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Elshaer N, Eldeeb AM, Aioub AA, Hashem AS, Ghosh S, Alkeridis LA, Alshehri MA, Shukry M, Almalki DA, Alkhatabi HA, Afifi M, AL-Farga A, Hendawy MA, El-Sobki AE. Zinc nanoparticles mitigate azoxystrobin and its nanoencapsulation-induced hepatic and renal toxicity in rats. Redox Rep 2025; 30:2491318. [PMID: 40254739 PMCID: PMC12010655 DOI: 10.1080/13510002.2025.2491318] [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: 04/22/2025] Open
Abstract
This study sought to ascertain if zinc nanoparticles (ZnNPs) could lessen the toxicity of azoxystrobin (AZ). This naturally occurring methoxyacrylate is one of the most often used fungicides in agriculture in male albino rats. Six sets of 60 mature male albino rats were randomly assigned: control (distilled water), Azoxystrobin formulation (AZOF), Azoxystrobin nano-formula (AZON), ZnNPs, AZOF + ZnNPs, and AZON + ZnNPs. Blood and tissues were obtained for further immunohistochemical, pathological, and biochemical examination. The results showed that exposure to AZOF and AZON significantly increased the levels of the oxidative stress indicators glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA). Additionally, AZOF significantly impacts liver function bioindicators, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. AZOF and AZON induced damage to the liver and kidney by disrupting vascular dilatation and causing hemorrhages, apoptosis, inflammatory lymphocytes, and necrosis. Furthermore, co-administration of ZnNPs with fungicides (AZOF and AZON) can gently enhance the alterations of oxidative stress and liver function bioindicators levels. These findings showed that ZnNPs could help male rats receiving AZ treat their histologically abnormal liver and kidney.
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Affiliation(s)
- Nashwa Elshaer
- Plant Protection Department, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | - Ahmed M. Eldeeb
- Plant Protection Department, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | - Ahmed A.A. Aioub
- Plant Protection Department, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | - Ahmed S. Hashem
- Stored Product Pests Research Department, Plant Protection Research Institute, Agricultural Research Center, Kafr El-Sheikh, Egypt
| | - Soumya Ghosh
- Natural & Medical Science Research Center, University of Nizwa, Nizwa, Oman
| | - Lamya Ahmed Alkeridis
- Department of Biology, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | | | - Mustafa Shukry
- Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Daklallah A. Almalki
- Biology Department, Faculty of Science and Arts, Al-Baha University, Al-Mikhwah, Saudi Arebia
| | - Hind A. Alkhatabi
- Department of Biological Sciences, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Mohamed Afifi
- Department of Biological Sciences, College of Science, University of Jeddah, Jeddah, Saudi Arabia
- Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Ammar AL-Farga
- Department of Biological Sciences, College of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Mohamed A. Hendawy
- Plant Protection Department, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | - Ahmed E.A. El-Sobki
- Plant Protection Department, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
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Kim ES. Molecular targets and therapies associated with poor prognosis of triple‑negative breast cancer (Review). Int J Oncol 2025; 66:52. [PMID: 40444482 PMCID: PMC12118953 DOI: 10.3892/ijo.2025.5758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Accepted: 05/07/2025] [Indexed: 06/02/2025] Open
Abstract
Triple‑negative breast cancer (TNBC) is a highly aggressive and heterogeneous subtype of BC characterized by the absence of estrogen, progesterone and human EGFR2 receptors. This lack of receptors renders it unresponsive to standard targeted therapies. Despite advances made in understanding the molecular landscape of TNBC, its poor prognosis and high recurrence rates underscore the urgent need for innovative therapeutic approaches. This review explores the effects of key prognostic markers, such as Ki‑67, programmed cell death ligand 1, BRCA1/2 mutations, E‑cadherin loss and EGFR alterations. It also examines critical pathways, including the PI3K/AKT/mTOR and mutant p53 pathways, which are prerequisites for TNBC progression and therapy resistance, and discusses the therapeutic potential of directly targeting these key molecules and their associated signaling pathways. In addition, recent advances in targeted therapies were highlighted, such as immune checkpoint inhibitors, and the statuses of emerging strategies were presented, such as chimeric antigen receptor‑T cell therapy and small inhibitory RNA‑based treatments. Given the molecular heterogeneity of TNBC, the importance of precision medicine was also discussed and it was emphasized that this approach is becoming an increasingly critical aspect of personalized treatment strategies. Resistance to existing therapies presents a major challenge to the effective treatment of TNBC, and thus, the development of future therapeutic strategies requires technical innovations. By integrating these insights, this review aims to provide a comprehensive overview of current and future means of improving TNBC outcomes.
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Affiliation(s)
- Eun-Sook Kim
- College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea
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Shukla IY, Ebada A, Bever N, Traylor JI, Wan B, Shah D, Barnett SL, Sun MZ. Prognostic value of MIB-1 index in meningioma: a retrospective cohort study to establish an optimal cutoff for recurrence and survival. J Neurooncol 2025:10.1007/s11060-025-05057-2. [PMID: 40353934 DOI: 10.1007/s11060-025-05057-2] [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: 03/19/2025] [Accepted: 04/18/2025] [Indexed: 05/14/2025]
Abstract
PURPOSE Predicting long-term outcomes after meningioma resection remains challenging. Ki-67/MIB-1 correlates with recurrence, yet its optimal cutoff is undefined. This study aims to establish a threshold that enhances risk stratification, improves recurrence prediction, and informs postoperative surveillance and adjuvant treatment strategies. METHODS This is retrospective study of patients who underwent meningioma resection. Receiver operating characteristic (ROC) analysis determined the optimal MIB-1 cutoff for predicting recurrence and survival, providing area under the curve (AUC). This cutoff was then applied in Kaplan-Meier survival analyses and multivariable Cox regressions, controlling for age, sex, tumor diameter, tumor location, extent of resection, and adjuvant radiotherapy. RESULTS A total of 404 patients were included. Median age was 55.0 years (range: 16-85) and 72.3% were female. The cohort primarily consisted of WHO Grade 1 (69.6%) and Grade 2 (30.0%) meningiomas. An optimal MIB-1 index cutoff of 4.1% was identified using ROC analysis with the Youden index for predicting recurrence (AUC = 0.661, p < 0.001) and survival (AUC = 0.717, p < 0.001). 241 patients (59.7%) had a MIB-1 < 4.1%, and 163 (40.3%) had a MIB-1 ≥ 4.1%. Patients with MIB-1 ≥ 4.1% had a higher risk of recurrence (HR = 2.9, p = 0.009) and mortality (HR = 2.8, p = 0.036). Patients with MIB-1 ≥ 4.1% demonstrated shorter recurrence-free survival (RFS) (119.0 vs. 129.0 months, p < 0.001) and overall survival (OS) (163.0 vs. 229.0 months, p < 0.001). CONCLUSION We identified an optimal and actionable MIB-1 index cutoff of 4.1% which independently predicted recurrence, mortality, and shorter RFS and OS for patients undergoing meningioma resection. As the first study to establish and validate this threshold, our findings highlight its potential as an adjunct prognostic tool to refine risk stratification and guide postoperative management.
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Affiliation(s)
- Ishav Y Shukla
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ali Ebada
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Nicholas Bever
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jeffrey I Traylor
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Bingchun Wan
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Darsh Shah
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Samuel L Barnett
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Matthew Z Sun
- Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Martino F, Ilardi G, Varricchio S, Russo D, Di Crescenzo RM, Staibano S, Merolla F. A deep learning model to predict Ki-67 positivity in oral squamous cell carcinoma. J Pathol Inform 2024; 15:100354. [PMID: 38148967 PMCID: PMC10750186 DOI: 10.1016/j.jpi.2023.100354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 08/14/2023] [Accepted: 11/16/2023] [Indexed: 12/28/2023] Open
Abstract
Anatomical pathology is undergoing its third revolution, transitioning from analogical to digital pathology and incorporating new artificial intelligence technologies into clinical practice. Aside from classification, detection, and segmentation models, predictive models are gaining traction since they can impact diagnostic processes and laboratory activity, lowering consumable usage and turnaround time. Our research aimed to create a deep-learning model to generate synthetic Ki-67 immunohistochemistry from Haematoxylin and Eosin (H&E) stained images. We used 175 oral squamous cell carcinoma (OSCC) from the University Federico II's Pathology Unit's archives to train our model to generate 4 Tissue Micro Arrays (TMAs). We sectioned one slide from each TMA, first stained with H&E and then re-stained with anti-Ki-67 immunohistochemistry (IHC). In digitised slides, cores were disarrayed, and the matching cores of the 2 stained were aligned to construct a dataset to train a Pix2Pix algorithm to convert H&E images to IHC. Pathologists could recognise the synthetic images in only half of the cases in a specially designed likelihood test. Hence, our model produced realistic synthetic images. We next used QuPath to quantify IHC positivity, achieving remarkable levels of agreement between genuine and synthetic IHC. Furthermore, a categorical analysis employing 3 Ki-67 positivity cut-offs (5%, 10%, and 15%) revealed high positive-predictive values. Our model is a promising tool for collecting Ki-67 positivity information directly on H&E slides, reducing laboratory demand and improving patient management. It is also a valuable option for smaller laboratories to easily and quickly screen bioptic samples and prioritise them in a digital pathology workflow.
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Affiliation(s)
- Francesco Martino
- Dedalus HealthCare, Division of Diagnostic Imaging IT, Gertrude-Frohlich-Sandner-Straße 1, Wien 1100, Austria
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Gennaro Ilardi
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Silvia Varricchio
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Daniela Russo
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Rosa Maria Di Crescenzo
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Stefania Staibano
- Department of Advanced Biomedical Sciences, University of Naples, Via Pansini, 5, Naples 80131, Italy
| | - Francesco Merolla
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, Via De Sanctis, Campobasso 86100, Italy
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Bates M, Mohamed BM, Lewis F, O'Toole S, O'Leary JJ. Biomarkers in high grade serous ovarian cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189224. [PMID: 39581234 DOI: 10.1016/j.bbcan.2024.189224] [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: 01/28/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024]
Abstract
High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. HGSC patients typically present with advanced disease, which is often resistant to chemotherapy and recurs despite initial responses to therapy, resulting in the poor prognosis associated with this disease. There is a need to utilise biomarkers to manage the various aspects of HGSC patient care. In this review we discuss the current state of biomarkers in HGSC, focusing on the various available immunohistochemical (IHC) and blood-based biomarkers, which have been examined for their diagnostic, prognostic and theranostic potential in HGSC. These include various routine clinical IHC biomarkers such as p53, WT1, keratins, PAX8, Ki67 and p16 and clinical blood-borne markers and algorithms such as CA125, HE4, ROMA, RMI, ROCA, and others. We also discuss various components of the liquid biopsy as well as a number of novel IHC biomarkers and non-routine blood-borne biomarkers, which have been examined in various ovarian cancer studies. We also discuss the future of ovarian cancer biomarker research and highlight some of the challenges currently facing the field.
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Affiliation(s)
- Mark Bates
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland.
| | - Bashir M Mohamed
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Faye Lewis
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Sharon O'Toole
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin, Ireland
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Hong B, Xu Y, Xiao Y, Yu X. Comparison of MIB-1-Specific Membrane Staining in Hyalinising Trabecular Tumor Using Mainstream Automated Immunohistochemical Staining Platforms. J Clin Lab Anal 2024; 38:e25113. [PMID: 39447085 PMCID: PMC11584304 DOI: 10.1002/jcla.25113] [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: 06/11/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND MIB-1, a monoclonal antibody against Ki-67, exhibits specific membrane staining in the immunohistochemistry of hyalinising trabecular tumor (HTT). This specific staining pattern is crucial in diagnosing HTT. Although manual immunohistochemical staining remains the established method for MIB-1 staining, this process is complicated, inconsistent, and prone to false negatives. METHODS This study aimed to explore whether the classical reaction pattern can be replicated by utilizing the current mainstream automated immunohistochemical staining platforms. Furthermore, we examined the effect of different conditions on staining efficiency and their value in clinical diagnosis assistance. RESULTS Specimens obtained from eight and six cases of HTT and non-HTT, respectively, from a single center were stained using the manual staining method and the Dako Autostainer Link 48 (AS48), Dako Omnis, Ventana BenchMark ULTRA, and Leica BOND-III automated immunohistochemical staining platforms. The Autostainer Link 48 was found to be the most stable staining platform, while the BenchMark ULTRA with primary antibody incubation at room temperature (RT) and the Omnis platform with antigen retrieval at pH 9.0 were able to reproduce membrane-positive staining for MIB-1 in the HTT specimens. CONCLUSIONS Our results offer crucial reference value for clinical diagnostic assistance.
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Affiliation(s)
- Bo Hong
- Department of PathologyThe Second Affiliated Hospital, Zhejiang University School of MedicineHangzhouZhejiangPeople's Republic of China
| | - Yanfei Xu
- Department of PathologyQuzhou Second People's HospitalQuzhouZhejiangPeople's Republic of China
| | - Yufei Xiao
- Department of Clinical LaboratoryThe Second Affiliated Hospital, Zhejiang University School of MedicineHangzhouZhejiangPeople's Republic of China
| | - Xiaoyan Yu
- Department of PathologyThe Second Affiliated Hospital, Zhejiang University School of MedicineHangzhouZhejiangPeople's Republic of China
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Zhang X, Lin Y, He D, Sun M, Xu L, Chang Z, Liu Z, Li B. 18F-Fluoro-2-Deoxyglucose Positron Emission Tomography/Computed Tomography Measures of Spatial Heterogeneity for Predicting Platinum Resistance of High-Grade Serous Ovarian Cancer. Cancer Med 2024; 13:e70287. [PMID: 39435561 PMCID: PMC11494247 DOI: 10.1002/cam4.70287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 08/02/2024] [Accepted: 09/22/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND The purpose of this study is to construct models for predicting platinum resistance in high-grade serous ovarian cancer (HGSOC) derived from quantitative spatial heterogeneity indicators obtained from 18F-FDG PET/CT images. METHODS A retrospective study was conducted on patients diagnosed with HGSOC. Quantitative indicators of spatial heterogeneity were generated using conventional features and Haralick texture features from both CT and PET images. Three groups of predictive models (conventional, heterogeneity, and integrated) were built. Each group's optimal model was the one with the highest area under curve (AUC). Postoperative immunohistochemical staining for Ki-67 and p53 was conducted. The correlation between the heterogeneity indicators and scores for Ki-67 and p53 was assessed by Spearman's correlation coefficient (ρ). RESULTS A total of 286 patients (54.6 ± 9.3 years) were enrolled. And 107 spatial heterogeneity indicators were extracted. The optimal models for each group were obtained using the Gradient Boosting Machine (GBM) algorithm. There was an AUC of 0.790 (95% CI: 0.696, 0.885) in the conventional model for the validation set, and an AUC of 0.904 (95% CI: 0.842, 0.966) in the heterogeneity model for the validation set. The integrated model achieved the highest predictive performance, with an AUC value of 0.928 (95% CI: 0.872, 0.984) for the validation set. Spearman's correlation showed that HU_Kurtosis had the strongest correlation with p53 scores with ρ = 0.718, while cluster site entropy had the strongest correlation with Ki-67 scores with ρ = 0.753. CONCLUSIONS Adding quantitative spatial heterogeneity indicators derived from PET/CT images can improve the prediction of platinum resistance in patients with HGSOC. Spatial heterogeneity indicators were related to Ki-67 and p53 scores.
