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1
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Huang Y, Eng W, Shao C, Cheng G, Qiang C, Peng W, Yang S, Liu S. Synthesis, Preclinical Characterizations and Imaging Studies of [ 18F]AlF-Labeled NY104, a CAIX-Targeting Diagnostic Agent. J Labelled Comp Radiopharm 2025; 68:e4142. [PMID: 40152075 DOI: 10.1002/jlcr.4142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/29/2025]
Abstract
The protein carbonic anhydrase IX (CAIX) is highly expressed in clear cell renal cell carcinoma (ccRCC), and its restrictive expression in healthy tissues makes CAIX an attractive diagnostic target. The purpose of this study was to synthesize and evaluate [18F]AlF-NY104, a small-molecule CAIX-targeting PET agent in a preclinical ccRCC model. The radiolabeling parameters for [18F]AlF-NY104 have been optimized, including the solvent volume and reaction temperature. The high-purity product was synthesized by using an automated multifunctional module Mortenon M1, leading to nondecay-corrected radiochemical yields over 50% (n = 3). [18F]AlF-NY104 showed excellent tumor targeting capability and afforded high-quality microPET/CT imaging in the OS-RC-2 tumor model (15.01 ± 0.76 %ID/g [mean ± SEM]). The radiation exposure from [18F]AlF-NY104 is estimated to be 4.44 mSv for adult male and female human subjects, which is well below the FDA recommended whole-body single exposure limit of 30 mSv. Our investigation revealed that [18F]AlF-NY104 can be conveniently and efficiently radiolabeled by using an automated module. [18F]AlF-NY104 exhibited many outstanding properties, such as rapid uptake in tumor, rapid clearance through the kidney, and low uptake in most normal organs. Moreover, the high accumulation of [18F]AlF-NY104 in tumors in CAIX-positive models offers an alternative diagnostic strategy for patients with ccRCC.
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Affiliation(s)
- Yu Huang
- Hubei NO.3 People's Hospital of Jianghan University, Wuhan, China
| | - Waisi Eng
- Norroy Bioscience Co., LTD, Wuxi, China
| | | | | | | | - Wei Peng
- Norroy Bioscience Co., LTD, Wuxi, China
| | - Si Yang
- Norroy Bioscience Co., LTD, Wuxi, China
| | - Shiguo Liu
- Hubei NO.3 People's Hospital of Jianghan University, Wuhan, China
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2
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Zalles N, Williamson SR. What Is New in Pathologic Diagnosis and Classification of the Common Renal Cell Neoplasms? Surg Pathol Clin 2025; 18:133-155. [PMID: 39890301 DOI: 10.1016/j.path.2024.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2025]
Abstract
Diagnostic challenges remain among the common renal cell carcinoma (RCC) subtypes. High-grade clear cell RCC may have deceptive patterns, for example BAP1-deficient tumors. Subtyping type 1 and 2 papillary RCC is no longer recommended, as former type 2 tumors may now be contain other diagnostic entities, such as FH-deficient RCC, MITF family RCC, or others. Clear cell papillary tumor is no longer considered carcinoma due to its highly favorable behavior. However, imperfect examples are best considered clear cell RCC. Oncocytic renal neoplasm of low malignant potential has been proposed as a borderline category in the absence of overt malignant features.
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Affiliation(s)
- Nicole Zalles
- Department of Pathology and Laboratory Medicine, Cleveland Clinic, 9500 Euclid Avenue L25, Cleveland, OH 44195, USA
| | - Sean R Williamson
- Department of Pathology and Laboratory Medicine, Cleveland Clinic, 9500 Euclid Avenue L25, Cleveland, OH 44195, USA.
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3
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O'Connell RP, Liaw K, Wellhausen N, Chuckran CA, Bhojnagarwala PS, Bordoloi D, Park D, Shupin N, Kulp D, June CH, Weiner D. Format-tuning of in vivo-launched bispecific T cell engager enhances efficacy against renal cell carcinoma. J Immunother Cancer 2024; 12:e008733. [PMID: 38834201 PMCID: PMC11163651 DOI: 10.1136/jitc-2023-008733] [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: 05/02/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND Advanced clear cell renal cell carcinoma (ccRCC) is a prevalent kidney cancer for which long-term survival rates are abysmal, though immunotherapies are showing potential. Not yet clinically vetted are bispecific T cell engagers (BTEs) that activate T cell-mediated cancer killing through intercellular synapsing. Multiple BTE formats exist, however, with limited cross-characterizations to help optimize new drug design. Here, we developed BTEs to treat ccRCC by targeting carbonic anhydrase 9 (CA9) while characterizing the persistent BTE (PBTE) format and comparing it to a new format, the persistent multivalent T cell engager (PMTE). These antibody therapies against ccRCC are developed as both recombinant and synthetic DNA (synDNA) medicines. METHODS Antibody formatting effects on binding kinetics were assessed by flow cytometry and intercellular synaptic strength assays while potency was tested using T-cell activation and cytotoxicity assays. Mouse models were used to study antibody plasma and tumor pharmacokinetics, as well as antitumor efficacy as both recombinant and synDNA medicines. Specifically, three models using ccRCC cell line xenografts and human donor T cells in immunodeficient mice were used to support this study. RESULTS Compared with a first-generation BTE, we show that the PBTE reduced avidity, intercellular synaptic strength, cytotoxic potency by as much as 33-fold, and ultimately efficacy against ccRCC tumors in vivo. However, compared with the PBTE, we demonstrate that the PMTE improved cell avidity, restored intercellular synapses, augmented cytotoxic potency by 40-fold, improved tumor distribution pharmacokinetics by 2-fold, and recovered synDNA efficacy in mouse tumor models by 20-fold. All the while, the PMTE displayed a desirable half-life of 4 days in mice compared with the conventional BTE's 2 hours. CONCLUSIONS With impressive efficacy, the CA9-targeted PMTE is a promising new therapy for advanced ccRCC, which can be effectively delivered through synDNA. The highly potent PMTE format itself is a promising new tool for future applications in the multispecific antibody space.
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Affiliation(s)
- Ryan P O'Connell
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Vaccine & Immunotherapy Center, Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Kevin Liaw
- Vaccine & Immunotherapy Center, Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Nils Wellhausen
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | | | | | - Devivasha Bordoloi
- Vaccine & Immunotherapy Center, Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Daniel Park
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Vaccine & Immunotherapy Center, Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Nicholas Shupin
- Vaccine & Immunotherapy Center, Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Daniel Kulp
- Vaccine & Immunotherapy Center, Wistar Institute, Philadelphia, Pennsylvania, USA
| | - Carl H June
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Parker Institute for Cancer Immunotherapy, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - David Weiner
- Vaccine & Immunotherapy Center, Wistar Institute, Philadelphia, Pennsylvania, USA
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Bisbal Lopez L, Ravazza D, Bocci M, Zana A, Principi L, Dakhel Plaza S, Galbiati A, Gilardoni E, Scheuermann J, Neri D, Pignataro L, Gennari C, Cazzamalli S, Dal Corso A. Ex vivo mass spectrometry-based biodistribution analysis of an antibody-Resiquimod conjugate bearing a protease-cleavable and acid-labile linker. Front Pharmacol 2023; 14:1320524. [PMID: 38125888 PMCID: PMC10731371 DOI: 10.3389/fphar.2023.1320524] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 11/24/2023] [Indexed: 12/23/2023] Open
Abstract
Immune-stimulating antibody conjugates (ISACs) equipped with imidazoquinoline (IMD) payloads can stimulate endogenous immune cells to kill cancer cells, ultimately inducing long-lasting anticancer effects. A novel ISAC was designed, featuring the IMD Resiquimod (R848), a tumor-targeting antibody specific for Carbonic Anhydrase IX (CAIX) and the protease-cleavable Val-Cit-PABC linker. In vitro stability analysis showed not only R848 release in the presence of the protease Cathepsin B but also under acidic conditions. The ex vivo mass spectrometry-based biodistribution data confirmed the low stability of the linker-drug connection while highlighting the selective accumulation of the IgG in tumors and its long circulatory half-life.
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Affiliation(s)
| | | | - Matilde Bocci
- R&D Department, Philochem AG, Otelfingen, Switzerland
| | | | | | | | | | | | - Jörg Scheuermann
- Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
| | - Dario Neri
- R&D Department, Philochem AG, Otelfingen, Switzerland
- Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland
- Philogen S.p.A, Siena, Italy
| | - Luca Pignataro
- Chemistry Department, Università degli Studi di Milano, Milano, Italy
| | - Cesare Gennari
- Chemistry Department, Università degli Studi di Milano, Milano, Italy
| | | | - Alberto Dal Corso
- Chemistry Department, Università degli Studi di Milano, Milano, Italy
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Bhise K, Gavande NS, Iyer AK. Leveraging hypoxia in triple-negative breast cancer as a promising treatment strategy. Drug Discov Today 2023; 28:103761. [PMID: 37660983 DOI: 10.1016/j.drudis.2023.103761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 08/08/2023] [Accepted: 08/29/2023] [Indexed: 09/05/2023]
Abstract
Current treatment strategies for triple-negative breast cancer (TNBC) are based upon conventional chemotherapy, immunotherapy, or a combination of both. The treatment regimen for chemotherapy is often a combination of two or more drugs, either dose dense or low dose for synergy. Anthracyclines, alkylating agents, antimicrotubule agents, and antimetabolites for early-stage TNBC; and antimetabolites, non-taxane microtubule inhibitors, and cross-linker platinums for late-stage TNBC are usually administered in the clinical setting. Newer options for patients with advanced TNBC, such as poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors, have recently emerged for cases where surgery is not a viable option and the disease has metastasized. This review outlines the current trends in hypoxia-inspired treatment strategies for TNBC with a focus on clinical trials.
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Affiliation(s)
- Ketki Bhise
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA
| | - Navnath S Gavande
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA; Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, MI, USA
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI, USA; Molecular Imaging Program, Karmanos Cancer Institute, Detroit, MI, USA.
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6
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Pini GM, Lucianò R, Colecchia M. Cystic Clear Cell Renal Cell Carcinoma: A Morphological and Molecular Reappraisal. Cancers (Basel) 2023; 15:3352. [PMID: 37444462 DOI: 10.3390/cancers15133352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
A wide variety of renal neoplasms can have cystic areas. These can occur for different reasons: some tumors have an intrinsic cystic architecture, while others exhibit pseudocystic degeneration of necrotic foci or they have cystically dilated renal tubules constrained by stromal neoplastic cells. Clear cell renal cell carcinoma (CCRCC), either solid or cystic, is the most frequent type of renal cancer. While pseudocysts are found in high-grade aggressive CCRCC, cystic growth is associated with low-grade indolent cases. The latter also form through a cyst-dependent molecular pathway, and they are more frequent in patients suffering from VHL disease. The differential diagnosis of multilocular cystic renal neoplasm of low malignant potential and clear cell papillary renal cell tumor can be especially hard and requires a focused macroscopical and microscopical pathological analysis. As every class of renal tumor includes cystic forms, knowledge of the criteria required for a differential diagnosis is mandatory.
