Journal of Pathology and Translational Medicine

Original Articles

Paricalcitol prevents MAPK pathway activation and inflammation in adriamycin-induced kidney injury in rats: Amanda Lima Deluque, Lucas Ferreira de Almeida, Beatriz Magalhães Oliveira, Cláudia Silva Souza, Ana Lívia Dias Maciel, Heloísa Della Coletta Francescato, Cleonice Giovanini, Roberto Silva Costa, Terezila Machado Coimbra; J Pathol Transl Med. 2024;58(5):219-228. Published online August 27, 2024; DOI: https://doi.org/10.4132/jptm.2024.07.12

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Background
Activation of the mitogen-activated protein kinase (MAPK) pathway induces uncontrolled cell proliferation in response to inflammatory stimuli. Adriamycin (ADR)-induced nephropathy (ADRN) in rats triggers MAPK activation and pro-inflammatory mechanisms by increasing cytokine secretion, similar to chronic kidney disease (CKD). Activation of the vitamin D receptor (VDR) plays a crucial role in suppressing the expression of inflammatory markers in the kidney and may contribute to reducing cellular proliferation. This study evaluated the effect of pre-treatment with paricalcitol on ADRN in renal inflammation mechanisms.
Methods
Male Sprague-Dawley rats were implanted with an osmotic minipump containing activated vitamin D (paricalcitol, Zemplar, 6 ng/day) or vehicle (NaCl 0.9%). Two days after implantation, ADR (Fauldoxo, 3.5 mg/kg) or vehicle (NaCl 0.9%) was injected. The rats were divided into four experimental groups: control, n = 6; paricalcitol, n = 6; ADR, n = 7 and, ADR + paricalcitol, n = 7.
Results
VDR activation was demonstrated by increased CYP24A1 in renal tissue. Paricalcitol prevented macrophage infiltration in the glomeruli, cortex, and outer medulla, prevented secretion of tumor necrosis factor-α, and interleukin-1β, increased arginase I and decreased arginase II tissue expressions, effects associated with attenuation of MAPK pathways, increased zonula occludens-1, and reduced cell proliferation associated with proliferating cell nuclear antigen expression. Paricalcitol treatment decreased the stromal cell-derived factor 1α/chemokine C-X-C receptor type 4/β-catenin pathway.
Conclusions
Paricalcitol plays a renoprotective role by modulating renal inflammation and cell proliferation. These results highlight potential targets for treating CKD.

Citations

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Perirenal fat differs in patients with chronic kidney disease receiving different vitamin D-based treatments: a preliminary study
Ana Checa-Ros, Antonella Locascio, Owahabanun-Joshua Okojie, Pablo Abellán-Galiana, Luis D’Marco
BMC Nephrology.2025;[Epub] CrossRef

Senescent tumor cells in colorectal cancer are characterized by elevated enzymatic activity of complexes 1 and 2 in oxidative phosphorylation: Jun Sang Shin, Tae-Gyu Kim, Young Hwa Kim, So Yeong Eom, So Hyun Park, Dong Hyun Lee, Tae Jun Park, Soon Sang Park, Jang-Hee Kim; J Pathol Transl Med. 2023;57(6):305-314. Published online November 7, 2023; DOI: https://doi.org/10.4132/jptm.2023.10.09

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Background
Cellular senescence is defined as an irreversible cell cycle arrest caused by various internal and external insults. While the metabolic dysfunction of senescent cells in normal tissue is relatively well-established, there is a lack of information regarding the metabolic features of senescent tumor cells.
Methods
Publicly available single-cell RNA-sequencing data from the GSE166555 and GSE178341 datasets were utilized to investigate the metabolic features of senescent tumor cells. To validate the single-cell RNA-sequencing data, we performed senescence-associated β-galactosidase (SA-β-Gal) staining to identify senescent tumor cells in fresh frozen colorectal cancer tissue. We also evaluated nicotinamide adenine dinucleotide dehydrogenase–tetrazolium reductase (NADH-TR) and succinate dehydrogenase (SDH) activity using enzyme histochemical methods and compared the staining with SA-β-Gal staining. MTT assay was performed to reveal the complex 1 activity of the respiratory chain in in-vitro senescence model.
Results
Single-cell RNA-sequencing data revealed an upregulation in the activity of complexes 1 and 2 in oxidative phosphorylation, despite overall mitochondrial dysfunction in senescent tumor cells. Both SA-β-Gal and enzyme histochemical staining using fresh frozen colorectal cancer tissues indicated a high correlation between SA-β-Gal positivity and NADH-TR/SDH staining positivity. MTT assay showed that senescent colorectal cancer cells exhibit higher absorbance in 600 nm wavelength.
Conclusions
Senescent tumor cells exhibit distinct metabolic features, characterized by upregulation of complexes 1 and 2 in the oxidative phosphorylation pathway. NADH-TR and SDH staining represent efficient methods for detecting senescent tumor cells in colorectal cancer.

