad spectrum of therapeutic options, including locoregional therapy, somatostatin analogs (SSAs), targeted therapies, peptide-receptor radionuclide therapy (PRRT), and chemotherapy, are available. The present review summarizes the main key issues regarding the clinical management of these tumors, providing a specific highlight on their therapeutic approach.
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Affiliation(s)
- Ludovica Magi
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Via di Grottarossa 1035, 00189, Rome, Italy
| | - Matteo Marasco
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Via di Grottarossa 1035, 00189, Rome, Italy
| | - Maria Rinzivillo
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Via di Grottarossa 1035, 00189, Rome, Italy
| | - Antongiulio Faggiano
- Endocrinology Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Via Di Grottarrossa 1035, 00189, Rome, Italy
| | - Francesco Panzuto
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Via di Grottarossa 1035, 00189, Rome, Italy.
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, Via di Grottarossa 1035, 00189, Rome, Italy.
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14
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Jacoba IM, Weber HC. Biomarkers in gastroenteropancreatic neuroendocrine neoplasms. Curr Opin Endocrinol Diabetes Obes 2023; 30:175-180. [PMID: 36895178 DOI: 10.1097/med.0000000000000805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
PURPOSE OF REVIEW Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) represent a heterogenous group of rare tumors emanating from neuroendocrine cells that are clinically silent for prolonged periods of time without detection. Traditional biomarkers lack sufficiently high enough specificity and sensitivity for these tumors and their secreted products. New molecules are sought to improve accuracy of detection and monitoring of GEP-NENs. The purpose of this review is to highlight recent advances in the discovery of novel biomarkers and their potential characteristics and utility as markers of GEP-NENs. RECENT FINDINGS Several recent GEP-NEN investigations regarding NETest demonstrate superior sensitivity and specificity in diagnosis and disease monitoring as compared with chromogranin A. Among several tissue-based emergent candidate molecules as biomarkers for GEP-NEN INSM1 has demonstrated consistently excellent characteristics when compared with traditional markers including chromogranin A, synaptophysin, and CD56. SUMMARY For the diagnosis and clinical monitoring of NEN, there still exists a considerable need for better biomarkers. Novel technology has resulted in a promising liquid biopsy for the detection and monitoring of GEP-NENs. The search for improved tissue biomarkers has resulted in identification of one potential candidate whereas several others remain in the investigatory phase.
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Affiliation(s)
- Isa Mulingbayan Jacoba
- Boston Medical Center/Boston University Chobanian & Avedisian School of Medicine, Department of Pathology & Laboratory Medicine
| | - H Christian Weber
- Boston Medical Center/Boston University Chobanian & Avedisian School of Medicine, Department of Pathology & Laboratory Medicine
- Department of Medicine
- VA Boston Healthcare System, Section of Gastroenterology and Hepatology, Boston, Massachusetts, USA
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15
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Matrood S, Melms LE, Bartsch DK, Di Fazio P. The Expression of Autophagy-Associated Genes Represents a Valid Footprint for Aggressive Pancreatic Neuroendocrine Neoplasms. Int J Mol Sci 2023; 24:3636. [PMID: 36835048 PMCID: PMC9966877 DOI: 10.3390/ijms24043636] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/17/2023] Open
Abstract
Pancreatic neuroendocrine neoplasms (pNEN) are rare and heterogeneous tumors. Previous investigations have shown that autophagy can be a target for cancer therapy. This study aimed to determine the association between the expression of autophagy-associated gene transcripts and clinical parameters in pNEN. In total, 54 pNEN specimens were obtained from our human biobank. The patient characteristics were retrieved from the medical record. RT-qPCR was performed to assess the expression of the autophagic transcripts BECN1, MAP1LC3B, SQSTM1, UVRAG, TFEB, PRKAA1, and PRKAA2 in the pNEN specimens. A Mann-Whitney U test was used to detect differences in the expression of autophagic gene transcripts between different tumor characteristics. This study showed that G1 sporadic pNEN have a higher expression of autophagic genes compared to G2. Lymphatic and distant metastasis occurred significantly more often in pNEN with a decreased expression of the autophagic genes. Within sporadic pNEN, the insulinomas express higher levels of autophagic transcripts than gastrinomas and non-functional pNEN. MEN1-associated pNEN show a higher expression of autophagic genes than sporadic pNEN. In summary, a decreased expression of autophagic transcripts distinguishes metastatic from non-metastatic sporadic pNEN. The significance of autophagy as a molecular marker for prognosis and therapy decisions needs to be further investigated.
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Affiliation(s)
- Sami Matrood
- Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, 35043 Marburg, Germany
| | - Leander Edwin Melms
- Institute for Artificial Intelligence, University Hospital Marburg, Philipps-University Marburg, 35043 Marburg, Germany
| | - Detlef Klaus Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, 35043 Marburg, Germany
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, 35043 Marburg, Germany
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16
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Ruggeri RM, Benevento E, De Cicco F, Fazzalari B, Guadagno E, Hasballa I, Tarsitano MG, Isidori AM, Colao A, Faggiano A. Neuroendocrine neoplasms in the context of inherited tumor syndromes: a reappraisal focused on targeted therapies. J Endocrinol Invest 2023; 46:213-234. [PMID: 36038743 DOI: 10.1007/s40618-022-01905-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 08/16/2022] [Indexed: 01/25/2023]
Abstract
PURPOSE Neuroendocrine neoplasms can occur as part of inherited disorders, usually in the form of well-differentiated, slow-growing tumors (NET). The main predisposing syndromes include: multiple endocrine neoplasias type 1 (MEN1), associated with a large spectrum of gastroenteropancreatic and thoracic NETs, and type 4 (MEN4), associated with a wide tumour spectrum similar to that of MEN1; von Hippel-Lindau syndrome (VHL), tuberous sclerosis (TSC), and neurofibromatosis 1 (NF-1), associated with pancreatic NETs. In the present review, we propose a reappraisal of the genetic basis and clinical features of gastroenteropancreatic and thoracic NETs in the setting of inherited syndromes with a special focus on molecularly targeted therapies for these lesions. METHODS Literature search was systematically performed through online databases, including MEDLINE (via PubMed), and Scopus using multiple keywords' combinations up to June 2022. RESULTS Somatostatin analogues (SSAs) remain the mainstay of systemic treatment for NETs, and radiolabelled SSAs can be used for peptide-receptor radionuclide therapy for somatostatin receptor (SSTR)-positive NETs. Apart of these SSTR-targeted therapies, other targeted agents have been approved for NETs: the mTOR inhibitor everolimus for lung, gastroenteropatic and unknown origin NET, and sunitinib, an antiangiogenic tyrosine kinase inhibitor, for pancreatic NET. Novel targeted therapies with other antiangiogenic agents and immunotherapies have been also under evaluation. CONCLUSIONS Major advances in the understanding of genetic and epigenetic mechanisms of NET development in the context of inherited endocrine disorders have led to the recognition of molecular targetable alterations, providing a rationale for the implementation of treatments and development of novel targeted therapies.
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Affiliation(s)
- R M Ruggeri
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Messina, AOU Policlinico "Gaetano Martino" University Hospital, 98125, Messina, Italy.
| | - E Benevento
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
| | - F De Cicco
- SSD Endocrine Disease and Diabetology, ASL TO3, Pinerolo, TO, Italy
| | - B Fazzalari
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - E Guadagno
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
| | - I Hasballa
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - M G Tarsitano
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - A M Isidori
- Gruppo NETTARE, Policlinico Umberto I, Università Sapienza, Rome, Italy
| | - A Colao
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
- UNESCO Chair "Education for Health and Sustainable Development", Federico II University, Naples, Italy
| | - A Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
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Meng YF, Fan ZY, Yang J, Li YZ, Liu SJ, Gao CH, Gao X, Pang CY, Zhan HX. The characteristics of serum lipid spectrum in PanNENs and its correlation with clinicopathological features and prognosis. Front Endocrinol (Lausanne) 2023; 14:1137911. [PMID: 37033225 PMCID: PMC10081680 DOI: 10.3389/fendo.2023.1137911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 03/13/2023] [Indexed: 04/11/2023] Open
Abstract
BACKGROUND The role of dyslipidemia in pancreatic neuroendocrine tumors (PanNENs) is unclear. The aim of this study is to analyze the characteristics of serum lipid spectrum in PanNENs, and the effect of the variation in lipid profile on the development of PanNENs clinicopathological features and prognosis. METHODS All PanNENs patients between November 2012 and September 2020 in the authors' research center were identified from patient medical records and databases. A total of 185 with PanNENs patients were ultimately included in this study, including 100 nonfunctional PanNENs and 85 insulinomas. Clinicopathologic features, serum lipid level and overall survival results were retrospectively analyzed using statistical methods. RESULTS In 185 PanNENs, 95 (51.4%) patients appear to have dyslipidemia. Patients with insulinoma had a lower proportion of abnormal HDL than those with nonfunctional PanNENs (10.6% vs 23%, P=0.026). The mean serum HDL levels of insulinomas were 0.131 mmol/L higher than the NF-PanNENs (1.306 ± 0.324 vs 1.175 ± 0.315, P=0.006). In multivariate logistic analysis, high levels of HDL are negatively correlated to tumor size (OR 0.233, 95% CI: 0.069-0.790, P=0.019), but HDL was not associated with pathological grade or metastasis. And a correlation has been found between hypercholesterolemia and the original location of the tumor (OR:0.224, 95%CI: 0.066-0.753, P =0.016). In addition, the outcome of the survival analysis revealed that dyslipidemia did not influence the prognosis of PanNENs patients (P>0.05). CONCLUSIONS HDL was negatively correlated with the tumor size of PanNENs. The serum HDL level of insulinoma patients is higher than nonfunctional PanNENs.