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Affiliation(s)
- Xin Zhang
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningPeople's Republic of China
| | - Yuhe Lin
- Department of OncologyShengjing Hospital of China Medical UniversityShenyangLiaoningPeople's Republic of China
| | - Dianning He
- School of Health ManagementChina Medical UniversityShenyangLiaoningPeople's Republic of China
| | - Mingli Sun
- Department of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyangLiaoningPeople's Republic of China
| | - Lanlan Xu
- Department of RadiologyShengjing Hospital of China Medical UniversityShenyangLiaoningPeople's Republic of China
| | - Zhihui Chang
- Department of RadiologyShengjing Hospital of China Medical UniversityShenyangLiaoningPeople's Republic of China
| | - Zhaoyu Liu
- Department of RadiologyShengjing Hospital of China Medical UniversityShenyangLiaoningPeople's Republic of China
| | - Beibei Li
- Department of RadiologyShengjing Hospital of China Medical UniversityShenyangLiaoningPeople's Republic of China
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Attia MS, Ayman F, Attia MS, Yahya G, Zahra MH, Khalil MMI, Diab AAA. Mitigating diabetes-related complications: Empowering metformin with cholecalciferol and taurine supplementation in type 2 diabetic rats. World J Diabetes 2024; 15:1778-1792. [PMID: 39192867 PMCID: PMC11346095 DOI: 10.4239/wjd.v15.i8.1778] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 06/30/2024] [Accepted: 07/17/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Type 2 diabetes is one of the most prevalent chronic diseases worldwide, significantly impacting patients' quality of life. Current treatment options like metformin (MET) effectively counteract hyperglycemia but fail to alleviate diabetes-associated complications such as retinopathy, neuropathy, nephropathy, hepatopathy, and cardiovascular diseases. AIM To propose the supplementation of cholecalciferol (CHO) and taurine (TAU) to enhance MET efficacy in controlling diabetes while minimizing the risk of associated complications. METHODS The study involved sixty rats, including ten non-diabetic control rats and fifty experimental rats with type 2 diabetes induced by streptozotocin. The experimental rats were further subdivided into positive control and treatment subgroups. The four treatment groups were randomly allocated to a single MET treatment or MET combined with supplements either CHO, TAU, or both. RESULTS Diabetic rats exhibited elevated levels of glucose, insulin, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), glycated hemoglobin%, lipid markers, aspartate aminotransferase, and malondialdehyde, along with reduced levels of antioxidant enzymes (catalase and superoxide dismutase). The administration of CHO and TAU supplements alongside MET in diabetic rats led to a noticeable recovery of islet mass. The antioxidative, anti-inflammatory, and anti-apoptotic properties of the proposed combination therapy significantly ameliorated the aforementioned abnormalities. CONCLUSION The supplementation of CHO and TAU with MET showed the potential to significantly improve metabolic parameters and protect against diabetic complications through its antioxidative, anti-inflammatory, and anti-apoptotic effects.
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Affiliation(s)
- Mai S Attia
- Department of Zoology, Faculty of Science, Zagazig 44519, Egypt
| | - Fadwa Ayman
- Department of Zoology, Faculty of Science, Zagazig 44519, Egypt
| | - Mohamed S Attia
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig 44519, Egypt
| | - Galal Yahya
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Mansour H Zahra
- Department of Zoology, Faculty of Science, Zagazig 44519, Egypt
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Lo A, Greenzaid JD, Gantz HY, Chodri K, Feldman SR. Clinical pharmacokinetics and pharmacodynamics of topical non-biological therapies for psoriasis patients. Expert Opin Drug Metab Toxicol 2024; 20:235-248. [PMID: 38553411 DOI: 10.1080/17425255.2024.2337749] [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: 02/06/2024] [Accepted: 03/27/2024] [Indexed: 04/04/2024]
Abstract
INTRODUCTION Psoriasis is a chronic inflammatory cutaneous disease that causes patients psychosocial distress. Topical therapies are utilized for mild-to-moderate disease and for more severe disease in conjunction with systemic therapies. Topical corticosteroids are a cornerstone of treatment for psoriasis, but long-term use can cause stria and cutaneous atrophy and as well as systemic side effects such as topical steroid withdrawal. Non-steroidal topical therapies tend to be safer than topical corticosteroids for long-term use. AREAS COVERED We conducted a literature review on the pharmacokinetic (PK) and pharmacodynamic (PD) properties of topical therapies for psoriasis. We discuss how the PK and PD characteristics of these therapies inform clinicians on efficacy and toxicity when prescribing for patients. EXPERT OPINION Topical corticosteroids, used intermittently, are very safe and effective. Long-term, continuous use of topical corticosteroids can cause systemic side effects. Several generic and newly approved non-steroidal options are available, but no head-to-head studies compare the effectiveness of the generics (vitamin D analogs, tacrolimus, pimecrolimus) against the newer therapies (roflumilast, tapinarof). Patients often do not respond to topical therapies due to poor adherence to treatment regimens. For patients resistant to topical treatment, phototherapy or systemic therapy may be an option.
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Affiliation(s)
- Angela Lo
- University of Central Florida College of Medicine, Orlando, FL, USA
| | - Jonathan D Greenzaid
- Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Hannah Y Gantz
- Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Kamran Chodri
- Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Steven R Feldman
- Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
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Tomasik A, Stelmachowska-Banaś M, Maksymowicz M, Czajka-Oraniec I, Raczkiewicz D, Zieliński G, Kunicki J, Zgliczyński W. Pathologic Characteristics of Somatotroph Pituitary Tumors-An Observational Single-Center Study. Biomedicines 2023; 11:3315. [PMID: 38137536 PMCID: PMC10741635 DOI: 10.3390/biomedicines11123315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/26/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023] Open
Abstract
The pathologic evaluation of a tumor tissue is an essential part of an acromegaly patient's assessment. This study aimed to analyze the pathologic characteristics of pituitary tumors in patients with acromegaly. The demographic data, in addition to the hormonal, imaging, and pathologic results of 120 patients with acromegaly after pituitary surgery, were extracted from the Polish Acromegaly Registry. We compared sparsely and densely granulated tumors, GH(+), mixed GH(+)/PRL(+) and plurihormonal tumors, α-subunit-positive and α-subunit-negative tumors, and tumors of various Ki-67 indices in terms of the abovementioned features. Sparsely granulated tumors were more frequent in women than in men (p = 0.001) and in younger patients (p = 0.011), and they were larger (p < 0.001) compared to densely granulated tumors. Tumors with positive α-subunit were smaller (p = 0.013), showed extrasellar extension less often (p = 0.039), and were more often densely granulated (p < 0.001) compared to α-subunit-negative tumors. Patients with a higher Ki-67 index were younger (p < 0.001) and more often diagnosed with genetic syndromes (p = 0.02); they had higher GH concentrations (p = 0.007), larger tumors (p = 0.006), and cavernous sinus invasions more frequently (p = 0.022). Conclusions: The pathologic characteristics of somatotroph pituitary tumors are associated with patient's age, sex, hormonal results, tumor size, and the degree of extrasellar expansion.
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Affiliation(s)
- Agnieszka Tomasik
- Department of Endocrinology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland
| | | | - Maria Maksymowicz
- Department of Cancer Pathomorphology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
| | - Izabella Czajka-Oraniec
- Department of Endocrinology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland
| | - Dorota Raczkiewicz
- Department of Medical Statistics, School of Public Health, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland
| | - Grzegorz Zieliński
- Department of Neurosurgery, Military Institute of Medicine, 04-141 Warsaw, Poland
| | - Jacek Kunicki
- Department of Neurosurgery, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
| | - Wojciech Zgliczyński
- Department of Endocrinology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland
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Gown AM. The Biomarker Ki-67: Promise, Potential, and Problems in Breast Cancer. Appl Immunohistochem Mol Morphol 2023; 31:478-484. [PMID: 36730064 DOI: 10.1097/pai.0000000000001087] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 10/19/2022] [Indexed: 02/03/2023]
Abstract
Ki-67 is a nuclear protein serendipitously discovered by monoclonal antibody selection in the early 1980s. While it has been applied for decades in the context of breast cancer as a putative prognostic and, more recently, predictive, biomarker, even after all this time there is incomplete agreement as to the validity of the immunohistochemical assays employed for Ki-67 assessment, given possible effects of the disparate methodologies employed and possible confounding preanalytical, analytical, and interpretive variables. In this brief review, the history of Ki-67 and the problems, particularly with the analytical and interpretive variables, are highlighted through a selective review of the published literature. The contributions of the International Ki-67 Breast Cancer Working Group are highlighted, and in particular, the recommendations made by this group are reviewed. The potential of Ki-67 as a biomarker for breast cancer has not yet been fully realized, but an understanding of the power as well as the limitations of the methods of Ki-67 assessment are important if this biomarker can realize its potential.
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Affiliation(s)
- Allen M Gown
- Department of Pathology, University of British Columbia, Vancouver, BC
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12
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Huang J, Zhang Q, Luo Y. Evaluation and optimization of the immunohistochemistry antigen retrieval methods on mouse decalcified joint tissues. J Immunol Methods 2023; 513:113424. [PMID: 36626964 DOI: 10.1016/j.jim.2023.113424] [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: 04/07/2022] [Revised: 10/31/2022] [Accepted: 01/06/2023] [Indexed: 01/09/2023]
Abstract
To evaluate and optimize antigen retrieval (AR) methods for the detection of NF-κB, interleukin-1β, interleukin-6, interferon regulatory factor 5 and matrix metalloproteinase-3 expression in mouse joint tissue using immunohistochemistry (IHC). This study evaluated the differences in several AR methods, including pressure cooking (PC), microwave treatment (MW), water bath cooking (WB), trypsin retrieval (TYR), improved water bath cooking (IWB), and enhanced alkaline pH of IWB (EIWB), in tissue integrity maintenance and IHC staining specificity. The AR methods of TYR and IWB maintained the integrity of the tissue to a great extent. The PC, MW, WB, and EIWB resulted in tissue detachment and were not appropriate for subsequent IHC staining. TYR maintained better tissue morphology and staining intensity than IWB, while the IWB retrieval method had a higher percentage of IHC-positive staining and a less nonspecific background. Both the TYR and IWB AR methods were suitable for IHC staining and could effectively resolve the challenges of tissue detachment, insufficient staining, and nonspecific background in paraffin sections of mouse decalcified joint tissues.
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Affiliation(s)
- Jianbo Huang
- Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, PR China; Laboratory of Ultrasound Medicine, Department of Ultrasound, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Qiuping Zhang
- Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Yubin Luo
- Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, PR China.
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13
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Osteopontin and Ki-67 expression in World Health Organization graded canine meningioma. J Comp Pathol 2023; 201:41-48. [PMID: 36706466 DOI: 10.1016/j.jcpa.2022.12.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 10/20/2022] [Accepted: 12/22/2022] [Indexed: 01/26/2023]
Abstract
Osteopontin (OPN) is a matrix protein involved in tumour initiation and progression. In human meningioma, OPN has been correlated with World Health Organization (WHO) grade, brain invasion and recurrence. The aim of this study was to investigate OPN as a possible malignancy marker in canine meningioma by correlating its expression to WHO grade and proliferative activity as measured by the Ki-67 labelling index (LI). Thirty-five formalin-fixed, paraffin-embedded canine meningioma samples were classified according to the current human WHO classification. Evaluation of OPN expression was performed by immunohistochemical (IHC) labelling and calculation of the OPN intensity score (IS), OPN IHC score and Allred score. The scores were compared with WHO grades, Ki-67 LI, location and invasiveness. Nineteen meningiomas were graded as WHO grade I (54.3%), nine as grade II (25.7%) and seven as grade III (20.0%). Twenty-six tumours were located intracranially, four were retrobulbar and five were spinal meningiomas. In all specimens OPN expression was detected in moderate to high degrees. Neither the OPN scores nor the Ki-67 LIs were correlated with WHO grades. However, the OPN IS and OPN IHC score were significantly higher in WHO grade I samples compared with grade II samples (P <0.05). The OPN IS and OPN IHC score were significantly lower in meningioma samples that invaded surrounding tissues (P = 0.01 and 0.019, respectively). The results indicate a generally high expression of OPN in canine meningioma independent of WHO grade. Further research into the role of OPN as a possible therapeutic target or predictor of recurrence is warranted.
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Finkelman BS, Zhang H, Hicks DG, Turner BM. The Evolution of Ki-67 and Breast Carcinoma: Past Observations, Present Directions, and Future Considerations. Cancers (Basel) 2023; 15:808. [PMID: 36765765 PMCID: PMC9913317 DOI: 10.3390/cancers15030808] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/19/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
The 1983 discovery of a mouse monoclonal antibody-the Ki-67 antibody-that recognized a nuclear antigen present only in proliferating cells represented a seminal discovery for the pathologic assessment of cellular proliferation in breast cancer and other solid tumors. Cellular proliferation is a central determinant of prognosis and response to cytotoxic chemotherapy in patients with breast cancer, and since the discovery of the Ki-67 antibody, Ki-67 has evolved as an important biomarker with both prognostic and predictive potential in breast cancer. Although there is universal recognition among the international guideline recommendations of the value of Ki-67 in breast cancer, recommendations for the actual use of Ki-67 assays in the prognostic and predictive evaluation of breast cancer remain mixed, primarily due to the lack of assay standardization and inconsistent inter-observer and inter-laboratory reproducibility. The treatment of high-risk ER-positive/human epidermal growth factor receptor-2 (HER2) negative breast cancer with the recently FDA-approved drug abemaciclib relies on a quantitative assessment of Ki-67 expression in the treatment decision algorithm. This further reinforces the urgent need for standardization of Ki-67 antibody selection and staining interpretation, which will hopefully lead to multidisciplinary consensus on the use of Ki-67 as a prognostic and predictive marker in breast cancer. The goals of this review are to highlight the historical evolution of Ki-67 in breast cancer, summarize the present literature on Ki-67 in breast cancer, and discuss the evolving literature on the use of Ki-67 as a companion diagnostic biomarker in breast cancer, with consideration for the necessary changes required across pathology practices to help increase the reliability and widespread adoption of Ki-67 as a prognostic and predictive marker for breast cancer in clinical practice.