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Affiliation(s)
- Giacomo Maria Pini
- Department of Pathology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Roberta Lucianò
- Department of Pathology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Maurizio Colecchia
- IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132 Milan, Italy
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Verhoeff SR, Oosting SF, Elias SG, van Es SC, Gerritse SL, Angus L, Heskamp S, Desar IM, Menke-van der Houven van Oordt CW, van der Veldt AA, Arens AI, Brouwers AH, Eisses B, Mulders PF, Hoekstra OS, Zwezerijnen GJ, van der Graaf WT, Aarntzen EH, Oyen WJ, van Herpen CM. [89Zr]Zr-DFO-girentuximab and [18F]FDG PET/CT to Predict Watchful Waiting Duration in Patients with Metastatic Clear-cell Renal Cell Carcinoma. Clin Cancer Res 2023; 29:592-601. [PMID: 36394882 PMCID: PMC9890134 DOI: 10.1158/1078-0432.ccr-22-0921] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/11/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022]
Abstract
PURPOSE Watchful waiting (WW) can be considered for patients with metastatic clear-cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with <2 International Metastatic RCC Database Consortium criteria and ≤2 metastatic sites [referred to as watch and wait ("W&W") criteria]. The IMaging PAtients for Cancer drug SelecTion-Renal Cell Carcinoma study objective was to assess the predictive value of [18F]FDG PET/CT and [89Zr]Zr-DFO-girentuximab PET/CT for WW duration in patients with mccRCC. EXPERIMENTAL DESIGN Between February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n = 14) and intermediate (n = 26) prognosis. Baseline contrast-enhanced CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT images coregistered to PET/CT. High and low uptake groups were defined on the basis of median geometric mean SUVmax of RECIST-measurable lesions across patients. RESULTS The median WW time was 16.1 months [95% confidence interval (CI): 9.0-31.7]. The median WW period was shorter in patients with high [18F]FDG tumor uptake than those with low uptake (9.0 vs. 36.2 months; HR, 5.6; 95% CI: 2.4-14.7; P < 0.001). Patients with high [89Zr]Zr-DFO-girentuximab tumor uptake had a median WW period of 9.3 versus 21.3 months with low uptake (HR, 1.7; 95% CI: 0.9-3.3; P = 0.13). Patients with "W&W criteria" had a longer median WW period of 21.3 compared with patients without: 9.3 months (HR, 1.9; 95% CI: 0.9-3.9; Pone-sided = 0.034). Adding [18F]FDG uptake to the "W&W criteria" improved the prediction of WW duration (P < 0.001); whereas [89Zr]Zr-DFO-girentuximab did not (P = 0.53). CONCLUSIONS In patients with good- or intermediate-risk mccRCC, low [18F]FDG uptake is associated with prolonged WW. This study shows the predictive value of the "W&W criteria" for WW duration and shows the potential of [18F]FDG-PET/CT to further improve this.
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Affiliation(s)
- Sarah R. Verhoeff
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Sjoukje F. Oosting
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Sjoerd G. Elias
- Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Suzanne C. van Es
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Sophie L. Gerritse
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Medical Oncology, Amsterdam UMC location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Lindsay Angus
- Departments of Medical Oncology and Radiology & Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Sandra Heskamp
- Department of Radiology, Nuclear Medicine and Anatomy, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Ingrid M.E. Desar
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
| | | | - Astrid A.M. van der Veldt
- Departments of Medical Oncology and Radiology & Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Anne I.J. Arens
- Department of Radiology, Nuclear Medicine and Anatomy, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Adrienne H. Brouwers
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Bertha Eisses
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Peter F.A. Mulders
- Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Otto S. Hoekstra
- Department of Radiology and Nuclear Medicine, Amsterdam UMC location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Gerben J.C. Zwezerijnen
- Department of Radiology and Nuclear Medicine, Amsterdam UMC location VUMC, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Winette T.A. van der Graaf
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Erik H.J.G. Aarntzen
- Department of Radiology, Nuclear Medicine and Anatomy, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Wim J.G. Oyen
- Department of Radiology, Nuclear Medicine and Anatomy, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Radiology and Nuclear Medicine, Rijnstate, Arnhem, the Netherlands.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Carla M.L. van Herpen
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.,Corresponding Author: Carla M.L. van Herpen, Radboud University Nijmegen Medical Center, Nijmegen 6500 HB, the Netherlands. Phone: 312-4361-4038; Fax: 312-4361-5025; E-mail:
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8
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Larroquette M, Lefort F, Heraudet L, Bernhard JC, Ravaud A, Domblides C, Gross-Goupil M. Therapeutic Management of Metastatic Clear Cell Renal Cell Carcinoma: A Revolution in Every Decade. Cancers (Basel) 2022; 14:6230. [PMID: 36551715 PMCID: PMC9777357 DOI: 10.3390/cancers14246230] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/13/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010-2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival.
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Affiliation(s)
- Mathieu Larroquette
- Department of Medical Oncology, University Hospital of Bordeaux, 33000 Bordeaux, France
- Faculty of Medicine, University of Bordeaux, 33000 Bordeaux, France
| | - Félix Lefort
- Department of Medical Oncology, University Hospital of Bordeaux, 33000 Bordeaux, France
| | - Luc Heraudet
- Department of Medical Oncology, University Hospital of Bordeaux, 33000 Bordeaux, France
- Faculty of Medicine, University of Bordeaux, 33000 Bordeaux, France
| | - Jean-Christophe Bernhard
- Faculty of Medicine, University of Bordeaux, 33000 Bordeaux, France
- Department of Urology, University Hospital of Bordeaux, 33000 Bordeaux, France
| | - Alain Ravaud
- Department of Medical Oncology, University Hospital of Bordeaux, 33000 Bordeaux, France
- Faculty of Medicine, University of Bordeaux, 33000 Bordeaux, France
| | - Charlotte Domblides
- Department of Medical Oncology, University Hospital of Bordeaux, 33000 Bordeaux, France
- Faculty of Medicine, University of Bordeaux, 33000 Bordeaux, France
| | - Marine Gross-Goupil
- Department of Medical Oncology, University Hospital of Bordeaux, 33000 Bordeaux, France
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9
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Chen Q, Lu L, Ma W. Efficacy, Safety, and Challenges of CAR T-Cells in the Treatment of Solid Tumors. Cancers (Basel) 2022; 14:5983. [PMID: 36497465 PMCID: PMC9739567 DOI: 10.3390/cancers14235983] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/18/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Immunotherapy has been the fifth pillar of cancer treatment in the past decade. Chimeric antigen receptor (CAR) T-cell therapy is a newly designed adoptive immunotherapy that is able to target and further eliminate cancer cells by engaging with MHC-independent tumor-antigens. CAR T-cell therapy has exhibited conspicuous clinical efficacy in hematological malignancies, but more than half of patients will relapse. Of note, the efficacy of CAR T-cell therapy has been even more disappointing in solid tumors. These challenges mainly include (1) the failures of CAR T-cells to treat highly heterogeneous solid tumors due to the difficulty in identifying unique tumor antigen targets, (2) the expression of target antigens in non-cancer cells, (3) the inability of CAR T-cells to effectively infiltrate solid tumors, (4) the short lifespan and lack of persistence of CAR T-cells, and (5) cytokine release syndrome and neurotoxicity. In combination with these characteristics, the ideal CAR T-cell therapy for solid tumors should maintain adequate T-cell response over a long term while sparing healthy tissues. This article reviewed the status, clinical application, efficacy, safety, and challenges of CAR T-cell therapies, as well as the latest progress of CAR T-cell therapies for solid tumors. In addition, the potential strategies to improve the efficacy of CAR T-cells and prevent side effects in solid tumors were also explored.
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Affiliation(s)
- Qiuqiang Chen
- Key Laboratory for Translational Medicine, The First Affiliated Hospital, Huzhou University School of Medicine, Huzhou 313000, China
| | - Lingeng Lu
- Department of Chronic Disease Epidemiology, School of Medicine, Yale School of Public Health, New Haven, CT 06520, USA
- Yale Cancer Center and Center for Biomedical Data Science, Yale University, 60 College Street, New Haven, CT 06520, USA
| | - Wenxue Ma
- Sanford Stem Cell Clinical Center, Moores Cancer Center, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
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10
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Taylor AS, Skala SL. Tumors masquerading as type 2 papillary renal cell carcinoma: pathologists' ever-expanding differential diagnosis for a heterogeneous group of entities. Urol Oncol 2022; 40:499-511. [PMID: 34116938 DOI: 10.1016/j.urolonc.2021.04.043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 03/22/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023]
Abstract
Although papillary renal cell carcinoma has historically been classified as either type 1 or type 2, data from The Cancer Genome Atlas (TCGA) has demonstrated significant genomic heterogeneity in tumors classified as "type 2 papillary renal cell carcinoma" (T2PRCC). Papillary renal cell carcinoma is expected to have a favorable clinical course compared to clear cell renal cell carcinoma (CCRCC). However, tumors with poor outcome more similar to CCRCC were included in the T2PRCC cohort studied by the TCGA. The differential diagnosis for T2PRCC includes a variety of other renal tumors, including aggressive entities such as TFE3 translocation-associated renal cell carcinoma, TFEB-amplified renal cell carcinoma, fumarate hydratase-deficient renal cell carcinoma, high-grade CCRCC, and collecting duct carcinoma. Accurate classification of these tumors is important for prognostication and selection of therapy.
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Affiliation(s)
- Alexander S Taylor
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI
| | - Stephanie L Skala
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI.
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11
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de Campos NSP, de Oliveira Beserra A, Pereira PHB, Chaves AS, Fonseca FLA, da Silva Medina T, dos Santos TG, Wang Y, Marasco WA, Suarez ER. Immune Checkpoint Blockade via PD-L1 Potentiates More CD28-Based than 4-1BB-Based Anti-Carbonic Anhydrase IX Chimeric Antigen Receptor T Cells. Int J Mol Sci 2022; 23:ijms23105448. [PMID: 35628256 PMCID: PMC9141239 DOI: 10.3390/ijms23105448] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 02/01/2023] Open
Abstract
The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to ≅108 CAR T cells/kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here, we tested CD8α/4-1BB compared to CD28-based anti-CAIX CAR peripheral blood mononuclear cells (PBMCs) releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a ≅107 CAR PBMCs cells/kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, the T cell exhaustion status in peripheral CD4 T cells, additionally to CD8, was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon the administration of a 107 CAR PMBCs cells/kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.
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Affiliation(s)
| | - Adriano de Oliveira Beserra
- A.C. Camargo Cancer Center, Centro Internacional de Pesquisa, Sao Paulo 01508-010, SP, Brazil; (A.d.O.B.); (P.H.B.P.); (A.S.C.); (T.d.S.M.); (T.G.d.S.)
| | - Pedro Henrique Barbosa Pereira
- A.C. Camargo Cancer Center, Centro Internacional de Pesquisa, Sao Paulo 01508-010, SP, Brazil; (A.d.O.B.); (P.H.B.P.); (A.S.C.); (T.d.S.M.); (T.G.d.S.)
| | - Alexandre Silva Chaves
- A.C. Camargo Cancer Center, Centro Internacional de Pesquisa, Sao Paulo 01508-010, SP, Brazil; (A.d.O.B.); (P.H.B.P.); (A.S.C.); (T.d.S.M.); (T.G.d.S.)
| | - Fernando Luiz Affonso Fonseca
- Laboratório de Análises Clínicas, Centro Universitário Faculdade de Medicina do ABC, Santo Andre 09060-870, SP, Brazil;
- Departamento de Ciências Farmacêuticas, Universidade Federal de Aso Paulo, Diadema 09920-000, SP, Brazil
| | - Tiago da Silva Medina
- A.C. Camargo Cancer Center, Centro Internacional de Pesquisa, Sao Paulo 01508-010, SP, Brazil; (A.d.O.B.); (P.H.B.P.); (A.S.C.); (T.d.S.M.); (T.G.d.S.)
| | - Tiago Goss dos Santos
- A.C. Camargo Cancer Center, Centro Internacional de Pesquisa, Sao Paulo 01508-010, SP, Brazil; (A.d.O.B.); (P.H.B.P.); (A.S.C.); (T.d.S.M.); (T.G.d.S.)
| | - Yufei Wang
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
| | - Wayne Anthony Marasco
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;
- Department of Medicine, Harvard Medical School, Boston, MA 02215, USA
- Correspondence: (W.A.M.); (E.R.S.)
| | - Eloah Rabello Suarez
- Center for Natural and Human Sciences, Federal University of ABC, Santo Andre 09210-580, SP, Brazil;
- Correspondence: (W.A.M.); (E.R.S.)