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18
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Ptasnuka M, Truskovs A, Ozolins A, Narbuts Z, Sperga M, Plaudis H. Sporadic pancreatic neuroendocrine neoplasms: A retrospective clinicopathological and outcome analysis from a Latvian study group. Front Surg 2023; 10:1131333. [PMID: 37021091 PMCID: PMC10069647 DOI: 10.3389/fsurg.2023.1131333] [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: 12/24/2022] [Accepted: 03/03/2023] [Indexed: 04/07/2023] Open
Abstract
Background Although pancreatic neuroendocrine neoplasms (PNEN) are rare, there has been a constant increase in incidence. Furthermore, PNEN present unique clinical behaviors and long-term survival can be expected even in the presence of metastases as compared with ductal adenocarcinoma of the pancreas. Determining the best therapeutic approach and proper timing of therapy requires knowledge of reliable prognostic factors. Therefore, the aim of this study was to explore clinicopathological features, treatment, and survival outcomes of patients with PNEN based on Latvian gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) registry data. Method Patients with confirmed PNEN at Riga East Clinical University Hospital and Pauls Stradins Clinical University Hospital, between 2008 and 2020, were retrospectively analyzed. Data were collected and included in EUROCRINE, an open-label international endocrine surgical registry. Results In total, 105 patients were included. The median age at diagnosis was 64 years (IQR 53.0-70.0) for males and 61 years (IQR 52.5-69.0) for females. In 77.1% of patients, tumors were hormonally nonfunctional. Among those with functioning PNEN, 10.5% of patients presented with hypoglycemia and were diagnosed with insulinoma, 6.7% of patients presented with symptoms related to carcinoid syndrome; 30.5% of patients showed distant metastases at the time of diagnosis, and surgery was performed in 67.6% of patients. Notably, for five patients with nonfunctional PNEN <2 cm, a "watch and wait" approach was used; none of the patients developed metastatic disease. The median length of hospital stay was 8 days (IQR 5-13). Major postoperative complications were found in 7.0% of patients, and reoperation was conducted for 4.2% of patients, due to postpancreatectomy bleeding (2/71) and abdominal collection (1/71). The median follow-up period was 34 months (IQR 15.0-68.8). The OS at the last follow-up was 75.2% (79/105). The observed 1-, 5- and 10-year survival rates were 87.0, 71.2 and 58.0, respectively. Seven of the surgically treated patients had tumor recurrence. The median time of recurrence was 39 months (IQR 19.0-95.0). A univariable Cox proportional hazard analysis provided evidence that a nonfunctional tumor, a larger tumor size, the presence of distant metastases, a higher tumor grade, and the tumor stage were strong, negative predictors of OS. Conclusion Our study represents the general trends of clinicopathological features and treatment of PNEN in Latvia. For PNEN patients, tumor functionality, size, distant metastases, grade, and stage may be useful to predict OS and must be confirmed in further studies. Furthermore, a "surveillance" strategy might be safe for selected patients with small asymptomatic PNEN.
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Affiliation(s)
- Margarita Ptasnuka
- Department of General and Emergency Surgery, Riga East Clinical University Hospital, Riga, Latvia
- Correspondence: Margarita Ptasnuka
| | - Arturs Truskovs
- Department of Surgery, Pauls Stradiņš Clinical University Hospital, Riga, Latvia
- Department of Surgery, Riga Stradiņš University, Riga, Latvia
| | - Arturs Ozolins
- Department of Surgery, Pauls Stradiņš Clinical University Hospital, Riga, Latvia
- Department of Surgery, Riga Stradiņš University, Riga, Latvia
| | - Zenons Narbuts
- Department of Surgery, Pauls Stradiņš Clinical University Hospital, Riga, Latvia
- Department of Surgery, Riga Stradiņš University, Riga, Latvia
| | - Maris Sperga
- Department of Surgery, Riga Stradiņš University, Riga, Latvia
- Department of Infectious Pathology, Pathology Center, Riga, Latvia
| | - Haralds Plaudis
- Department of General and Emergency Surgery, Riga East Clinical University Hospital, Riga, Latvia
- Department of Surgery, Riga Stradiņš University, Riga, Latvia
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Liu X, Chen B, Chen J, Su Z, Sun S. The incidence, prevalence, and survival analysis of pancreatic neuroendocrine tumors in the United States. J Endocrinol Invest 2022:10.1007/s40618-022-01985-2. [PMID: 36522587 DOI: 10.1007/s40618-022-01985-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 09/27/2022] [Indexed: 12/23/2022]
Abstract
PURPOSE The incidence of pancreatic neuroendocrine tumors (pNETs) was increasing. The main purpose of this study was to statistically analyze the incidence and prevalence of pNETs and the main risk factors for the prognosis. METHODS Based on the Surveillance, Epidemiology, and End Results (SEER) database, with three registries integrated, this study comprehensively displayed the annual age adjust incidence of pNETs from 1975 to 2018, the estimated 20-year limited-duration prevalence, and conducted the univariate and multivariate survival analysis. RESULTS The incidence of pNETs has increased to about 1.5 per 100,000 population, and the prevalence has reached about 0.008% with the aged, Grade 1 and nonfunctional tumors accounting for the majority. The average median overall survival (OS), 5-year survival rate, and median disease-free survival (DFS) of pNETs patients from 1975 to 2018 were 85 months, 57.55%, and 220 months, respectively. From 2000 to 2018, the median OS was 94 months, and the 5-year survival rate was 59.94%. In multivariate survival analysis, the greatest risk factor was Grade 3&4 with HR = 3.62 (3.10-4.28), followed by distant stage with HR = 2.77 (2.28-3.36), and aged over 80 years old with HR = 2.26 (1.33-3.83). Surgery was a protective prognostic factor with HR = 0.34 (0.29-0.40). CONCLUSION The incidence and prevalence of pNETs were still increasing, but the trend was gradual and aging in recent years. The survival time of pNETs was longer but has not changed much in recent years. The degrees of malignancy, stage, and operation were the most important prognosis factors.
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Affiliation(s)
- X Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - B Chen
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - J Chen
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Z Su
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - S Sun
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
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Sex-Based Clinicopathologic and Survival Differences Among Patients with Pancreatic Neuroendocrine Tumors. J Gastrointest Surg 2022; 26:2321-2329. [PMID: 35915373 DOI: 10.1007/s11605-022-05345-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/30/2022] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Sex-based differences in survival have emerged among patients with pancreatic neuroendocrine tumors (PNETs). Mechanisms driving these differences remain poorly understood. We aimed to further characterize sex-based clinicopathologic and survival differences among patients with PNETs and correlate divergent mutational signatures in these patients. METHODS The National Cancer Database (NCDB) was queried for PNET patients diagnosed 2004-2017 who underwent surgery. Clinicopathologic features were analyzed by sex. The overall survival (OS) of men and women by disease stage was compared using the Kaplan-Meier method. Differences in PNET mutational signatures were analyzed by querying the American Association for Cancer Research Genomics Evidence Neoplasia Information (AACR-GENIE) Cohort v11.0-public. Frequencies of mutational signatures were compared by Fischer's exact (FE) test, adjusting for multiple testing via the Benjamini-Hochberg correction. RESULTS About 15,202 patients met inclusion criteria from the NCDB; 51.9% were men and 48.1% were women. Men more frequently had tumors > 2 cm than women and more commonly had poorly or undifferentiated tumors. Despite this, lymph node positivity and distant metastases were similar. Differences in OS were only seen among those with early stage rather than stage 3 or 4 disease. MEN1 and DAXX mutations were more frequent among men with PNETs, whereas TP53 mutations were more frequent among women when assessed by FE test. However, neither of these mutational differences maintained statistical significance when adjusted for multiple testing. CONCLUSION Compared to women, men have larger tumors but similar rates of distant metastases at time of surgery. OS differences appear to be driven by patients with early-stage disease without clearly identifiable differences in mutational signatures between the sexes.
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Development and validation of a combined nomogram model based on deep learning contrast-enhanced ultrasound and clinical factors to predict preoperative aggressiveness in pancreatic neuroendocrine neoplasms. Eur Radiol 2022; 32:7965-7975. [PMID: 35389050 DOI: 10.1007/s00330-022-08703-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/21/2022] [Accepted: 02/25/2022] [Indexed: 01/03/2023]
Abstract
OBJECTIVES This study aimed to develop and validate a combined nomogram model based on deep learning (DL) contrast-enhanced ultrasound (CEUS) and clinical factors to preoperatively predict the aggressiveness of pancreatic neuroendocrine neoplasms (PNENs). METHODS In this retrospective study, consecutive patients with histologically proven PNENs underwent CEUS examination at the initial work-up between January 2010 and October 2020. Patients were randomly allocated to the training and test sets. Typical sonographic and enhanced images of PNENs were selected to fine-tune the SE-ResNeXt-50 network. A combined nomogram model was developed by incorporating the DL predictive probability with clinical factors using multivariate logistic regression analysis. The utility of the proposed model was evaluated using receiver operator characteristic, calibration, and decision curve analysis. RESULTS A total of 104 patients were evaluated, including 80 (mean age ± standard deviation, 47 years ± 12; 56 males) in the training set and 24 (50 years ± 12; 14 males) in the test set. The DL model displayed effective image recognition with an AUC of 0.81 (95%CI: 0.62-1.00) in the test set. The combined nomogram model that incorporated independent clinical risk factors, such as tumor size, arterial enhancement level, and DL predictive probability, showed strong discrimination, with an AUC of 0.85 (95%CI: 0.69-1.00) in the test set with good calibration. Decision curve analysis verified the clinical usefulness of the combined nomogram. CONCLUSIONS The combined nomogram model could serve as a preoperative, noninvasive, and precise evaluation tool to differentiate aggressive and non-aggressive PNENs. KEY POINTS • Tumor size (odds ratio [OR], 1.58; p = 0.02), arterial enhancement level (OR, 0.04; p = 0.008), and deep learning predictive probability (OR, 288.46; p < 0.001) independently predicted aggressiveness of pancreatic neuroendocrine neoplasms preoperatively. • The combined model predicted aggressiveness better than the clinical model (AUC: 0.97 vs. 0.87, p = 0.009), achieving AUC values of 0.97 and 0.85 in the training set and the test set, respectively.