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Affiliation(s)
| | | | | | - Bradley M. Turner
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14620, USA
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15
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Predicting Prognosis and Platinum Resistance in Ovarian Cancer: Role of Immunohistochemistry Biomarkers. Int J Mol Sci 2023; 24:ijms24031973. [PMID: 36768291 PMCID: PMC9916805 DOI: 10.3390/ijms24031973] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/17/2022] [Accepted: 12/20/2022] [Indexed: 01/20/2023] Open
Abstract
Ovarian cancer is a lethal reproductive tumour affecting women worldwide. The advancement in presentation and occurrence of chemoresistance are the key factors for poor survival among ovarian cancer women. Surgical debulking was the mainstay of systemic treatment for ovarian cancer, which was followed by a successful start to platinum-based chemotherapy. However, most women develop platinum resistance and relapse within six months of receiving first-line treatment. Thus, there is a great need to identify biomarkers to predict platinum resistance before enrolment into chemotherapy, which would facilitate individualized targeted therapy for these subgroups of patients to ensure better survival and an improved quality of life and overall outcome. Harnessing the immune response through immunotherapy approaches has changed the treatment way for patients with cancer. The immune outline has emerged as a beneficial tool for recognizing predictive and prognostic biomarkers clinically. Studying the tumour microenvironment (TME) of ovarian cancer tissue may provide awareness of actionable targets for enhancing chemotherapy outcomes and quality of life. This review analyses the relevance of immunohistochemistry biomarkers as prognostic biomarkers in predicting chemotherapy resistance and improving the quality of life in ovarian cancer.
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16
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Hassan ST, Mohamed AF, AbdelAllah NH, Zedan H. Evaluation of MMR live attenuated vaccine oncolytic potential using Ehrlich ascites carcinoma in a murine model. Med Oncol 2023; 40:6. [PMID: 36308603 PMCID: PMC9617820 DOI: 10.1007/s12032-022-01866-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 10/02/2022] [Indexed: 01/17/2023]
Abstract
MMR vaccine is a common vaccine that contains oncolytic viruses (Measles, Mumps, and Rubella) and could be used as a potential anti-cancer treatment. In this study, we assessed the anti-tumor activity of the MMR vaccine against Ehrlich ascites carcinoma (EAC) solid tumor induced in mice. The in vitro assay showed that vaccine IC50 in EAC was approximately 200 CCID50. The vaccine was intratumorally administrated twice weekly in EAC-bearing mice. The antitumor response of the vaccine was measured by tumor growth, survival rate, histopathologic examination, flow cytometry analysis, and body biochemical parameters. The MMR vaccine demonstrated a substantial reduction of tumor growth and prolongation of life span as well. The proliferation marker was significantly lower in the vaccine-treated group. Moreover, the apoptosis key parameter Casp-3 was also higher in the vaccine-treated group. The vaccine somewhat restored the deterioration of the biochemical parameters (LDH, GOT, GPT, MDA, NO, and PON-1) in the tumor-bearing mice. Finally, this study indicated the potential antitumor effect of MMR vaccine via anti‑proliferative, apoptotic activities, and modulating the antioxidant parameters. This study opens a new field of inquiry for future research on the vaccine's anti-cancer properties.
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Affiliation(s)
- Sara T. Hassan
- Laboratory Evaluation Administration, Egyptian Drug Authority, Giza, 12654 Egypt
| | - Aly F. Mohamed
- International Center for Training and Advanced Researches (ICTAR-Egypt), Cairo, Egypt
| | | | - Hamdallah Zedan
- grid.7776.10000 0004 0639 9286Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, 11562 Egypt
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17
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Othman EM, Hamada HA, Mohamed GI, Abdallah GA, Ahmed ZS, Al-Shenqiti AM, Kadry AM. Clinical and histopathological responses to bee venom phonophoresis in treating venous and diabetic ulcers: a single-blind randomized controlled trial. Front Med (Lausanne) 2023; 10:1085544. [PMID: 37153087 PMCID: PMC10157245 DOI: 10.3389/fmed.2023.1085544] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/21/2023] [Indexed: 05/09/2023] Open
Abstract
Introduction Chronic venous and diabetic ulcers are hard to treat that cause patients long time of suffering as well as significant healthcare and financial costs. Purpose The conducted study was to evaluate the efficacy of bee venom (BV) phonophoresis on the healing of chronic unhealed venous and/or diabetic foot ulcers Also, to compare the healing rate of diabetic and venous ulcers. Methodology The study included 100 patients (71 males and 29 females) with an age range of 40-60 years' old who had chronic unhealed venous leg ulcers of grade I, grade II, or diabetic foot ulcers with type II diabetes mellitus. They randomly assigned into four equal groups of 25: Group A (diabetic foot ulcer study group) and group C (venous ulcer study group) who both received conservative treatment of medical ulcer care and phonophoresis with BV gel, in addition to group B (diabetic foot ulcer control group) and group D (venous ulcer control group) who both received conservative treatment of medical ulcer care and received ultrasound sessions only without BV gel. Wound surface area (WSA) and ulcer volume measurement (UVM) were used to assess the ulcer healing pre-application (P0), post-6 weeks of treatment (P1), and after 12 weeks of treatment (P2). In addition to Ki-67 immunohistochemistry was used to evaluate the cell proliferative in the granulation tissue of ulcers pre-application (P0) and after 12 weeks of treatment (P2) for all groups. Results This research revealed a statistical significance improvement (p ≤ 0.0) in the WSA, and UVM with no significant difference between study groups after treatment. Regarding Ki-67 immunohistochemistry showed higher post treatment values in the venous ulcer group in comparison to the diabetic foot ulcer group. Conclusion Bee venom (BV) provided by phonophoresis is effective adjuvant treatment in accelerating venous and diabetic foot ulcer healing with higher proliferative effect on venous ulcer. Clinical trial registration www.ClinicalTrials.gov, identifier: NCT05285930.
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Affiliation(s)
- Eman M. Othman
- Department for Surgery, Faculty of Physical Therapy, Cairo University, Cairo, Egypt
| | - Hamada Ahmed Hamada
- Department for Biomechanics, Faculty of Physical Therapy, Cairo University, Cairo, Egypt
| | - Ghada I. Mohamed
- Department of Basic Science, Faculty of Physical Therapy, Cairo University, Cairo, Egypt
| | - Ghada A. Abdallah
- Department of Basic Science, Faculty of Physical Therapy, Cairo University, Cairo, Egypt
| | - Zeinab S. Ahmed
- Department of Cardiovascular, Respiratory Disorder and Geriatrics, Faculty of Physical Therapy, Cairo University, Cairo, Egypt
| | | | - Ahmed Mahmoud Kadry
- Faculty of Physical Therapy, Kafrelsheikh University, Kafr el-Sheikh, Egypt
- *Correspondence: Ahmed Mahmoud Kadry
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18
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Trant AA, Chagpar A, Wei W, Neumeister V, Rimm D, Stavris K, Lurie B, Frederick C, Andrejeva L, Raghu M, Killelea B, Horowitz N, Lannin D, Knill-Selby E, Sturrock T, Hofstatter E. The Effect of Black Cohosh on Ki67 expression and Tumor Volume: A Pilot Study of Ductal Carcinoma in Situ Patients. Integr Cancer Ther 2022; 21:15347354221137290. [PMID: 36444764 PMCID: PMC9716631 DOI: 10.1177/15347354221137290] [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] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Black cohosh (BC) (Cimicifuga racemosa) may prevent and treat breast cancer through anti-proliferative, pro-apoptotic, anti-estrogenic, and anti-inflammatory effects. This study sought to evaluate the effect of BC on tumor cellular proliferation, measured by Ki67 expression, in a pre-operative window trial of ductal carcinoma in situ (DCIS) patients. METHODS Patients were treated pre-operatively for 2 to 6 weeks with BC extract. Eligible subjects were those who had DCIS on core biopsy. Ki67 was measured using automated quantitative immunofluorescence (AQUA) pre/post-operatively. Ki67, tumor volume, and hormone changes were assessed with 2-sided Wilcoxon signed-rank tests, α = .05. RESULTS Thirty-one patients were treated for an average of 24.5 days (median 25; range 15-36). Ki67 decreased non-significantly (n = 26; P = .20; median pre-treatment 1280, post-treatment 859; range pre-treatment 175-7438, post-treatment 162-3370). Tumor volume, estradiol, and FSH did not change significantly. No grade 3 or 4 adverse events were reported. CONCLUSIONS BC use showed no significant impact on cellular proliferation, tumor volume, or invasive disease upgrade rates in DCIS patients. It was well-tolerated, with no observed significant toxicities. Further study is needed to elucidate BC's role in breast cancer treatment and prevention.ClinicalTrials.gov Identifier: NCT01628536https://clinicaltrials.gov/ct2/show/NCT01628536.
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Affiliation(s)
| | | | - Wei Wei
- Yale School of Medicine, New Haven, CT, USA
| | | | - David Rimm
- Yale School of Medicine, New Haven, CT, USA
| | | | | | | | | | | | | | | | | | | | | | - Erin Hofstatter
- Yale School of Medicine, New Haven, CT, USA,Erin Hofstatter, Yale School of Medicine, 333 Cedar St., PO Box 208032 New Haven, CT 05620, USA.
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Jie D, Liu Z, He W, Wang S, Teng H, Xu J. Clinical features, radiological findings, and prognostic factors for primary intracranial chordoid meningioma. Front Neurol 2022; 13:1002088. [PMID: 36438949 PMCID: PMC9684187 DOI: 10.3389/fneur.2022.1002088] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 10/10/2022] [Indexed: 04/09/2024] Open
Abstract
OBJECTIVES Chordoid meningioma (CM) is an infrequent histologic subtype of meningiomas. Owing to its low occurrence, this subtype has been rarely described. Our subject was to explore the clinical features, radiological characteristics, and prognostic factors of primary intracranial chordoid meningioma. METHODS We reviewed the medical records and collected follow-up information of 34 cases who had been surgically treated and histologically diagnosed with CM at the Department of Neurosurgery, West-China Hospital of Sichuan University, from January 2009 to December 2021. RESULTS Among all 7,950 meningioma cases, the proportion of primary intracranial CM was 0.43% (34/7,950). The median diagnosis age was 47 (ranging from 12 to 74) and the gender ratio (male to female) was 2.1:1. For radiological features, heterogeneous enhancement, skull base, and ventricular localization, cystic degeneration and dural tail sign were common in CM cases. In treatment, gross total resection (GTR) was achieved in 22/34 cases (64.7%) and subtotal resection (STR) was achieved in 12/34 cases (35.3%). Further, 11/34 patients (32.4%) had received postoperative adjuvant radiotherapy (RT). The follow-up duration ranged from 4 to 157 months after operation. The progression rate was 20.7% (6/29) and the median of PFS was 38 months. By survival analysis, accepting adjuvant radiotherapy and achieving GTR were correlated with longer progression-free survival for prognosis. CONCLUSION CM is a rare subtype of meningiomas. In our series, it mainly involved adults and did not show a predilection for women compared with meningiomas in general. For a better prognosis, gross total resection and postoperative adjuvant radiotherapy are recommended. Nevertheless, due to the restriction of the series sample, patients lost for follow-up and inherent biases of a retrospective study, more cases and a shorter follow-up duration are needed for better management of chordoid meningioma.
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Affiliation(s)
- Danyang Jie
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Zhiyong Liu
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China
| | - Wenbo He
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Shumin Wang
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Haibo Teng
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Jianguo Xu
- Department of Neurosurgery, West China Hospital of Sichuan University, Chengdu, China
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20
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Kreipe H, Harbeck N, Christgen M. Clinical validity and clinical utility of Ki67 in early breast cancer. Ther Adv Med Oncol 2022; 14:17588359221122725. [PMID: 36105888 PMCID: PMC9465566 DOI: 10.1177/17588359221122725] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/10/2022] [Indexed: 11/25/2022] Open
Abstract
Ki67 represents an immunohistochemical nuclear localized marker that is widely
used in surgical pathology. Nuclear immunoreactivity for Ki67 indicates that
cells are cycling and are in G1- to S-phase. The percentage of Ki67-positive
tumor cells (Ki67 index) therefore provides an estimate of the growth fraction
in tumor specimens. In breast cancer (BC), tumor cell proliferation rate is one
of the most relevant prognostic markers and Ki67 is consequently helpful in
prognostication similar to histological grading and mRNA profiling-based BC risk
stratification. In BCs treated with short-term preoperative endocrine therapy,
Ki67 dynamics enable distinguishing between endocrine sensitive and resistant
tumors. Despite its nearly universal use in pathology laboratories worldwide, no
internationally accepted consensus has yet been achieved for some methodological
details related to Ki67 immunohistochemistry (IHC). Controversial issues refer
to choice of IHC antibody clones, scoring methods, inter-laboratory
reproducibility, and the potential value of computer-assisted imaging analysis
and/or artificial intelligence for Ki67 assessment. Prospective clinical trials
focusing on BC treatment have proven that Ki67, as determined by standardized
central pathology assessment, is of clinical validity. Clinical utility has been
demonstrated in huge observational studies.