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Cellular Aging and Senescence in Cancer: A Holistic Review of Cellular Fate Determinants
Muhammad Tufail, Yu-Qi Huang, Jia-Ju Hu, Jie Liang, Cai-Yun He, Wen-Dong Wan, Can-Hua Jiang, Hong Wu, Ning Li
Aging and disease.2024;[Epub] CrossRef
Real-time assessment of relative mitochondrial ATP synthesis response against inhibiting and stimulating substrates (MitoRAISE)
Eun Sol Chang, Kyoung Song, Ji-Young Song, Minjung Sung, Mi-Sook Lee, Jung Han Oh, Ji-Yeon Kim, Yeon Hee Park, Kyungsoo Jung, Yoon-La Choi
Cancer & Metabolism.2024;[Epub] CrossRef

Prognostic significance of viable tumor size measurement in hepatocellular carcinomas after preoperative locoregional treatment: Yoon Jung Hwang, Youngeun Lee, Hyunjin Park, Yangkyu Lee, Kyoungbun Lee, Haeryoung Kim; J Pathol Transl Med. 2021;55(5):338-348. Published online September 2, 2021; DOI: https://doi.org/10.4132/jptm.2021.07.26

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Background
Preoperative locoregional treatment (LRT) for hepatocellular carcinoma (HCC) often induces intratumoral necrosis without affecting the overall tumor size, and residual viable tumor size (VTS) on imaging is an important clinical parameter for assessing post-treatment response. However, for surgical specimens, it is unclear whether the VTS would be more relevant to prognosis compared to total tumor size (TTS).
Methods
A total of 142 surgically resected solitary HCC cases were retrospectively reviewed. The TTS and VTS were assessed by applying the modified Response Evaluation Criteria in Solid Tumors method to the resected specimens, and correlated with the clinicopathological features and survival.
Results
As applying VTS, 13/142 cases (9.2%) were down-staged to ypT1a. Although the survival analysis results for overall survival according to TTS or VTS were similar, VTS was superior to predict disease-free survival (DFS; p = .023) compared to TTS (p = .08). In addition, multivariate analysis demonstrated VTS > 2 cm to be an independent predictive factor for decreased DFS (p = .001). In the subpopulation of patients with LRT (n = 54), DFS in HCCs with TTS or VTS > 2 cm were significantly shorter than those with TTS or VTS ≤ 2 cm (p = .047 and p = .001, respectively). Interestingly, HCCs with TTS > 2 cm but down-staged to VTS ≤ 2 cm after preoperative LRT had similar survival to those with TTS ≤ 2 cm.
Conclusions
Although the prognostic impact of tumor size was similar regardless of whether TTS or VTS was applied, reporting VTS may help to increase the number of candidates for surgery in HCC patients with preoperative LRT.

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PET-Assessed Metabolic Tumor Volume Across the Spectrum of Solid-Organ Malignancies: A Review of the Literature
Anusha Agarwal, Chase J. Wehrle, Sangeeta Satish, Paresh Mahajan, Suneel Kamath, Shlomo Koyfman, Wen Wee Ma, Maureen Linganna, Jamak Modaresi Esfeh, Charles Miller, David C. H. Kwon, Andrea Schlegel, Federico Aucejo
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Measures for response assessment in HCC treatment
Fereshteh Yazdanpanah, Omar Al-Daoud, Moein Moradpour, Stephen Hunt
Hepatoma Research.2024;[Epub] CrossRef
Machine Learning for Dynamic Prognostication of Patients With Hepatocellular Carcinoma Using Time-Series Data: Survival Path Versus Dynamic-DeepHit HCC Model
Lujun Shen, Yiquan Jiang, Tao Zhang, Fei Cao, Liangru Ke, Chen Li, Gulijiayina Nuerhashi, Wang Li, Peihong Wu, Chaofeng Li, Qi Zeng, Weijun Fan
Cancer Informatics.2024;[Epub] CrossRef
Construction and validation of a novel signature based on epithelial-mesenchymal transition–related genes to predict prognosis and immunotherapy response in hepatocellular carcinoma by comprehensive analysis of the tumor microenvironment
Biao Gao, Yafei Wang, Shichun Lu
Functional & Integrative Genomics.2023;[Epub] CrossRef
Cellular senescence affects energy metabolism, immune infiltration and immunotherapeutic response in hepatocellular carcinoma
Biao Gao, Yafei Wang, Shichun Lu
Scientific Reports.2023;[Epub] CrossRef

Reviews

Hepatocellular adenomas: recent updates: Haeryoung Kim, Young Nyun Park; J Pathol Transl Med. 2021;55(3):171-180. Published online April 7, 2021; DOI: https://doi.org/10.4132/jptm.2021.02.27

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Abstract PDF

Hepatocellular adenoma (HCA) is a heterogeneous entity, from both the histomorphological and molecular aspects, and the resultant subclassification has brought a strong translational impact for both pathologists and clinicians. In this review, we provide an overview of the recent updates on HCA from the pathologists’ perspective and discuss several practical issues and pitfalls that may be useful for diagnostic practice.