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22
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Fu M, Yu L, Yang L, Chen Y, Chen X, Hu Q, Sun H. Predictive value of the preoperative prognostic nutritional index for postoperative progression in patients with pancreatic neuroendocrine neoplasms. Front Nutr 2022; 9:945833. [PMID: 36159473 PMCID: PMC9493178 DOI: 10.3389/fnut.2022.945833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Objective The preoperative nutritional status of cancer patients is closely related to prognosis. The prognostic nutritional index (PNI) has been shown to predict the prognosis of a variety of tumors, but its study in pancreatic neuroendocrine neoplasms (pNENs) is lacking. The aim of the present study is to investigate the predictive value of the preoperative PNI for postoperative progression in patients with pNENs. Methods The medical records of 181 patients with pNENs, who underwent surgery, were retrospectively analyzed. A time-dependent receiver operating characteristic (ROC) curve was plotted to determine the optimal cut-off value of the preoperative PNI. Correlations between the preoperative PNI and clinicopathological parameters were analyzed using multiple linear regression. A Kaplan-Meier curve was applied to assess the progression-free survival (PFS) rate, which was tested using a log rank. Univariate and multivariate Cox proportional risk regression models were used to analyze the predictive value of the preoperative PNI on prognosis. Results The optimal cut-off value of the preoperative PNI was 48.275. The patients were divided into a high PNI group (PNI > 48.275, n = 92) and a low PNI group (PNI ≤ 48.275, n = 89). The proportion of patients with tumor progression after surgery was significantly higher in the low PNI group compared with that in the high PNI group (P = 0.004). The Kaplan-Meier curve showed that the PFS rate after surgery was significantly lower in the low PNI group compared with that in the high PNI group (P = 0.026). The preoperative PNI was an independent predictor of PFS (HR: 2.727, 95% CI: 1.174∼6.333, P = 0.020). Conclusion The preoperative PNI has a predictive value for postoperative progression in patients with pNENs.
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Affiliation(s)
- Mengfei Fu
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China
| | - Li Yu
- Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liu Yang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China
| | - Yang Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China
| | - Xiao Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China
| | - Qinyu Hu
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China
| | - Hui Sun
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Provincial Clinical Research Center for Diabetes and Metabolic Disorders, Wuhan, China
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Hackeng WM, Assi HA, Westerbeke FHM, Brosens LAA, Heaphy CM. Prognostic and Predictive Biomarkers for Pancreatic Neuroendocrine Tumors. Surg Pathol Clin 2022; 15:541-554. [PMID: 36049835 DOI: 10.1016/j.path.2022.05.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Pancreatic neuroendocrine tumors (PanNETs) represent a clinically challenging disease because these tumors vary in clinical presentation, natural history, and prognosis. Novel prognostic biomarkers are needed to improve patient stratification and treatment options. Several putative prognostic and/or predictive biomarkers (eg, alternative lengthening of telomeres, alpha-thalassemia/mental retardation, X-linked (ATRX)/Death Domain Associated Protein (DAXX) loss) have been independently validated. Additionally, recent transcriptomic and epigenetic studies focusing on endocrine differentiation have identified PanNET subtypes that display similarities to either α-cells or β-cells and differ in clinical outcomes. Thus, future prospective studies that incorporate genomic and epigenetic biomarkers are warranted and have translational potential for individualized therapeutic and surveillance strategies.
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Affiliation(s)
- Wenzel M Hackeng
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Hussein A Assi
- Department of Medicine, Boston University School of Medicine, 820 Harrison Avenue, FGH 2011, Boston, MA 02118, USA
| | - Florine H M Westerbeke
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Lodewijk A A Brosens
- Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Christopher M Heaphy
- Department of Medicine, Boston University School of Medicine, 650 Albany Street, Room 444, Boston, MA 02118, USA; Department of Pathology & Laboratory Medicine, Boston University School of Medicine, 650 Albany Street, Room 444, Boston, MA 02118, USA.
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24
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Angelico R, Siragusa L, Pathirannehalage Don CB, Sensi B, Billeci F, Vattermoli L, Padial B, Palmieri G, Anselmo A, Coppola A, Tisone G, Manzia TM. Pancreatic Adeno-MiNEN, a Rare Newly Defined Entity with Challenging Diagnosis and Treatment: A Case Report with Systematic Literature Review and Pooled Analysis. J Clin Med 2022; 11:jcm11175021. [PMID: 36078951 PMCID: PMC9457227 DOI: 10.3390/jcm11175021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
Mixed neuroendocrine non-neuroendocrine neoplasms (MiNEN) are a peculiar entity that can occur throughout the whole gastrointestinal trait, and pancreatic localization is rare. Their main characteristic is the presence of at least a neuroendocrine and an epithelial component, each accounting for at least 30% of the tumour mass. The presence of epithelial ductal component defines adeno-MiNEN. We report a case of a 59-year-old woman affected by pancreatic adeno-MiNEN with challenging diagnosis and successfully treated. A systematic literature review and pooled analysis was also performed, aiming to define the management and outcomes of pancreatic adeno-MiNEN. Out of 190 identified records, 15 studies including 28 patients affected by pancreatic-adeno-MiNEN were included in the analysis. Pancreatic adeno-MiNEN occurred mainly in males (82.8%) and at a mean age of 61.7 (range: 24–82) years. Pre-operative diagnosis was possible only in 14.2% of cases. At presentation, the majority had already advanced disease (TNM stage III (53.8%) and stage IV 19.3%). Adjuvant therapy was performed in 55% of patients, and the tumour recurrence rate was in 30% of cases. Median disease-free survival (DFS) was 12 months (range: 0–216 months) with a 5-year DFS of 16.6%, while the median overall survival (OS) was 12 months (range: 0–288 months) with a 5-year OS of 23.5%. Pancreatic adeno-MiNENs are rare; as they have very heterogenous behaviour, they are rarely diagnosed preoperatively and have poor prognosis. Treatment of localised MiNEN still relies on radical surgical resection, which seems essential to achieve a good oncological prognosis. International registry on MiNEN is necessary to improve the knowledge on this rare tumour and to improve its outcomes.
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Affiliation(s)
- Roberta Angelico
- HPB and Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Leandro Siragusa
- HPB and Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
| | | | - Bruno Sensi
- HPB and Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Federica Billeci
- HPB and Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Leonardo Vattermoli
- Department of Diagnostic Imaging and Interventional Radiology, Tor Vergata University of Rome, 00133 Rome, Italy
| | - Belen Padial
- Histopathologic Unit, Tor Vergata University of Rome, 00133 Rome, Italy
| | | | - Alessandro Anselmo
- HPB and Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Alessandro Coppola
- Department of Surgery, University Campus Bio-Medico of Rome, 00128 Rome, Italy
| | - Giuseppe Tisone
- HPB and Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
- Correspondence:
| | - Tommaso Maria Manzia
- HPB and Transplant Unit, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy
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Quan L, Liu Y, Cui W, Wang X, Zhang W, Wang Z, Guo C, Lu C, Hu F, Chen X. The associations between serum high-density lipoprotein cholesterol levels and malignant behavior in pancreatic neuroendocrine neoplasms. Lipids Health Dis 2022; 21:58. [PMID: 35842659 PMCID: PMC9287928 DOI: 10.1186/s12944-022-01669-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/04/2022] [Indexed: 02/07/2023] Open
Abstract
Background The role of serum high-density lipoprotein cholesterol (HDL-c) in tumorigenesis are observed in several endocrine-related cancers. However, its role in pancreatic neuroendocrine neoplasms (PNENs) has not been understood. In the current study, the relationship between HDL-c levels and malignant behavior in PNENs was explored. Methods One hundred ninety-seven patients with histopathology confirmed PNENs were included. PNENs were divided into three grades (G1, G2 and G3) as 2017 WHO classification based on ki67 index and mitosis count. The demographic data, clinical information, tumor morphological and pathological features (organs invasion, lymph node metastasis, vascular invasion and perineural invasion), and serum tumor biomarkers were collected. The relationships between HDL-c levels and malignant behaviors in PNENs were analyzed using logistic regression analysis. Models were also developed for the identification of high grade PNENs. Results The levels of serum HDL-c in G2/G3 tumor were significantly lower than that in G1 tumor (P = 0.031). However, no such difference was found between G3 and G1/G2. The proportions of low HDL-c (≤ 0.9 mmol/L) were higher in high-grade PNENs (G2/G3 or G3) than those in low-grade (G1 or G1/G2) (29.0 vs 15.2%, P = 0.032; 37.0 vs 20.5%, P = 0.023). The risk of G2/G3 tumors in patients with high serum HDL-c levels was decreased (odds ratio (OR) = 0.35, 95% confidence interval (CI): 0.12–0.99). Similarly, the risk of G3 PNENs increased in patients with low HDL-c levels (OR = 2.51, 95%CI:1.12–5.60). HDL-c level was also associated with a high ki67 index (> 55%) (OR = 0.10, 95%CI: 0.02–0.51) and neuroendocrine carcinoma G3 (OR = 0.21, 95%CI: 0.06–0.80). The area under the curve (AUC) of HDL-c + tumor size + age was 0.85 (95% CI: 0.79–0.91) in identifying G2/G3 PNENs, and HDL-c (> 0.9 mmol/L) + tumor size + age had an AUC of 0.77 (95% CI: 0.70–0.84) in identifying G3 PNENs. HDL-c level was associated with lymph node metastasis (OR = 0.24, 95%CI:0.08–0.99). Conclusion Serum HDL-c levels were significantly associated with malignant behaviors in PNENs, in particular to tumor grade and lymph node metastasis.
