RESUMO
This study systematically reviewed the role of diffusion-weighted imaging (DWI) in the assessment of molecular prognostic biomarkers in breast cancer, focusing on the correlation of apparent diffusion coefficient (ADC) with hormone receptor status and prognostic biomarkers. Our meta-analysis includes data from 52 studies examining ADC values in relation to estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and Ki-67 status. The results indicated significant differences in ADC values among different receptor statuses, with ER-positive, PgR-positive, HER2-negative, and Ki-67-positive tumors having lower ADC values compared to their negative counterparts. This study also highlights the potential of advanced DWI techniques such as intravoxel incoherent motion and non-Gaussian DWI to provide additional insights beyond ADC. Despite these promising findings, the high heterogeneity among the studies underscores the need for standardized DWI protocols to improve their clinical utility in breast cancer management.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Imagem de Difusão por Ressonância Magnética , Humanos , Neoplasias da Mama/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Antígeno Ki-67/metabolismo , Antígeno Ki-67/análiseRESUMO
OBJECTIVE: The aim of the study was evaluate the diagnostic performance of [68Ga]Ga-DOTA-TOC and [18F]FDG PET/CT in patients with histologically proven neuroendocrine tumors (NETs), as well as the correlation of the visualized findings with the tumor grade. MATERIAL AND METHODS: We included 50 patients with NETs who underwent both [68Ga]Ga-DOTA-TOC and [18F]FDG PET/TC. The pooled sensitivity of both scans was compared, as well as [68Ga]Ga-DOTA-TOC and [18F]FDG for each tumor grade (grade 1/G1, grade 2/G2 and grade 3/G3). Also, the sensitivity of [68Ga]Ga-DOTA-TOC and [18F]FDG as a function of the continuous variable Ki-67 was investigated. Finally, the number of lesions detected by both PET radiopharmaceuticals for each tumor grade was compared. RESULTS: The pooled sensitivity of both PET/CT (96%) was higher than [68Ga]Ga-DOTA-TOC (84%) and [18F]FDG (44%) separately, with statistically significant differences. The sensitivity of [68Ga]Ga-DOTA-TOC was higher than [18F]FDG in both G1 (pâ¯=â¯0.004) and G2 (pâ¯<â¯0.001). In G3 the performance of both scans detected disease in 100% of this subgroup. The sensitivity of [68Ga]Ga-DOTA-TOC and [18F]FDG PET/CT correlated significantly with the Ki-67 proliferative index. In G2 patients the number of lesions detected with [68Ga]Ga-DOTA-TOC was higher than [18F]FDG. CONCLUSIONS: The performance of both PET/CT, particularly in G2 and G3, demonstrates the molecular heterogeneity of metastatic NETs and contributes to the selection of a more appropriate treatment, particularly in those high-grade patients who may benefit from radionuclide therapy (PRRT).
Assuntos
Fluordesoxiglucose F18 , Antígeno Ki-67 , Tumores Neuroendócrinos , Compostos Organometálicos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tumores Neuroendócrinos/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Feminino , Compostos Radiofarmacêuticos/farmacocinética , Idoso , Antígeno Ki-67/análise , Adulto , Octreotida/análogos & derivados , Gradação de Tumores , Sensibilidade e Especificidade , Estudos Retrospectivos , Radioisótopos de Gálio , Idoso de 80 Anos ou maisRESUMO
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.
Assuntos
Neoplasias da Mama , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imuno-Histoquímica , Antígeno Ki-67/análise , PrognósticoRESUMO
Ki-67 assessment is a key step in the diagnosis of neuroendocrine neoplasms (NENs) from all anatomic locations. Several challenges exist related to quantifying the Ki-67 proliferation index due to lack of method standardization and inter-reader variability. The application of digital pathology coupled with machine learning has been shown to be highly accurate and reproducible for the evaluation of Ki-67 in NENs. We systematically reviewed all published studies on the subject of Ki-67 assessment in pancreatic NENs (PanNENs) employing digital image analysis (DIA). The most common advantages of DIA were improvement in the standardization and reliability of Ki-67 evaluation, as well as its speed and practicality, compared to the current gold standard approach of manual counts from captured images, which is cumbersome and time consuming. The main limitations were attributed to higher costs, lack of widespread availability (as of yet), operator qualification and training issues (if it is not done by pathologists), and most importantly, the drawback of image algorithms counting contaminating non-neoplastic cells and other signals like hemosiderin. However, solutions are rapidly developing for all of these challenging issues. A comparative meta-analysis for DIA versus manual counting shows very high concordance (global coefficient of concordance: 0.94, 95% CI: 0.83-0.98) between these two modalities. These findings support the widespread adoption of validated DIA methods for Ki-67 assessment in PanNENs, provided that measures are in place to ensure counting of only tumor cells either by software modifications or education of non-pathologist operators, as well as selection of standard regions of interest for analysis. NENs, being cellular and monotonous neoplasms, are naturally more amenable to Ki-67 assessment. However, lessons of this review may be applicable to other neoplasms where proliferation activity has become an integral part of theranostic evaluation including breast, brain, and hematolymphoid neoplasms.