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Prognostic role of selection criteria for liver transplantation in patients with hepatocellular carcinoma: Review and bibliometric
Pamela Scarlett Espinoza Loyola, Diana Laura Muratalla Bautista, Karen Adela Hernández Bautista, Elizabeth Gil White, José Antonio González Moreno, Daniel Angel Torres del Real, Víctor Manuel Páez Zayas, Carla Escorza-Molina, Fernando Mondragón Rodríguez,
iLIVER.2024; 3(1): 100077. CrossRef
ACG Clinical Guideline: Focal Liver Lesions
Catherine Frenette, Mishal Mendiratta-Lala, Reena Salgia, Robert J. Wong, Bryan G. Sauer, Anjana Pillai
American Journal of Gastroenterology.2024; 119(7): 1235. CrossRef
Hepatocellular adenoma update: diagnosis, molecular classification, and clinical course
Sarah Poetter-Lang, Ahmed Ba-Ssalamah, Nina Bastati, Sami A Ba-Ssalamah, Jacqueline C Hodge, Giuseppe Brancatelli, Valérie Paradis, Valérie Vilgrain
British Journal of Radiology.2024; 97(1163): 1740. CrossRef
Fatal rupture of hepatic adenomatosis: Autopsy case and review of the literature
Sarra Ben Abderrahim, Khouloud Chérif, Zeineb Nfikha, Sarra Gharsallaoui, Imen El Aini, Maher Jedidi, Moncef Mokni, Mohamed Ben Dhiab
Journal of Forensic Sciences.2023; 68(4): 1393. CrossRef
Large Hepatocellular Adenoma Presenting with Iron Deficiency Anemia: A Case Report
Young Kwon Koh, Su Hyun Yoon, Sung Han Kang, Hyery Kim, Ho Joon Im, Suhyeon Ha, Jung-Man Namgoong, Kyung-Nam Koh
Clinical Pediatric Hematology-Oncology.2023; 30(1): 25. CrossRef
A Case Report on a Giant Hepatic Inflammatory Adenoma in a Young Female That Presented as Spontaneous Intrahepatic Hematoma
Andreas Kyvetos, Panagiota Voukelatou, Ioannis Vrettos, Spyridon Pantzios , Ioannis Elefsiniotis
Cureus.2023;[Epub] CrossRef
Advances in Histological and Molecular Classification of Hepatocellular Carcinoma
Joon Hyuk Choi, Swan N. Thung
Biomedicines.2023; 11(9): 2582. CrossRef
Estrobolome and Hepatocellular Adenomas—Connecting the Dots of the Gut Microbial β-Glucuronidase Pathway as a Metabolic Link
Sandica Bucurica, Mihaela Lupanciuc, Florentina Ionita-Radu, Ion Stefan, Alice Elena Munteanu, Daniela Anghel, Mariana Jinga, Elena Laura Gaman
International Journal of Molecular Sciences.2023; 24(22): 16034. CrossRef
Hepatocellular adenoma: what we know, what we do not know, and why it matters
Paulette Bioulac‐Sage, Annette S H Gouw, Charles Balabaud, Christine Sempoux
Histopathology.2022; 80(6): 878. CrossRef

Liquid biopsy using extracellular vesicle–derived DNA in lung adenocarcinoma: In Ae Kim, Jae Young Hur, Hee Joung Kim, Seung Eun Lee, Wan Seop Kim, Kye Young Lee; J Pathol Transl Med. 2020;54(6):453-461. Published online October 8, 2020; DOI: https://doi.org/10.4132/jptm.2020.08.13

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Abstract PDF

Blood liquid biopsy has emerged as a way of overcoming the clinical limitations of repeat biopsy by testing for the presence of acquired resistance mutations to therapeutic agents. Despite its merits of repeatability and non-invasiveness, this method is currently only used as a supplemental test due to a relatively low sensitivity rate of 50%–60%, and cannot replace tissue biopsy. The circulating tumor DNAs used in blood liquid biopsies are passive products of fragmented DNA with a short half-life released following tumor cell death; the low sensitivity seen with liquid blood biopsy results from this instability, which makes increasing the sensitivity of this test fundamentally difficult. Extracellular vesicles (EVs) are ideal carriers of cancer biomarkers, as cancer cells secret an abundance of EVs, and the contents of tumor cell-originated EVs reflect the molecular and genetic composition of parental cells. In addition, EV-derived DNAs (EV DNAs) consist of large-sized genomic DNAs and tumor-specific oncogenic mutant DNAs. For these reasons, liquid biopsy using EV DNA has the potential to overcome issues arising from tissue shortages associated with small biopsies, which are often seen in lung cancer patients, and the biopsy product can be used in other diagnostic methods, such as epidermal growth factor receptor (EGFR) mutation testing and next-generation sequencing (NGS). A higher sensitivity can be achieved when EV DNAs obtained from bronchoalveolar lavage fluid (BALF) are used rather than those from blood. BALF, when obtained close to the tumor site, is a promising liquid biopsy tool, as it enables the gathering of both cellular and non-cellular fractions of the tumor microenvironment, and provides increased diagnostic sensitivity when compared to blood.

