Evidence map›Paper›PMID 33849943›Full record

ArticleGut2022

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

Wenzel M Hackeng, Lodewijk A A Brosens, Joo Young Kim, Roderick O'Sullivan, You-Na Sung, Ta-Chiang Liu, Dengfeng Cao, Michelle Heayn, Jacqueline Brosnan-Cashman, Soyeon An and 46 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Gut, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
91citing papers in PubMed, 3 pooled it
14.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

91 citing papers in PubMed, 3 syntheses or guidelines pooled it, 140 citations in OpenAlex.

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  9. Distinct Malignant Cell States and Myeloid Glutamate Signaling Associated with Aggressive Pancreatic Neuroendocrine Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
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31 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

56 authors at 19 institutions in 6 countries.

Wenzel M Hackeng *Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands singhiad@upmc.edu wenzelhackeng@gmail.com l.a.a.brosens@umcutrecht.nl heaphyc@bu.edu.ORCID 0000-0001-6795-179X
Lodewijk A A Brosens *Department of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands singhiad@upmc.edu wenzelhackeng@gmail.com l.a.a.brosens@umcutrecht.nl heaphyc@bu.edu.ORCID 0000-0003-1341-8994
Joo Young KimDepartment of Pathology, Nowon Eulji Medical Center, Eulji University, Seoul, Republic of Korea.
Roderick O'SullivanDepartment of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
You-Na SungDepartment of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Ta-Chiang LiuDepartment of Pathology and Immunology, Washington University School of Medicine, St, Louis, MO, USA.
Dengfeng CaoDepartment of Pathology and Immunology, Washington University School of Medicine, St, Louis, MO, USA.
Michelle HeaynDepartment of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Jacqueline Brosnan-CashmanDepartment of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Soyeon AnDepartment of Pathology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Republic of Korea.
Folkert H M MorsinkDepartment of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Charlotte M HeidsmaDepartment of Surgery, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Gerlof D ValkDepartment of Endocrinology and Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Menno R VriensDepartment of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
Els Nieveen van DijkumDepartment of Surgery, Amsterdam University Medical Center, Amsterdam, The Netherlands.
G Johan A OfferhausDepartment of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.ORCID 0000-0003-2683-3986
Koen M A DreijerinkDepartment of Pathology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Herbert ZehDepartment of Clinical Sciences, Surgery, University of Texas Southwestern, Dallas, TX, USA.
Amer H ZureikatDepartment of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Melissa HoggDepartment of Surgery, NorthShore University Health System, Evanston, IL, USA.
Kenneth LeeDepartment of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
David GellerDepartment of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
J Wallis MarshDepartment of Surgery, West Virginia University Health Sciences Center, Morgantown, WV, USA.
Alessandro PanicciaDepartment of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Melanie OngchinDepartment of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
James F PingpankDepartment of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Nathan BaharyDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Muaz AijaziDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.ORCID 0000-0003-1629-8895
Randall BrandDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Jennifer ChennatDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Rohit DasDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Kenneth E FasanellaDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Asif KhalidDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Kevin McGrathDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Savreet SarkariaDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Harkirat SinghDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Adam SlivkaDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Michael NalesnikDepartment of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Xiaoli HanDepartment of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Marina N NikiforovaDepartment of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Rita Teresa LawlorARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
Andrea MafficiniARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
Boris RusevARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
Vincenzo CorboARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
Claudio LuchiniDepartment of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.ORCID 0000-0003-4901-4908
Samantha BersaniDepartment of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy.
Antonio PeaThe Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy.
Sara CingarliniThe Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy.
Luca LandoniENETS Center of Excellence, University and Hospital Trust of Verona, Verona, Italy.
Roberto SalviaENETS Center of Excellence, University and Hospital Trust of Verona, Verona, Italy.
Massimo MilioneDepartment of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Michele MilellaENETS Center of Excellence, University and Hospital Trust of Verona, Verona, Italy.
Aldo ScarpaARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.ORCID 0000-0003-1678-739X
Seung-Mo HongDepartment of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Christopher M Heaphy *Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA singhiad@upmc.edu wenzelhackeng@gmail.com l.a.a.brosens@umcutrecht.nl heaphyc@bu.edu.ORCID 0000-0003-4264-1810
Aatur D Singhi *Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA singhiad@upmc.edu wenzelhackeng@gmail.com l.a.a.brosens@umcutrecht.nl heaphyc@bu.edu.ORCID 0000-0003-3930-7096
University of Pittsburgh Medical Center · USUtrecht University · NLAquinas Institute of Theology · USUniversity of Verona · ITUniversity Hospital Foundation · CAAmsterdam University Medical Centers · NLUlsan College · KRUniversity Medical Center Utrecht · NLWashington University in St. Louis · USBoston University · USEulji University · KREuropean Neuroendocrine Tumor Society · DEFondazione IRCCS Istituto Nazionale dei Tumori · ITJohns Hopkins University · USNorthShore University HealthSystem · USSouthwestern University · USThe Catholic University of Korea Incheon St. Mary's Hospital · KRUniversity of Pittsburgh · USWest Virginia University · US

Funding

VECTOR CORE FACILITYP30CA047904 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI JOHN C. BYRD · 1988 to 2026
$158.0M
Pittsburgh Liver Research CenterP30DK120531 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DAVID A GELLER · 2019 to 2026
$10.9M
Inhibition of the ALT pathway by interfering with Poly-ADP-Ribose metabolismR01CA207209 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Roderick O'Sullivan · 2016 to 2026
$3.6M
The Prognostic Significance and Mechanistic Determination of Chromatin Remodeling Biomarkers in Non-Functional Pancreatic Neuroendocrine TumorR37CA263622 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Aatur Dilip Singhi · 2021 to 2026
$3.4M
NCI NIH HHS P30 CA047904NCI NIH HHS R01 CA207209NCI NIH HHS R37 CA263622NIDDK NIH HHS P30 DK120531
6 · The paper itself

Abstract

objectiveRecent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown.

designAn international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS).

resultsATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%).

conclusionsATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.

Indexed as

alpha-ThalassemiaIntellectual DisabilityNeuroendocrine TumorsPancreatic NeoplasmsCo-Repressor ProteinsGenes, HomeoboxHomeodomain ProteinsHumansMolecular ChaperonesNeoplasm Recurrence, LocalNuclear ProteinsTelomereTranscription FactorsX-linked Nuclear ProteinARX protein, humanATRX protein, humanCo-Repressor ProteinsDAXX protein, humanHomeodomain ProteinsMolecular ChaperonesNuclear ProteinsTranscription FactorsX-linked Nuclear Proteinneuroendocrine tumorspancreatic endocrine tumourpancreatic islet cellpancreatic pathologypancreatic surgery

Identifiers

PMID33849943
PMCPMC8511349
OpenAlexW3156669433

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.