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12
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Manić L, Wallace D, Onganer PU, Taalab YM, Farooqi AA, Antonijević B, Buha Djordjevic A. Epigenetic mechanisms in metal carcinogenesis. Toxicol Rep 2022; 9:778-787. [PMID: 36561948 PMCID: PMC9764177 DOI: 10.1016/j.toxrep.2022.03.037] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/16/2022] [Accepted: 03/26/2022] [Indexed: 12/25/2022] Open
Abstract
Many metals exhibit genotoxic and/or carcinogenic effects. These toxic metals can be found ubiquitously - in drinking water, food, air, general use products, in everyday and occupational settings. Exposure to such carcinogenic metals can result in serious health disorders, including cancer. Arsenic, cadmium, chromium, nickel, and their compounds have already been recognized as carcinogens by the International Agency for Research on Cancer. This review summarizes a wide range of epigenetic mechanisms contributing to carcinogenesis induced by these metals, primarily including, but not limited to, DNA methylation, miRNA regulation, and histone posttranslational modifications. The mechanisms are described and discussed both from a metal-centric and a mechanism-centric standpoint. The review takes a broad perspective, putting the mechanisms in the context of real-life exposure, and aims to assist in guiding future research, particularly with respect to the assessment and control of exposure to carcinogenic metals and novel therapy development.
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Affiliation(s)
- Luka Manić
- Department of Toxicology “Akademik Danilo Soldatović”, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - David Wallace
- School of Biomedical Science, Oklahoma State University Center for Health Sciences, Tulsa, United States
| | - Pinar Uysal Onganer
- Cancer Research Group, School of Life Sciences, University of Westminster, London, UK
| | - Yasmeen M. Taalab
- Institute of Forensic and Traffic Medicine, University of Heidelberg, Voßstraße 2, 69115 Heidelberg, Germany,Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Mansoura University, Dakahlia Governate 35516, Egypt
| | - Ammad Ahmad Farooqi
- Laboratory for Translational Oncology and Personalized Medicine, RLMC, Lahore, Pakistan
| | - Biljana Antonijević
- Department of Toxicology “Akademik Danilo Soldatović”, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Aleksandra Buha Djordjevic
- Department of Toxicology “Akademik Danilo Soldatović”, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia,Correspondence to: Department of Toxicology “Akademik Danilo Soldatović”, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia.
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de Campos NSP, Souza BS, da Silva GCP, Porto VA, Chalbatani GM, Lagreca G, Janji B, Suarez ER. Carbonic Anhydrase IX: A Renewed Target for Cancer Immunotherapy. Cancers (Basel) 2022; 14:cancers14061392. [PMID: 35326544 PMCID: PMC8946730 DOI: 10.3390/cancers14061392] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/03/2022] [Accepted: 03/08/2022] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Carbonic anhydrase IX (CAIX) has been explored for a long time as a therapeutic target in the fight against clear cell renal cell carcinoma and several hypoxic tumors, usually offering modest results followed by adverse effects. However, recent studies using different antibodies and adoptive cell therapies against CAIX have generated exciting prospects for the immunotherapy of these tumors. This complete review will approach the past and future of anti-CAIX immunotherapies. Abstract The carbonic anhydrase isoform IX (CAIX) enzyme is constitutively overexpressed in the vast majority of clear cell renal cell carcinoma (ccRCC) and can also be induced in hypoxic microenvironments, a major hallmark of most solid tumors. CAIX expression is restricted to a few sites in healthy tissues, positioning this molecule as a strategic target for cancer immunotherapy. In this review, we summarized preclinical and clinical data of immunotherapeutic strategies based on monoclonal antibodies (mAbs), fusion proteins, chimeric antigen receptor (CAR) T, and NK cells targeting CAIX against different types of solid malignant tumors, alone or in combination with radionuclides, cytokines, cytotoxic agents, tyrosine kinase inhibitors, or immune checkpoint blockade. Most clinical studies targeting CAIX for immunotherapy were performed using G250 mAb-based antibodies or CAR T cells, developed primarily for bioimaging purposes, with a limited clinical response for ccRCC. Other anti-CAIX mAbs, CAR T, and NK cells developed with therapeutic intent presented herein offered outstanding preclinical results, justifying further exploration in the clinical setting.
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Affiliation(s)
- Najla Santos Pacheco de Campos
- Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, SP, Brazil; (N.S.P.C.); (B.S.S.); (G.C.P.S.); (V.A.P.); (G.L.)
| | - Bruna Santos Souza
- Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, SP, Brazil; (N.S.P.C.); (B.S.S.); (G.C.P.S.); (V.A.P.); (G.L.)
| | - Giselle Correia Próspero da Silva
- Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, SP, Brazil; (N.S.P.C.); (B.S.S.); (G.C.P.S.); (V.A.P.); (G.L.)
| | - Victoria Alves Porto
- Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, SP, Brazil; (N.S.P.C.); (B.S.S.); (G.C.P.S.); (V.A.P.); (G.L.)
| | - Ghanbar Mahmoodi Chalbatani
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Cancer Research, Luxembourg Institute of Health, 1445 Luxembourg, Luxembourg;
| | - Gabriela Lagreca
- Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, SP, Brazil; (N.S.P.C.); (B.S.S.); (G.C.P.S.); (V.A.P.); (G.L.)
| | - Bassam Janji
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Cancer Research, Luxembourg Institute of Health, 1445 Luxembourg, Luxembourg;
- Correspondence: (B.J.); (E.R.S.)
| | - Eloah Rabello Suarez
- Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, SP, Brazil; (N.S.P.C.); (B.S.S.); (G.C.P.S.); (V.A.P.); (G.L.)
- Correspondence: (B.J.); (E.R.S.)
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14
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Akgul M, Williamson SR. Immunohistochemistry for the diagnosis of renal epithelial neoplasms. Semin Diagn Pathol 2021; 39:1-16. [PMID: 34823973 DOI: 10.1053/j.semdp.2021.11.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/28/2021] [Accepted: 11/04/2021] [Indexed: 02/06/2023]
Abstract
Despite the increasing number of newly identified renal neoplasms, the diagnosis of renal cell carcinoma (RCC) can usually be reached with careful histologic examination and a limited immunohistochemical (IHC) panel. Clear cell, papillary, chromophobe RCC and oncocytoma account for more than 90% of renal neoplasia in adults, and sophisticated ancillary tools are usually unnecessary. Renal tumors with entity-defining genetic alterations may ultimately require molecular confirmation via cytogenetics or sequencing technologies, such as RCC with TFE3, TFEB, or ALK gene rearrangements, or TFEB amplified RCC. In fumarate hydratase-deficient and succinate dehydrogenase-deficient RCC, highly specific IHC markers can strongly suggest the diagnosis. In the metastatic setting, PAX8 and carbonic anhydrase 9 are among the most helpful markers for confirming RCC and clear cell type, respectively; however, caution should be exercised in the absence of a current or historical renal mass. In diagnostically challenging cases, such as renal eosinophilic tumors with low-grade nuclear features, or infiltrative high-grade tumors, careful examination coupled with a judicious panel of IHC markers usually resolves the diagnosis. This review offers concise algorithms for diagnosis of kidney neoplasia with the latest recognized, provisional, and emerging entities to daily pathology practice.
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Affiliation(s)
- Mahmut Akgul
- Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY, 12208, USA
| | - Sean R Williamson
- Department of Pathology, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA.
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15
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Flitcroft JG, Verheyen J, Vemulkar T, Welbourne EN, Rossi SH, Welsh SJ, Cowburn RP, Stewart GD. Early detection of kidney cancer using urinary proteins: a truly non-invasive strategy. BJU Int 2021; 129:290-303. [PMID: 34570419 DOI: 10.1111/bju.15601] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVES To review urinary protein biomarkers as potential non-invasive, easily obtainable, early diagnostic tools in renal cell carcinoma (RCC). METHODS A PubMed database search was performed up to the year 2020 to identify primary studies reporting potential urinary protein biomarkers for RCC. Separate searches were conducted to identify studies describing appropriate methods of developing cancer screening programmes and detection of cancer biomarkers. RESULTS Several urinary protein biomarkers are under validation for RCC diagnostics, e.g. aquaporin-1, perilipin-2, carbonic anhydrase-9, Raf-kinase inhibitory protein, nuclear matrix protein-22, 14-3-3 Protein β/α and neutrophil gelatinase-associated lipocalin. However, none has yet been validated or approved for clinical use due to low sensitivity or specificity, inconsistencies in appropriate study design, or lack of external validation. CONCLUSIONS Evaluation of biomarkers' feasibility, sample preparation and storage, biomarker validation, and the application of novel technologies may provide a solution that maximises the potential for a truly non-invasive biomarker in early RCC diagnostics.
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Affiliation(s)
- Jordan G Flitcroft
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
| | - Jeroen Verheyen
- Department of Surgery, Addenbrookes Hospital, University of Cambridge, Cambridge, UK
| | - Tarun Vemulkar
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
| | - Emma N Welbourne
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
| | - Sabrina H Rossi
- Department of Surgery, Addenbrookes Hospital, University of Cambridge, Cambridge, UK
| | - Sarah J Welsh
- Department of Surgery, Addenbrookes Hospital, University of Cambridge, Cambridge, UK
| | - Russell P Cowburn
- Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
| | - Grant D Stewart
- Department of Surgery, Addenbrookes Hospital, University of Cambridge, Cambridge, UK
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16
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New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod Pathol 2021; 34:1392-1424. [PMID: 33664427 DOI: 10.1038/s41379-021-00779-w] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 02/11/2021] [Accepted: 02/11/2021] [Indexed: 12/28/2022]
Abstract
The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.
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Aldera AP, Govender D. Carbonic anhydrase IX: a regulator of pH and participant in carcinogenesis. J Clin Pathol 2021; 74:jclinpath-2020-207073. [PMID: 33619217 DOI: 10.1136/jclinpath-2020-207073] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/31/2020] [Accepted: 01/24/2021] [Indexed: 11/04/2022]
Abstract
Carbonic anhydrase IX (CAIX) is a transmembrane metalloenzyme which is upregulated in tumour cells under hypoxic conditions. CAIX expression is induced by the accumulation of hypoxia-inducible factor-1α and has several downstream effects, including acidification of the extracellular pH, loss of cellular adhesion and increased tumour cell migration. CAIX is upregulated in a variety of solid organ tumours and has prognostic implications. High CAIX protein expression is a marker of poor prognosis in breast, lung, ovarian and bladder carcinomas. Conversely, low expression is an indicator of poor prognosis in clear cell renal cell carcinoma (CCRCC). CAIX immunohistochemistry is useful diagnostically to identify metastatic CCRCC, and the recently recognised clear cell papillary renal cell carcinoma. There is much interest in targeting CAIX with monoclonal antibodies and small molecule inhibitors. There are several small molecule inhibitors under development which have shown promising results in clinical trials. In this paper, we provide an overview of the role of CAIX in tumourigenesis and outline its use as a prognostic, diagnostic and therapeutic biomarker.