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Circulating Extracellular Vesicles as Promising Biomarkers for Precession Diagnostics: A Perspective on Lung Cancer
Sunil Vasu, Vinith Johnson, Archana M, K. Anki Reddy, Uday Kumar Sukumar
ACS Biomaterials Science & Engineering.2025; 11(1): 95. CrossRef
Diagnostic performance of metagenomic next-generation sequencing among hematological malignancy patients with bloodstream infections after antimicrobial therapy
Yueyi Xu, Miaoxin Peng, Tong Zhou, Yonggong Yang, Peipei Xu, Ting Xie, Xuefang Cao, Bing Chen, Jian Ouyang
Journal of Infection.2025; 90(2): 106395. CrossRef
Nanobiotechnology: A smart platform of the future transform liquid biopsy era
Srijan Goswami, Palas Samanta, Manab Deb Adhikari
The Journal of Liquid Biopsy.2024; 3: 100137. CrossRef
Mesenchymal stem/stromal cells: dedicator to maintain tumor homeostasis
Juncun Yao, Li Sun, Feng Gao, Wei Zhu
Human Cell.2024;[Epub] CrossRef
Extracellular Vesicle-DNA: The Next Liquid Biopsy Biomarker for Early Cancer Diagnosis?
Irène Tatischeff
Cancers.2023; 15(5): 1456. CrossRef
Isolation of extracellular vesicles from human plasma samples: The importance of controls
Migmar Tsamchoe, Stephanie Petrillo, Anthoula Lazaris, Peter Metrakos
Biotechnology Journal.2023;[Epub] CrossRef
The role of extracellular vesicles in non-small-cell lung cancer, the unknowns, and how new approach methodologies can support new knowledge generation in the field
Sive Mullen, Dania Movia
European Journal of Pharmaceutical Sciences.2023; 188: 106516. CrossRef
Silicon microfabrication technologies for biology integrated advance devices and interfaces
Vuslat B. Juska, Graeme Maxwell, Pedro Estrela, Martyn E. Pemble, Alan O'Riordan
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Bronchoalveolar Lavage as Potential Diagnostic Specimens to Genetic Testing in Advanced Nonsmall Cell Lung Cancer
Xuwen Lin, Yazhou Cai, Chenyu Zong, Binbin Chen, Di Shao, Hao Cui, Zheng Li, Ping Xu
Technology in Cancer Research & Treatment.2023;[Epub] CrossRef
In-Cell Labeling Coupled to Direct Analysis of Extracellular Vesicles in the Conditioned Medium to Study Extracellular Vesicles Secretion with Minimum Sample Processing and Particle Loss
Anissa Viveiros, Vaibhavi Kadam, John Monyror, Luis Carlos Morales, Desmond Pink, Aja M. Rieger, Simonetta Sipione, Elena Posse de Chaves
Cells.2022; 11(3): 351. CrossRef
Recent advances in liquid biopsy in cancers: Diagnosis, disease state and treatment response monitoring
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Clinical and Translational Discovery.2022;[Epub] CrossRef
Cell-Secreted Vesicles: Novel Opportunities in Cancer Diagnosis, Monitoring and Treatment
Cristina Catoni, Veronica Di Paolo, Elisabetta Rossi, Luigi Quintieri, Rita Zamarchi
Diagnostics.2021; 11(6): 1118. CrossRef
DNA-Loaded Extracellular Vesicles in Liquid Biopsy: Tiny Players With Big Potential?
Susana García-Silva, Miguel Gallardo, Héctor Peinado
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Characteristics and Clinical Application of Extracellular Vesicle-Derived DNA
Jae Young Hur, Kye Young Lee
Cancers.2021; 13(15): 3827. CrossRef
Bronchoalveolar Lavage as a Potential Diagnostic Specimens to Genetic Testing in Advanced Lung Cancer
Xuwen Lin, Xueying Wang, Yazhou Cai, Chenyu Zong, Dawei Liu, Jiming Yu, Chenxin Zhou, Jing Yao, Zheng Li, ping xu
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Leona Chitoiu, Alexandra Dobranici, Mihaela Gherghiceanu, Sorina Dinescu, Marieta Costache
International Journal of Molecular Sciences.2020; 21(22): 8550. CrossRef

Original Articles

Guanabenz Acetate Induces Endoplasmic Reticulum Stress–Related Cell Death in Hepatocellular Carcinoma Cells: Hyo Jeong Kang, Hyang Sook Seol, Sang Eun Lee, Young-Ah Suh, Jihun Kim, Se Jin Jang, Eunsil Yu; J Pathol Transl Med. 2019;53(2):94-103. Published online January 16, 2019; DOI: https://doi.org/10.4132/jptm.2019.01.14

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Abstract PDF Supplementary Material

Background
Development of chemotherapeutics for the treatment of advanced hepatocellular carcinoma (HCC) has been lagging. Screening of candidate therapeutic agents by using patient-derived preclinical models may facilitate drug discovery for HCC patients.
Methods
Four primary cultured HCC cells from surgically resected tumor tissues and six HCC cell lines were used for high-throughput screening of 252 drugs from the Prestwick Chemical Library. The efficacy and mechanisms of action of the candidate anti-cancer drug were analyzed via cell viability, cell cycle assays, and western blotting.
Results
Guanabenz acetate, which has been used as an antihypertensive drug, was screened as a candidate anti-cancer agent for HCC through a drug sensitivity assay by using the primary cultured HCC cells and HCC cell lines. Guanabenz acetate reduced HCC cell viability through apoptosis and autophagy. This occurred via inhibition of growth arrest and DNA damage-inducible protein 34, increased phosphorylation of eukaryotic initiation factor 2α, increased activating transcription factor 4, and cell cycle arrest.
Conclusions
Guanabenz acetate induces endoplasmic reticulum stress–related cell death in HCC and may be repositioned as an anti-cancer therapeutic agent for HCC patients.