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Affiliation(s)
- Hans Kreipe
- Institute of Pathology, Hannover Medical School, Carl-Neubergstraße 1, Hannover 30625, Germany
| | - Nadia Harbeck
- Brustzentrum der Universität München (LMU) Frauenklinik Maistrasse-Innenstadt und Klinikum Großhadern, Germany
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21
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Skjervold AH, Pettersen HS, Valla M, Opdahl S, Bofin AM. Visual and digital assessment of Ki-67 in breast cancer tissue - a comparison of methods. Diagn Pathol 2022; 17:45. [PMID: 35524221 PMCID: PMC9074355 DOI: 10.1186/s13000-022-01225-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 04/12/2022] [Indexed: 11/23/2022] Open
Abstract
Background In breast cancer (BC) Ki-67 cut-off levels, counting methods and inter- and intraobserver variation are still unresolved. To reduce inter-laboratory differences, it has been proposed that cut-off levels for Ki-67 should be determined based on the in-house median of 500 counted tumour cell nuclei. Digital image analysis (DIA) has been proposed as a means to standardize assessment of Ki-67 staining in tumour tissue. In this study we compared digital and visual assessment (VA) of Ki-67 protein expression levels in full-face sections from a consecutive series of BCs. The aim was to identify the number of tumour cells necessary to count in order to reflect the growth potential of a given tumour in both methods, as measured by tumour grade, mitotic count and patient outcome. Methods A series of whole sections from 248 invasive carcinomas of no special type were immunohistochemically stained for Ki-67 and then assessed by VA and DIA. Five 100-cell increments were counted in hot spot areas using both VA and DIA. The median numbers of Ki-67 positive tumour cells were used to calculate cut-off levels for Low, Intermediate and High Ki-67 protein expression in both methods. Results We found that the percentage of Ki-67 positive tumour cells was higher in DIA compared to VA (medians after 500 tumour cells counted were 22.3% for VA and 30% for DIA). While the median Ki-67% values remained largely unchanged across the 100-cell increments for VA, median values were highest in the first 1-200 cells counted using DIA. We also found that the DIA100 High group identified the largest proportion of histopathological grade 3 tumours 70/101 (69.3%). Conclusions We show that assessment of Ki-67 in breast tumours using DIA identifies a greater proportion of cases with high Ki-67 levels compared to VA of the same tumours. Furthermore, we show that diagnostic cut-off levels should be calibrated appropriately on the introduction of new methodology.
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Affiliation(s)
- Anette H Skjervold
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Erling Skjalgssons gate 1, Trondheim, Norway.
| | - Henrik Sahlin Pettersen
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Erling Skjalgssons gate 1, Trondheim, Norway.,Department of Pathology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Marit Valla
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Erling Skjalgssons gate 1, Trondheim, Norway.,Department of Pathology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Signe Opdahl
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Anna M Bofin
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Erling Skjalgssons gate 1, Trondheim, Norway
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22
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Al-Asmari KM, Altayb HN, Al-Attar AM, Qahl SH, Al-Thobaiti SA, Abu Zeid IM. Arabica coffee and olive oils mitigate malathion-induced nephrotoxicity in rat: In silico, immunohistochemical and biochemical evaluation. Saudi J Biol Sci 2022; 29:103307. [PMID: 35602869 PMCID: PMC9120970 DOI: 10.1016/j.sjbs.2022.103307] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/21/2022] [Accepted: 05/06/2022] [Indexed: 11/24/2022] Open
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23
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Lourenço BC, Guimarães-Teixeira C, Flores BCT, Miranda-Gonçalves V, Guimarães R, Cantante M, Lopes P, Braga I, Maurício J, Jerónimo C, Henrique R, Lobo J. Ki67 and LSD1 Expression in Testicular Germ Cell Tumors Is Not Associated with Patient Outcome: Investigation Using a Digital Pathology Algorithm. Life (Basel) 2022; 12:life12020264. [PMID: 35207551 PMCID: PMC8875543 DOI: 10.3390/life12020264] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/05/2022] [Accepted: 02/08/2022] [Indexed: 12/27/2022] Open
Abstract
TGCTs represent a model of curable disease afflicting especially young men. Defining tumor biological characteristics is crucial to increase current knowledge and tailor the best clinical management. Ki67, a potential prognostic marker, still exhibits heterogenous associations with patient outcomes, thus bringing the need of corroboration with larger cohorts in clinical practice. LSD1, an epigenetic enzyme, represents a future target for epigenetic drugs that may lower treatment-associated morbidity. This study aimed to assess Ki67/LSD1 immunoexpression across all TGCT histological subtypes and correlate it with clinicopathological features. Results were compared with an in silico analysis of the TCGA database. Immunohistochemistry for Ki67 and LSD1 was carried out in a cohort of 157 TGCT tumor samples and assessed using a digital pathology algorithm. LSD1 protein expression was explored in TGCT cell lines, including ATRA-differentiated clones. There was a significant positive correlation between Ki67 and LSD1 H-scores (rs = 0.182, p = 0.037). Ki67 positivity percentage and H-score were significantly higher in non-seminomas (p = 0.0316 and 0.0113, respectively). Expression was not significantly different according to clinicopathological features, including stage, IGCCCG prognosis-based system, or relapse/progression-free survival, which was corroborated by in silico analysis. Our study, making use of digital image analysis, does not confirm the utility of these biomarkers in a daily practice cohort. Although not affecting patient outcome in our cohort, LSD1 is expressed overall in TGCTs, suggesting sensitivity to LSD1 inhibitors.
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Affiliation(s)
- Beatriz Chaves Lourenço
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), 4200-072 Porto, Portugal; (B.C.L.); (R.G.); (M.C.); (P.L.)
| | - Catarina Guimarães-Teixeira
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (C.G.-T.); (B.C.T.F.); (V.M.-G.); (C.J.)
| | - Bianca C. T. Flores
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (C.G.-T.); (B.C.T.F.); (V.M.-G.); (C.J.)
| | - Vera Miranda-Gonçalves
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (C.G.-T.); (B.C.T.F.); (V.M.-G.); (C.J.)
- Department of Pathology and Molecular Immunology, ICBAS–School of Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
| | - Rita Guimarães
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), 4200-072 Porto, Portugal; (B.C.L.); (R.G.); (M.C.); (P.L.)
| | - Mariana Cantante
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), 4200-072 Porto, Portugal; (B.C.L.); (R.G.); (M.C.); (P.L.)
| | - Paula Lopes
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), 4200-072 Porto, Portugal; (B.C.L.); (R.G.); (M.C.); (P.L.)
| | - Isaac Braga
- Department of Urology, Portuguese Oncology Institute of Porto (IPOP), 4200-072 Porto, Portugal;
| | - Joaquina Maurício
- Department of Medical Oncology, Portuguese Oncology Institute of Porto (IPOP), 4200-072 Porto, Portugal;
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (C.G.-T.); (B.C.T.F.); (V.M.-G.); (C.J.)
- Department of Pathology and Molecular Immunology, ICBAS–School of Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
| | - Rui Henrique
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), 4200-072 Porto, Portugal; (B.C.L.); (R.G.); (M.C.); (P.L.)
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (C.G.-T.); (B.C.T.F.); (V.M.-G.); (C.J.)
- Department of Pathology and Molecular Immunology, ICBAS–School of Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
- Correspondence: (R.H.); or (J.L.)
| | - João Lobo
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), 4200-072 Porto, Portugal; (B.C.L.); (R.G.); (M.C.); (P.L.)
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal; (C.G.-T.); (B.C.T.F.); (V.M.-G.); (C.J.)
- Department of Pathology and Molecular Immunology, ICBAS–School of Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513 Porto, Portugal
- Correspondence: (R.H.); or (J.L.)
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Braschi B, Seal RL, Tweedie S, Jones TE, Bruford EA. The risks of using unapproved gene symbols. Am J Hum Genet 2021; 108:1813-1816. [PMID: 34626580 DOI: 10.1016/j.ajhg.2021.09.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The use of approved nomenclature in publications is vital to enable effective scientific communication and is particularly crucial when discussing genes of clinical relevance. Here, we discuss several examples of cases where the failure of researchers to use a HUGO Gene Nomenclature Committee (HGNC)-approved symbol in publications has led to confusion between unrelated human genes in the literature. We also inform authors of the steps they can take to ensure that they use approved nomenclature in their manuscripts and discuss how referencing HGNC IDs can remove ambiguity when referring to genes that have previously been published with confusing alias symbols.
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25
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Budak Ö, Bostancı MS, Kurtoğlu E, Toprak V. Decreased ovarian reserve and ovarian morphological alterations in female rat offspring exposed to a ketogenic maternal diet. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2021; 67:1415-1420. [PMID: 35018968 DOI: 10.1590/1806-9282.20210518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 08/14/2021] [Indexed: 11/22/2022]
Abstract
OBJECTIVE This study evaluates the effects of a ketogenic diet on morphology and follicle reserve. METHOD Sixteen Sprague-Dawley rats were randomized into two groups: standard diet group (n=8) and ketogenic diet group (n=8). Rats were time mated. Dams were permitted to deliver spontaneously. The animals were monitored for the onset of puberty. All the rats were weighed and anesthetized, serum anti-Müllerian hormone level was measured, and the oviducts were removed. The morphological characteristics of follicles were determined and total ovarian volumes were calculated. RESULTS The mean ovarian volume was statistically significantly lower in the ketogenic diet group compared to the standard diet group (14.41±0.99 mm3 versus 18.89±1.28 mm3) (p=0.000). The mean number of antral follicles was 13.63±1.80 in the standard diet group and 4.462±0.760 in the ketogenic diet group. The mean ovarian weight of the ketogenic diet group was significantly lower than that of the standard diet group (0.42±0.06 g versus 0.815±107 g). The mean anti-Müllerian hormone levels were significantly higher in the standard diet group compared to the ketogenic diet group (1.023±4.75 ng/mL versus 0.69±0.07 ng/mL) (p=0.000). The mean percentage of staining of Ki-67 was 35.28±4.75 in the standard diet group and 16.98±3.33 in the ketogenic diet group (p=0.000). CONCLUSION Maternal ketogenic diet reduces ovarian follicular reserve in female offspring and has important implications for maintaining reproductive potential at a population level.
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Affiliation(s)
- Özcan Budak
- Sakarya University, Faculty of Medicine, Department of Histology and Embryology and Artificial Reproductive Techniques - Sakarya, Turkey
| | - Mehmet Sühha Bostancı
- Sakarya University, Faculty of Medicine, Department of Obstetrics and Gynecology and Artificial Reproductive Techniques - Sakarya, Turkey
| | - Erdal Kurtoğlu
- Erciyes University, Faculty of Medicine, Department of Anatomy - Kayseri, Turkey
| | - Veysel Toprak
- Private Tatvan Can Hospital, Department of Obstetrics and Gynecology - Bitlis, Turkey
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26
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Davey MG, Hynes SO, Kerin MJ, Miller N, Lowery AJ. Ki-67 as a Prognostic Biomarker in Invasive Breast Cancer. Cancers (Basel) 2021; 13:4455. [PMID: 34503265 PMCID: PMC8430879 DOI: 10.3390/cancers13174455] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/31/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022] Open
Abstract
The advent of molecular medicine has transformed breast cancer management. Breast cancer is now recognised as a heterogenous disease with varied morphology, molecular features, tumour behaviour, and response to therapeutic strategies. These parameters are underpinned by a combination of genomic and immunohistochemical tumour factors, with estrogen receptor (ER) status, progesterone receptor (PgR) status, human epidermal growth factor receptor-2 (HER2) status, Ki-67 proliferation indices, and multigene panels all playing a contributive role in the substratification, prognostication and personalization of treatment modalities for each case. The expression of Ki-67 is strongly linked to tumour cell proliferation and growth and is routinely evaluated as a proliferation marker. This review will discuss the clinical utility, current pitfalls, and promising strategies to augment Ki-67 proliferation indices in future breast oncology.
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Affiliation(s)
- Matthew G. Davey
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland, H91 YR71 Galway, Ireland; (M.J.K.); (N.M.); (A.J.L.)
- Department of Surgery, Galway University Hospitals, H91 YR71 Galway, Ireland
| | - Sean O. Hynes
- Department of Histopathology, National University of Ireland, H91 YR71 Galway, Ireland;
| | - Michael J. Kerin
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland, H91 YR71 Galway, Ireland; (M.J.K.); (N.M.); (A.J.L.)
| | - Nicola Miller
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland, H91 YR71 Galway, Ireland; (M.J.K.); (N.M.); (A.J.L.)
| | - Aoife J. Lowery
- Discipline of Surgery, The Lambe Institute for Translational Research, National University of Ireland, H91 YR71 Galway, Ireland; (M.J.K.); (N.M.); (A.J.L.)
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27
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Remnant L, Kochanova NY, Reid C, Cisneros-Soberanis F, Earnshaw WC. The intrinsically disorderly story of Ki-67. Open Biol 2021; 11:210120. [PMID: 34375547 PMCID: PMC8354752 DOI: 10.1098/rsob.210120] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 07/13/2021] [Indexed: 01/14/2023] Open
Abstract
Ki-67 is one of the most famous marker proteins used by histologists to identify proliferating cells. Indeed, over 30 000 articles referring to Ki-67 are listed on PubMed. Here, we review some of the current literature regarding the protein. Despite its clinical importance, our knowledge of the molecular biology and biochemistry of Ki-67 is far from complete, and its exact molecular function(s) remain enigmatic. Furthermore, reports describing Ki-67 function are often contradictory, and it has only recently become clear that this proliferation marker is itself dispensable for cell proliferation. We discuss the unusual organization of the protein and its mRNA and how they relate to various models for its function. In particular, we focus on ways in which the intrinsically disordered structure of Ki-67 might aid in the assembly of the still-mysterious mitotic chromosome periphery compartment by controlling liquid-liquid phase separation of nucleolar proteins and RNAs.
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Affiliation(s)
- Lucy Remnant
- Wellcome Centre for Cell Biology, University of Edinburgh, ICB, Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK
| | - Natalia Y. Kochanova
- Wellcome Centre for Cell Biology, University of Edinburgh, ICB, Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK
| | - Caitlin Reid
- Wellcome Centre for Cell Biology, University of Edinburgh, ICB, Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK
| | - Fernanda Cisneros-Soberanis
- Wellcome Centre for Cell Biology, University of Edinburgh, ICB, Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK
| | - William C. Earnshaw
- Wellcome Centre for Cell Biology, University of Edinburgh, ICB, Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK
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28
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Fouda MA, Day EL, Zurakowski D, Scott RM, Smith ER, Marcus KJ, Fehnel KP. Predictors of progression in radiation-induced versus nonradiation-induced pediatric meningiomas: a large single-institution surgical experience. J Neurosurg Pediatr 2021; 28:160-166. [PMID: 34116509 DOI: 10.3171/2021.1.peds20819] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/11/2021] [Indexed: 11/06/2022]
Abstract
OBJECTIVE The goal in this study was to outline unique differences between radiation-induced and nonradiation-induced pediatric meningiomas and to identify independent risk factors of tumor recurrence/progression. METHODS This is a retrospective cohort study of all pediatric meningiomas diagnosed and surgically treated at the authors' institution between 1993 and 2017. Multivariable Cox regression was applied to identify independent risk factors for tumor recurrence/progression. RESULTS Thirty-five patients were identified. The primary etiology was nonradiation-induced (n = 24: n = 3 with neurofibromatosis type 2) or radiation-induced (n = 11: acute lymphoblastic leukemia [n = 5], medulloblastoma [n = 4], germ cell tumor [n = 1], and primitive neuroectodermal tumor [n = 1]) meningioma. The mean age at time of diagnosis was 10.7 ± 5.7 years for nonradiation-induced and 17.3 ± 3.5 years for radiation-induced meningiomas. Overall, 8/24 patients with nonradiation-induced meningioma experienced either recurrence or progression of the tumor. Of the 8 patients with tumor recurrence or progression, the pathological diagnosis was clear cell meningioma (n = 3: 2 recurrent and 1 progressive); grade I (n = 2 progressive); grade I with atypical features (n = 2: 1 recurrent and 1 progressive); or atypical meningioma (n = 1 recurrent). None of the patients with radiation-induced meningioma experienced recurrence or progression. Predictors of tumor recurrence/progression by univariate analysis included age at time of diagnosis ≤ 10 years (p = 0.002), histological subtype clear cell meningioma (p = 0.003), and primary etiology nonradiation-induced meningioma (p = 0.04), and there was a notable trend with elevated MIB-1 staining index (SI) (p = 0.09). There was no significant difference between nonradiation-induced and radiation-induced meningiomas (p = 0.258), although there was a trend between recurrent and nonrecurrent meningiomas (p = 0.09). Multivariate Cox regression, adjusted for length of follow-up, identified younger age at diagnosis (p = 0.004) and a higher MIB-1 SI (p = 0.044) as independent risk factors for recurrence. Elevated MIB-1 SI statistically correlated with atypia (p < 0.001). However, there was no significant statistical correlation between tumor recurrence/progression and atypia (p = 0.2). CONCLUSIONS Younger patient age and higher MIB-1 SI are independent risk factors for recurrence. Atypia was not a predictor of recurrence.