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Affiliation(s)
- Li Quan
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Yongkang Liu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Wenjing Cui
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Xinru Wang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Weixiao Zhang
- Department of Radiology, Nanjing Sir Run Run Hospital, Nanjing Medical University, 210029, Nanjing, China
| | - Zhongqiu Wang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Chuangen Guo
- Department of Radiology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Chao Lu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
| | - Feixiang Hu
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Xiao Chen
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China. .,Institute of Radiation Medicine, Fudan University, Shanghai, 200032, China.
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Ma ST, Wang DY, Liu YB, Tan HJ, Ge YY, Chi Y, Zhang BL. Prognostic factors of primary neuroendocrine breast cancer: A population-based study. Cancer Med 2022; 11:2533-2540. [PMID: 35499193 PMCID: PMC9249978 DOI: 10.1002/cam4.4557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 09/09/2021] [Accepted: 12/30/2021] [Indexed: 11/06/2022] Open
Abstract
Background Primary neuroendocrine breast carcinomas (NEBCs) are an extremely rare and underrecognized subtype of mammalian carcinoma. The prognostic factors for NEBCs remain controversial. Methods In this multicenter retrospective study, the prognostic factors for patients with primary NEBCs who underwent surgery and had a pathologically confirmed diagnosis of neuroendocrine carcinoma in China and the United States were examined. The endpoints were disease‐free survival (DFS) and overall survival (OS). Results A total of 51 Chinese patients and 98 US patients were included. In the Chinese cohort, tumor grade and Ki‐67 levels were prognostic factors for DFS in univariate analysis (hazard ratio [HR] = 5.11 [1.67–15.60], p = 0.004; HR = 57.70 [6.36–523.40], p < 0.001, respectively) and multivariate analysis (HR = 100.52 [1.33–7570.21], p = 0.037; HR = 31.47 [1.05–945.82], p = 0.047, respectively). In the US cohort, age was an important prognostic factor for OS in univariate analysis (HR = 1.09 [1.04–1.15], p = 0.001). The random effects model for the combined cohorts revealed age and positive expression of estrogen receptor (ER) as potential prognostic factors for OS (HR = 1.08 [1.01–1.14], p = 0.015; HR = 0.10 [0.02–0.44], p = 0.003, respectively). Conclusions Tumor grade and Ki‐67 levels are important prognostic factors for DFS of patients with primary NEBCs. Age and ER status are important prognostic factors for OS of patients with primary NEBCs.
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Affiliation(s)
- Shu-Tao Ma
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ding-Yuan Wang
- Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi-Bing Liu
- Third Clinical Medical College, Jilin University, Changchun, China
| | - Hui-Jing Tan
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yue-Yue Ge
- Department of Geriatric Medicine, National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology; Chinese Academy of Medical Sciences, Beijing, China
| | - Yihebali Chi
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bai-Lin Zhang
- Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Abstract
The basic pancreatic lesions include location, size, shape, number, capsule, calcification/calculi, hemorrhage, cystic degeneration, fibrosis, pancreatic duct alterations, and microvessel. One or more basic lesions form a kind of pancreatic disease. As recognizing the characteristic imaging features of pancreatic basic lesions and their relationships with pathology aids in differentiating the variety of pancreatic diseases. The purpose of this study is to review the pathological and imaging features of the basic pancreatic lesions.
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Are We Undertreating Black Patients with Nonfunctional Pancreatic Neuroendocrine Tumors? Critical Analysis of Current Surveillance Guidelines by Race. J Am Coll Surg 2022; 234:599-606. [PMID: 35380181 PMCID: PMC8988469 DOI: 10.1097/xcs.0000000000000105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Pancreatic neuroendocrine tumor (PNET) survival outcomes differ by race. Current recommendations for surveillance of PNETs less than 2 cm in size are based on low malignant potential and low rates of lymph node metastases (LNM). We investigated whether these guidelines are universally applicable regardless of race. STUDY DESIGN A multi-institutional analysis of patients with resected, nonfunctional, sporadic PNETs was performed initially using the US Neuroendocrine Study Group dataset with the National Cancer Database as a validation dataset. Patients with distant metastatic disease were excluded from analysis. RESULTS A total of 453 (388 White and 65 Black) and 5,532 patients (4,772 White and 760 Black) were analyzed in the initial and validation datasets, respectively. White patients had a low incidence of LNM in tumors of less than 2 cm in both datasets (5% and 12%, respectively), which increased with tumor size. However, the incidence of LNM in Black patients was similar in the initial and validation datasets for tumors sized less than 2 cm (23% and 21%) and 2 to 3 cm (21% and 29%). Black patients had a significantly higher incidence of LNM in tumors less than 2 cm in size in the initial and validation datasets (p < 0.01) compared with White patients. CONCLUSIONS The current recommendation for surveillance of PNETs of less than 2 cm in size is likely based on a low rate of LNM seen in a predominantly White population. The incidence of LNM in Black patients with tumors less than 2 cm in size is clinically relevant and concerning. Current guidelines may not be universally applicable, and a more aggressive approach to resection in Black patients with small PNETs may be warranted.
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The Potential Prognostic Value of Dual-Imaging PET Parameters Based on 18F-FDG and 18F-OC for Neuroendocrine Neoplasms. Mol Imaging 2022; 2022:6511179. [PMID: 35368455 PMCID: PMC8959579 DOI: 10.1155/2022/6511179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/29/2022] [Accepted: 02/03/2022] [Indexed: 11/18/2022] Open
Abstract
Background To identify parameters based on dual-imaging 18F-AlF-NOTA-octreotide (18F-OC) and 18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) for predicting the prognosis of neuroendocrine neoplasms (NENs). Materials and Methods Sixty-six patients (age: mean ± standard deviation (SD): 51.8 ± 11.8 years) who underwent both 18F-OC and 18F-FDG PET/CT imaging were enrolled in our retrospective study. The following PET parameters were measured: the maximum standardized uptake value (SUVmax) and the volumetric parameters—18F-OC SSR-derived tumor volume (TV) and somatostatin receptor expression (SRE, TV multiplied by the mean standardized uptake value (SUVmean)) and the 18F-FDG-derived multiple tumor volume (MTV) and tumor lesion glycolysis (TLG). The NETPET grade based on dual-imaging PET images was assessed. Progression-free survival (PFS) was set as an endpoint. Univariate and multivariate survival analyses were performed for PET parameters and clinical tumor data. Results In the univariate survival analyses of clinical information, PFS was significantly associated with age (>45.5 vs ≤45.5, years, P < 0.034) and the presence of bone metastases (P = 0.04). Higher values for the 18F-FDG and 18F-OC volumetric parameters and the NETPET grade were adverse factors for PFS according to the dual-imaging PET parameters. In the multivariate survival analysis, the NETPET grade and SRE were predictors of PFS in NEN patients. Conclusion The NETPET grade is a potential noninvasive prognostic biomarker for NENs.
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Siebenhüner AR, Langheinrich M, Friemel J, Schaefer N, Eshmuminov D, Lehmann K. Orchestrating Treatment Modalities in Metastatic Pancreatic Neuroendocrine Tumors-Need for a Conductor. Cancers (Basel) 2022; 14:1478. [PMID: 35326628 PMCID: PMC8946777 DOI: 10.3390/cancers14061478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/28/2022] [Accepted: 03/10/2022] [Indexed: 12/11/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are a vast growing disease. Over 50% of these tumors are recognized at advanced stages with lymph node, liver, or distant metastasis. An ongoing controversy is the role of surgery in the metastatic setting as dedicated systemic treatments have emerged recently and shown benefits in randomized trials. Today, liver surgery is an option for advanced pNETs if the tumor has a favorable prognosis, reflected by a low to moderate proliferation index (G1 and G2). Surgery in this well-selected population may prolong progression-free and overall survival. Optimal selection of a treatment plan for an individual patient should be considered in a multidisciplinary tumor board. However, while current guidelines offer a variety of modalities, there is so far only a limited focus on the right timing. Available data is based on small case series or retrospective analyses. The focus of this review is to highlight the right time-point for surgery in the setting of the multimodal treatment of an advanced pancreatic neuroendocrine tumor.