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Affiliation(s)
- Alessandro Pietro Aldera
- Division of Anatomical Pathology, University of Cape Town, Cape Town, South Africa
- JDW Pathology Inc, Cape Town, South Africa
| | - Dhirendra Govender
- Division of Anatomical Pathology, University of Cape Town, Cape Town, South Africa
- Anatomical Pathology, Pathcare Cape Town, Cape Town, South Africa
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18
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Chen S, Zhang N, Zhang E, Wang T, Jiang L, Wang X, Zheng J. A Novel m 6A Gene Signature Associated With Regulatory Immune Function for Prognosis Prediction in Clear-Cell Renal Cell Carcinoma. Front Cell Dev Biol 2021; 8:616972. [PMID: 33553151 PMCID: PMC7858250 DOI: 10.3389/fcell.2020.616972] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/09/2020] [Indexed: 12/13/2022] Open
Abstract
The important role of N6-methyladenosine (m6A) RNA methylation regulator in carcinogenesis and progression of clear-cell renal cell carcinoma (ccRCC) is poorly understood by now. In this study, we performed comprehensive analyses of m6A RNA methylation regulators in 975 ccRCC samples and 332 adjacent normal tissues and identified ccRCC-related m6A regulators. Moreover, the m6A diagnostic score based on ccRCC-related m6A regulators could accurately distinguish ccRCC from normal tissue in the Meta-cohort, which was further validated in the independent GSE-cohort and The Cancer Genome Atlas-cohort, with an area under the curve of 0.924, 0.867, and 0.795, respectively. Effective survival prediction of ccRCC by m6A risk score was also identified in the Cancer Genome Atlas training cohort and verified in the testing cohort and the independent GSE22541 cohort, with hazard ratio values of 3.474, 1.679, and 2.101 in the survival prognosis, respectively. The m6A risk score was identified as a risk factor of overall survival in ccRCC patients by the univariate Cox regression analysis, which was further verified in both the training cohort and the independent validation cohort. The integrated nomogram combining m6A risk score and predictable clinicopathologic factors could accurately predict the survival status of the ccRCC patients, with an area under the curve values of 85.2, 82.4, and 78.3% for the overall survival prediction in 1-, 3- and 5-year, respectively. Weighted gene co-expression network analysis with functional enrichment analysis indicated that m6A RNA methylation might affect clinical prognosis through regulating immune functions in patients with ccRCC.
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Affiliation(s)
- Siteng Chen
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ning Zhang
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Encheng Zhang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tao Wang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liren Jiang
- Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiang Wang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junhua Zheng
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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19
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Lin H, Zhang H, Cheng Y, Zhang C. Solitary Metastasis in the Mediastinal Lymph Node After Radical Nephrectomy for Clear Cell Renal Cell Carcinoma: A Case Report and Literature Review. Front Oncol 2020; 10:593142. [PMID: 33392088 PMCID: PMC7773822 DOI: 10.3389/fonc.2020.593142] [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: 08/09/2020] [Accepted: 11/17/2020] [Indexed: 12/04/2022] Open
Abstract
Background Renal cell carcinoma can metastasize to virtually any anatomical site throughout the body, especially the lung, bone, lymph nodes, liver, and brain. However, it is extremely rare for renal cell carcinoma to metastasize solely to the mediastinal lymph node more than 15 years after radical nephrectomy. Case Presentation The case we present here is that of a 50-year-old Chinese male with an isolated posterior mediastinal lymph node metastasis of clear cell renal cell carcinoma 16 years after radical nephrectomy. However, based on imaging examination, the mass was clinically misdiagnosed as Castleman’s disease before operation. Following surgical excision of the mass, it was finally judged to be a metastasis from clear cell renal cell carcinoma according to the patient’s medical history and immunohistochemical findings. Currently, there is no clinical or radiological finding the recurrence of metastasis after 10 months of follow-up. Conclusion We report a case of solitary metastasis in the posterior mediastinal lymph node 16 years after radical nephrectomy for clear cell renal cell carcinoma. Given the long disease-free interval between primary renal cell carcinoma to isolated mediastinal lymph node metastasis, it is important to conduct a lifelong regular follow-up, including thoracic computed tomography. In addition, surgical resection remains the best method of treatment for mediastinal lymph node metastases from clear cell renal cell carcinoma if the metastatic lesion is limited.
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Affiliation(s)
- Hang Lin
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Heng Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yuanda Cheng
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China.,Human Engineering Research Center for Pulmonary Nodules Precise Diagnosis and Treatment, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China
| | - Chunfang Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China.,Human Engineering Research Center for Pulmonary Nodules Precise Diagnosis and Treatment, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.,Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China
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20
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Baniak N, Flood TA, Buchanan M, Dal Cin P, Hirsch MS. Carbonic anhydrase IX (CA9) expression in multiple renal epithelial tumour subtypes. Histopathology 2020; 77:659-666. [PMID: 32639054 DOI: 10.1111/his.14204] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 07/02/2020] [Indexed: 12/21/2022]
Abstract
AIMS Renal epithelial neoplasms (RENs) can be difficult to subclassify, owing to overlapping morphological features. Carbonic anhydrase 9 (CA9) is a common biomarker for clear cell renal cell carcinoma (CCRCC); however, the sensitivity and specificity across REN subtypes are less clear. The aim of this study was to investigate CA9 expression in RENs, especially those in the differential diagnosis with CCRCC and less common entities, to determine its reliability as a diagnostic biomarker. METHODS AND RESULTS CA9 immunostaining was performed on 262 RENs, including 119 CCRCCs and 143 non-CCRCC. Immunostaining was evaluated as negative (0%), rare (1+, 1-10%), focal (2+, 11-50%), or diffuse (3+, >50%). CCRCCs were 3+ CA9-positive in 93% of cases; 4% were CA9-negative. Sixty-seven percent of papillary renal cell carcinomas (RCCs) were 1+/2+ CA9-positive, whereas 33% were CA9-negative. Chromophobe RCCs were nearly always CA9-negative (93%), with 7% showing rare cell reactivity. Clear cell tubulopapillary RCCs (CCTPRCCs) were consistently 3+ CA9-positive, but with a cup-like staining pattern. Fifty-three percent of Xp11.2 RCCs were CA9-negative; however, 6% were 3+ CA9-positive and 12% were 2+ CA9-positive. Two of eight fumarate hydratase-deficient RCCs were 3+ CA9-positive. A small subset of the remaining RCCs showed rare to focal CA9 expression. All oncocytomas and eosinophilic solid and cystic RCCs were CA9-negative. CONCLUSIONS Overall, diffuse CA9 expression was identified in nearly all CCRCCs and in all CCTPRCCs (high sensitivity); however, CA9 was not entirely specific. At least focal CA9 expression can been seen in a subset of many RCCs, and such findings should be taken into consideration with other morphological, immunophenotypic and clinical findings.
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Affiliation(s)
- Nicholas Baniak
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Trevor A Flood
- Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, Canada
| | - Mark Buchanan
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Paola Dal Cin
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michelle S Hirsch
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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21
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Ramachandran K, M R B, Jojo A, Pooleri GK, Thomas A. Role of CAIX Expression in Conventional Renal Cell Carcinomas as a Diagnostic Marker and its Prognostic Importance. Indian J Surg Oncol 2020; 12:79-84. [PMID: 33994732 DOI: 10.1007/s13193-020-01076-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 04/07/2020] [Indexed: 10/23/2022] Open
Abstract
Significant advances in understanding of the biology of renal cell carcinoma (RCC) have been achieved recently, which led to novel targeted therapies, revolutionising the management of patients with advanced disease. To date, there are no molecular markers which can reliably predict RCC outcome. We investigated whether a novel kidney cancer marker, carbonic anhydrase IX (CAIX), is associated with progression and survival. A retrospective study was done on patients diagnosed with renal cell carcinoma over a period of 5 years. Immunohistochemical analysis using a CAIX monoclonal antibody was performed on paraffin-embedded blocks from patients treated with nephrectomy for clear cell RCC. Patients were segregated into two categories based on CA IX expression as CA IX ≤ 85% and CA IX > 85%. A comparison was made based on the survival (from date of diagnosis) with CA IX expression. Correlation of CA IX expression and TNM staging, nuclear grading, tumour volume and age was statistically studied using Student's t test. The association between survival and CA IX was done using Mann-Whitney test. The association of CA IX with rest of the prognostic variables were analysed using Fisher's exact test. In our study, CA IX expression > 85% had longer survival compared with those with lower expression ≤ 85%. A significant statistical association was seen with CAIX and lymphovascular emboli, major vessel, perinephric fat, renal sinus fat involvement and distant metastasis. CAIX reflects significant changes in tumour biology that predicts clinical outcome and identify high-risk patients for adjuvant immunotherapy and CAIX targeted therapies.
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Affiliation(s)
| | - Bindhu M R
- Department of Pathology, Amrita Institute of Medical Science, Kochi, Kerala India
| | - Annie Jojo
- Department of Pathology, Amrita Institute of Medical Science, Kochi, Kerala India
| | - Ginil Kumar Pooleri
- Department of Urology, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala 682041 India
| | - Appu Thomas
- Department of Urology, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala 682041 India
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Williamson SR, Gill AJ, Argani P, Chen YB, Egevad L, Kristiansen G, Grignon DJ, Hes O. Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: III: Molecular Pathology of Kidney Cancer. Am J Surg Pathol 2020; 44:e47-e65. [PMID: 32251007 PMCID: PMC7289677 DOI: 10.1097/pas.0000000000001476] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Renal cell carcinoma (RCC) subtypes are increasingly being discerned via their molecular underpinnings. Frequently this can be correlated to histologic and immunohistochemical surrogates, such that only simple targeted molecular assays, or none at all, are needed for diagnostic confirmation. In clear cell RCC, VHL mutation and 3p loss are well known; however, other genes with emerging important roles include SETD2, BAP1, and PBRM1, among others. Papillary RCC type 2 is now known to include likely several different molecular entities, such as fumarate hydratase (FH) deficient RCC. In MIT family translocation RCC, an increasing number of gene fusions are now described. Some TFE3 fusion partners, such as NONO, GRIPAP1, RBMX, and RBM10 may show a deceptive fluorescence in situ hybridization result due to the proximity of the genes on the same chromosome. FH and succinate dehydrogenase deficient RCC have implications for patient counseling due to heritable syndromes and the aggressiveness of FH-deficient RCC. Immunohistochemistry is increasingly available and helpful for recognizing both. Emerging tumor types with strong evidence for distinct diagnostic entities include eosinophilic solid and cystic RCC and TFEB/VEGFA/6p21 amplified RCC. Other emerging entities that are less clearly understood include TCEB1 mutated RCC, RCC with ALK rearrangement, renal neoplasms with mutations of TSC2 or MTOR, and RCC with fibromuscular stroma. In metastatic RCC, the role of molecular studies is not entirely defined at present, although there may be an increasing role for genomic analysis related to specific therapy pathways, such as for tyrosine kinase or MTOR inhibitors.