Citations

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Current trends and future prospects of drug repositioning in gastrointestinal oncology
Nayeralsadat Fatemi, Mina Karimpour, Hoda Bahrami, Mohammad Reza Zali, Vahid Chaleshi, Andrea Riccio, Ehsan Nazemalhosseini-Mojarad, Mehdi Totonchi
Frontiers in Pharmacology.2024;[Epub] CrossRef
ER stress signaling at the interphase between MASH and HCC
Younis Hazari, Eric Chevet, Béatrice Bailly-Maitre, Claudio Hetz
Hepatology.2024;[Epub] CrossRef
Small molecules for impairing endoplasmic reticulum in cancer
Tripti Mishra, Navneet Dubey, Sudipta Basu
Organic & Biomolecular Chemistry.2024; 22(44): 8689. CrossRef
Guanabenz acetate, an antihypertensive drug repurposed as an inhibitor of Escherichia coli biofilm
Arakkaveettil Kabeer Farha, Olivier Habimana, Harold Corke, Olaya Rendueles
Microbiology Spectrum.2024;[Epub] CrossRef
The integrated stress response in cancer progression: a force for plasticity and resistance
Caleb L. Lines, Morgan J. McGrath, Tanis Dorwart, Crystal S. Conn
Frontiers in Oncology.2023;[Epub] CrossRef
Endoplasmic reticulum stress: Multiple regulatory roles in hepatocellular carcinoma
Jiacheng Wu, Shan Qiao, Yien Xiang, Menying Cui, Xiaoxiao Yao, Ruixin Lin, Xuewen Zhang
Biomedicine & Pharmacotherapy.2021; 142: 112005. CrossRef
The two faces of the Integrated Stress Response in cancer progression and therapeutic strategies
Eugenia Licari, Luis Sánchez-del-Campo, Paola Falletta
The International Journal of Biochemistry & Cell Biology.2021; 139: 106059. CrossRef
Repurposing of Guanabenz acetate by encapsulation into long-circulating nanopolymersomes for treatment of triple-negative breast cancer
Yusuf A. Haggag, Mohamed Yasser, Murtaza M. Tambuwala, Suleiman S. El Tokhy, Mohammad Isreb, Ahmed A. Donia
International Journal of Pharmaceutics.2021; 600: 120532. CrossRef
Endoplasmic reticulum stress: New insights into the pathogenesis and treatment of retinal degenerative diseases
Marina S. Gorbatyuk, Christopher R. Starr, Oleg S. Gorbatyuk
Progress in Retinal and Eye Research.2020; 79: 100860. CrossRef
Delineating the role of eIF2α in retinal degeneration
Christopher R. Starr, Marina S. Gorbatyuk
Cell Death & Disease.2019;[Epub] CrossRef
Repositioning of Guanabenz in Conjugation with Gold and Silver Nanoparticles against Pathogenic Amoebae Acanthamoeba castellanii and Naegleria fowleri
Areeba Anwar, Mohammad Ridwane Mungroo, Ayaz Anwar, William J. Sullivan, Naveed Ahmed Khan, Ruqaiyyah Siddiqui
ACS Infectious Diseases.2019; 5(12): 2039. CrossRef

Quilty Lesions in the Endomyocardial Biopsies after Heart Transplantation: Haeyon Cho, Jin-Oh Choi, Eun-Seok Jeon, Jung-Sun Kim; J Pathol Transl Med. 2019;53(1):50-56. Published online December 26, 2018; DOI: https://doi.org/10.4132/jptm.2018.11.30

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Abstract PDF Supplementary Material

Background
The aim of this study was to investigate the clinical significance of Quilty lesions in endomyocardial biopsies (EMBs) of cardiac transplantation patients.
Methods
A total of 1190EMBs from 117 cardiac transplantation patients were evaluated histologically for Quilty lesions,acute cellular rejection, and antibody-mediated rejection. Cardiac allograft vasculopathy wasdiagnosed by computed tomography coronary angiography. Clinical information, including thepatients’ survival was retrieved by a review of medical records.
Results
Eighty-eight patients(75.2%) were diagnosed with Quilty lesions, which were significantly associated with acute cellularrejection, but not with acute cellular rejection ≥ 2R or antibody-mediated rejection. In patientsdiagnosed with both Quilty lesions and acute cellular rejection, the time-to-onset of Quilty lesionsfrom transplantation was longer than that of acute cellular rejections. We found a significant associationbetween Quilty lesions and cardiac allograft vasculopathy. No significant relationship wasfound between Quilty lesions and the patients’ survival.
Conclusions
Quilty lesion may be an indicator of previous acute cellular rejection rather than a predictor for future acute cellular rejection.

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The human myocardium harbors a population of naive B-cells with a distinctive gene expression signature conserved across species
Kevin C. Bermea, Nicolas Kostelecky, Sylvie T. Rousseau, Chieh-Yu Lin, Luigi Adamo
Frontiers in Immunology.2022;[Epub] CrossRef
Examination of tracheal allografts after long-term survival in dogs
Tao Lu, Yiwei Huang, Yulei Qiao, Yongxing Zhang, Yu Liu
European Journal of Cardio-Thoracic Surgery.2021; 59(1): 155. CrossRef
Essentials in the diagnosis of postoperative myocardial lesions similar to or unrelated to rejection in heart transplant
Costel Dumitru, Ancuta Zazgyva, Adriana Habor, Ovidiu Cotoi, Horațiu Suciu, Carmen Cotrutz, Bogdan Grecu, Ileana Anca Sin
Revista Romana de Medicina de Laborator.2021; 29(3): 307. CrossRef
Clinical outcome of donor heart with prolonged cold ischemic time: A single‐center study
Fazal Shafiq, Yixuan Wang, Geng Li, Zongtao Liu, Fei Li, Ying Zhou, Li Xu, Xingjian Hu, Nianguo Dong
Journal of Cardiac Surgery.2020; 35(2): 397. CrossRef
The XVth Banff Conference on Allograft Pathology the Banff Workshop Heart Report: Improving the diagnostic yield from endomyocardial biopsies and Quilty effect revisited
Jean-Paul Duong Van Huyen, Marny Fedrigo, Gregory A. Fishbein, Ornella Leone, Desley Neil, Charles Marboe, Eliot Peyster, Jan von der Thüsen, Alexandre Loupy, Michael Mengel, Monica P. Revelo, Benjamin Adam, Patrick Bruneval, Annalisa Angelini, Dylan V. M
American Journal of Transplantation.2020; 20(12): 3308. CrossRef