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Affiliation(s)
- Alexander R. Siebenhüner
- Clinic for Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland
- ENETS Center of Excellence Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland;
| | - Melanie Langheinrich
- Department of Visceral Surgery, University Hospital Greifswald, Ferdinand-Sauerbruch-Strasse, D-17475 Greifswald, Germany;
| | - Juliane Friemel
- Institute for Pathologie, University Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland;
| | - Niklaus Schaefer
- Department of Nuclear Medicine, University Hospital Lausanne, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland;
| | - Dilmurodjon Eshmuminov
- Department of Surgery and Transplantation, University Hospital of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland;
| | - Kuno Lehmann
- ENETS Center of Excellence Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland;
- Department of Surgery and Transplantation, University Hospital of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland;
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Shyr BS, Shyr BU, Chen SC, Shyr YM, Wang SE. Impact of tumor grade on pancreatic neuroendocrine tumors. Asian J Surg 2022; 45:2659-2663. [PMID: 35246343 DOI: 10.1016/j.asjsur.2022.01.094] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 11/30/2021] [Accepted: 01/07/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND/OBJECTIVE Pancreatic neuroendocrine tumors (P-NETs) are highly heterogeneous with wide spectrum of biological behaviors and growth patterns. Here, we aimed to assess the impact of tumor grading on P-NETs prognosis and survival outcomes. METHODS Patients with P-NET were recruited to determine correlations between grades and clinicopathological factors, survival outcomes and prognostic factors. RESULT A total of 152 patients with P-NETs were enrolled. G1 P-NET were associated with significantly lower rates of perineural invasion, lymphovascular invasion, lymph node involvement and distant metastasis. The pancreatic head was the most common location of P-NETs. The 1-year, 5-year and 10-year overall survival rates of the patients were 94.4%, 89.1% and 78.8%, respectively. Majority of pancreatic neuroendocrine carcinoma (P-NEC) were unresectable (90.9%), and P-NECs patients had poor survival rates (1-year, 20% and no 5-year). Male sex, tumor size ≥2.5 cm, perineural invasion, lymph node invasion, metastasis, and advanced stage were significantly associated with poorer survival outcomes. Tumor grade and sex were independent survival predictors. Moreover, tumor grade was the most powerful prognostic factor. CONCLUSIONS Tumor grade, sex, perineural invasion, tumor size, lymph node involvement, metastasis, and stage are survival predictors for patients with P-NETs. Tumor grade is the most powerful independent prognostic factor.
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Affiliation(s)
- Bor-Shiuan Shyr
- Division of General Surgery, Departments of Surgery, Taipei Veterans General Hospital, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Bor-Uei Shyr
- Division of General Surgery, Departments of Surgery, Taipei Veterans General Hospital, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Shih-Chin Chen
- Division of General Surgery, Departments of Surgery, Taipei Veterans General Hospital, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yi-Ming Shyr
- Division of General Surgery, Departments of Surgery, Taipei Veterans General Hospital, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Shin-E Wang
- Division of General Surgery, Departments of Surgery, Taipei Veterans General Hospital, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC.
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Lee L, Ramos-Alvarez I, Jensen RT. Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies. Cancers (Basel) 2022; 14:cancers14051250. [PMID: 35267558 PMCID: PMC8909561 DOI: 10.3390/cancers14051250] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/08/2022] [Accepted: 02/23/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Tumor resistance, both primary and acquired, is leading to increased complexity in the nonsurgical treatment of patients with advanced panNENs, which would be greatly helped by reliable prognostic/predictive factors. The importance in identifying resistance is being contributed to by the increased array of possible treatments available for treating resistant advanced disease; the variable clinical course as well as response to any given treatment approach of patients within one staging or grading system, the advances in imaging which are providing increasing promising results/parameters that correlate with grading/outcome/resistance, the increased understanding of the molecular pathogenesis providing promising prognostic markers, all of which can contribute to selecting the best treatment to overcome resistance disease. Several factors have been identified that have prognostic/predictive value for identifying development resistant disease and affecting overall survival (OS)/PFS with various nonsurgical treatments of patients with advanced panNENs. Prognostic factors identified for patients with advanced panNENs for both OS/PFSs include various clinically-related factors (clinical, laboratory/biological markers, imaging, treatment-related factors), pathological factors (histological, classification, grading) and molecular factors. Particularly important prognostic factors for the different treatment modalities studies are the recent grading systems. Most prognostic factors for each treatment modality for OS/PFS are not specific for a given treatment option. These advances have generated several controversies and new unanswered questions, particularly those related to their possible role in predicting the possible sequence of different anti-tumor treatments in patients with different presentations. Each of these areas is reviewed in this paper. Abstract Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
- National Kyushu Cancer Center, Department of Hepato-Biliary-Pancreatology, Fukuoka 811-1395, Japan
| | - Irene Ramos-Alvarez
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
- Correspondence: ; Tel.: +1-301-496-4201
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Trends in Incidence and Survival of Patients with Pancreatic Neuroendocrine Neoplasm, 1987-2016. JOURNAL OF ONCOLOGY 2022; 2021:4302675. [PMID: 34976056 PMCID: PMC8716229 DOI: 10.1155/2021/4302675] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 11/11/2021] [Indexed: 01/27/2023]
Abstract
Background Pancreatic neuroendocrine neoplasm (pNEN), with the lowest 5-year survival rates in neuroendocrine tumors (NETs), exerts great threat to human health. Because large-scale population research aimed at pNEN is rare, we aimed to explore the tendencies and differences of changes in incidences and survival rates of pNEN in each decade from 1987 to 2016 and evaluate the impacts of age, sex, race, socioeconomic status (SES), and grade. Methods Data on pNEN cases from 1987 to 2016 were extracted from the Surveillance, Epidemiology, and End Results Program (SEER) database. Kaplan-Meier, Cox proportional hazards regression analyses, and relative survival rates (RSRs) were used to identify risk factors for pNEN. Results The incidence and survival duration of pNEN increase every decade due to medical developments. The disparities of long-term survival in different age, sex, and grade groups expanded over time while that in race and SES groups narrowed. Older age and higher grade are independent risk factors for poorer survival. Females have lower incidence and longer survival than males. Prognosis of Black patients and poor (medium and high poverty) patients improved. Conclusions This study depicted changes in incidence and survival rates of pNEN over the past three decades and evaluated potential risk factors related to pNEN, benefiting future prediction of vulnerable and clinical options.
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Liao T, Su T, Huang L, Li B, Feng LH. Development and validation of a novel nomogram for predicting survival rate in pancreatic neuroendocrine neoplasms. Scand J Gastroenterol 2022; 57:85-90. [PMID: 34592854 DOI: 10.1080/00365521.2021.1984571] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Over the past decades, the incidence and prevalence of pancreatic neuroendocrine neoplasms (pNENs) have steadily increased. However, accurate prediction of the prognosis and treatment of this condition are currently challenging. This study aims to develop and validate a personalized nomogram to predict the survival of patients with pNENs. MATERIALS AND METHODS A total of 9739 patients with pNENs were downloaded from the Surveillance, Epidemiology, and End Results (SEER) database. Subsequently, the patients were randomly assigned to a derivation cohort (n = 6874) and a validation cohort (n = 2865). The survival of patients was assessed using the Cox proportional hazards (PHs) regression analysis. Then, the nomogram that predicted 3-and 5-year survival rates were developed in the derivation cohort. Further, the predictive performance of the nomogram was evaluated through discrimination and calibration. RESULTS The Cox regression analysis revealed that age, differentiation, the extent of tumor, M staging, and surgery were independent prognostic predictors for pNENs. The nomogram showed superior discrimination capability than AJCC staging in both derived and validation cohorts (C-index: 0.874 versus 0.721 and 0.833 versus 0.721). The calibration curves showed that the practical and predicted survival rates effectively coincided, specifically for the 3-year survival rate. CONCLUSION Our nomogram is a valuable tool for the prediction of the survival rate for patients with pNENs; this may promote individualized prognostic evaluation and treatment.
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Affiliation(s)
- Tianbao Liao
- Department of President's Office, Youjiang Medical University for Nationalities, Baise, China.,Philippine Christian University Center for International Education, Manila City, Philippine
| | - Tingting Su
- Department of ECG Diagnostics, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Lina Huang
- Department of Comprehensive Internal Medicine, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Bixun Li
- Department of Comprehensive Internal Medicine, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Lu-Huai Feng
- Department of Comprehensive Internal Medicine, Guangxi Medical University Cancer Hospital, Nanning, China
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Hou J, Yang Y, Chen N, Chen D, Hu S. Prognostic Value of Volume-Based Parameters Measured by SSTR PET/CT in Neuroendocrine Tumors: A Systematic Review and Meta-Analysis. Front Med (Lausanne) 2021; 8:771912. [PMID: 34901087 PMCID: PMC8662524 DOI: 10.3389/fmed.2021.771912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 10/19/2021] [Indexed: 12/16/2022] Open
Abstract
Purpose: A meta-analysis was conducted to investigate the value of the volume parameters based on somatostatin receptor (SSTR)-positron emission tomography (PET) in predicting the prognosis in patients with neuroendocrine tumors (NETs). Material: PUBMED, EMBASE, Cochrane library, and Web of Knowledge were searched from January 1990 to May 2021 for studies evaluating prognostic value of volume-based parameters of SSTR PET/CT in NETs. The terms used were "volume," "positron emission tomography," "neuroendocrine tumors," and "somatostatin receptor." Pooled hazard ratio (HR) values were calculated to assess the correlations between volumetric parameters, including total tumor volume (TTV) and total-lesion SSTR expression (TL-SSTR), with progression-free survival (PFS) and overall survival (OS). Heterogeneity and subgroup analysis were performed. Funnel plots, Begg's and Egger's test were used to assess possible underlying publication bias. Results: Eight eligible studies involving 593 patients were included in the meta-analysis. In TTV, the pooled HRs of its prognostic value of PFS and OS were 2.24 (95% CI: 1.73-2.89; P < 0.00001) and 3.54 (95% CI, 1.77-7.09; P = 0.0004), respectively. In TL-SSTR, the pooled HR of the predictive value was 1.61 (95% CI, 0.48-5.44, P = 0.44) for PFS. Conclusion: High TTV was associated with a worse prognosis for PFS and OS in with patients NETs. The TTV of SSTR PET is a potential objective prognosis predictor.