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Affiliation(s)
| | - Emily L Day
- 1Department of Neurosurgery, Boston Children's Hospital
| | - David Zurakowski
- 2Division of Biostatistics, Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children's Hospital
| | | | - Edward R Smith
- 1Department of Neurosurgery, Boston Children's Hospital
- 4Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts
| | - Karen J Marcus
- 3Division of Radiation Oncology, Boston Children's Hospital; and
- 4Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts
| | - Katie P Fehnel
- 1Department of Neurosurgery, Boston Children's Hospital
- 4Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts
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Lai S, Long X, Wu P, Liu J, Seery S, Hou H, Liu M, Li Y, Wang J. Developing a nomogram for predicting intravesical recurrence after radical nephroureterectomy: a retrospective cohort study of mainland Chinese patients. Jpn J Clin Oncol 2021; 51:1132-1141. [PMID: 33634310 DOI: 10.1093/jjco/hyab017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE To evaluate the role of Ki-67 in predicting subsequent intravesical recurrence following radical nephroureterectomy and to develop a predictive nomogram for upper tract urothelial carcinoma patients. METHODS This retrospective analysis involved 489 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy with bladder cuff excision. The data set was randomly split into a training cohort of 293 patients and a validation cohort of 196 patients. Immunohistochemical analysis was used to assess the immunoreactivity of the biomarker Ki-67 in the tumor tissues. A multivariable Cox regression model was utilized to identify independent intravesical recurrence predictors after radical nephroureterectomy before constructing a nomographic model. Predictive accuracy was quantified using time-dependent receiver operating characteristic curve. Decision curve analysis was performed to evaluate the clinical benefit of models. RESULTS With a median follow-up of 54 months, intravesical recurrence developed in 28.2% of this sample (n = 137). Tumor location, multifocality, pathological T stage, surgical approach, bladder cancer history and Ki-67 expression levels were independently associated with intravesical recurrence (all P < 0.05). The full model, which intercalated Ki-67 with traditional clinicopathological parameters, outperformed both the basic model and Xylinas' model in terms of discriminative capacity (all P < 0.05). Decision-making analysis suggests that the more comprehensive model can also improve patients' net benefit. CONCLUSIONS This new model, which intercalates the Ki-67 biomarker with traditional clinicopathological factors, appears to be more sensitive than nomograms previously tested across mainland Chinese populations. The findings suggest that Ki-67 could be useful for determining risk-stratified surveillance protocols following radical nephroureterectomy and in generating an individualized strategy based around intravesical recurrence predictions.
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Affiliation(s)
- Shicong Lai
- Department of Urology, Beijing Hospital, Beijing, China.,National Center of Gerontology, Beijing, China.,Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.,Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xingbo Long
- Department of Urology, Beijing Hospital, Beijing, China.,National Center of Gerontology, Beijing, China.,Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.,Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Pengjie Wu
- Department of Urology, Beijing Hospital, Beijing, China.,National Center of Gerontology, Beijing, China.,Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Jianyong Liu
- Department of Urology, Beijing Hospital, Beijing, China.,National Center of Gerontology, Beijing, China.,Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.,Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Samuel Seery
- School of Humanities and Social Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Division of Health Research, Faculty of Health and Medicine, Lancaster University, Lancaster, UK
| | - Huimin Hou
- Department of Urology, Beijing Hospital, Beijing, China.,National Center of Gerontology, Beijing, China.,Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Ming Liu
- Department of Urology, Beijing Hospital, Beijing, China.,National Center of Gerontology, Beijing, China.,Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.,Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yuan Li
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Jianye Wang
- Department of Urology, Beijing Hospital, Beijing, China.,National Center of Gerontology, Beijing, China.,Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.,Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Seki H, Higeta K, Sakurai T, Sakurada A, Kinoshita T, Shimizu K. Feasibility Study of Nanoparticle Albumin-Bound-Paclitaxel and S-1 Followed by Epirubicin/Cyclophosphamide as Neoadjuvant Chemotherapy in Patients With Operable Breast Cancer: A Prospective Study. Clin Breast Cancer 2021; 22:235-243. [PMID: 34289949 DOI: 10.1016/j.clbc.2021.06.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/10/2021] [Accepted: 06/13/2021] [Indexed: 11/03/2022]
Abstract
BACKGROUND The efficacy and safety of nanoparticle albumin-bound (nab)-paclitaxel combined with S-1 in patients with operable breast cancer is uncertain. We evaluated the feasibility of this combination followed by epirubicin/cyclophosphamide (EC) as neoadjuvant chemotherapy in such patients. PATIENTS AND METHODS This was an open-label, single-arm, phase II, single-institution prospective study of 4 cycles of nab-paclitaxel (260 mg/m2) administered intravenously on day 1 in combination with S-1 (65 mg/m2 orally twice daily) on days 1 to 14 every 21 days followed by EC as neoadjuvant chemotherapy. RESULTS Of 30 patients, 1 required a dose interruption for nab-paclitaxel combined with S-1; 4 required a dose reduction for nab-paclitaxel, 1 for S-1, and 4 for EC. Mean relative dose intensities of nab-paclitaxel, S-1, and EC were 98.0%, 99.3%, and 98.2%, respectively. Overall clinical response rate was 96.7%. In histological response, grade 3, pathological complete response (pCR; ypT0/is and ypN0) rate was 63.3% and grade 2b (near pCR) was 3.3%. pCR was observed in 57.1% of luminal B human epidermal growth factor receptor type 2 (HER2)-negative patients, 55.6% of luminal B HER2-positive patients, 100% of HER2-positive patients, and 57.1% of triple-negative breast cancer patients. Grade 3/4 neutropenia was observed in 1 patient during nab-paclitaxel combined with S-1 and in 7 during EC treatments. The most frequent nonhematological severe adverse events were grade 3 peripheral neuropathy in 2 patients and grade 3 arthralgia in 2 patients during nab-paclitaxel combined with S-1. CONCLUSION Tri-weekly nab-paclitaxel with S-1 followed by EC is effective and well tolerated as neoadjuvant chemotherapy in patients with operable breast cancer.
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Affiliation(s)
- Hirohito Seki
- Department of Breast Surgery, Saitama Medical Center, Saitama, Japan.
| | - Kaori Higeta
- Department of Pharmacy, Saitama Medical Center, Saitama, Japan
| | - Takashi Sakurai
- Department of Breast Surgery, Saitama Medical Center, Saitama, Japan
| | - Akihisa Sakurada
- Department of Breast Surgery, Saitama Medical Center, Saitama, Japan
| | | | - Ken Shimizu
- Department of Pathology, Saitama Medical Center, Saitama, Japan
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Gerigk M, Bulstrode H, Shi HH, Tönisen F, Cerutti C, Morrison G, Rowitch D, Huang YYS. On-chip perivascular niche supporting stemness of patient-derived glioma cells in a serum-free, flowable culture. LAB ON A CHIP 2021; 21:2343-2358. [PMID: 33969368 PMCID: PMC8204159 DOI: 10.1039/d1lc00271f] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/03/2021] [Indexed: 05/05/2023]
Abstract
Glioblastoma multiforme (GBM) is the most common and the most aggressive type of primary brain malignancy. Glioblastoma stem-like cells (GSCs) can migrate in vascular niches within or away from the tumour mass, increasing tumour resistance to treatments and contributing to relapses. To study individual GSC migration and their interactions with the perivasculature of the tumour microenvironment, there is a need to develop a human organotypic in vitro model. Herein, we demonstrated a perivascular niche-on-a-chip, in a serum-free condition with gravity-driven flow, that supported the stemness of patient-derived GSCs and foetal neural stem cells grown in a three-dimensional environment (3D). Endothelial cells from three organ origins, (i) human brain microvascular endothelial cells (hCMEC/D3), (ii) human umbilical vein endothelial cells (HUVECs) and, (iii) human lung microvascular endothelial cells (HMVEC-L) formed rounded microvessels within the extracellular-matrix integrated microfluidic chip. By optimising cell extraction protocols, systematic studies were performed to evaluate the effects of serum-free media, 3D cell cultures, and the application of gravity-driven flow on the characteristics of endothelial cells and their co-culture with GSCs. Our results showed the maintenance of adherent and tight junction markers of hCMEC/D3 in the serum-free culture and that gravity-driven flow was essential to support adequate viability of both the microvessel and the GSCs in co-culture (>80% viability at day 3). Endpoint biological assays showed upregulation of neovascularization-related genes (e.g., angiopoietins, vascular endothelial growth factor receptors) in endothelial cells co-cultured with GSCs in contrast to the neural stem cell reference that showed insignificant changes. The on-chip platform further permitted live-cell imaging of GSC - microvessel interaction, enabling quantitative analysis of GSC polarization and migration. Overall, our comparative genotypic (i.e. qPCR) and phenotypic (i.e. vessel permeability and GSC migration) studies showed that organotypic (brain cancer cells-brain endothelial microvessel) interactions differed from those within non-tissue specific vascular niches of human origin. The development and optimization of this on-chip perivascular niche, in a serum-free flowable culture, could provide the next level of complexity of an in vitro system to study the influence of glioma stem cells on brain endothelium.
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Affiliation(s)
- Magda Gerigk
- Department of Engineering, University of Cambridge, UK. and The Nanoscience Centre, University of Cambridge, UK
| | - Harry Bulstrode
- Department of Clinical Neuroscience, University of Cambridge, UK
| | - HaoTian Harvey Shi
- Department of Mechanical & Industrial Engineering, University of Toronto, Canada and Department of Engineering, University of Cambridge, UK.
| | - Felix Tönisen
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboudumc, Netherlands and Department of Engineering, University of Cambridge, UK.
| | - Camilla Cerutti
- Randall Centre of Cell & Molecular Biophysics, King's College London, UK
| | | | - David Rowitch
- Department of Paediatrics, University of Cambridge, UK
| | - Yan Yan Shery Huang
- Department of Engineering, University of Cambridge, UK. and The Nanoscience Centre, University of Cambridge, UK
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Sanaksenaho G, Mutanen A, Godbole N, Hukkinen M, Merras-Salmio L, Kivisaari R, Kyrönlahti A, Pihlajoki M, Lohi J, Heikinheimo M, Pakarinen MP. Compromised duodenal mucosal integrity in children with short bowel syndrome after adaptation to enteral autonomy. J Pediatr Surg 2021; 56:966-974. [PMID: 33131778 DOI: 10.1016/j.jpedsurg.2020.09.065] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/23/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Intestinal adaptation has been extensively studied experimentally, but very limited data is available on human subjects. In this study we assessed intestinal adaption in humans with short bowel syndrome (SBS). METHODS We comparatively evaluated mucosal hyperplasia, inflammation, barrier function and nutrient transport using histology, immunohistochemistry and qPCR for selected 52 key genes in duodenal biopsies obtained from children with SBS after weaning off parenteral nutrition (n = 33), and matched controls without intestinal pathology (n = 12). Small bowel dilatation was assessed from contrast small bowel series. RESULTS Duodenal mucosa of SBS children showed increased histologic inflammation of lamina propria (p = 0.033) and mucosal mRNA expression of tumor necrosis factor (p = 0.027), transforming growth factor (TGF)-β2 (p = 0.006) and caveolin-1 (CAV1; p = 0.001). Villus height, crypt depth, enterocyte proliferation, apoptosis and expression of proliferation and nutrient transport genes remained unchanged. Pathologic small bowel dilatation reduced crypt depth (p = 0.045) and downregulated mRNA expression of interleukin (IL)-6 by three-fold (p = 0.008), while correlating negatively with IL6 (r = -0.609, p = 0.004). Loss of ileocecal valve (ICV) upregulated mRNA expression of toll-like receptor 4 (TLR4), TGF-β1, CAV1, several apoptosis regulating genes, and mRNA expression of zonulin (p < 0.05 for all). CONCLUSIONS Despite successful adaptation to enteral autonomy, duodenal mucosa of SBS children displayed histologic and molecular signs of abnormal inflammation and regulation of epithelial permeability, whereas no structural or molecular signs of adaptive hyperplasia or enhanced nutrient transport were observed. Excessive dilatation of the remaining small bowel paralleled impaired duodenal crypt homeostasis, while absence of ICV modified regulation of mucosal inflammation, regeneration and permeability. LEVEL OF EVIDENCE II.