C-reactive Protein Overexpression in the Background Liver of Hepatitis B Virus–Associated Hepatocellular Carcinoma Is a Prognostic Biomarker: Jin Ho Shin, Eunsil Yu, Eun Na Kim, Chong Jai Kim; J Pathol Transl Med. 2018;52(5):267-274. Published online July 27, 2018; DOI: https://doi.org/10.4132/jptm.2018.07.14

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Abstract PDF

Background
Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC). Peripheral blood C-reactive protein (CRP) concentration and CRP overexpression in HCC cells are proven to be prognostic markers for HCC, but the significance of CRP expression in non-neoplastic hepatocytes, which are the primary origin of CRP, has not been studied. This study was conducted to determine the clinicopathologic significance of CRP immunoreactivity in the background liver of HBV-associated HCC.
Methods
CRP immunostaining was done on tissue microarrays of non-neoplastic liver tissues obtained from surgically resected, treatment-naïve HBV-associated HCCs (n = 156). The relationship between CRP immunoreactivity and other clinicopathologic parameters including cancer-specific survival was analyzed. CRP immunoreactivity was determined using a 4-tier grading system: grades 0, 1, 2, and 3.
Results
CRP was positive in 139 of 156 cases (89.1%) of non-neoplastic liver in patients with HCCs: grade 1 in 83 cases (53.2%); grade 2 in 50 cases (32.1%); and grade 3 in six cases (3.8%). The patients with diffuse CRP immunoreactivity (grade 3) had decreased cancer-specific survival (p = .031) and a tendency for shorter interval before early recurrence (p = .050). The degree of CRP immunoreactivity correlated with serum CRP concentration (p < .001).
Conclusions
CRP immunoreactivity in non-neoplastic liver is a novel biomarker for poor cancer-specific survival of HBV-associated HCC and correlates with serum CRP concentration.

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Analysis of Inflammatory and Thyroid Hormone Levels Based on Hepatitis A and B Virus Immunity Status: Age and Sex Stratification
Hyeokjun Yun, Jae-Sik Jeon, Jae Kyung Kim
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Ferritin and procalcitonin serve as discriminative inflammatory biomarkers and can predict the prognosis of severe fever with thrombocytopenia syndrome in its early stages
Keping Chen, Huidi Sun, Yu Geng, Chuankun Yang, Chun Shan, Yuxin Chen
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Lihe Che, Zedong Wang, Na Du, Liang Li, Yinghua Zhao, Kaiyu Zhang, Quan Liu
Frontiers in Microbiology.2022;[Epub] CrossRef
Hepatocellular adenomas: recent updates
Haeryoung Kim, Young Nyun Park
Journal of Pathology and Translational Medicine.2021; 55(3): 171. CrossRef
A prospective follow-up study of the relationship between high-sensitivity C-reactive protein and primary liver cancer
Sarah Tan Siyin, Tong Liu, Wenqiang Li, Nan Yao, Guoshuai Xu, Jun Qu, Yajun Chen
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CRP Levels in Viral Hepatitis: A Meta-Analysis Study
Sukhpal Singh, Abhishek Bansal, Pardeep Kumar
International Journal of Infection.2020;[Epub] CrossRef

Case Study

Combined Hepatocellular Carcinoma and Neuroendocrine Carcinoma with Ectopic Secretion of Parathyroid Hormone: A Case Report and Review of the Literature: Hyun Jung Kwon, Ji-Won Kim, Haeryoung Kim, YoungRok Choi, Soomin Ahn; J Pathol Transl Med. 2018;52(4):232-237. Published online May 25, 2018; DOI: https://doi.org/10.4132/jptm.2018.05.17

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Abstract PDF

Primary combined hepatocellular carcinoma (HCC) and neuroendocrine carcinoma is a rare entity, and so is hypercalcemia due to ectopic parathyroid hormone (PTH) secretion by tumor. A 44-year old man with hepatitis B virus associated chronic liver disease presented with a hepatic mass. Hemihepatectomy discovered the mass as combined HCC and poorly differentiated cholangiocarcinoma. During adjuvant chemoradiation therapy, he presented with nausea, and multiple systemic metastases were found. Laboratory tests revealed hypercalcemia with markedly elevated PTH and neuron specific enolase. Parathyroid scan showed normal uptake in parathyroid glands, suggestive of ectopic PTH secretion. Subsequently, immunohistochemistry of neuroendocrine marker was performed on the primary lesion, and confirmed the neuroendocrine differentiation in non-HCC component. The patient died 71 days after surgery. This report may suggest the possibility of ectopic PTH secretion by neuroendocrine carcinoma of hepatic origin causing hypercalcemia. Caution for neuroendocrine differentiation should be exercised when diagnosing poorly differentiated HCC.

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Mei Luo, Xiaoxia Yu, Zhongpei Chen, Zhenhan Li
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Review

Extracellular Vesicles and the Promise of Continuous Liquid Biopsies: Don Armstrong, Derek E. Wildman; J Pathol Transl Med. 2018;52(1):1-8. Published online January 15, 2018; DOI: https://doi.org/10.4132/jptm.2017.05.21

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Abstract PDF

The rapid and accurate diagnosis of patients with minimally invasive procedures was once only found in science fiction. However, the discovery of extracellular vesicles (EVs) and their near ubiquity in body fluids, coupled with the advent of inexpensive next generation sequencing techniques and EV purification protocols, promises to make science fiction a reality. Purifying and sequencing the RNA content of EV from routine blood draws and urine samples are likely to enable pathologists and physicians to diagnose and track the progress of diseases in many inaccessible tissues in the near future. Here we present the evolutionary background of EV, summarize the biology of EV formation and cargo selection, and discuss the current barriers to making continuous liquid biopsies through the use of EV a science reality.