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Affiliation(s)
- Jiale Hou
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Yi Yang
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Na Chen
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Dengming Chen
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Shuo Hu
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Biological Nanotechnology, Changsha, China.,National Clinical Research Center for Geriatric Disorders (XIANGYA), Xiangya Hospital, Central South University, Changsha, China
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36
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Aysal A, Agalar C, Egeli T, Unek T, Oztop I, Obuz F, Sagol O. Reconsideration of Clinicopathologic Prognostic Factors in Pancreatic Neuroendocrine Tumors for Better Determination of Adverse Prognosis. Endocr Pathol 2021; 32:461-472. [PMID: 34283399 DOI: 10.1007/s12022-021-09687-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/13/2021] [Indexed: 02/04/2023]
Abstract
The question of how successful we are in predicting pancreatic neuroendocrine tumors (panNET) with poor prognosis has not been fully answered yet. The aim of this study was to investigate the effects of clinicopathological features on prognosis and to determine their validity in prediction of prognosis and whether a better prognostic classification can be made. Fifty-six patients who underwent pancreatic resection for pancreatic neuroendocrine tumor were included. The associations between clinicopathological parameters and prognosis were evaluated statistically. Efficiencies of different thresholds for tumor size, mitotic count, and Ki67 proliferation index for prognosis prediction were compared. Vascular invasion was statistically associated with high tumor grade, advanced pT stage, and mortality rate. The presence of non-functional tumor, lymphatic invasion, and > 10 cm tumor size were significantly related to shorter overall survival. Advanced pT stage (pT3-4), > 5 cm tumor size, and high tumor grade (grades 2-3) were significantly associated with shorter disease-free survival. The mortality rate showed the strongest statistical significance with mitotic count when grouped as 1: < 2, 2: 2-10, and 3: > 10 mitosis/ 2 mm2. The 10% threshold value for Ki67 index was more successful in predicting adverse prognosis. Among the morphologic variants, the ductulo-insular variant was the most promising to have positive prognostic value in our series, although no statistical significance was detected. In conclusion, threshold values of 5 cm and 10 cm for tumor size, 10% for Ki67 proliferation index, and 10/2 mm2 for mitotic count and vascular and lymphatic invasion assessed separately are potential prognostic candidates for better stratification of panNETs.
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Affiliation(s)
- Anil Aysal
- Department of Pathology, Dokuz Eylul University School of Medicine, Izmir, Turkey.
| | - Cihan Agalar
- Department of General Surgery, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Tufan Egeli
- Department of General Surgery, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Tarkan Unek
- Department of General Surgery, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Ilhan Oztop
- Department of Medical Oncology, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Funda Obuz
- Department of Radiology, Dokuz Eylul University School of Medicine, Izmir, Turkey
| | - Ozgul Sagol
- Department of Pathology, Dokuz Eylul University School of Medicine, Izmir, Turkey
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Lu X, Yan S, Koral KA, Chen Z. Surufatinib for the treatment of advanced extrapancreatic neuroendocrine tumors. Expert Rev Anticancer Ther 2021; 21:917-926. [PMID: 34142932 DOI: 10.1080/14737140.2021.1944110] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Introduction: Surufatinib (also known as HMPL-012, sulfatinib) is a novel oral tyrosine kinase inhibitor (TKI), which has the dual activity of anti-angiogenesis and immune regulation. In December 2020, surufatinib was approved as a monotherapy for unresectable locally advanced or metastatic, progressive nonfunctioning, well differentiated (grade 1 or 2) extrapancreatic neuroendocrine tumors (epNETs) in China.Areas covered: In this paper, the chemical properties, mechanism of action, pharmacokinetics, clinical efficacy, safety, and tolerability of surufatinib for treatment of advanced extrapancreatic NETs are introduced in detail. We performed a systematic review of the literature in PubMed and the following keywords were used: 'surufatinib,' 'sulfatinib' and 'HMPL-012.'Expert opinion: Surufatinib is a potent, selective, and small-molecule TKI that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor 1 (FGFR1) and colony stimulating factor 1 receptor (CSF1R). Surufatinib showed an acceptable safety profile and encouraging antitumor activity in patients with advanced epNETs. The most frequently observed adverse events (AEs) were hypertension and proteinuria. Surufatinib provides a new treatment option for patients with advanced epNETs. More clinical trials of surufatinib are ongoing to develop a combination of therapy strategies and new indications for malignancies.
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Affiliation(s)
- Xiuhua Lu
- Department of Clinical Pharmacy, Linyi Central Hospital, Linyi, Shandong, China
| | - Shibin Yan
- Department of Hematology, Linyi Central Hospital, Linyi, Shandong, China
| | - Kelly Ann Koral
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Zhongguang Chen
- Department of Clinical Pharmacy, Linyi Central Hospital, Linyi, Shandong, China
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Cukier M, Vergara R, Mendez-Rios JD, Castillo O, Barrera I, Tello E, El Achtar O, Loo Y, Tapia H, Perez G, Peña M. Neuroendocrine tumors in Panama: A nationwide database analysis. Mol Clin Oncol 2021; 15:157. [PMID: 34178328 PMCID: PMC8220651 DOI: 10.3892/mco.2021.2319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Neuroendocrine tumors (NETs) comprise a heterogenous group of rare malignancies, which are increasing in incidence worldwide. To further understand the epidemiology of NETs in the Republic of Panama, the present study used two study groups, which included patients from several hospitals and clinics throughout the country, who were referred to the three largest national reference centers: The Complejo Hospitalario Metropolitano, Hospital Santo Tomas and Instituto Oncologico Nacional. These two groups comprised a retrospective cohort, which included cases reported between 2016 and 2017, and a second cohort, which was retrospective, but data were continuously collected from patients diagnosed with NETs between 2018 and 2019. Data from 157 patients with NETs reported that 83% of patients were in the 40-80 years old age group. The majority of cases (46%) presented as grade G1 tumors, while 29% were G3. Computerized tomography scans with contrast, and analysis of the Ki-67 biomarker and immunohistology markers (chromogranin A and synaptophysin) was performed in the majority of the cases. The results revealed that the most frequent anatomical sites for the primary tumor were the colorectum (17.2%), pancreas (12.7%) and stomach (12.1%), and the most frequent organ with metastasis was the liver, accounting for 34% of all cases. In conclusion, the present study is the first comprehensive study of NET in Panama to the best of our knowledge, which provides evidence of the demographic characteristics of the population, clinical features and overall survival for the affected population in this Central American country.
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Affiliation(s)
- Moises Cukier
- Department of Surgical Oncology, Instituto Oncologico Nacional, Panama City, Panama 0816, Republic of Panama
| | - Ruth Vergara
- Department of Pathology, Instituto Oncologico Nacional, Panama City, Panama 0816, Republic of Panama
| | - Jorge D Mendez-Rios
- Department of Genetics and Cytogenetics, Caja de Seguro Social, Panama City, Panama 0824, Republic of Panama.,Department of Genetics, School of Medicine, Universidad Interamericana de Panama, Panama City, Panama 0820, Republic of Panama
| | - Omar Castillo
- Department of Medical Oncology, Instituto Oncologico Nacional, Panama City, Panama 0816, Republic of Panama
| | - Irma Barrera
- Department of Pathology, Instituto Oncologico Nacional, Panama City, Panama 0816, Republic of Panama
| | - Eliecer Tello
- Department of General Surgery, Caja de Seguro Social, Panama City, Panama 0824, Republic of Panama
| | - Olivia El Achtar
- Department of Surgical Oncology, Instituto Oncologico Nacional, Panama City, Panama 0816, Republic of Panama
| | - Yong Loo
- Department of Medical Oncology, Instituto Oncologico Nacional, Panama City, Panama 0816, Republic of Panama
| | - Hector Tapia
- Department of Radiology and Interventionism, Instituto Oncologico Nacional, Panama City, Panama 0816, Republic of Panama
| | - Guadalupe Perez
- Department of Endocrinology, Caja de Seguro Social, Panama City, Panama 0824, Republic of Panama
| | - Maximino Peña
- Department of Gastroenterology, Instituto Oncologico Nacional, Panama City, Panama 0816, Republic of Panama
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Soczomski P, Jurecka-Lubieniecka B, Krzywon A, Cortez AJ, Zgliczynski S, Rogozik N, Oczko-Wojciechowska M, Pawlaczek A, Bednarczuk T, Jarzab B. A Direct Comparison of Patients With Hereditary and Sporadic Pancreatic Neuroendocrine Tumors: Evaluation of Clinical Course, Prognostic Factors and Genotype-Phenotype Correlations. Front Endocrinol (Lausanne) 2021; 12:681013. [PMID: 34122352 PMCID: PMC8194819 DOI: 10.3389/fendo.2021.681013] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 05/10/2021] [Indexed: 12/11/2022] Open
Abstract
Introduction Pancreatic neuroendocrine tumors (PNETs) in hereditary syndromes pose a significant challenge to clinicians. The rarity of these syndromes and PNETs itself make it difficult to directly compare them with sporadic PNETs. Despite research suggesting differences between these two entities, the same approach is used in hereditary and sporadic PNETs. Methods We included 63 patients with hereditary PNET (GpNET) and 145 with sporadic PNET (SpNET) in a retrospective observational study. Clinical and genetic data were collected in two Polish endocrine departments from January 2004 to February 2020. Only patients with confirmed germline mutations were included in the GpNET cohort. We attempted to establish prognostic factors of metastases and overall survival in both groups and genotype-phenotype correlations in the GpNET group. Results Patients with GpNET were younger and diagnosed earlier, whereas their tumors were smaller and more frequently multifocal compared with patients with SpNET. Metastases occurred more frequently in the SpNET group, and their appearance was associated with tumor size in both groups. GpNET patients had longer overall survival (OS). OS was affected by age, age at diagnosis, sex, grade, stage, tumor diameter, occurrence and localization of metastases, type of treatment, and comorbidities. In the MEN1 group, carriers of frameshift with STOP codon, splice site, and missense mutations tended to have less advanced disease, while patients with mutations in exon 2 tended to have metastases more frequently. Conclusions Direct comparisons of GpNET and SpNET demonstrate significant differences in the clinical courses of both entities, which should force different approaches. A larger group of patients with GpNET should be assessed to confirm genotype-phenotype correlations.