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Affiliation(s)
- Galina Sanaksenaho
- Division of Pediatric Surgery, Pediatric Liver and Gut Research Group, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Annika Mutanen
- Division of Pediatric Surgery, Pediatric Liver and Gut Research Group, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Nimish Godbole
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Maria Hukkinen
- Division of Pediatric Surgery, Pediatric Liver and Gut Research Group, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Laura Merras-Salmio
- Department of Pediatric Gastroenterology, Pediatric Liver and Gut Research Group, Children's Hospital, Pediatric Research Centre, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Reetta Kivisaari
- HUS Medical Imaging Center, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Antti Kyrönlahti
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Marjut Pihlajoki
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jouko Lohi
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Markku Heikinheimo
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Mikko P Pakarinen
- Division of Pediatric Surgery, Pediatric Liver and Gut Research Group, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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Parry S, Dowsett M, Dodson A. UK NEQAS ICC & ISH Ki-67 Data Reveal Differences in Performance of Primary Antibody Clones. Appl Immunohistochem Mol Morphol 2021; 29:86-94. [PMID: 33337635 PMCID: PMC7993918 DOI: 10.1097/pai.0000000000000899] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 11/16/2020] [Indexed: 01/09/2023]
Abstract
We examined data from 374 laboratories staining for Ki-67 as part of external quality assessment over 8 runs between 2013 and 2017 (total data sets=2601). One of 5 primary antibodies was used for 94.8% of submissions, with MIB-1 (Agilent Dako) comprising 58.8% of the total. Examining assessment score as a continuous variable showed the 30-9 (Ventana) and K2 (Leica Biosystems) clones were associated with the highest mean scores (17.0; 95% confidence interval, 16.8-17.2 and 16.3; 95% confidence interval, 15.9-16.6, respectively). Stain quality was not significantly different between them. Both were associated with significantly better staining compared with MIB-1 (Agilent Dako), MM1 (Leica Biosystems), and SP6 from various suppliers (P<0.05). Similarly, categorical assessment of "Good" versus "Not good" staining quality showed that the 30-9 and K2 clones were both significantly associated with "Good" staining (both P<0.001). Other methodological parameters were examined for significant primary antibody-specific effects; none were seen for 30-9, K2, or SP6. The MM1 clone was more likely to be associated with good quality staining when it was used with Leica Biosystems sourced antigen retrieval, detection, and platform, all statistically significant at P<0.01. MIB-1 was more likely to be associated with good quality staining results when it was used with Agilent Dako antigen retrieval, detection, and staining platforms (P<0.0001), and less likely at the same significance level when used with Leica Biosystems reagents and equipment. The data presented here show the importance of not just primary antibody choice but also matching that choice to other methodological factors.
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Affiliation(s)
- Suzanne Parry
- UK National External Quality Assessment Scheme for Immunocytochemistry and In-Situ Hybridisation
| | - Mitch Dowsett
- Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK
| | - Andrew Dodson
- UK National External Quality Assessment Scheme for Immunocytochemistry and In-Situ Hybridisation
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Martino F, Varricchio S, Russo D, Merolla F, Ilardi G, Mascolo M, dell’Aversana GO, Califano L, Toscano G, De Pietro G, Frucci M, Brancati N, Fraggetta F, Staibano S. A Machine-learning Approach for the Assessment of the Proliferative Compartment of Solid Tumors on Hematoxylin-Eosin-Stained Sections. Cancers (Basel) 2020; 12:cancers12051344. [PMID: 32466184 PMCID: PMC7281627 DOI: 10.3390/cancers12051344] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 05/20/2020] [Indexed: 01/19/2023] Open
Abstract
We introduce a machine learning-based analysis to predict the immunohistochemical (IHC) labeling index for the cell proliferation marker Ki67/MIB1 on cancer tissues based on morphometrical features extracted from hematoxylin and eosin (H&E)-stained formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples. We provided a proof-of-concept prediction of the Ki67/MIB1 IHC positivity of cancer cells through the definition and quantitation of single nuclear features. In the first instance, we set our digital framework on Ki67/MIB1-stained OSCC (oral squamous cell carcinoma) tissue sample whole slide images, using QuPath as a working platform and its integrated algorithms, and we built a classifier in order to distinguish tumor and stroma classes and, within them, Ki67-positive and Ki67-negative cells; then, we sorted the morphometric features of tumor cells related to their Ki67 IHC status. Among the evaluated features, nuclear hematoxylin mean optical density (NHMOD) presented as the best one to distinguish Ki67/MIB1 positive from negative cells. We confirmed our findings in a single-cell level analysis of H&E staining on Ki67-immunostained/H&E-decolored tissue samples. Finally, we tested our digital framework on a case series of oral squamous cell carcinomas (OSCC), arranged in tissue microarrays; we selected two consecutive sections of each OSCC FFPE TMA (tissue microarray) block, respectively stained with H&E and immuno-stained for Ki67/MIB1. We automatically detected tumor cells in H&E slides and generated a “false color map” (FCM) based on NHMOD through the QuPath measurements map tool. FCM nearly coincided with the actual immunohistochemical result, allowing the prediction of Ki67/MIB1 positive cells in a direct visual fashion. Our proposed approach provides the pathologist with a fast method of identifying the proliferating compartment of the tumor through a quantitative assessment of the nuclear features on H&E slides, readily appreciable by visual inspection. Although this technique needs to be fine-tuned and tested on larger series of tumors, the digital analysis approach appears to be a promising tool to quickly forecast the tumor’s proliferation fraction directly on routinely H&E-stained digital sections.
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Affiliation(s)
- Francesco Martino
- Department of Advanced Biomedical Sciences, Pathology Unit, University of Naples Federico II, 80131 Naples, Italy; (F.M.); (S.V.); (G.I.); (M.M.); (S.S.)
| | - Silvia Varricchio
- Department of Advanced Biomedical Sciences, Pathology Unit, University of Naples Federico II, 80131 Naples, Italy; (F.M.); (S.V.); (G.I.); (M.M.); (S.S.)
| | - Daniela Russo
- Department of Advanced Biomedical Sciences, Pathology Unit, University of Naples Federico II, 80131 Naples, Italy; (F.M.); (S.V.); (G.I.); (M.M.); (S.S.)
- Correspondence: (D.R.); (F.M.)
| | - Francesco Merolla
- Department of Medicine and Health Sciences “V. Tiberio”, University of Molise, 86100 Campobasso, Italy
- Correspondence: (D.R.); (F.M.)
| | - Gennaro Ilardi
- Department of Advanced Biomedical Sciences, Pathology Unit, University of Naples Federico II, 80131 Naples, Italy; (F.M.); (S.V.); (G.I.); (M.M.); (S.S.)
| | - Massimo Mascolo
- Department of Advanced Biomedical Sciences, Pathology Unit, University of Naples Federico II, 80131 Naples, Italy; (F.M.); (S.V.); (G.I.); (M.M.); (S.S.)
| | | | - Luigi Califano
- Department of Maxillofacial Surgery, University of Naples “Federico II”, 80131 Naples, Italy; (G.O.d’A.); (L.C.)
| | - Guglielmo Toscano
- Healthcare Informatics Services, A.O.U. Federico II, 80131 Naples, Italy;
| | - Giuseppe De Pietro
- Institute for High Performance Computing and Networking of National Research Council of Italy, ICAR-CNR, 80131 Naples, Italy; (G.D.P.); (M.F.); (N.B.)
| | - Maria Frucci
- Institute for High Performance Computing and Networking of National Research Council of Italy, ICAR-CNR, 80131 Naples, Italy; (G.D.P.); (M.F.); (N.B.)
| | - Nadia Brancati
- Institute for High Performance Computing and Networking of National Research Council of Italy, ICAR-CNR, 80131 Naples, Italy; (G.D.P.); (M.F.); (N.B.)
| | - Filippo Fraggetta
- Pathology Unit, Azienda Ospedaliera per l’Emergenza Cannizzaro Hospital, 95126 Catania, Italy;
| | - Stefania Staibano
- Department of Advanced Biomedical Sciences, Pathology Unit, University of Naples Federico II, 80131 Naples, Italy; (F.M.); (S.V.); (G.I.); (M.M.); (S.S.)
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35
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Kwon SM, Kim JH, Yoo HJ, Kim YH, Hong SH, Cho YH, Kim CJ, Nam SJ. Predictive factors for high-grade transformation in benign meningiomas. Clin Neurol Neurosurg 2020; 195:105897. [PMID: 32505062 DOI: 10.1016/j.clineuro.2020.105897] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/11/2020] [Accepted: 05/03/2020] [Indexed: 12/23/2022]
Abstract
OBJECTIVE Although they are generally slow-growing benign tumors, meningiomas may recur after surgery with transformation into atypical meningiomas. The purpose of this study was to investigate the radiological and histopathological factors that predict the risk of tumor progression from a benign to an atypical meningioma. PATIENTS AND METHODS All patients treated for recurrent meningiomas in whom the tumor showed histopathologically confirmed high-grade transformation (HGT) from a benign to an atypical meningioma between 2001 and 2017 were included. To evaluate the predictors of transformation, patient medical records documenting the diagnosis of a benign meningioma at the first surgery prior to second surgery with HGT were reviewed. Each patient was matched with four age- and sex-matched controls who were treated for a benign meningioma. The control group comprised all patients without any recurrence for at least 60 months. RESULTS Fourteen patients with benign meningioma underwent HGT and were included. The median time interval of transformation was 63 months (range, 19-132 months). Multivariate analysis indicated that an increased mitotic index (odds ratio [OR], 10.409; 95 % confidence interval [CI], 1.297-83.549; P = 0.027) was a significant predictor of transformation. Prominent peritumoral edema (OR, 33.822; 95 % CI, 0.935-223.688; P = 0.054) did not reach the statistical significance. CONCLUSION An increased mitotic index may be used as the predictor for HGT of benign meningiomas. Although these tumors with a high risk for transformation do not meet the diagnostic criteria for atypical meningiomas, they may require more attentive observation and management than other benign meningiomas.
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Affiliation(s)
- Sae Min Kwon
- Department of Neurosurgery, Dongsan Medical Center, Keimyung University School of Medicine, Daegu, South Korea
| | - Jeong Hoon Kim
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
| | - Hee Jun Yoo
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Young-Hoon Kim
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Seok Ho Hong
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Young Hyun Cho
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chang Jin Kim
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Soo Jeong Nam
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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36
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Liang Q, Ma D, Gao RF, Yu KD. Effect of Ki-67 Expression Levels and Histological Grade on Breast Cancer Early Relapse in Patients with Different Immunohistochemical-based Subtypes. Sci Rep 2020; 10:7648. [PMID: 32376868 PMCID: PMC7203155 DOI: 10.1038/s41598-020-64523-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 04/09/2020] [Indexed: 12/17/2022] Open
Abstract
This retrospective analysis evaluated the interaction between Ki-67 and histological grade and their prognostic role in different breast cancer subtypes. In total, 2,573 breast cancer patients underwent surgery, and their histological grade and Ki-67 values were evaluated by breast pathologists. The median Ki-67 index was 15%, which was used as the cut-off for low/high Ki-67 expression. Recurrence-free survival (RFS) was calculated and compared, and the results indicated that Ki-67 expression was significantly associated with histological grade in all breast cancer patients (p < 0.001) and in each immunohistochemical (IHC)-based subtype (p < 0.001). Both high Ki-67 expression and grade 3 tumours were independent predictors of inferior RFS in all patients, especially in those with luminal-like tumours (p < 0.05). Ki-67 was an independent prognostic factor for RFS in grade 1, 2 patients with luminal-like tumours (adjusted hazard ratio [HR] = 1.92, 95% confidence interval [CI]: 1.22-3.03, p = 0.005), but not in the other subtypes. Similarly, histological grade predicted shorter RFS in patients with low Ki-67 expression who had luminal-like tumours (adjusted HR = 2.12, 95% CI: 1.13-3.99, p = 0.02) but not in the other subtypes. Conversely, Ki-67 showed no prognostic value for patients with grade 3 tumours and vice versa.
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Affiliation(s)
- Qin Liang
- Department of Breast Surgery, Shanxi Provincial People's Hospital, Shanxi Medical University, Taiyuan, P.R. China
| | - Ding Ma
- Department of Breast Surgery, Cancer Center and Cancer Institute, Fudan University, Shanghai, P.R. China
| | - Run-Fang Gao
- Department of Breast Surgery, Shanxi Provincial People's Hospital, Shanxi Medical University, Taiyuan, P.R. China
| | - Ke-Da Yu
- Department of Breast Surgery, Cancer Center and Cancer Institute, Fudan University, Shanghai, P.R. China.
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37
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Wei Q, Huang L, Li J, Chen B, Xie B, Teng H, Chen L, Jiang Y. The beneficial effects of Agaricus blazei Murrill on hepatic antioxidant enzymes and the pancreatic tissue recovery in streptozotocin-induced diabetic rats. J Food Biochem 2020; 44:e13170. [PMID: 32160646 DOI: 10.1111/jfbc.13170] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 02/01/2020] [Accepted: 02/05/2020] [Indexed: 12/12/2022]
Abstract
Agaricus blazei Murrill (ABM), is a medicinal mushroom, has beneficial effects on diabetes mellitus. In this study, ABM extracts (ethanol extract, EE and ethyl acetate extract, EA) were evaluated to explore the beneficial effect on hepatic antioxidant activity and recovery of the pancreatic tissue in streptozotocin-induced diabetic rats. The hepatic antioxidant activities of ABM extracts were analyzed by superoxide dismutase, catalase activity, glutathione, aspartate transaminase, and alanine transaminase. Moreover, the effects of ABM extracts on pancreatic tissue restoration were investigated by histopathological analysis. The results revealed that the EA showed a better protective effect on hepatic antioxidant activity and recovery of the impaired pancreatic tissues, compared to EE. The results suggested that ABM treatment could effectively reduce oxidative stress and contribute to pancreatic tissue recovery. Therefore, ABM could be used as a functional food to control diabetes. PRACTICAL APPLICATIONS: The research may contribute to the development of ABM as functional foods or dietary supplements for diabetes in the future.
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Affiliation(s)
- Qi Wei
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Linxiang Huang
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Jie Li
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Bingzhi Chen
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Baogui Xie
- Mycological Research Center, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Hui Teng
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Lei Chen
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Yuji Jiang
- College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, China
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38
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Gates EDH, Lin JS, Weinberg JS, Hamilton J, Prabhu SS, Hazle JD, Fuller GN, Baladandayuthapani V, Fuentes D, Schellingerhout D. Guiding the first biopsy in glioma patients using estimated Ki-67 maps derived from MRI: conventional versus advanced imaging. Neuro Oncol 2020; 21:527-536. [PMID: 30657997 DOI: 10.1093/neuonc/noz004] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Undersampling of gliomas at first biopsy is a major clinical problem, as accurate grading determines all subsequent treatment. We submit a technological solution to reduce the problem of undersampling by estimating a marker of tumor proliferation (Ki-67) using MR imaging data as inputs, against a stereotactic histopathology gold standard. METHODS MR imaging was performed with anatomic, diffusion, permeability, and perfusion sequences, in untreated glioma patients in a prospective clinical trial. Stereotactic biopsies were harvested from each patient immediately prior to surgical resection. For each biopsy, an imaging description (23 parameters) was developed, and the Ki-67 index was recorded. Machine learning models were built to estimate Ki-67 from imaging inputs, and cross validation was undertaken to determine the error in estimates. The best model was used to generate graphical maps of Ki-67 estimates across the whole brain. RESULTS Fifty-two image-guided biopsies were collected from 23 evaluable patients. The random forest algorithm best modeled Ki-67 with 4 imaging inputs (T2-weighted, fractional anisotropy, cerebral blood flow, Ktrans). It predicted the Ki-67 expression levels with a root mean square (RMS) error of 3.5% (R2 = 0.75). A less accurate predictive result (RMS error 5.4%, R2 = 0.50) was found using conventional imaging only. CONCLUSION Ki-67 can be predicted to clinically useful accuracies using clinical imaging data. Advanced imaging (diffusion, perfusion, and permeability) improves predictive accuracy over conventional imaging alone. Ki-67 predictions, displayed as graphical maps, could be used to guide biopsy, resection, and/or radiation in the care of glioma patients.