Assuntos
Neoplasias da Mama , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Biomarcadores Tumorais/análise , Proliferação de Células , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Antígeno Ki-67/análise , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Reprodutibilidade dos TestesRESUMO
Epithelial proliferation in the rat mammary gland is recommended in regulatory guidelines as an endpoint for assessment of the in vivo carcinogenic potential of insulin analogues. Epithelial proliferation is traditionally assessed by immunohistochemical staining of a proliferation marker, for example, 5-bromo-2'-deoxyuridine (BrdU) or Ki67, followed by labor-intensive manual counting of positive and negative cells. The aim of this study was to develop and validate an approach for image analysis based on artificial intelligence, which can be used for quantification of proliferation in rat mammary gland, independent of the choice of proliferation marker. Furthermore, the aim was to compare the markers BrdU, Ki67, and phosphorylated histone H3 (PHH3). A sequence of image analysis applications were developed, which allowed for quantification of proliferative activity in the mammary gland epithelium. These endpoints agreed well with manually counted labeling indices, with correlation coefficients in the range ≈0.92-0.93. In addition, all three proliferation markers were significantly correlated and could detect the variation in epithelial proliferation during the estrous cycle. In conclusion, image analysis can be used to quantify epithelial proliferation in the rat mammary gland and thereby replace time-consuming manual counting. Furthermore, BrdU, Ki67, and PHH3 can be used interchangeably to assess proliferation.
Assuntos
Inteligência Artificial , Bromodesoxiuridina/análise , Epitélio/química , Histonas/análise , Antígeno Ki-67/análise , Glândulas Mamárias Animais/química , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Bromodesoxiuridina/metabolismo , Proliferação de Células , Epitélio/metabolismo , Feminino , Histonas/metabolismo , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy and efficiency of p16/ki-67 dual stain in the identification of CIN2+ lesions, in Greek women with ASCUS or LSIL cytology. METHODS: A total of 200 women, 20 to 60 years old, were enrolled in the study. All samples were cytologically evaluated and performed for p16/ki-67 and high-risk HPV (HR-HPV) test. All patients were referred to colposcopy for biopsy and histological evaluation. Three cervical cancer (CC) screening strategies were designed and the total direct medical costs of the procedures during our clinical trial were evaluated, from a healthcare perspective. RESULTS: HPV 16 as expected was the most common HR-HPV type followed by HPV 31 and HPV 51. The risk for CIN2+ was significantly higher in HPV 16/18 positive cases. p16/ki-67 demonstrated a high sensitivity for CIN2+ identification in both ASCUS and LSIL groups (90.4% and 95%, respectively). HR-HPV test with sensitivity 52.3% and 65.5%, as well as colposcopy with sensitivity 14.3% and 36% respectively in ASCUS and LSIL group, showed inferior results compared to p16/ki-67. The specificity of p16/ki-67 for ASCUS and LSIL was 97.2% and 95.2% respectively, inferior only to colposcopy: 100% and 100%, lacking however statistical significance. HR-HPV test instead, presented the lowest specificity: 76.4% and 71.4% respectively in comparison to the other two methods. From a healthcare perspective, the costs and benefits of the tests implementation for the annual screening and triaging, in three CC screening strategies, were also calculated and discussed. CONCLUSIONS: The results of the study indicate that p16/ki-67 is a safe and rapid assay that could be used to detect CIN2+ among women with mild cervical lesions, presenting both high sensitivity and specificity and could minimize the psychological and economic burden of HPV screening.