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Case Study

Hepatocellular Carcinoma Arising in a Huge Hepatocellular Adenoma with Bone Marrow Metaplasia: Hyo Jeong Kang, Hui Jeong Jeong, So-Woon Kim, Eunsil Yu, Young-Joo Lee, So Yeon Kim, Jihun Kim; J Pathol Transl Med. 2018;52(4):226-231. Published online December 27, 2017; DOI: https://doi.org/10.4132/jptm.2017.11.12

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Abstract PDF

Hepatocellular adenoma (HCA) is the most common type of benign liver tumor, and its major complication is malignant transformation to hepatocellular carcinoma (HCC). Here, we report a case of HCC arising in HCA with bone marrow metaplasia in a 24-year-old Korean woman who presented with abdominal discomfort. A huge liver mass was found on abdominal ultrasonography. She underwent surgical hepatic resection, and the resected specimen was entirely involved by a 20-cm-sized tumor. Histological review revealed a well differentiated HCC arising from inflammatory HCA with β-catenin nuclear positivity and bone marrow metaplasia that contained hematopoietic cells. This case was unique because malignant transformation, inflammatory type HCA, β-catenin nuclear staining, and bone marrow metaplasia were simultaneously observed. Additionally, it should be noted that a large HCA with β-catenin activation can undergo malignant transformation and should be surgically resected in a timely manner.

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Spontaneous Occurrence of Various Types of Hepatocellular Adenoma in the Livers of Metabolic Syndrome-Associated Steatohepatitis Model TSOD Mice
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Original Articles

The Clinicopathological and Prognostic Significance of the Gross Classification of Hepatocellular Carcinoma: Yangkyu Lee, Hyunjin Park, Hyejung Lee, Jai Young Cho, Yoo-Seok Yoon, Young-Rok Choi, Ho-Seong Han, Eun Sun Jang, Jin-Wook Kim, Sook-Hyang Jeong, Soomin Ahn, Haeryoung Kim; J Pathol Transl Med. 2018;52(2):85-92. Published online November 24, 2017; DOI: https://doi.org/10.4132/jptm.2017.11.13

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Abstract PDF

Background
We aimed to determine the clinicopathological significance of the gross classification of hepatocellular carcinoma (HCC) according to the Korean Liver Cancer Association (KLCA) guidelines.
Methods
A retrospective analysis was performed on 242 cases of consecutively resected solitary primary HCC between 2003 and 2012 at Seoul National University Bundang Hospital. The gross classification (vaguely nodular [VN], expanding nodular [EN], multinodular confluent [MC], nodular with perinodular extension [NP], and infiltrative [INF]) was reviewed for all cases, and were correlated with various clinicopathological features and the expression status of “stemness”-related (cytokeratin 19 [CK19], epithelial cell adhesion molecule [EpCAM]), and epithelial-mesenchymal transition (EMT)–related (urokinase plasminogen activator receptor [uPAR] and Ezrin) markers.
Results
Significant differences were seen in overall survival (p=.015) and disease-free survival (p = .034) according to the gross classification; INF type showed the worst prognosis while VN and EN types were more favorable. When the gross types were simplified into two groups, type 2 HCCs (MC/NP/INF) were more frequently larger and poorly differentiated, and showed more frequent microvascular and portal venous invasion, intratumoral fibrous stroma and higher pT stages compared to type 1 HCCs (EN/VN) (p<.05, all). CK19, EpCAM, uPAR, and ezrin expression was more frequently seen in type 2 HCCs (p<.05, all). Gross classification was an independent predictor of both overall and disease-free survival by multivariate analysis (overall survival: p=.030; hazard ratio, 4.118; 95% confidence interval, 1.142 to 14.844; disease-free survival: p=.016; hazard ratio, 1.617; 95% confidence interval, 1.092 to 2.394).
Conclusions
The gross classification of HCC had significant prognostic value and type 2 HCCs were associated with clinicopathological features of aggressive behavior, increased expression of “stemness”- and EMT-related markers, and decreased survival.

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Prognosis of Hepatocellular Carcinoma after Liver Transplantation: Comparative Analysis with Partial Hepatectomy: Kyuho Lee, Kyoung-Bun Lee, Nam-Joon Yi, Kyung-Suk Suh, Ja-June Jang; J Pathol Transl Med. 2017;51(1):79-86. Published online December 25, 2016; DOI: https://doi.org/10.4132/jptm.2016.10.13