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Affiliation(s)
- Evan D H Gates
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center (UT MDACC), Houston, Texas.,UT MDACC UTHealth Graduate School of Biomedical Sciences, Houston, Texas
| | - Jonathan S Lin
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center (UT MDACC), Houston, Texas.,Baylor College of Medicine, Houston, Texas.,Department of Bioengineering, Rice University, Houston, Texas
| | | | - Jackson Hamilton
- Department of Diagnostic Radiology, UT MDACC, Houston, Texas.,Radiology Partners, Houston, Texas
| | | | - John D Hazle
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center (UT MDACC), Houston, Texas
| | | | | | - David Fuentes
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center (UT MDACC), Houston, Texas
| | - Dawid Schellingerhout
- Department of Diagnostic Radiology, UT MDACC, Houston, Texas.,Department of Cancer Systems Imaging, UT MDACC, Houston, Texas
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39
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Al-Jaghthmi OHA, Zeid IELDMELAA. Hypoglycemic and hepatoprotective effect of Rhizophora mucronata and Avicennia marina against streptozotocin-induced diabetes in male rats. J Adv Vet Anim Res 2020; 7:177-185. [PMID: 32219125 PMCID: PMC7096112 DOI: 10.5455/javar.2020.g408] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 12/25/2019] [Accepted: 12/30/2019] [Indexed: 11/25/2022] Open
Abstract
Objectives: Aqueous extracts of Rhizophora mucronata and Avicennia marina leaves were investigated for their hepatoprotective potential in diabetic rats. Materials and methods: One hundred twenty male albino rats were randomly assigned to eight equal groups (n = 15). The first group (control) comprised normal healthy rats, while the second to fifth groups were intraperitoneally injected with a single dose of streptozotocin (STZ) [60 mg/kg body weight (BW)] for induction of diabetes. Group 2 was kept as positive diabetic control, while groups 3–5 were orally treated with aqueous extracts of R. mucronata (400 mg/kg BW), A. marina (400 mg/kg BW) and with a combination of ½ a dose of the two plants, respectively, for six weeks. Groups 6–8 were non-diabetic rats that orally received aqueous extracts of R. mucronata (400 mg/kg BW), A. marina (400 mg/kg BW), and a combination of ½ a dose of the two plants, respectively, for 6 weeks. Results: STZ-induced diabetic rats showed a significant reduction in serum glucose and liver enzymes, increased serum insulin, Homeostasis Model Assessment of β-cells (HOMA-β), and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). Histopathological and immunohistochemical examinations of the liver revealed improved pathologic criteria in the plant extract treated diabetic rats compared with the remarkable changes which had been seen in STZ-induced diabetic rats. Conclusion: This study suggests that the aqueous extract of R. mucronata or its combination with A. marina showed potent hypoglycemic and hepatoprotective effects for liver dysfunction, as well as histopathological and immunohistochemical changes in the liver of STZ-induced diabetic rats.
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Affiliation(s)
| | - Isam ELDin Mohamed ELAmin Abu Zeid
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.,Princess Dr. Najla Bint Saud Al-Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah, Saudi Arabia
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40
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Sanaksenaho G, Mutanen A, Godbole N, Kyrönlahti A, Koivusalo A, Lohi J, Pihlajoki M, Heikinheimo M, Pakarinen MP. Parenteral Nutrition-Dependent Children With Short-Bowel Syndrome Lack Duodenal-Adaptive Hyperplasia but Show Molecular Signs of Altered Mucosal Function. JPEN J Parenter Enteral Nutr 2020; 44:1291-1300. [PMID: 31985858 DOI: 10.1002/jpen.1763] [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: 09/01/2019] [Revised: 10/30/2019] [Accepted: 12/04/2019] [Indexed: 11/09/2022]
Abstract
BACKGROUND Although adaptive mucosal growth of the remaining small intestine is an essential compensatory mechanism to bowel resection in experimental short-bowel syndrome (SBS), only scarce clinical data are available. We studied structural and molecular mechanisms of intestinal adaptation in children with SBS. METHODS Fourteen patients, who had been dependent on parenteral nutrition (PN) since neonatal period for a median (interquartile range)1.4 (0.7-6.5) years, were studied at the age of 1.5 (1.0-6.5) years. Median length of remaining small bowel was 33 (12-60) cm, and 6 patients had their ileocecal valve preserved. Six children without gastrointestinal disorders served as age-matched and gender-matched controls. All patients underwent duodenal biopsies. Mucosal microarchitecture, proliferation, apoptosis, inflammation, and epithelial-barrier function were addressed using histology, immunohistochemistry, and quantitative real-time polymerase chain reaction. RESULTS Villus height, crypt depth, enterocyte proliferation, and apoptosis were similar in patients and matched controls. Messenger RNA (mRNA) expression of numerous genes regulating gut epithelial-barrier function (TGFB2, CAV1, CLDN1, MUC2, and NLRC4) was significantly altered. Of various nutrient transporters studied, only expression of SLC2A1 encoding facilitative glucose transporter GLUT1 was increased among patients, whereas RNA expression of genes encoding sodium-dependent glucose, sterol, fatty-acid, and peptide transport remained unchanged. CONCLUSION Duodenal mucosal hyperplasia has a limited role in mediating physiological adaptation following intestinal resection among PN-dependent children with SBS. Further clinical studies addressing functional significance of the observed alterations in mucosal RNA expression are warranted.
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Affiliation(s)
- Galina Sanaksenaho
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Annika Mutanen
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Nimish Godbole
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Antti Kyrönlahti
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Antti Koivusalo
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jouko Lohi
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Marjut Pihlajoki
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Markku Heikinheimo
- Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Mikko P Pakarinen
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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41
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Sakurai R, Kaira K, Miura Y, Sunaga N, Saito R, Oyama T, Hisada T, Yamada M. Clinical significance of topoisomerase-II expression in patients with advanced non-small cell lung cancer treated with amrubicin. Thorac Cancer 2020; 11:426-435. [PMID: 31901017 PMCID: PMC6997014 DOI: 10.1111/1759-7714.13289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/08/2019] [Accepted: 12/08/2019] [Indexed: 11/11/2022] Open
Abstract
Background Amrubicin chemotherapy is a treatment option for patients with non‐small cell lung cancer (NSCLC) after third‐line treatment in Japan. Although topoisomerase‐II (Topo‐II), a target of amrubicin, has been reported to be a prognostic or predictive marker for chemosensitivity and clinical outcomes in various types of malignancies, its effects in the Japanese population remain unknown. Methods Data regarding 44 patients with advanced NSCLC treated with amrubicin between April 2004 and May 2014 were retrospectively analyzed. We evaluated the expression levels of Topo‐II by immunohistochemical staining of tumor specimens obtained via biopsy or surgical resection. Results The majority of enrolled patients were men (68%) with a median age of 67 (range, 43–78) years. The most common histological type was adenocarcinoma (70%). High Topo‐II expression was observed in 13 (30%) of the 44 patients. The median progression‐free survival and overall survival (OS) durations were 1.8 and 8.8 months, respectively. While there was no significant association between Topo‐II expression and progression‐free survival, patients with low Topo‐II expression had significantly longer OS than did those with high Topo‐II expression. Good performance status and low expression of Topo‐II were all significantly associated with a favorable OS. Conclusion Low expression of Topo‐II was identified as an independent prognostic factor for longer survival in patients with NSCLC receiving amrubicin, a Topo‐II inhibitor. Key points
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Affiliation(s)
- Reiko Sakurai
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Kyoichi Kaira
- Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Hidaka, Japan
| | - Yosuke Miura
- Division of Allergy and Respiratory Medicine, Integrative Center of Internal Medicine, Gunma University Hospital, Maebashi, Japan
| | - Noriaki Sunaga
- Division of Allergy and Respiratory Medicine, Integrative Center of Internal Medicine, Gunma University Hospital, Maebashi, Japan
| | - Ryusei Saito
- Departments of Respiratory Medicine, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan
| | - Tetsunari Oyama
- Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Takeshi Hisada
- Gunma University Graduate School of Health Science, Maebashi, Japan
| | - Masanobu Yamada
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
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High Mib-1-score correlates with new cranial nerve deficits after surgery for frontal skull base meningioma. Neurosurg Rev 2019; 44:381-387. [PMID: 31834543 DOI: 10.1007/s10143-019-01222-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/01/2019] [Accepted: 12/06/2019] [Indexed: 12/13/2022]
Abstract
Postoperative new cranial nerve deficits comprise severe concomitant morbidity in skull base meningioma surgery. Therefore, long-term cranial nerve integrity represents an important outcome measure. In the current study, we analyzed our institutional database in order to identify risk factors for postoperative new cranial nerve morbidity in the course of frontobasal meningioma surgery. Between 2009 and 2017, 195 patients were surgically treated for frontobasal meningioma at the authors' institution. Postoperative cranial nerve function was assessed immediately after surgery as well as 12 months postoperatively. A univariate and multivariate analysis was performed to identify factors influencing favorable postoperative cranial nerve outcome. Tumors with histological Mib-1-labeling indices > 5% were associated with a significantly higher percentage of new cranial nerve deficits immediately after surgery compared with those with Mib-1-labeling indices ≤ 5% (39% versus 20%, p = 0.029). Elevated Mib-1-labeling indices could be correlated with high CD68-positive macrophage staining (54% for Mib-1 index > 5% versus 19% for Mib-1 index ≤ 5%, p = 0.001). Elevated Mib-1-labeling index correlates with initial new cranial nerve dysfunction after resection of frontal skull base meningioma. With regard to elevated CD68-positive macrophage staining in high Mib-1-positive meningiomas, initial postoperative new cranial nerve morbidity might partly reflect macrophage-based inflammatory immune responses.
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Liu W, Zhao ZM, Liu YL, Pan HF, Lin LZ. Weipiling ameliorates gastric precancerous lesions in Atp4a -/- mice. Altern Ther Health Med 2019; 19:318. [PMID: 31744486 PMCID: PMC6862855 DOI: 10.1186/s12906-019-2718-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 10/15/2019] [Indexed: 01/24/2023]
Abstract
Background Altered cellular metabolism is considered to be one of the hallmarks of cancer (Coller, Am J Pathol 184:4–17, 2014; Kim and Bae, Curr Opin Hematol 25:52–59, 2018). However, few studies have investigated the role of metabolism in the development of gastric precancerous lesions (GPLs). Weipiling (WPL), a traditional Chinese medicine formula for treatment of GPLs. In this study, we evaluated the amelioration of GPLs by WPL and investigated the possible role of WPL in regulating glucose metabolism. Methods Firstly, the major components of WPL are chemically characterized by HPLC analytical method. In this study, we chose the Atp4a−/− mouse model (Spicer etal., J Biol Chem 275:21555–21565, 2000) for GPL analysis. Different doses of WPL were administered orally to mice for 10 weeks. Next, the pathological changes of gastric mucosa were assessed by the H&E staining and AB-PAS staining. In addition, TUNEL staining was used to evaluate apoptosis, and we further used immunohistochemically labelled CDX2, MUC2, ki-67, PTEN, and p53 proteins to assess the characteristic changes of gastric mucosa in precancerous lesions. The levels of such transporters as HK-II, PKM2, ENO1, MPC1, and LDHA were determined by Western blot analysis. Finally, we assessed the expression of mTOR, HIF-1α, AMPK, Rheb, TSC1 and TSC2 protein in the gastric mucosa of Atp4a−/−mice. Results In this work, we evaluated the protective effect of WPL on gastric mucosa in mice with precancerous lesions. The aberrant apoptosis in gastric mucosa of gastric pre-cancerous lesions was controlled by WPL (P<0.05). Furthermore, WPL suppressed the expression of CDX2, MUC2, ki-67, PTEN and p53, as the levels of these proteins decreased significantly compared with the model group (P<0.05). In parallel, WPL significantly suppressed the expression of transporters, such as HK-II, PKM2, ENO1, MPC1 and LDHA (P<0.05). In addition, mTOR, HIF-1a, AMPK, Rheb, TSC1 and TSC2 protein levels in gastric mucosa of Atp4a−/− mice in the high- and low-dose WPL groups were significantly lower than those in the model group (P<0.05), while the expression of TSC1 and TSC2 protein was significantly higher (P<0.05). Conclusions Conclusively, WPL could ameliorate GPLs in Atp4a−/− mice by inhibiting the expression of transporters and suppressing the aberrant activation of mTOR/HIF-1α.
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Sun Y, Dos Santos A, Balayan A, Deng SX. Evaluation of Cryopreservation Media for the Preservation of Human Corneal Stromal Stem Cells. Tissue Eng Part C Methods 2019; 26:37-43. [PMID: 31686624 DOI: 10.1089/ten.tec.2019.0195] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Introduction: Human corneal stromal stem cells (CSSCs) have gained increasing attention in the treatment of corneal stromal scars. In view of this, the preparation and storage of CSSCs are critical to maintaining the regenerative potential of CSSCs. The goal of the study was to investigate the human serum (HS) concentration in the cryomedia that could best preserve CSSCs. Materials and Methods: Three different cryopreservation media, varying in HS concentration were evaluated in their ability to preserve the viability and phenotype of CSSCs: 2% HS (FS1), 4% HS (FS2), and 90% HS (FS3). After thawing, CSSCs morphology, recovery rate, cell proliferation, relative gene expression of CSSC markers (ABCG2, SOX2, NANOG, PAX6, and SIX3), and their anti-inflammatory response (level of TNFAIP6) were compared with those of unfrozen CSSCs (control). Results: Cryopreserved CSSCs had similar cell morphology as the control. Cell viability was significantly higher using FS2 (92.7 ± 1.3%) compared with FS1 (88 ± 0.8%, p = 0.018). Doubling times of CSSCs were maintained in all cryopreserved conditions, as in the control (p > 0.05), which were 0.9 ± 0.1 days and 1.8 ± 0.0 days at passages 3 and 4, then increased to 18.2 ± 1.9 days at passage 6 (p > 0.05). The expression level of stem cell/progenitor cell markers investigated was not affected by the cryopreservation with any of the three media. In addition, cryopreserved CSSCs have a similar expression level of TNFAIP6 after stimulation with proinflammatory cytokines as the control (p > 0.05). Conclusion: Our results indicated that all three cryopreservation media maintained CSSCs phenotype after undergoing one freezing/thawing cycle. Impact Statement Corneal stromal stem cells (CSSCs) offer an alternative for the treatment of corneal stromal scars. Cryopreservation of CSSCs is necessary as it enables feasibility of using CSSCs as a cell therapy candidate. The current study shows that media used to cryopreserve CSSCs could be optimized to maintain cell viability, phenotype, and potency of CSSCs after thawing.