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MESH Headings
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Renal Cell/diagnosis
- Carcinoma, Renal Cell/genetics
- Carcinoma, Renal Cell/metabolism
- Carcinoma, Renal Cell/pathology
- Humans
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Kidney Neoplasms/diagnosis
- Kidney Neoplasms/genetics
- Kidney Neoplasms/metabolism
- Kidney Neoplasms/pathology
- Mutation
- Neoplasm Metastasis
- Neoplastic Syndromes, Hereditary/diagnosis
- Neoplastic Syndromes, Hereditary/genetics
- Neoplastic Syndromes, Hereditary/metabolism
- Neoplastic Syndromes, Hereditary/pathology
- Pathology, Clinical
- Pathology, Molecular
- Prognosis
- Societies, Medical
- Urology
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Affiliation(s)
- Sean R Williamson
- Department of Pathology and Laboratory Medicine and Henry Ford Cancer Institute, Henry Ford Health System
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI
| | - Anthony J Gill
- NSW Health Pathology, Department of Anatomical Pathology
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards
- Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Pedram Argani
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ying-Bei Chen
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lars Egevad
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | | | - David J Grignon
- Department of Pathology, Indiana University School of Medicine, Indianapolis, IN
| | - Ondrej Hes
- Department of Pathology, Charles University, Medical Faculty and Charles University Hospital Plzen, Pilsen, Czechia
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Kim M, Joo JW, Lee SJ, Cho YA, Park CK, Cho NH. Comprehensive Immunoprofiles of Renal Cell Carcinoma Subtypes. Cancers (Basel) 2020; 12:cancers12030602. [PMID: 32150988 PMCID: PMC7139472 DOI: 10.3390/cancers12030602] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/25/2020] [Accepted: 03/03/2020] [Indexed: 12/13/2022] Open
Abstract
In recent years, renal epithelial tumors have been among the fastest reclassifying tumors, requiring updates to the tumor classification system. Nonetheless, immunohistochemistry (IHC) remains the most widely used tool for renal epithelial tumors. In this proposal, we aimed to create the most efficient IHC panel for categorizing the diverse subtypes of renal tumors, and to find out more specific immunohistochemical results in each subtype or each antibody. A total of 214 renal tumors were analyzed using 10 possible IHC markers to differentiate subtypes, including three major renal cell carcinoma (RCC) subtypes, clear-cell type (50 cases), papillary type (50 cases), and chromophobe type (20 cases), and minor subtypes (MiT RCC, 13 cases; collecting duct carcinoma, 5 cases; and oncocytoma, 10 cases). A triple immunomarker (cytokeratin 7 (CK7)-carbonic anhydrase IX (CAIX)- alpha-methylacyl-CoA racemase (AMACR)) panel is useful in particular high-grade clear-cell tumors. If IHC remains ambiguous, the use of an adjunctive panel can be suggested, including CD10, epithelial membrane antigen, cathepsin K, c-kit, hepatocyte nuclear factor 1-β, and E-cadherin. For an efficient immunohistochemical strategy for subtyping of RCC, we conclude that the CK7-CAIX-AMACR panel is the best primary choice for screening subtyping.
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Affiliation(s)
- Moonsik Kim
- Deptartment of Pathology, Yonsei University College of Medicine, Seoul 03722, Korea; (M.K.); (J.W.J.); (S.J.L.)
| | - Jin Woo Joo
- Deptartment of Pathology, Yonsei University College of Medicine, Seoul 03722, Korea; (M.K.); (J.W.J.); (S.J.L.)
| | - Seok Joo Lee
- Deptartment of Pathology, Yonsei University College of Medicine, Seoul 03722, Korea; (M.K.); (J.W.J.); (S.J.L.)
| | - Yoon Ah Cho
- Deptartment of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Cheol Keun Park
- Deptartment of Pathology, Armed Forces Capital Hospital, Seongnam 13574, Korea;
| | - Nam Hoon Cho
- Deptartment of Pathology, Yonsei University College of Medicine, Seoul 03722, Korea; (M.K.); (J.W.J.); (S.J.L.)
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722, Korea
- Correspondence: ; Tel.: +82-2-2228-1767; Fax: +82-2-362-0860
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24
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Terrén I, Orrantia A, Mikelez-Alonso I, Vitallé J, Zenarruzabeitia O, Borrego F. NK Cell-Based Immunotherapy in Renal Cell Carcinoma. Cancers (Basel) 2020; 12:cancers12020316. [PMID: 32013092 PMCID: PMC7072691 DOI: 10.3390/cancers12020316] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 01/14/2020] [Accepted: 01/23/2020] [Indexed: 02/06/2023] Open
Abstract
Natural killer (NK) cells are cytotoxic lymphocytes that are able to kill tumor cells without prior sensitization. It has been shown that NK cells play a pivotal role in a variety of cancers, highlighting their relevance in tumor immunosurveillance. NK cell infiltration has been reported in renal cell carcinoma (RCC), the most frequent kidney cancer in adults, and their presence has been associated with patients’ survival. However, the role of NK cells in this disease is not yet fully understood. In this review, we summarize the biology of NK cells and the mechanisms through which they are able to recognize and kill tumor cells. Furthermore, we discuss the role that NK cells play in renal cell carcinoma, and review current strategies that are being used to boost and exploit their cytotoxic capabilities.
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Affiliation(s)
- Iñigo Terrén
- Immunopathology Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain; (I.T.); (A.O.); (I.M.-A.); (J.V.); (O.Z.)
| | - Ane Orrantia
- Immunopathology Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain; (I.T.); (A.O.); (I.M.-A.); (J.V.); (O.Z.)
| | - Idoia Mikelez-Alonso
- Immunopathology Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain; (I.T.); (A.O.); (I.M.-A.); (J.V.); (O.Z.)
- CIC biomaGUNE, 20014 Donostia-San Sebastián, Spain
| | - Joana Vitallé
- Immunopathology Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain; (I.T.); (A.O.); (I.M.-A.); (J.V.); (O.Z.)
| | - Olatz Zenarruzabeitia
- Immunopathology Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain; (I.T.); (A.O.); (I.M.-A.); (J.V.); (O.Z.)
| | - Francisco Borrego
- Immunopathology Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain; (I.T.); (A.O.); (I.M.-A.); (J.V.); (O.Z.)
- Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain
- Correspondence: ; Tel.: +34-94-600-6000 (ext. 7079)
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25
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hERG1 and CA IX expression are associated with disease recurrence in surgically resected clear cell renal carcinoma. Eur J Surg Oncol 2019; 46:209-215. [PMID: 31679954 DOI: 10.1016/j.ejso.2019.10.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 10/22/2019] [Accepted: 10/25/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND In search of novel prognostic biomarkers for clear cell renal carcinoma (ccRCC), we analysed the expression of several proteins related to angiogenesis and hypoxia. METHODS A monocentric study on 30 consecutive surgical samples from surgically-treated ccRCC patients with a 10-year follow up was performed. The following proteins were analysed by immunohistochemistry: Vascular Endothelial Growth Factor- A (VEGF-A), Platelet-Derived Growth Factor β Receptor (PDGFRβ), VEGF-receptor 1 (Flt1), VEGF-receptor 2 (KDR), Glucose Transporter 1 (GLUT1), Carbonic anhydrase IX (CA-IX) and the hERG1 potassium channel. Data were analysed in conjunction with the clinico-pathological characteristics of the patients and follow up. RESULTS All the proteins were expressed in the samples, with statistically significant associations of VEGF-A with PDGFRβ and Flt1 and hERG1 with CA IX. Notably, hERG1 and CAIX co-immunoprecipitated in primary ccRCC samples and survival analysis showed that the positivity for hERG1 and CA IX had a negative impact on Recurrence Free Survival (RFS) at the univariate analysis. At the multivariate analysis only hERG1 maintained its statistically significant negative impact. CONCLUSIONS hERG1 expression can be exploited to predict recurrence in surgically-treated ccRCC patients. hERG1 channels form a multiprotein complex with the pH regulator CA IX in primary ccRCC samples their potential use as therapeutic target might be suggested.
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26
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Elbanna M, Orillion AR, Damayanti NP, Adelaiye-Ogala R, Shen L, Miles KM, Chintala S, Ciamporcero E, Ramakrishnan S, Ku SY, Rex K, Caenepeel S, Coxon A, Pili R. Dual Inhibition of Angiopoietin-TIE2 and MET Alters the Tumor Microenvironment and Prolongs Survival in a Metastatic Model of Renal Cell Carcinoma. Mol Cancer Ther 2019; 19:147-156. [PMID: 31582532 DOI: 10.1158/1535-7163.mct-18-1202] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 06/24/2019] [Accepted: 09/26/2019] [Indexed: 12/14/2022]
Abstract
Receptor tyrosine kinase inhibitors have shown clinical benefit in clear cell renal cell carcinoma (ccRCC), but novel therapeutic strategies are needed. The angiopoietin/Tie2 and MET pathways have been implicated in tumor angiogenesis, metastases, and macrophage infiltration. In our study, we used trebananib, an angiopoietin 1/2 inhibitor, and a novel small-molecule MET kinase inhibitor in patient-derived xenograft (PDX) models of ccRCC. Our goal was to assess the ability of these compounds to alter the status of tumor-infiltrating macrophages, inhibit tumor growth and metastases, and prolong survival. Seven-week-old SCID mice were implanted subcutaneously or orthotopically with human ccRCC models. One month postimplantation, mice were treated with angiopoietin 1/2 inhibitor trebananib (AMG 386), MET kinase inhibitor, or combination. In our metastatic ccRCC PDX model, RP-R-02LM, trebananib alone, and in combination with a MET kinase inhibitor, significantly reduced lung metastases and M2 macrophage infiltration (P = 0.0075 and P = 0.0205, respectively). Survival studies revealed that treatment of the orthotopically implanted RP-R-02LM tumors yielded a significant increase in survival in both trebananib and combination groups. In addition, resection of the subcutaneously implanted primary tumor allowed for a significant survival advantage to the combination group compared with vehicle and both single-agent groups. Our results show that the combination of trebananib with a MET kinase inhibitor significantly inhibits the spread of metastases, reduces infiltrating M2-type macrophages, and prolongs survival in our highly metastatic ccRCC PDX model, suggesting a potential use for this combination therapy in treating patients with ccRCC.
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Affiliation(s)
- May Elbanna
- Genitourinary Cancers Program, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana
| | - Ashley R Orillion
- Genitourinary Cancers Program, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana.,Department of Cellular and Molecular Biology, University at Buffalo, Roswell Park Cancer Institute, Buffalo, New York
| | - Nur P Damayanti
- Genitourinary Cancers Program, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana
| | - Remi Adelaiye-Ogala
- Genitourinary Cancers Program, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana.,Department of Cancer Pathology and Prevention, University at Buffalo, Roswell Park Cancer Institute, Buffalo, New York
| | - Li Shen
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York
| | - Kiersten Marie Miles
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York
| | - Sreenivasulu Chintala
- Genitourinary Cancers Program, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana
| | - Eric Ciamporcero
- Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy
| | - Swathi Ramakrishnan
- Department of Cancer Pathology and Prevention, University at Buffalo, Roswell Park Cancer Institute, Buffalo, New York
| | - Sheng-Yu Ku
- Department of Cancer Pathology and Prevention, University at Buffalo, Roswell Park Cancer Institute, Buffalo, New York
| | - Karen Rex
- Oncology Research, Amgen Inc., Thousand Oaks, California
| | - Sean Caenepeel
- Oncology Research, Amgen Inc., Thousand Oaks, California
| | - Angela Coxon
- Oncology Research, Amgen Inc., Thousand Oaks, California
| | - Roberto Pili
- Genitourinary Cancers Program, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana.