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Affiliation(s)
- Przemysław Soczomski
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Beata Jurecka-Lubieniecka
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Aleksandra Krzywon
- Department of Biostatistics and Bioinformatics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Alexander Jorge Cortez
- Department of Biostatistics and Bioinformatics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Stanisław Zgliczynski
- Department of Internal Diseases and Endocrinology, Medical University of Warsaw, Warsaw, Poland
| | - Natalia Rogozik
- Department of Internal Diseases and Endocrinology, Medical University of Warsaw, Warsaw, Poland
| | - Małgorzata Oczko-Wojciechowska
- Laboratory of Molecular Diagnostics and Functional Genomics, Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Agnieszka Pawlaczek
- Laboratory of Molecular Diagnostics and Functional Genomics, Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Tomasz Bednarczuk
- Department of Internal Diseases and Endocrinology, Medical University of Warsaw, Warsaw, Poland
| | - Barbara Jarzab
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
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Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Thakker RV. Multiple Endocrine Neoplasia Type 1: Latest Insights. Endocr Rev 2021; 42:133-170. [PMID: 33249439 PMCID: PMC7958143 DOI: 10.1210/endrev/bnaa031] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Indexed: 02/06/2023]
Abstract
Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroendocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.
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Affiliation(s)
| | | | - Nancy D Perrier
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Gerlof D Valk
- University Medical Center Utrecht, CX Utrecht, the Netherlands
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Xie S, Li L, Wang X, Li L. Development and validation of a nomogram for predicting the overall survival of patients with gastroenteropancreatic neuroendocrine neoplasms. Medicine (Baltimore) 2021; 100:e24223. [PMID: 33466202 PMCID: PMC7808509 DOI: 10.1097/md.0000000000024223] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 12/15/2020] [Indexed: 01/05/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasing in incidence. Clinicians urgently need a method that can effectively predict the prognosis of GEP-NENs.A total of 14770 GEP-NENs patients with pathologically confirmed between 1975 and 2016 were obtained from the surveillance, epidemiology, and end results database. All the patients were divided into primary (n = 10377) and validation (n = 4393) cohorts based on the principle of random grouping. Multivariate Cox proportional hazards proportional hazards regression analysis was performed to evaluate predictors associated with overall survival, and a nomogram was constructed based on the primary cohort. An independent external validation cohort and comparison with the eighth edition American Joint Committee on Cancer TNM staging system were subsequently used to assess the predictive performance of the nomogram.The multivariate Cox model indicated that age, tumour differentiation, and distant metastases were independent predictors associated with overall survival. With respect to the primary cohort, the nomogram exhibited better discriminatory power than the TNM classification (C-index: 0.821 vs 0.738). Discrimination was also superior to that of TNM classification for the validation cohort (C-index: 0.823 vs 0.738). The calibrated nomogram predicted 3- and 5-years survival rate that closely corresponded to the actual survival rate.This study developed and validated a prognostic nomogram applied to patients with GEP-NENs, which may help clinicians make reasonable prognostic judgments and treatment plans to a certain extent.
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Affiliation(s)
- Si Xie
- Department of Hepatobiliary Surgery, The Affiliated Tumor Hospital of Guangxi Medical University
- Department of Gastrointestinal Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Lei Li
- Department of Gastrointestinal Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Xiaotong Wang
- Department of Gastrointestinal Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Lequn Li
- Department of Hepatobiliary Surgery, The Affiliated Tumor Hospital of Guangxi Medical University
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Chen J, Yang Y, Liu Y, Kan H. Prognosis analysis of patients with pancreatic neuroendocrine tumors after surgical resection and the application of enucleation. World J Surg Oncol 2021; 19:11. [PMID: 33436017 PMCID: PMC7805225 DOI: 10.1186/s12957-020-02115-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
Objective To investigate the prognostic factors of patients with pancreatic neuroendocrine tumor (pNETs) after surgical resection, and to analyze the value of enucleation for pNETs without distant metastasis that are well-differentiated (G1) and have a diameter ≤ 4 cm. Methods Data from pNET patients undergoing surgical resection between 2004 and 2017 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan–Meier analysis and log-rank testing were used for the survival comparisons. Adjusted HRs with 95% CIs were calculated using univariate and multivariate Cox regression models to estimate the prognostic factors. P < 0.05 was regarded as statistically significant. Results This study found that female, cases diagnosed after 2010, and pancreatic body/tail tumors were protective factors for good survival, while histological grade G3, a larger tumor size, distant metastasis, AJCC 8th stage III-IV and age over 60 were independent prognostic factors for a worse OS/CSS. For the pNETs that were well-differentiated (G1) and had a tumor diameter ≤ 4 cm, the type of surgery was an independent factor for the long-term prognosis of this group. Compared with pancreaticoduodenectomy and total pancreatectomy, patients who were accepted enucleation had better OS/CSS. Conclusion For pNETs patients undergoing surgical resection, sex, year of diagnosis, tumor location, pathological grade, tumor size, distant metastasis, race, and age were independent prognostic factors associated with the OS/CSS of patients. For pNETs patients with G1 and a tumor diameter less than 4 cm, if the tumor was located over 3 mm from the pancreatic duct, enucleation may be a wise choice.
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Affiliation(s)
- Junzhang Chen
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Ave, Guangzhou, 510515, Guangdong Province, China
| | - Yongyu Yang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Ave, Guangzhou, 510515, Guangdong Province, China
| | - Yuanhua Liu
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Ave, Guangzhou, 510515, Guangdong Province, China
| | - Heping Kan
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Ave, Guangzhou, 510515, Guangdong Province, China.
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Viúdez A, Crespo G, Gómez Dorronsoro ML, Arozarena I, Marín-Méndez JJ, Custodio A, Benavent M, Goñi S, García-Paredes B, Hernando J, Durantez M, Alonso V, Riesco MDC, López C, Jiménez-Fonseca P, San Vicente BL, González-Borja I, Sevilla I, Hernández-Garcia I, Carmona-Bayonas A, Capdevila J, Pérez-Sanz J, García-Carbonero R, Pérez-Ricarte L, Llanos M, Vera R, De Jesús Acosta A. Usefulness of an immunohistochemical score in advanced pancreatic neuroendocrine tumors treated with CAPTEM or everolimus. Pancreatology 2021; 21:215-223. [PMID: 33358592 DOI: 10.1016/j.pan.2020.12.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic neuroendocrine tumors are rare neoplasms for which few predictive and/or prognostic biomarkers have been validated. Our previous work suggested the potential of the combined expression of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) as prognostic factors for relapse and survival. METHODS In this new multicenter study we evaluated immunohistochemistry expression in 76 patients with advanced PanNET who were treated with capecitabine-temozolomide or everolimus. Based on the immunohistochemistry panel, an immunohistochemistry prognostic score (IPS) was developed. RESULTS In patients treated with capecitabine and temozolomide, low IPS was an independent prognostic factor for progression-free-survival and overall-survival. Similar findings were observed with highest IPS for overall-survival in patients treated with everolimus. CONCLUSION From our knowledge, it is the first time that a simple IPS could be useful to predict outcome for patients with metastatic pancreatic neuroendocrine tumors treated with everolimus or capecitabine and temozolomide.
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Affiliation(s)
- Antonio Viúdez
- Department of Medical Oncology, Complejo Hospitalario de Navarra (CHN), Institute for Health Research (Idisna), Pamplona, Spain; OncobionaTras Unit. Navarrabiomed, CHN, Universidad Pública de Navarra (UPNA), Idisna, Pamplona, Spain.