Assuntos
Colo do Útero/patologia , Inibidor p16 de Quinase Dependente de Ciclina/análise , Técnicas Citológicas , Detecção Precoce de Câncer/métodos , Antígeno Ki-67/análise , Neoplasias do Colo do Útero/diagnóstico , Adulto , Alphapapillomavirus/classificação , Alphapapillomavirus/isolamento & purificação , Biomarcadores Tumorais/análise , Colo do Útero/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Triagem , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Adulto JovemRESUMO
AIMS: The nuclear proliferation biomarker Ki67 plays potential prognostic and predictive roles in breast cancer treatment. However, the lack of interpathologist consistency in Ki67 assessment limits the clinical use of Ki67. The aim of this article was to report a solution utilising an artificial intelligence (AI)-empowered microscope to improve Ki67 scoring concordance. METHODS AND RESULTS: We developed an AI-empowered microscope in which the conventional microscope was equipped with AI algorithms, and AI results were provided to pathologists in real time through augmented reality. We recruited 30 pathologists with various experience levels from five institutes to assess the Ki67 labelling index on 100 Ki67-stained slides from invasive breast cancer patients. In the first round, pathologists conducted visual assessment on a conventional microscope; in the second round, they were assisted with reference cards; and in the third round, they were assisted with an AI-empowered microscope. Experienced pathologists had better reproducibility and accuracy [intraclass correlation coefficient (ICC) = 0.864, mean error = 8.25%] than inexperienced pathologists (ICC = 0.807, mean error = 11.0%) in visual assessment. Moreover, with reference cards, inexperienced pathologists (ICC = 0.836, mean error = 10.7%) and experienced pathologists (ICC = 0.875, mean error = 7.56%) improved their reproducibility and accuracy. Finally, both experienced pathologists (ICC = 0.937, mean error = 4.36%) and inexperienced pathologists (ICC = 0.923, mean error = 4.71%) improved the reproducibility and accuracy significantly with the AI-empowered microscope. CONCLUSION: The AI-empowered microscope allows seamless integration of the AI solution into the clinical workflow, and helps pathologists to obtain higher consistency and accuracy for Ki67 assessment.
Assuntos
Inteligência Artificial , Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Interpretação de Imagem Assistida por Computador/métodos , Antígeno Ki-67/análise , Microscopia/métodos , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/instrumentação , Microscopia/instrumentação , Variações Dependentes do Observador , Patologia Clínica/instrumentação , Patologia Clínica/métodos , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
OBJECTIVES: The Ki-67 proliferation index is integral to gastroenteropancreatic neuroendocrine tumor (GEP-NET) assessment. Automated Ki-67 measurement would aid clinical workflows, but adoption has lagged owing to concerns of nonequivalency. We sought to address this concern by comparing 2 digital image analysis (DIA) platforms to manual counting with same-case/different-hotspot and same-hotspot/different-methodology concordance assessment. METHODS: We assembled a cohort of GEP-NETs (n = 20) from 16 patients. Two sets of Ki-67 hotspots were manually counted by three observers and by two DIA platforms, QuantCenter and HALO. Concordance between methods and observers was assessed using intraclass correlation coefficient (ICC) measures. For each comparison pair, the number of cases within ±0.2xKi-67 of its comparator was assessed. RESULTS: DIA Ki-67 showed excellent correlation with manual counting, and ICC was excellent in both within-hotspot and case-level assessments. In expert-vs-DIA, DIA-vs-DIA, or expert-vs-expert comparisons, the best-performing was DIA Ki-67 by QuantCenter, which showed 65% cases within ±0.2xKi-67 of manual counting. CONCLUSIONS: Ki-67 measurement by DIA is highly correlated with expert-assessed values. However, close concordance by strict criteria (>80% within ±0.2xKi-67) is not seen with DIA-vs-expert or expert-vs-expert comparisons. The results show analytic noninferiority and support widespread adoption of carefully optimized and validated DIA Ki-67.