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Abstract
INTRODUCTION The physiologic importance of fast CO2/HCO3- interconversion in various tissues requires the presence of carbonic anhydrase (CA, EC 4.2.1.1). Fourteen CA isozymes are present in humans, all of them being used as biomarkers. AREAS COVERED A great number of patents and articles were focused on the use of CA isozymes as biomarkers for various diseases and syndromes in the recent years, in an ascending trend over the last decade. The review highlights the most important studies related with each isozyme and covers the most recent patent literature. EXPERT OPINION The CAs biomarker research area expanded significantly in recent years, shifting from the predominant use of CA IX and CA XII in cancer diagnostic, staging, and prognosis towards a wider use of CA isozymes as disease biomarkers. CA isozymes are currently used either alone, in tandem with other CA isozymes and/or in combination with other proteins for the detection, staging, and prognosis of a huge repertoire of human dysfunctions and diseases, ranging from mild transformation of the normal tissues to extreme shifts in tissue organization and function. The techniques used for their detection/quantitation and the state-of-the-art in each clinical application are presented through relevant clinical examples and corresponding statistical data.
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Affiliation(s)
- Sabina Zamanova
- a Department of Pharmaceutical Sciences and Moulder Center of Drug Discovery Research , Temple University School of Pharmacy , Philadelphia , PA , USA
| | - Ahmed M Shabana
- a Department of Pharmaceutical Sciences and Moulder Center of Drug Discovery Research , Temple University School of Pharmacy , Philadelphia , PA , USA
| | - Utpal K Mondal
- a Department of Pharmaceutical Sciences and Moulder Center of Drug Discovery Research , Temple University School of Pharmacy , Philadelphia , PA , USA
| | - Marc A Ilies
- a Department of Pharmaceutical Sciences and Moulder Center of Drug Discovery Research , Temple University School of Pharmacy , Philadelphia , PA , USA.,b Temple Fox Chase Cancer Center , Philadelphia , PA , USA
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29
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Yu GH, Glaser LJ, Gustafson KS. Role of Ancillary Techniques in Fluid Cytology. Acta Cytol 2019; 64:52-62. [PMID: 31018204 DOI: 10.1159/000496568] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 01/02/2019] [Indexed: 01/11/2023]
Abstract
The cytologic evaluation of serous effusions may be challenging for a number of reasons. Distinction of benign, reactive conditions from malignancy represents the main focus when examining these specimens. The morphologic diagnosis of malignancy may be difficult due to the relative paucity of abnormal cells. In other situations, cellularity is not an issue, but the ability to confidently identify a second, foreign (i.e., tumor) population within a background mesothelial cells on the basis of cytomorphologic features alone may pose problems. Cases with definitive morphologic evidence of malignancy may require additional studies in order to determine the tumor subtype and, in the case of carcinoma, the primary site of origin. Cases in which a definitive and precise diagnosis of malignancy is made may be optimal candidates for further molecular testing in order to gain prognostic information and guide personal therapeutic decisions. Finally, while an inflammatory or infectious condition can be suggested on the basis of cellular components and associated background elements, the identification of causative agent(s) may be difficult without additional studies. In all of these situations, the use of ancillary studies and techniques is critical; their utility and appropriate application are the subject of this review.
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Affiliation(s)
- Gordon H Yu
- Hospital of the University of Pennsylvania, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA,
| | - Laurel J Glaser
- Hospital of the University of Pennsylvania, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Karen S Gustafson
- Hospital of the University of Pennsylvania, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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30
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Histological (Sub)Classifications and Their Prognostic Impact in Renal Cell Carcinoma. Urol Oncol 2019. [DOI: 10.1007/978-3-319-42623-5_60] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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31
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Mboge MY, Chen Z, Wolff A, Mathias JV, Tu C, Brown KD, Bozdag M, Carta F, Supuran CT, McKenna R, Frost SC. Selective inhibition of carbonic anhydrase IX over carbonic anhydrase XII in breast cancer cells using benzene sulfonamides: Disconnect between activity and growth inhibition. PLoS One 2018; 13:e0207417. [PMID: 30452451 PMCID: PMC6242694 DOI: 10.1371/journal.pone.0207417] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 10/30/2018] [Indexed: 12/11/2022] Open
Abstract
Carbonic anhydrases (CAs) have been linked to tumor progression, particularly membrane-bound CA isoform IX (CA IX). The role of CA IX in the context of breast cancer is to regulate the pH of the tumor microenvironment. In contrast to CA IX, expression of CA XII, specifically in breast cancer, is associated with better outcome despite performing the same catalytic function. In this study, we have structurally modeled the orientation of bound ureido-substituted benzene sulfonamides (USBs) within the active site of CA XII, in comparison to CA IX and cytosolic off-target CA II, to understand isoform specific inhibition. This has identified specific residues within the CA active site, which differ between isoforms that are important for inhibitor binding and isoform specificity. The ability of these sulfonamides to block CA IX activity in breast cancer cells is less effective than their ability to block activity of the recombinant protein (by one to two orders of magnitude depending on the inhibitor). The same is true for CA XII activity but now they are two to three orders of magnitude less effective. Thus, there is significantly greater specificity for CA IX activity over CA XII. While the inhibitors block cell growth, without inducing cell death, this again occurs at two orders of magnitude above the Ki values for inhibition of CA IX and CA XII activity in their respective cell types. Surprisingly, the USBs inhibited cell growth even in cells where CA IX and CA XII expression was ablated. Despite the potential for these sulfonamides as chemotherapeutic agents, these data suggest that we reconsider the role of CA activity on growth potentiation.
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Affiliation(s)
- Mam Y. Mboge
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States of America
| | - Zhijuan Chen
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States of America
| | - Alyssa Wolff
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States of America
| | - John V. Mathias
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States of America
| | - Chingkuang Tu
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States of America
| | - Kevin D. Brown
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States of America
| | - Murat Bozdag
- University of Florence, NEUROFARBA Department, Sezione di Farmaceutica e Nutraceutica, Sesto Fiorentino (Florence), Italy
| | - Fabrizio Carta
- University of Florence, NEUROFARBA Department, Sezione di Farmaceutica e Nutraceutica, Sesto Fiorentino (Florence), Italy
| | - Claudiu T. Supuran
- University of Florence, NEUROFARBA Department, Sezione di Farmaceutica e Nutraceutica, Sesto Fiorentino (Florence), Italy
| | - Robert McKenna
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States of America
| | - Susan C. Frost
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, United States of America
- * E-mail:
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Marks IS, Gardeen SS, Kurdziel SJ, Nicolaou ST, Woods JE, Kularatne SA, Low PS. Development of a Small Molecule Tubulysin B Conjugate for Treatment of Carbonic Anhydrase IX Receptor Expressing Cancers. Mol Pharm 2018; 15:2289-2296. [PMID: 29715036 DOI: 10.1021/acs.molpharmaceut.8b00139] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Carbonic anhydrase IX (CAIX) is a membrane-spanning zinc metalloenzyme that catalyzes the reversible consumption of CO2 and water to form H+ + HCO3-. Many human cancers upregulate CAIX to help control the pH in their hypoxic microenvironments. The consequent overexpression of CAIX on malignant cells and low expression on normal tissues render CAIX a particularly attractive target for small molecule inhibitors, antibody-drug conjugates, and ligand-targeted drugs. In this study, CAIX-targeted fluorescent reporter molecules were initially exploited to investigate CAIX-specific binding to multiple cancer cell lines, where they were shown to display potent and selective binding to CAIX positive cells. A small molecule CAIX-targeted tubulysin B conjugate was then synthesized and examined for its ability to kill CAIX-expressing tumor cells in vitro. Potent therapeutic conjugates were subsequently tested in vivo and demonstrated to eliminate solid human tumor xenografts in murine tumor models without exhibiting overt signs of toxicity. Because most solid tumors contain hypoxic regions where CAIX is overexpressed, development of a method to selectively deliver drugs to these hypoxic regions could aid in the therapy of otherwise difficult to treat tumors.
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Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 2018; 7:34341-55. [PMID: 27145284 PMCID: PMC5085160 DOI: 10.18632/oncotarget.9114] [Citation(s) in RCA: 257] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 04/16/2016] [Indexed: 01/03/2023] Open
Abstract
Advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC) have led to improved progression-free survival of many patients; however the therapies are toxic, rarely achieve durable long-term complete responses and are not curative. Herein we used a single bicistronic lentiviral vector to develop a new combination immunotherapy that consists of human anti-carbonic anhydrase IX (CAIX)-targeted chimeric antigen receptor (CAR) T cells engineered to secrete human anti-programmed death ligand 1 (PD-L1) antibodies at the tumor site. The local antibody delivery led to marked immune checkpoint blockade. Tumor growth diminished 5 times and tumor weight reduced 50–80% when compared with the anti-CAIX CAR T cells alone in a humanized mice model of ccRCC. The expression of PD-L1 and Ki67 in the tumors decreased and an increase in granzyme B levels was found in CAR T cells. The anti-PD-L1 IgG1 isotype, which is capable of mediating ADCC, was also able to recruit human NK cells to the tumor site in vivo. These armed second-generation CAR T cells empowered to secrete human anti-PD-L1 antibodies in the ccRCC milieu to combat T cell exhaustion is an innovation in this field that should provide renewed potential for CAR T cell immunotherapy of solid tumors where limited efficacy is currently seen.
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Shen HP, Hsiao YH, Yang SF, Liu YF, Ko JL, Wang PH. Single nucleotide polymorphisms and haplotypes of carbonic anhydrase 9 can predict invasive squamous cell carcinoma of uterine cervix. Int J Med Sci 2018; 15:587-594. [PMID: 29725249 PMCID: PMC5930460 DOI: 10.7150/ijms.23359] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 03/02/2018] [Indexed: 12/27/2022] Open
Abstract
This study aimed to explore the involvement of carbonic anhydrase 9 (CA9) single nucleotide polymorphisms (SNPs) in the development of invasive cancer of uterine cervix for Taiwanese women. Ninety-seven patients with cervical invasive squamous cell carcinoma and 88 with preinvasive squamous cell lesions as well as 324 control women were recruited. Two CA9 SNPs in exons, including rs2071676 (+201, G/A) in exon 1 and rs3829078 (+1081, A/G) in exon 7, rs1048638 (+1584, C/A) in 3'-untranslated region of exon 11, as well as an 18-base pair deletion/insertion (376deltion393) in exon 1 were selected and their genotypic distributions were determined by real-time polymerase chain reaction. Haplotype was then constructed with rs2071676, 376del393, rs3829078 and rs1048638 in order. The results revealed that Taiwanese women with genotypes CA or CA/AA in CA9 SNP rs1048638 displayed a more risk in developing cervical invasive cancer, assigning wild genotype CC as a reference. AA in SNP rs2071676 tended to increase the risk of developing cervical invasive cancer, using GG/GA as a reference. When women had the diplotypes, carrying at least one haplotype A1AA (one mutant allele A in rs2071676, no deletion in 376del393, no mutant allele A in rs3829078 and one mutant allele A in rs1048638), they were significantly susceptible to cervical invasive cancer. In conclusion, CA9 SNP rs1048638 and haplotype A1AA are associated with the susceptibility of cervical invasive squamous cell carcinoma for Taiwanese women.