| | - Guillermo Crespo
- Department of Medical Oncology, Hospital Universitario Burgos, Burgos, Spain
| | | | | | | | - Ana Custodio
- Department of Medical Oncology, Hospital Universitario La Paz, Madrid, Spain
| | - Marta Benavent
- Department of Medical Oncology, Hospital Universitario Virgen del Rocio, Sevilla, Spain
| | - Saioa Goñi
- OncobionaTras Unit. Navarrabiomed, CHN, Universidad Pública de Navarra (UPNA), Idisna, Pamplona, Spain
| | | | - Jorge Hernando
- Department of Medical Oncology, Hospital Universitario Vall D'Hebron, Barcelona, Spain
| | - Maika Durantez
- Cancer Signalling, Navarrabiomed, CHN, Idisna, Pamplona, Spain
| | - Vicente Alonso
- Department of Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | | | - Carlos López
- Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - Paula Jiménez-Fonseca
- Department of Medical Oncology, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | | | - Iranzu González-Borja
- OncobionaTras Unit. Navarrabiomed, CHN, Universidad Pública de Navarra (UPNA), Idisna, Pamplona, Spain
| | - Isabel Sevilla
- Department of Medical Oncology, Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - Irene Hernández-Garcia
- Department of Medical Oncology, Complejo Hospitalario de Navarra (CHN), Institute for Health Research (Idisna), Pamplona, Spain
| | - Alberto Carmona-Bayonas
- Department of Medical Oncology, Hospital Universitario Morales Meseguer, UMU, IMI, Murcia, Spain
| | - Jaume Capdevila
- Department of Medical Oncology, Hospital Universitario Vall D'Hebron, Barcelona, Spain
| | - Jairo Pérez-Sanz
- OncobionaTras Unit. Navarrabiomed, CHN, Universidad Pública de Navarra (UPNA), Idisna, Pamplona, Spain
| | | | - Leyre Pérez-Ricarte
- Department of Medical Oncology, Complejo Hospitalario de Navarra (CHN), Institute for Health Research (Idisna), Pamplona, Spain
| | - Marta Llanos
- Department of Medical Oncology, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Ruth Vera
- Department of Medical Oncology, Complejo Hospitalario de Navarra (CHN), Institute for Health Research (Idisna), Pamplona, Spain
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He R, Zhang W, Chen S, Liu Y, Yang W, Li J. Transcriptional Profiling Reveals the Regulatory Role of DNER in Promoting Pancreatic Neuroendocrine Neoplasms. Front Genet 2020; 11:587402. [PMID: 33329729 PMCID: PMC7728999 DOI: 10.3389/fgene.2020.587402] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 11/05/2020] [Indexed: 02/04/2023] Open
Abstract
Wnt/β-catenin and NOTCH signaling contribute to the pathogenesis and growth of (PanNENs). The wnt and Notch signaling pathways form an integrated signaling device termed "wntch" and regulate stochastic cell fate decisions, suggesting the essentiality of Wnt/Notch interactions in disease progression. However, the function of Wnt/Notch interactions in PanNENs is unclear. We analyzed RNA sequencing (RNA-seq) data to identify differentially expressed lncRNAs, mRNAs and pathways according to enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with PanNENs. RNA-seq analysis revealed that the levels of the lncRNA XLOC_221242 and the mRNA encoding Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER) were significantly increased in tumor tissues compared with normal tissues (n = 3). Protein-protein interaction (PPI) prediction combined with transcriptional profiling data analysis revealed that DNER expression levels were positively correlated with those of DNA-binding factor (RBPJ), S phase kinase-associated protein 1 (Skp1), CTNNB1 and Cadherin-2 (CDH2), which promote PanNEN tumorigenesis and progression. These results were consistent with those of immunohistochemical analysis of DNER, RBPJ, SKP1, CTNNB1, and CDH2 expression (n = 15). These findings provide compelling clinical and molecular evidence supporting the conclusion that DNER and the related RBPJ, SKP1, CTNNB1, and CDH2 signaling contribute to PanNEN tumorigenesis and progression by activating wnt/Notch interactions.
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Affiliation(s)
- Rui He
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wunai Zhang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuo Chen
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yang Liu
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wenbin Yang
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Junhui Li
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Ito T, Jensen RT. Perspectives on the current pharmacotherapeutic strategies for management of functional neuroendocrine tumor syndromes. Expert Opin Pharmacother 2020; 22:685-693. [PMID: 33131345 DOI: 10.1080/14656566.2020.1845651] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: In the past, controlling the hormone-excess-state was the main determinant of survival in Functional-Neuroendocrine-Neoplasm-syndromes (F-NENs). This was difficult because the pharmacological-armamentarium available was limited. Recently, new therapeutic strategies have increased but it also generated controversies/uncertainties.Areas covered: The authors briefly review: established/proposed F-NENs; the rationale for treatments; the recommended initial-pharmacotherapeutic-approach to controlling F-NENs hormone-excess-state; the secondary-approaches if the initial approach fails or resistance develops; and the approach to deal with the malignant nature of the NEN. Also discussed are controversies/uncertainties related to new treatments.Expert opinion: Unfortunately, except for patients with insulinomas (>90-95%), gastrinomas (<20-40%), a minority with the other F-panNENs and 0-<1% with Carcinoid-syndrome is curative-surgery possible. Except for insulinomas, gastrinomas, and ACTHomas, long-acting somatostatin-analogs are the initial-pharmacological-treatments for hormone-excess-state. For insulinomas prior to surgery/malignancy, diazoxide is the initial drug-treatment; for gastrinomas, oral PPIs; and for ACTHomas, steroidogenesis inhibitors. There are now several secondary pharmacotherapeutic treatments. Surgery and liver-directed therapies also have a role in selected patients. Particularly promising is the recent results with PRRT for the hormone-excess-state, independent of its anti-growth effect. The sequence to use various agents and the approach to syndrome diagnosis while taking various agents remains unclear/controversial in many cases.
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Affiliation(s)
- Tetsuhide Ito
- Neuroendocrine Tumor Centre, Fukuoka Sanno Hospital, International University of Health and Welfare, Fukuoka, Japan
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Kim J, Hwang HK, Lee WJ, Kang CM. Minimally invasive vs open pancreatectomy for nonfunctioning pancreatic neuroendocrine tumors. World J Gastrointest Oncol 2020; 12:1133-1145. [PMID: 33133382 PMCID: PMC7579734 DOI: 10.4251/wjgo.v12.i10.1133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/17/2020] [Accepted: 09/14/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The mainstay of treating nonfunctioning-pancreatic neuroendocrine tumors(NF-PNETs) is surgical resection. However, minimally invasive approaches to pancreatic resection for treating NF-PNETs are not widely accepted, and the long-term oncological outcomes of such approaches remain unknown.
AIM To determine the short- and long-term outcomes of minimally invasive pancreatic resection conducted in patients with NF-PNETs.
METHODS Prospective databases from Severance Hospital were searched for 110 patients who underwent curative resection for NF-PNETs between January 2003 and August 2018.
RESULTS The proportion of minimally invasive surgery (MIS) procedures performed for NF-PNET increased to more than 75% after 2013. There was no significant difference in post-operative complications (P = 0.654), including pancreatic fistula (P = 0.890) and delayed gastric emptying (P = 0.652), between MIS and open approaches. No statistically significant difference was found in disease-free survival between the open approach group and the MIS group (median follow-up period, 28.1 mo; P = 0.428). In addition, the surgical approach (MIS vs open) was not found to be an independent prognostic factor in treating NF-PNET patients [Exp(β) = 1.062; P = 0.929].
CONCLUSION Regardless of the type of surgery, a minimally invasive approach can be safe and feasible for select NF-PNET patients.
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Affiliation(s)
- Juwan Kim
- Department of Surgery, Yonsei University College of Medicine, Severance Hospital, Seoul 03722, South Korea
| | - Ho Kyoung Hwang
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Woo Jung Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Chang Moo Kang
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, South Korea
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Chen BB. Artificial intelligence in pancreatic disease. Artif Intell Med Imaging 2020; 1:19-30. [DOI: 10.35711/aimi.v1.i1.19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/18/2020] [Accepted: 06/19/2020] [Indexed: 02/06/2023] Open
Abstract
In recent years, the application of artificial intelligence (AI) in radiology has been growing rapidly, fueled by the availability of large datasets, advances in computing power, and newly developed algorithms. Progress in AI applied to medical imaging analyses has transformed these images into quantitative data, termed radiomics. When combined with patients’ clinical data, these models, when developed by machine learning, have the potential to improve diagnostic, prognostic, and predictive accuracy. Currently, limited literature is available on the use of radiomics for pancreatic disease. Here, we will review recent studies in the application of AI in a variety of pancreatic diseases, mainly involving lesion detection, tumor characterization, tumor grading, response, and prognosis evaluation. Finally, we will also discuss the challenges and prospects in the field of radiomics for pancreatic disease.
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Affiliation(s)
- Bang-Bin Chen
- Department of Medical Imaging, National Taiwan University Hospital, Taipei 10016, Taiwan
- Department of Radiology, College of Medicine, National Taiwan University, Taipei 10016, Taiwan
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Sadowski SM, Pieterman CRC, Perrier ND, Triponez F, Valk GD. Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature. Endocr Relat Cancer 2020; 27:R145-R161. [PMID: 32229700 PMCID: PMC7304521 DOI: 10.1530/erc-19-0372] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification are limited. This systematic review aims to establish the current state of evidence regarding prognostic factors in MEN1-related NF-pNETs. We systematically searched four databases for studies assessing prognostic value of any factor on NF-pNET progression, development of distant metastases, and/or overall survival. In- and exclusion, critical appraisal and data-extraction were performed independently by two authors according to pre-defined criteria. Thirteen studies (370 unique patients) were included. Prognostic factors investigated were tumor size, timing of surgical resection, WHO grade, methylation, p27/p18 expression by immunohistochemistry (IHC), ARX/PDX1 IHC and alternative lengthening of telomeres. Results were complemented with evidence from studies in MEN1-related pNET for which data could not be separately extracted for NF-pNET and data from sporadic NF-pNET. We found that the most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs <2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs ≥2 cm. Grade 2 NF-pNETs should be considered high risk. The most promising and MEN1-relevant avenues of prognostic research are multi-analyte circulating biomarkers, tissue-based molecular factors and imaging-based prognostication. Multi-institutional collaboration between clinical, translation and basic scientists with uniform data and biospecimen collection in prospective cohorts should advance the field.
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Affiliation(s)
- S M Sadowski
- Endocrine Surgery, Surgical Oncology Program, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - C R C Pieterman
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - N D Perrier
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - F Triponez
- Thoracic and Endocrine Surgery and Faculty of Medicine, University Hospitals of Geneva, Geneva, Switzerland
| | - G D Valk
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
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