Assuntos
Antígeno Ki-67/análise , Biomarcadores Tumorais/análise , Proliferação de Células , Estudos de Coortes , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Neoplasias Intestinais , Gradação de Tumores , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Neoplasias GástricasRESUMO
AIMS: Ki67 is a well-established immunohistochemical marker associated with cell proliferation that has prognostic and predictive value in breast cancer. Quantitative evaluation of Ki67 is traditionally performed by assessing stained tissue slides with light microscopy. Automated image analysis systems have become available and, if validated, could provide greater standardisation and improved precision of Ki67 scoring. Here, we aimed to evaluate the use of the Cognition Master Professional Suite (CogM) image analysis software, which is a simple system for scoring Ki67 in primary breast cancer samples. METHODS AND RESULTS: Sections from 94 core-cut biopsies, 20 excision specimens and 29 pairs of core-cut biopsies and excision specimens were stained for Ki67 with MIB1 antibody and the Dako EnVision FLEX Detection System. Stained slides were scanned to convert them to digital data. Computer-based Ki67 scoring was performed with CogM. Manual Ki67 scoring assessment was conducted on previously stained sections from the same biopsies with a clinically validated system that had been calibrated against the risk of recurrence. A high correlation between manual and digital scores was observed [rCores = 0.92, 95% confidence interval (CI) 0.87-0.94, P < 0.0001; rExcisions = 0.95, 95% CI 0.86-0.98, P < 0.0001] and there was no significant bias between them (P = 0.45). There was also a high correlation of Ki67 scores between paired core-cut biopsies and excision specimens when CogM was used (r = 0.78, 95% CI 0.59-0.89, P < 0.0001). CONCLUSIONS: CogM image analysis allows for standardised automated Ki67 scoring that accurately replicates previously clinically validated and calibrated manual scores.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Processamento de Imagem Assistida por Computador/métodos , Antígeno Ki-67/análise , Anticorpos Antinucleares , Anticorpos Monoclonais , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Pós-Menopausa , Prognóstico , Projetos de Pesquisa , Software , Manejo de EspécimesRESUMO
BACKGROUND: The risk of malignancy in resected gastrointestinal stromal tumors (GISTs) depends on tumor size, location, and mitotic index. Reportedly, the Ki67 index has a prognostic value in resected GISTs. We aimed to analyze the accuracy of endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) samples with reference to Ki67 index, using surgical specimens as the gold standard. METHODS: Fifty-five patients who underwent EUS-FNA followed by surgical resection for gastric GISTs were retrospectively analyzed. Patients' age and sex; tumors' size and location; mitotic index, cell type, cellularity, pleomorphism, presence of ulceration, hemorrhage, necrosis, mucosal or serosal invasion, growth pattern, and Ki67 index based on pathology were investigated. RESULTS: Location in fundus, ulceration, hemorrhage, mucosal invasion, and Ki67 index in surgical specimens were significant in predicting high-risk groups (p < 0.05) on univariate analysis. Frequency of bleeding (p = 0.034) and the Ki67 index (p = 0.018) were the only independent significant factors in multivariate analysis. The optimal cutoff level of Ki67 was 5%, with 88.2% sensitivity and 52.8% specificity (p = 0.021). The mean Ki67 index was lower in EUS-FNA samples than in surgical specimens (2% [1-15] versus 10% [1-70], p = 0.001). The rank correlation coefficient value of Ki67 was 0.199 (p = 0.362) between EUS-FNA and surgical samples and showed no reliability for EUS-FNA samples. CONCLUSION: The Ki67 index in resected specimens correlated with high-risk GISTs, although it had no additive value to the current criteria. The Ki67 index in EUS-guided FNA samples is not a reliable marker of proliferation in GISTs.
Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Tumores do Estroma Gastrointestinal/metabolismo , Antígeno Ki-67/análise , Medição de Risco , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Endossonografia , Feminino , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Valores de Referência , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias Gástricas/patologiaRESUMO
The Prosigna® assay is a United States Food and Drug Administration (US-FDA) cleared molecular test for prognostic use in hormone receptor-positive stage I/II breast cancer in postmenopausal women. We analyzed histopathologic features of 79 cases with Prosigna® assay results and found a significant correlation between tumor size, grade, and Ki-67 labeling index with Prosigna® score (0-40, 41-60, and 61-100) and Prosigna® risk categories. Since the Prosigna® risk stratification is influenced by lymph node status, we designed an index that included lymph node status and the two most correlated variables (size and Ki-67 labeling index). This was termed the size, nodal, and Ki-67 (SiNK™) index and is calculated as follows: (size in mm) + (pN × 10) + (Ki-67 labeling index). The SiNK™ index was divided into ≤40 and >40 to test its prognostic significance in a well-characterized dataset of 106 ER+/HER2-negative stage I-II invasive breast cancers treated with standard multi-modality therapy with long term follow-up (average 101 months follow-up). Patients with SiNK™ ≤40 showed significantly improved distant recurrence-free survival (96% distant recurrence-free survival in SiNK™ ≤40 compared to 81% in SiNK™ >40; log-rank test p value: 0.0027). SiNK™ provides strong prognostic information in ERo+/HER2-negative breast cancers. SiNK™ index is simple to calculate using data from routine pathology reports. This should be further evaluated in larger datasets.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Adulto , Idoso , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Antígeno Ki-67/análise , Metástase Linfática/patologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , PrognósticoRESUMO
In this study, we examined the suitability of visible and infrared (Vis-NIR) hyperspectral imaging (HSI) for the quantification of prognostic markers in non-Hodgkin lymphoma on the example of the Ki67 proliferation index. Ki67 quantification was done on six follicular lymphomas (FLs) and 12 diffuse large B-cell lymphomas (DLBCLs) by applying classic immunohistochemistry. The Ki67 index was comparatively assessed visually, using HSI-based quantification and a digital imaging analysis (DIA) platform. There was no significant difference between visual assessment (VA), DIA, and HSI in FLs. For DLBCLs, VA resulted in significantly higher Ki67 values than HSI (pâ¯=â¯0.023) and DIA (pâ¯=â¯0.006). No such difference was seen comparing analysis by HSI and DIA (pâ¯=â¯0.724). Cohen's κ revealed a "substantial correlation" of Ki67 values for HSI and DIA in FLs and DLBCLs (κâ¯=â¯0.667 and 0.657). Here we provide the first evidence that, comparably to traditional DIA, HSI can be used reliably to quantify protein expression, as exemplified by the Ki67 proliferation index. By covering the near-infrared spectrum, HSI might offer additional information on the biochemical composition of pathological specimens, although our study could not show that HSI is clearly superior to conventional DIA. However, the analysis of multiplex immunohistochemistry might benefit from such an approach, especially if overlapping immunohistochemical reactions were possible. Further studies are needed to explore the impact of this method on the analysis and quantification of multiple marker expression in pathological specimens.