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Affiliation(s)
- Huang-Pin Shen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yi-Hsuan Hsiao
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yu-Fan Liu
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Jiunn-Liang Ko
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Po-Hui Wang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
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Gu YF, Cohn S, Christie A, McKenzie T, Wolff N, Do QN, Madhuranthakam AJ, Pedrosa I, Wang T, Dey A, Busslinger M, Xie XJ, Hammer RE, McKay RM, Kapur P, Brugarolas J. Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade. Cancer Discov 2017; 7:900-917. [PMID: 28473526 DOI: 10.1158/2159-8290.cd-17-0292] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 04/29/2017] [Accepted: 05/02/2017] [Indexed: 12/22/2022]
Abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutations, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with PAX8, a transcription factor frequently overexpressed in ccRCC, led to ccRCC of different grades. Bap1-deficient tumors were of high grade and showed greater mTORC1 activation than Pbrm1-deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1, in Pbrm1-deficient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specific drivers of ccRCC and histologic grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCCs arise from Bowman capsule cells.Significance: Determinants of tumor grade and aggressiveness across cancer types are poorly understood. Using ccRCC as a model, we show that Bap1 and Pbrm1 loss drives tumor grade. Furthermore, we show that the conversion from low grade to high grade can be promoted by activation of mTORC1. Cancer Discov; 7(8); 900-17. ©2017 AACR.See related commentary by Leung and Kim, p. 802This article is highlighted in the In This Issue feature, p. 783.
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Affiliation(s)
- Yi-Feng Gu
- Department of Internal Medicine, Hematology-Oncology Division, The University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Shannon Cohn
- Department of Internal Medicine, Hematology-Oncology Division, The University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Alana Christie
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Tiffani McKenzie
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Nicholas Wolff
- Department of Internal Medicine, Hematology-Oncology Division, The University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Quyen N Do
- Department of Radiology and the Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ananth J Madhuranthakam
- Department of Radiology and the Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ivan Pedrosa
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Radiology and the Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Tao Wang
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.,Quantitative Biomedical Research Center, Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Anwesha Dey
- Department of Molecular Oncology, Genentech, South San Francisco, California
| | | | - Xian-Jin Xie
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Clinical Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Robert E Hammer
- Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Renée M McKay
- Department of Internal Medicine, Hematology-Oncology Division, The University of Texas Southwestern Medical Center, Dallas, Texas.,Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Payal Kapur
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas. .,Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - James Brugarolas
- Department of Internal Medicine, Hematology-Oncology Division, The University of Texas Southwestern Medical Center, Dallas, Texas. .,Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas
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Offermann A, Kuempers C, Perner S. Histological (Sub)Classifications and Their Prognostic Impact in Renal Cell Carcinoma. Urol Oncol 2017. [DOI: 10.1007/978-3-319-42603-7_60-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Prognostic Factors for Renal Cell Carcinoma Subtypes Diagnosed According to the 2016 WHO Renal Tumor Classification: a Study Involving 928 Patients. Pathol Oncol Res 2016; 23:689-698. [PMID: 28032311 DOI: 10.1007/s12253-016-0179-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 12/21/2016] [Indexed: 10/20/2022]
Abstract
The morphotype and grade of renal cell carcinoma (RCC) in 928 nephrectomies were reclassified according to the 2016 WHO classification in order to analyze the distribution and outcomes of RCC subtypes in Hungary, to assess whether microscopic tumor necrosis is an independent prognostic factor in clear cell RCC, and to study whether a two-tiered grading (low/high) for clear cell and papillary RCC provides similar prognostic information to that of the four-tiered ISUP grading system. 83.4% of the cohort were clear cell, 6.9% papillary, 4.5% chromophobe, 2.3% unclassified, 1.1% Xp11 translocation, 1.1% clear cell papillary, 0.3% collecting duct and 0.1% mucinous tubular and spindle cell RCCs. RCC occurred in 16 patients with end-stage kidney disease and none of them displayed features of acquired cystic kidney disease-associated RCC. The 5-year survival rates were as follows: chromophobe 100%, clear cell papillary 100%, clear cell low-grade 96%, papillary type 1 92%, clear cell high-grade 63%, papillary type 2 65%, unclassified 46%, Xp11 translocation 20%, and collecting duct 0%. The 5-year survival rates in low-grade and high-grade papillary RCC were 95% and 59%, respectively. In clear cell RCC, only the grade, the stage and the positive surgical margin proved to be independent prognostic factors statistically. Overall, papillary RCC occurred relatively infrequently; microscopic tumor necrosis in clear cell RCC did not predict the outcome independently of the tumor grading; and the assignment of clear cell and papillary RCCs into low-grade or high-grade tumors was in terms of survival no worse than the ISUP grading.
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Li G, Feng G, Zhao A, Péoc’h M, Cottier M, Mottet N. CA9 as a biomarker in preoperative biopsy of small solid renal masses for diagnosis of clear cell renal cell carcinoma. Biomarkers 2016; 22:123-126. [DOI: 10.1080/1354750x.2016.1252948] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Guorong Li
- Department of Urology, CHU de Saint-Etienne, Saint-Etienne, France
| | - Gang Feng
- Clinical Genetics Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - An Zhao
- Laboratory of Cancer Research, Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Hangzhou, China
| | - Michel Péoc’h
- Laboratory of Pathology, CHU Saint-Etienne, Saint-Etienne, France
| | - Michèle Cottier
- Inserm U1059, F-42055, Saint-Etienne, France
- Laboratory of Cytopathology, CHU Saint-Etienne, Saint-Etienne, France
| | - Nicolas Mottet
- Department of Urology, CHU de Saint-Etienne, Saint-Etienne, France
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Hirsch MS, Signoretti S, Dal Cin P. Adult Renal Cell Carcinoma: A Review of Established Entities from Morphology to Molecular Genetics. Surg Pathol Clin 2016; 8:587-621. [PMID: 26612217 DOI: 10.1016/j.path.2015.09.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
According to the current World Health Organization (WHO), renal cell carcinomas (RCCs) that primarily affect adults are classified into 8 major subtypes. Additional emerging entities in renal neoplasia have also been recently recognized and these are discussed in further detail by Mehra et al (Emerging Entities in Renal Neoplasia, Surgical Pathology Clinics, 2015, Volume 8, Issue 4). In most cases, the diagnosis of a RCC subtype can be based on morphologic criteria, but in some circumstances the use of ancillary studies can aid in the diagnosis. This review discusses the morphologic, genetic, and molecular findings in RCCs previously recognized by the WHO, and provides clues to distinction from each other and some of the newer subtypes of RCC. As prognosis and therapeutic options vary for the different subtypes of RCC, accurate pathologic distinction is critical for patient care.
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Affiliation(s)
- Michelle S Hirsch
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
| | - Sabina Signoretti
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Paola Dal Cin
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
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Chang DK, Moniz RJ, Xu Z, Sun J, Signoretti S, Zhu Q, Marasco WA. Human anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivo. Mol Cancer 2015; 14:119. [PMID: 26062742 PMCID: PMC4464115 DOI: 10.1186/s12943-015-0384-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 05/11/2015] [Indexed: 12/17/2022] Open
Abstract
Background Carbonic anhydrase (CA) IX is a surface-expressed protein that is upregulated by the hypoxia inducible factor (HIF) and represents a prototypic tumor-associated antigen that is overexpressed on renal cell carcinoma (RCC). Therapeutic approaches targeting CAIX have focused on the development of CAIX inhibitors and specific immunotherapies including monoclonal antibodies (mAbs). However, current in vivo mouse models used to characterize the anti-tumor properties of fully human anti-CAIX mAbs have significant limitations since the role of human effector cells in tumor cell killing in vivo is not directly evaluated. Methods The role of human anti-CAIX mAbs on CAIX+ RCC tumor cell killing by immunocytes or complement was tested in vitro by antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) as well as on CAIX+ RCC cellular motility, wound healing, migration and proliferation. The in vivo therapeutic activity mediated by anti-CAIX mAbs was determined by using a novel orthotopic RCC xenograft humanized animal model and analyzed by histology and FACS staining. Results Our studies demonstrate the capacity of human anti-CAIX mAbs that inhibit CA enzymatic activity to result in immune-mediated killing of RCC, including nature killer (NK) cell-mediated ADCC, CDC, and macrophage-mediated ADCP. The killing activity correlated positively with the level of CAIX expression on RCC tumor cell lines. In addition, Fc engineering of anti-CAIX mAbs was shown to enhance the ADCC activity against RCC. We also demonstrate that these anti-CAIX mAbs inhibit migration of RCC cells in vitro. Finally, through the implementation of a novel orthotopic RCC model utilizing allogeneic human peripheral blood mononuclear cells in NOD/SCID/IL2Rγ−/− mice, we show that anti-CAIX mAbs are capable of mediating human immune response in vivo including tumor infiltration of NK cells and activation of T cells, resulting in inhibition of CAIX+ tumor growth. Conclusions Our findings demonstrate that these novel human anti-CAIX mAbs have therapeutic potential in the unmet medical need of targeted killing of HIF-driven CAIX+RCC. The orthotopic tumor xenografted humanized mouse provides an improved model to evaluate the in vivo anti-tumor capabilities of fully human mAbs for RCC therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0384-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- De-Kuan Chang
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, USA. .,Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA, USA.
| | - Raymond J Moniz
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, USA. .,Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA, USA.
| | - Zhongyao Xu
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, USA.
| | - Jiusong Sun
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, USA. .,Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA, USA.
| | - Sabina Signoretti
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, USA. .,Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Quan Zhu
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, USA. .,Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA, USA.
| | - Wayne A Marasco
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, USA. .,Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA, USA.
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Alshenawy HA. Immunohistochemical panel for differentiating renal cell carcinoma with clear and papillary features. J Microsc Ultrastruct 2015; 3:68-74. [PMID: 30023184 PMCID: PMC6014190 DOI: 10.1016/j.jmau.2015.01.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 12/02/2014] [Accepted: 01/26/2015] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES Renal cell carcinoma (RCC) in which clear cells with papillary architecture are present is a difficult diagnostic challenge. Clear cell RCC, rarely has papillary architecture. Papillary RCC rarely contains clear cells. However, two recently described types; clear cell papillary and Xp11 translocation RCC characteristically feature both papillary and clear cells. Accurate diagnosis has both prognostic and therapeutic implications. This study aims to highlight the helpful features of each of these entities to enable reproducible classification. METHODS Sixty RCC cases with clear cells and papillary architecture were selected and classified according to The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia and graded according to The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma then stained for CK7, carbonic anhydrase IX (CA IX), α-methylacyl-CoA-racemase (AMACR) and TFE-3. RESULTS The characteristic immunoprofile of Clear RCC is CK7-, AMACR-, CA IX+ and TFE3-, papillary RCC is CK7+, AMACR+, CAIX- and TFE3-, while for clear cell papillary RCC it is CK7+, AMACR-, CAIX+ and TFE3- and lastly Xp11 translocation RCC is CK7-, AMACR+, CAIX- and TFE3+. CONCLUSIONS Staining for CA IX, CK7, AMACR and TFE3 comprises a concise panel for distinguishing RCC with papillary and clear pattern.