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Abstract PDF

Background
Liver transplantation (LT) is the treatment of choice for hepatocellular carcinoma (HCC). The aim of this study was to investigate the recurrence rate of HCC after LT and prognostic factors for recurrence by comparing LT with non-transplanted resection. Methods: The participants were 338 patients who underwent LT between 1996 and 2012 at Seoul National University Hospital (LT group) and 520 HCC patients who underwent partial hepatectomy between 1995 and 2006 (control group, non-LT group). Results: In the LT group, 68 of 338 patients (19.8%) showed relapse, and the recurrence rate was lower than that in the non-LT group (64.9%, 357/520, p < .001). Stratification analysis by American Joint Committee on Cancer (AJCC) stage showed that the stage I-II LT group had a lower recurrence rate than the non-LT group. Univariate comparative analysis demonstrated that multiplicity of tumor, tumor size, gross type, Edmondson- Steiner (ES) nuclear grade, extent of tumor, angioinvasion, AJCC stage, Milan criteria, University of California at San Francisco criteria on explant pathology (all p < .001), positive expression of cytokeratin 19 (p = .002), and preoperative α-fetoprotein (AFP) (p < .001) were predictors of tumor recurrence. In multivariate analysis, LT, preoperative AFP, multiplicity of tumor, extent of tumor, size of tumor, and ES nuclear grade were independent prognostic factors. Conclusions: LT might have a protective effect against the late recurrence of stage I-II HCC compared to non-LT, and the prognostic factors for recurrence were similar to previously well-known prognostic factors for HCC.

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SIRT7, H3K18ac, and ELK4 Immunohistochemical Expression in Hepatocellular Carcinoma: Hye Seung Lee, Wonkyung Jung, Eunjung Lee, Hyeyoon Chang, Jin Hyuk Choi, Han Gyeom Kim, Aeree Kim, Baek-hui Kim; J Pathol Transl Med. 2016;50(5):337-344. Published online August 5, 2016; DOI: https://doi.org/10.4132/jptm.2016.05.20

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Abstract PDF

Background
SIRT7 is one of the histone deacetylases and is NAD-dependent. It forms a complex with ETS-like transcription factor 4 (ELK4), which deacetylates H3K18ac and works as a transcriptional suppressor. Overexpression of SIRT7 and deacetylation of H3K18ac have been shown to be associated with aggressive clinical behavior in some cancers, including hepatocellular carcinoma (HCC). The present study investigated the immunohistochemical expression of SIRT7, H3K18ac, and ELK4 in hepatocellular carcinoma.
Methods
A total of 278 HCC patients were enrolled in this study. Tissue microarray blocks were made from existing paraffin-embedded blocks. Immunohistochemical expressions of SIRT7, H3K18ac and ELK4 were scored and analyzed.
Results
High SIRT7 (p = .034), high H3K18ac (p = .001), and low ELK4 (p = .021) groups were associated with poor outcomes. Age < 65 years (p = .028), tumor size ≥ 5 cm (p = .001), presence of vascular emboli (p = .003), involvement of surgical margin (p = .001), and high American Joint Committee on Cancer stage (III&V) (p < .001) were correlated with worse prognoses. In multivariate analysis, H3K18ac (p = .001) and ELK4 (p = .015) were the significant independent prognostic factors.
Conclusions
High SIRT7 expression with poor overall survival implies that deacetylation of H3K18ac contributes to progression of HCC. High H3K18ac expression with poor prognosis is predicted due to a compensation mechanism. In addition, high ELK4 expression with good prognosis suggests another role of ELK4 as a tumor suppressor beyond SIRT7’s helper. In conclusion, we could assume that the H3K18ac deacetylation pathway is influenced by many other factors.

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Nuclear Expression of Hepatitis B Virus X Protein Is Associated with Recurrence of Early-Stage Hepatocellular Carcinomas: Role of Viral Protein in Tumor Recurrence: Jing Jin, Hae Yoen Jung, KyuHo Lee, Nam-Joon Yi, Kyung-Suk Suh, Ja-June Jang, Kyoung-Bun Lee; J Pathol Transl Med. 2016;50(3):181-189. Published online April 17, 2016; DOI: https://doi.org/10.4132/jptm.2016.03.18

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Abstract PDF

Background
Hepatitis B virus (HBV) plays well-known roles in tumorigenesis of hepatocellular carcinoma (HCC) in infected patients. However, HBV-associated protein status in tumor tissues and the relevance to tumor behavior has not been reported. Our study aimed to examine the expression of HBV-associated proteins in HCC and adjacent nontumorous tissue and their clinicopathologic implication in HCC patients.
Methods
HBV surface antigen (HBsAg), HBV core antigen (HBcAg), and HBV X protein (HBx) were assessed in 328 HBV-associated HCCs and in 155 matched nontumorous tissues by immunohistochemistry staining.
Results
The positive rates of HBsAg and cytoplasmic HBx staining in tumor tissue were lower than those in nontumorous tissue (7.3% vs. 57.4%, p < .001; 43.4% vs. 81.3%, p < .001). Conversely, nuclear HBx was detected more frequently in tumors than in nontumorous tissue (52.1% vs. 30.3%, p < .001). HCCs expressing HBsAg, HBcAg, or cytoplasmic HBx had smaller size; lower Edmondson-Steiner (ES) nuclear grade, pT stage, and serum alpha-fetoprotein, and less angioinvasion than HCCs not expressing HBV-associated proteins. Exceptionally, nuclear HBx-positive HCCs showed higher ES nuclear grade and more frequent large-vessel invasion than did nuclear HBx-negative HCCs. In survival analysis, only nuclear HBx-positive HCCs had shorter disease-free survival than nuclear HBx-negative HCCs in pT1 and ES nuclear grade 1–2 HCC subgroup (median, 126 months vs. 35 months; p = .015).
Conclusions
Our data confirmed that expression of normal HBV-associated proteins generally decreases in tumor cells in comparison to nontumorous hepatocytes, with the exception of nuclear HBx, which suggests that nuclear HBx plays a role in recurrence of well-differentiated and early-stage HCCs.

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