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Affiliation(s)
- Yuzhao Sun
- Department of Ophthalmology, Stein Eye Institute, University of California, Los Angeles, Los Angeles, California.,Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Aurelie Dos Santos
- Department of Ophthalmology, Stein Eye Institute, University of California, Los Angeles, Los Angeles, California
| | - Alis Balayan
- Department of Ophthalmology, Stein Eye Institute, University of California, Los Angeles, Los Angeles, California
| | - Sophie X Deng
- Department of Ophthalmology, Stein Eye Institute, University of California, Los Angeles, Los Angeles, California
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Gu Q, Feng Z, Liang Q, Li M, Deng J, Ma M, Wang W, Liu J, Liu P, Rong P. Machine learning-based radiomics strategy for prediction of cell proliferation in non-small cell lung cancer. Eur J Radiol 2019; 118:32-37. [PMID: 31439255 DOI: 10.1016/j.ejrad.2019.06.025] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 06/22/2019] [Accepted: 06/26/2019] [Indexed: 12/22/2022]
Abstract
PURPOSE To explore the feasibility and performance of machine learning-based radiomics classifier to predict the cell proliferation(Ki-67)in non-small cell lung cancer (NSCLC). METHODS 245 histopathological confirmed NSCLC patients who underwent CT scans were retrospectively included. The Ki-67 proliferation index (Ki-67 PI) were measured within 2 weeks after CT scans. A lesion volume of interest (VOI) was manually delineated and radiomics features were extracted by MaZda software from CT images. A random forest feature selection algorithm (RFFS) was used to reduce features. Six kinds of machine learning methods were used to establish radiomics classifiers, subjective imaging feature classifiers and combined classifiers, respectively. The performance of these classifiers was evaluated by the receiver operating characteristic curve (ROC) and compared with Delong test. RESULTS 103 radiomics features were extracted and 20 optimal features were selected using RFFS. Among the radiomics classifiers established by six machine learning methods, random forest-based radiomics classifier achieved the best performance (AUC = 0.776) in predicting the Ki-67 expression level with sensitivity and specificity of 0.726 and 0.661, which was better than that of subjective imaging classifiers (AUC = 0.625, P < 0.05). However, the combined classifiers did not improve the predictive performance (AUC = 0.780, P > 0.05), with sensitivity and specificity of 0.752 and 0.633. CONCLUSIONS The machine learning-based CT radiomics classifier in NSCLC can facilitate the prediction of the expression level of Ki-67 and provide a novel non-invasive strategy for assessing the cell proliferation.
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Affiliation(s)
- Qianbiao Gu
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha 410013, China; Department of Radiology, The People's Hospital of Hunan Province, The First Hospital Affiliated of Hunan Normal University, Changsha 410005, China
| | - Zhichao Feng
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Qi Liang
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Meijiao Li
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Jiao Deng
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Mengtian Ma
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Wei Wang
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Jianbin Liu
- Department of Radiology, The People's Hospital of Hunan Province, The First Hospital Affiliated of Hunan Normal University, Changsha 410005, China
| | - Peng Liu
- Department of Radiology, The People's Hospital of Hunan Province, The First Hospital Affiliated of Hunan Normal University, Changsha 410005, China
| | - Pengfei Rong
- Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha 410013, China.
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Ghoneum M, El-Din NKB, Mahmoud AZ, Tolentino L, Pan D, Hassan TA. Dietary baker's yeast sensitizes Ehrlich mammary adenocarcinoma to paclitaxel in mice bearing tumor. Oncol Rep 2019; 41:3155-3166. [PMID: 31002367 PMCID: PMC6489018 DOI: 10.3892/or.2019.7107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 12/13/2018] [Indexed: 01/14/2023] Open
Abstract
Baker's yeast, Saccharomyces cerevisiae, has been shown to sensitize a variety of breast cancer cell (BCC) lines to paclitaxel chemotherapy in vitro. The present study evaluated the ability of S. cerevisiae to sensitize BCCs to paclitaxel in animals bearing Ehrlich ascites carcinoma (EAC). Mice bearing EAC were intratumorally injected with dead S. cerevisiae (1x107 cells/ml) in the presence or absence of low- and high-dose paclitaxel [paclitaxel-L, 2 mg/kg body weight (BW) and paclitaxel-H, 10 mg/kg BW, respectively]. At 30 days post tumor inoculation, co-treatment with yeast plus paclitaxel-L showed improvements over paclitaxel-H alone, as measured by tumor weight (-64 vs. -53%), DNA damage (+79 vs. +62%), tumor cell apoptosis (+217 vs. +177%), cell proliferation (-56 vs. -42%) and Ki-67 marker (+95 vs. +40%). Histopathology and ultra-structural examinations showed that yeast plus paclitaxel-L enhanced apoptosis in EAC more than paclitaxel-H alone and caused comparable tumor necrosis. We conclude that baker's yeast may be used with low-dose chemotherapy to achieve the same potency as high-dose chemotherapy in mice bearing EAC. This suggests that baker's yeast may be an anticancer adjuvant and may have clinical implications for the treatment of breast cancer.
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Affiliation(s)
- Mamdooh Ghoneum
- Department of Surgery, Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Nariman K. Badr El-Din
- Department of Zoology, Faculty of Science, University of Mansoura, Mansoura 35516, Egypt
| | - Ashraf Z. Mahmoud
- Urology and Nephrology Center, University of Mansoura, Mansoura 35516, Egypt
| | - Lucilene Tolentino
- Department of Pathology, Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Deyu Pan
- Department of Preventive and Social Medicine, Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Tahia Ali Hassan
- Department of Zoology, Faculty of Science, University of Mansoura, Mansoura 35516, Egypt
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Yuan ZQ, Wang Q, Bao M. Symptomatic pulmonary sclerosing hemangioma: a rare case of a solitary pulmonary nodule in a woman of advanced age. J Int Med Res 2019; 47:2302-2308. [PMID: 30971157 PMCID: PMC6567762 DOI: 10.1177/0300060519840898] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Pulmonary sclerosing hemangioma (PSH) is a rare tumor that usually develops in middle-aged Asian women. PSH has four histological types (hemorrhagic, sclerotic, solid, and papillary) and often grows slowly in a lower lobe of the lung. Preoperative misdiagnosis frequently occurs because of the absence of specific clinical manifestations and imaging findings. Few reports have described PSH in women of advanced age. Case presentation: A 75-year-old woman presented to our hospital in China with a 5-day history of productive cough and intermittent hemoptysis. Computed tomography indicated bronchiectasis and a large mass in the left inferior lobe of the lung. Treatment of the bronchiectasis provided no symptom relief. The hemoptysis resolved following left lower pulmonary lobectomy, and PSH was pathologically diagnosed following surgery. At the time of this writing (after 6 months of follow-up), the tumor had not recurred, no metastases had been detected, and close follow-up was ongoing. Conclusions Both bronchiectasis and PSH can cause hemoptysis. This case demonstrates that PSH should be included as a differential diagnosis of hemoptysis in women of advanced age. For patients with chronic hemoptysis, the diagnosis of PSH should be considered if the therapeutic effect of bronchiectasis is poor.
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Affiliation(s)
- Zhu-Qing Yuan
- 1 Department of Respiratory Medicine, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Hubei, China
| | - Qian Wang
- 2 Department of Intensive Care Unit, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Hubei, China
| | - Min Bao
- 1 Department of Respiratory Medicine, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Hubei, China
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Riley A, Green V, Cheah R, McKenzie G, Karsai L, England J, Greenman J. A novel microfluidic device capable of maintaining functional thyroid carcinoma specimens ex vivo provides a new drug screening platform. BMC Cancer 2019; 19:259. [PMID: 30902086 PMCID: PMC6429713 DOI: 10.1186/s12885-019-5465-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 03/13/2019] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Though the management of malignancies has improved vastly in recent years, many treatment options lack the desired efficacy and fail to adequately augment patient morbidity and mortality. It is increasingly clear that patient response to therapy is unique to each individual, necessitating personalised, or 'precision' medical care. This demand extends to thyroid cancer; ~ 10% patients fail to respond to radioiodine treatment due to loss of phenotypic differentiation, exposing the patient to unnecessary ionising radiation, as well as delaying treatment with alternative therapies. METHODS Human thyroid tissue (n = 23, malignant and benign) was live-sliced (5 mm diameter × 350-500 μm thickness) then analysed or incorporated into a microfluidic culture device for 96 h (37 °C). Successful maintenance of tissue was verified by histological (H&E), flow cytometric propidium iodide or trypan blue uptake, immunohistochemical (Ki67 detection/ BrdU incorporation) and functional analysis (thyroxine [T4] output) in addition to analysis of culture effluent for the cell death markers lactate dehydrogenase (LDH) and dead-cell protease (DCP). Apoptosis was investigated by Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL). Differentiation was assessed by evaluation of thyroid transcription factor (TTF1) and sodium iodide symporter (NIS) expression (western blotting). RESULTS Maintenance of gross tissue architecture was observed. Analysis of dissociated primary thyroid cells using flow cytometry both prior to and post culture demonstrated no significant change in the proportion of viable cells. LDH and DCP release from on-chip thyroid tissue indicated that after an initial raised level of release, signifying cellular damage, detectable levels dropped markedly. A significant increase in apoptosis (p < 0.01) was observed after tissue was perfused with etoposide and JNK inhibitor, but not in control tissue incubated for the same time period. No significant difference in Ki-67 positivity or TTF1/NIS expression was detected between fresh and post-culture thyroid tissue samples, moreover BrdU positive nuclei indicated on-chip cellular proliferation. Cultured thyroid explants were functionally viable as determined by production of T4 throughout the culture period. CONCLUSIONS The described microfluidic platform can maintain the viability of thyroid tissue slices ex vivo for a minimum of four days, providing a platform for the assessment of thyroid tissue radioiodine sensitivity/adjuvant therapies in real time.
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Affiliation(s)
- Andrew Riley
- Faculty of Health Sciences, University of Hull, Kingston upon Hull, HU6 7RX UK
| | - Victoria Green
- Faculty of Health Sciences, University of Hull, Kingston upon Hull, HU6 7RX UK
| | - Ramsah Cheah
- Faculty of Health Sciences, University of Hull, Kingston upon Hull, HU6 7RX UK
| | - Gordon McKenzie
- Faculty of Health Sciences, University of Hull, Kingston upon Hull, HU6 7RX UK
- Hull York Medical School, University of Hull, Kingston upon Hull, HU6 7RX UK
| | - Laszlo Karsai
- Hull and East Yorkshire Hospitals NHS Trust, Kingston upon Hull, HU16 5JQ UK
| | - James England
- Hull and East Yorkshire Hospitals NHS Trust, Kingston upon Hull, HU16 5JQ UK
| | - John Greenman
- Faculty of Health Sciences, University of Hull, Kingston upon Hull, HU6 7RX UK
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The correlation between phosphorylated Histone H3 (PHH3) and p-STAT3 in Meningiomas. Clin Neurol Neurosurg 2019; 178:46-50. [DOI: 10.1016/j.clineuro.2019.01.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/19/2018] [Accepted: 01/24/2019] [Indexed: 12/26/2022]
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Qiu D, Cai W, Zhang Z, Li H, Zhou D. High Ki-67 expression is significantly associated with poor prognosis of ovarian cancer patients: evidence from a meta-analysis. Arch Gynecol Obstet 2019; 299:1415-1427. [PMID: 30761416 DOI: 10.1007/s00404-019-05082-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 02/02/2019] [Indexed: 02/08/2023]
Abstract
OBJECTIVE The prognostic significance of Ki-67 expression in patients with ovarian cancer was controversial in various studies. Therefore, we carried out a meta-analysis to determine the prognostic significance of Ki-67 in ovarian cancer patients. METHODS We searched PubMed, Cochrane Library, EMBASE, Web of Knowledge, China National Knowledge Infrastructure database and WanFang digital database for eligible studies from January 1, 1990 to June 1, 2017. The pooled hazard ratios and 95% confidence intervals were calculated to assess the prognostic significance of Ki-67 expression for overall survival in ovarian cancer patients. RESULTS Finally, 38 eligible studies and 5004 ovarian cancer patients were included in the current study. The pooled hazard ratio was 1.35 (95% confidence interval 1.24-1.46, P = 0.001) for overall survival in ovarian cancer patients. The funnel plot bias was obviously asymmetrical and Egger's test also detected significant publication bias (P = 0.001). The Contour-enhanced funnel plot with trim-and-fill method supplemented 11 dummy studies to balance the funnel plot and nine new supplementary studies were in area with statistical significance. Sensitivity analysis and cumulative meta-analysis further demonstrated that the association between high Ki-67 expression and poor overall survival of ovarian cancer patients was stable and reliable. CONCLUSIONS High Ki-67 expression is significantly related to poor overall survival and may serve as a prognostic biomarker for ovarian cancer patients.
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Affiliation(s)
- Dongmei Qiu
- Department of Obstetrics and Gynecology, The Affiliated Chencun Hospital of Shunde Hospital of Southern Medical University, Shunde, 528300, Guangdong, People's Republic of China
| | - Wanqiu Cai
- Department of Obstetrics and Gynecology, The Affiliated Chencun Hospital of Shunde Hospital of Southern Medical University, Shunde, 528300, Guangdong, People's Republic of China
| | - Zhiqiao Zhang
- Department of Internal Medicine, The Affiliated Chencun Hospital of Shunde Hospital, Southern Medical University, Shunde, 528300, Guangdong, People's Republic of China.
| | - Hongyan Li
- Department of Obstetrics and Gynecology, The Affiliated Chencun Hospital of Shunde Hospital of Southern Medical University, Shunde, 528300, Guangdong, People's Republic of China
| | - Dongmei Zhou
- Department of Obstetrics and Gynecology, The Affiliated Chencun Hospital of Shunde Hospital of Southern Medical University, Shunde, 528300, Guangdong, People's Republic of China
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