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Huang WJ, Jeng YM, Lai HS, Fong IU, Sheu FYB, Lai PL, Yuan RH. Expression of hypoxic marker carbonic anhydrase IX predicts poor prognosis in resectable hepatocellular carcinoma. PLoS One 2015; 10:e0119181. [PMID: 25738958 PMCID: PMC4349857 DOI: 10.1371/journal.pone.0119181] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 01/11/2015] [Indexed: 02/07/2023] Open
Abstract
Carbonic anhydrase IX (CA-IX), a hypoxia marker, correlates with tumor progression in a variety of human cancers. However, the role of CA-IX in hepatocellular carcinomas (HCCs) remains largely unknown. We examined the expression of 277 unifocal, resectable, primary HCC tumors using immunohistochemistry. The CA-IX protein was expressed in 110 of the 227 (48.5%) HCC tumors. The expression of CA-IX correlated with younger age (P = 0.0446), female sex (P = 0.0049), high serum α-fetoprotein levels (P<1x10-6), larger tumor size (P = 0.0031), high tumor grade P<1x10-6) and high tumor stage (P = 1.5x10-6). Patients with HCC tumors that expressed CA-IX were more likely to have lower 5-year disease-free survival (DFS; P = 0.0001) and 5-year overall survival (OS; P<1x10-6). The multivariate analysis indicated that CA-IX expression was an independent predictor for high tumor stage (P = 0.0047) and DFS (P = 0.0456), and a borderline predictor for OS (P = 0.0762). Furthermore, CA-IX expression predicted poor DFS and OS in patients with high tumor stage (P = 0.0004 and P<1x10-6, respectively). Interestingly, CA-IX expression might contribute to the worse prognosis of female patients with advanced HCCs. Our study indicates the expression of the CA-IX protein is a crucial predictor of poor prognosis in resectable HCC, and it is also an unfavorable prognostic predictor in HCC patients with high tumor stage.
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Affiliation(s)
- Wei-Ju Huang
- Graduate Institute of Pathology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
- Department of Nursing, Hsin-Sheng College of Medical Care and Management, No. 418, Gaoping Section, Zhongfeng Road, Longtan Township, Taoyuan County, 32544, Taiwan
| | - Yung-Ming Jeng
- Graduate Institute of Pathology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
- Department of Pathology, National Taiwan University Hospital and College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
| | - Hong-Shiee Lai
- Departments of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
| | - Iok-U Fong
- Graduate Institute of Pathology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
| | - Fang-Yu Bonnie Sheu
- Department of Biomedical Science, University of Illinois College of Medicine, 1601 Parkview Ave, Rockford, IL, 61107, United States of America
| | - Po-Lin Lai
- Department of Pathology, National Taiwan University Hospital and College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
| | - Ray-Hwang Yuan
- Departments of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, 10051, Taiwan
- Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 10051, Taiwan
- * E-mail:
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Alshenawy HA. Immunohistochemical Panel for Differentiating Renal Cell Carcinoma with Clear and Papillary Features. Pathol Oncol Res 2015; 21:893-9. [DOI: 10.1007/s12253-015-9898-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 01/06/2015] [Indexed: 12/17/2022]
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Lin XY, Zhang H, Tang N, Zhang XP, Zhang W, Wang EH, Han YC. Expression and diagnostic implications of carbonic anhydrase IX in several tumours with predominantly clear cell morphology. Histopathology 2015; 66:685-94. [PMID: 25431204 DOI: 10.1111/his.12536] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Accepted: 05/10/2014] [Indexed: 11/26/2022]
Abstract
AIMS High expression of carbonic anhydrase IX (CA IX) has been reported in clear cell renal cell carcinoma (ccRCC); few studies have reported CA IX expression in other tumours with predominantly clear cell morphology. The aim of study was to examine the expression and diagnostic implications of CA IX in these latter tumours. METHODS AND RESULTS An immunohistochemical study was performed of 159 tumours with predominantly clear cell morphology. The results showed that, in addition to primary (25/25) and metastatic (10/11) ccRCC, CA IX was also expressed in breast (2/2), pulmonary (3/5) and hepatic (1/4) clear cell carcinoma, urothelial carcinoma with clear cell change (3/6), clear cell meningioma (4/6) and ependymoma (2/3), haemangioblastoma (10/10), and clear cell hidradenoma (5/6). However, while strong and diffuse positivity for CA IX was observed in ccRCC, clear cell breast carcinoma, haemangioblastoma, and clear cell hidradenoma, the other cases showed predominantly focal positivity for CA IX. In particular, CA IX staining was often seen at the periphery of necrotic areas. CONCLUSIONS Our results indicate that strong and diffuse CA IX expression may be useful for differentiating ccRCC from several clear cell tumours, with the exception of clear cell breast carcinoma, haemangioblastoma, and clear cell hidradenoma.
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Affiliation(s)
- Xu-Yong Lin
- Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang, China
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Biomarkers for Renal Cell Carcinoma. KIDNEY CANCER 2015. [DOI: 10.1007/978-3-319-17903-2_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Li J, Zhang G, Wang X, Li XF. Is carbonic anhydrase IX a validated target for molecular imaging of cancer and hypoxia? Future Oncol 2015; 11:1531-41. [PMID: 25963430 PMCID: PMC4976829 DOI: 10.2217/fon.15.11] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The presence of hypoxia is a general feature of most solid malignancies, and hypoxia is considered as one of major factors for anticancer therapy failure. Carbonic anhydrase IX (CAIX) has been reported to be an endogenous hypoxia marker, CAIX monoclonal antibodies, their segments and inhibitors are developed for CAIX imaging. However, growing evidence indicates that CAIX expression under hypoxia condition may be cancer cell lines or cancer-type dependent. Here we review the current literature on CAIX and discuss the advantage and limitation of CAIX as a target for tumor hypoxia imaging. Accordingly, CAIX would be unreliable as a universal target for cancer and tumor hypoxia visualization.
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Affiliation(s)
- Jianbo Li
- Department of Nuclear Medicine, Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, China
- Department of Diagnostic Radiology, University of Louisville, 530 S Jackson Street, CCB-C07, Louisville, KY 40202, USA
| | - Guojian Zhang
- Department of Nuclear Medicine, Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, China
- Department of Diagnostic Radiology, University of Louisville, 530 S Jackson Street, CCB-C07, Louisville, KY 40202, USA
| | - Xuemei Wang
- Department of Nuclear Medicine, Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, China
| | - Xiao-Feng Li
- Department of Diagnostic Radiology, University of Louisville, 530 S Jackson Street, CCB-C07, Louisville, KY 40202, USA
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The potential of liposomes with carbonic anhydrase IX to deliver anticancer ingredients to cancer cells in vivo. Int J Mol Sci 2014; 16:230-55. [PMID: 25547490 PMCID: PMC4307245 DOI: 10.3390/ijms16010230] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 12/16/2014] [Indexed: 12/19/2022] Open
Abstract
Drug delivery nanocarriers, especially targeted drug delivery by liposomes are emerging as a class of therapeutics for cancer. Early research results suggest that liposomal therapeutics enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumors and active cellular uptake. Here, we highlight the features of immunoliposomes that distinguish them from previous anticancer therapies, and describe how these features provide the potential for therapeutic effects that are not achievable with other modalities. While a large number of studies has been published, the emphasis here is placed on the carbonic anhydrase IX (CA-IX) and the conjugated liposomes that are likely to open a new chapter on drug delivery system by using immunoliposomes to deliver anticancer ingredients to cancer cells in vivo.
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Lew M, Foo WC, Roh MH. Diagnosis of Metastatic Renal Cell Carcinoma on Fine-Needle Aspiration Cytology. Arch Pathol Lab Med 2014; 138:1278-85. [DOI: 10.5858/arpa.2014-0283-cc] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Fine-needle aspiration has assumed an increasingly important role in the diagnosis and management of patients with advanced stage cancer. Given its predilection for metastases to distant sites and organs at the time of presentation, metastatic renal cell carcinoma (RCC) is not infrequently encountered in the setting of fine-needle aspiration for initial diagnosis. In some instances, fine-needle aspiration may be the only opportunity to obtain diagnostic tissue to diagnose and subclassify RCC. Therefore, cytopathologists and cytotechnologists should be familiar with and recognize the cytomorphology of RCC and the ancillary studies that can be used to confirm and subclassify RCC. Herein, we describe a case of metastatic RCC initially diagnosed on fine-needle aspiration, discuss the cytomorphologic features of RCC subtypes, and review pertinent ancillary immunohistochemical and cytogenetic adjuncts.
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Affiliation(s)
- Madelyn Lew
- From the Department of Pathology (Drs Lew and Roh), University of Michigan Health System, Ann Arbor; and the Department of Pathology (Dr Foo), Duke University Medical Center, Durham, North Carolina
| | - Wen-Chi Foo
- From the Department of Pathology (Drs Lew and Roh), University of Michigan Health System, Ann Arbor; and the Department of Pathology (Dr Foo), Duke University Medical Center, Durham, North Carolina
| | - Michael H. Roh
- From the Department of Pathology (Drs Lew and Roh), University of Michigan Health System, Ann Arbor; and the Department of Pathology (Dr Foo), Duke University Medical Center, Durham, North Carolina
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49
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Ananthanarayanan V, Tretiakova M, Husain AN, Krausz T, Antic T. Carbonic anhydrase IX (CAIX) does not differentiate between benign and malignant mesothelium. Am J Clin Pathol 2014; 142:82-7. [PMID: 24926090 DOI: 10.1309/ajcp8bj8cjxuehzd] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
Abstract
OBJECTIVES To examine carbonic anhydrase IX (CAIX), a marker of renal cell carcinoma that recently has been described in malignant effusions. METHODS Pleural and peritoneal fluids with the following diagnoses-reactive (n = 23), carcinoma (n = 17), and "suspicious for mesothelioma" (n = 4)-were immunostained for CAIX, calretinin, Ber-EP4, and MOC31. A tissue microarray of epithelioid (n = 27) and sarcomatoid (n = 8) mesotheliomas and three cases of benign mesothelium were also immunostained for CAIX. RESULTS Mesothelial cells in both reactive (18/23) and malignant effusions (18/21) were positive for CAIX (P > .05). In carcinomatous effusions, CAIX expression was restricted to the mesothelial cells. Agreement between CAIX and calretinin expression was present in 89% of cases. In tissues, CAIX was positive in 100% of benign and 91% of malignant mesothelium. CONCLUSIONS CAIX can be a useful ancillary marker for identifying mesothelial cells. There is no difference in CAIX expression between benign and malignant mesothelium. Caution should be exercised while evaluating for metastasis from renal cell carcinoma.
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Affiliation(s)
| | | | | | | | - Tatjana Antic
- Department of Pathology, University of Chicago, Chicago, IL
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Kuroda N, Tanaka A, Ohe C, Nagashima Y. Recent advances of immunohistochemistry for diagnosis of renal tumors. Pathol Int 2014; 63:381-90. [PMID: 23957913 DOI: 10.1111/pin.12080] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Accepted: 06/24/2013] [Indexed: 12/28/2022]
Abstract
The recent classification of renal tumors has been proposed according to genetic characteristics as well as morphological difference. In this review, we summarize the immunohistochemical characteristics of each entity of renal tumors. Regarding translocation renal cell carcinoma (RCC), TFE3, TFEB and ALK protein expression is crucial in establishing the diagnosis of Xp11.2 RCC, renal carcinoma with t(6;11)(p21;q12), and renal carcinoma with ALK rearrangement, respectively. In dialysis-related RCC, neoplastic cells of acquired cystic disease-associated RCC are positive for alpha-methylacyl-CoA racemase (AMACR), but negative for cytokeratin (CK) 7, whereas clear cell papillary RCC shows the inverse pattern. The diffuse positivity for carbonic anhydrase 9 (CA9) is diagnostic for clear cell RCC. Co-expression of CK7 and CA9 is characteristic of multilocular cystic RCC. CK7 and AMACR are excellent markers for papillary RCC and mucinous tubular and spindle cell carcinoma. CD82 and epithelial-related antigen (MOC31) may be helpful in the distinction between chromophobe RCC and renal oncocytoma. WT1 and CD57 highlights the diagnosis of metanephric adenoma. The combined panel of PAX2 and PAX8 may be useful in the diagnosis of metastatic RCC.
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Affiliation(s)
- Naoto Kuroda
- Department of Diagnostic Pathology, Kochi Red Cross Hospital, Kochi, Japan.
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