Assuntos
Antígenos de Neoplasias/análise , Imageamento Hiperespectral/métodos , Antígeno Ki-67/análise , Linfoma não Hodgkin/diagnóstico por imagem , Linfoma de Burkitt/diagnóstico por imagem , Linfoma de Burkitt/patologia , Proliferação de Células , Análise Custo-Benefício , Humanos , Imageamento Hiperespectral/economia , Raios Infravermelhos , Linfoma Folicular/diagnóstico por imagem , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Índice Mitótico , Projetos Piloto , Prognóstico , Processamento de Sinais Assistido por ComputadorRESUMO
Acetamide (CAS 60-35-5) is detected in common foods. Chronic rodent bioassays led to its classification as a group 2B possible human carcinogen due to the induction of liver tumors in rats. We used a toxicogenomics approach in Wistar rats gavaged daily for 7 or 28 days at doses of 300 to 1500 mg/kg/day (mkd) to determine a point of departure (POD) and investigate its mode of action (MoA). Ki67 labeling was increased at doses ≥750 mkd up to 3.3-fold representing the most sensitive apical endpoint. Differential gene expression analysis by RNA-Seq identified 1110 and 1814 differentially expressed genes in male and female rats, respectively, following 28 days of treatment. Down-regulated genes were associated with lipid metabolism while up-regulated genes included cell signaling, immune response, and cell cycle functions. Benchmark dose (BMD) modeling of the Ki67 labeling index determined the BMD10 lower confidence limit (BMDL10) as 190 mkd. Transcriptional BMD modeling revealed excellent concordance between transcriptional POD and apical endpoints. Collectively, these results indicate that acetamide is most likely acting through a mitogenic MoA, though specific key initiating molecular events could not be elucidated. A POD value of 190 mkd determined for cell proliferation is suggested for risk assessment purposes.
Assuntos
Acetamidas/toxicidade , Carcinógenos/toxicidade , Contaminação de Alimentos , Neoplasias Hepáticas/genética , Modelos Biológicos , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Simulação por Computador , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunidade/efeitos dos fármacos , Imunidade/genética , Antígeno Ki-67/análise , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Masculino , RNA-Seq , Ratos , Ratos Wistar , Medição de Risco/métodos , Testes de Toxicidade Crônica/métodos , Regulação para Cima/efeitos dos fármacosRESUMO
A general concern exists that cervical cancer screening using human papillomavirus (HPV) testing may lead to considerable overtreatment. We evaluated the trade-off between benefits and overtreatment among different screening strategies differing by primary tests (cytology, p16/Ki-67, HPV alone or in combinations), interval, age and diagnostic follow-up algorithms. A Markov state-transition model calibrated to the Austrian epidemiological context was used to predict cervical cancer cases, deaths, overtreatments and incremental harm-benefit ratios (IHBR) for each strategy. When considering the same screening interval, HPV-based screening strategies were more effective compared to cytology or p16/Ki-67 testing (e.g., relative reduction in cervical cancer with biennial screening: 67.7% for HPV + Pap cotesting, 57.3% for cytology and 65.5% for p16/Ki-67), but were associated with increased overtreatment (e.g., 19.8% more conizations with biennial HPV + Papcotesting vs. biennial cytology). The IHBRs measured in unnecessary conizations per additional prevented cancer-related death were 31 (quinquennial Pap + p16/Ki-67-triage), 49 (triennial Pap + p16/Ki-67-triage), 58 (triennial HPV + Pap cotesting), 66 (biennial HPV + Pap cotesting), 189 (annual Pap + p16/Ki-67-triage) and 401 (annual p16/Ki-67 testing alone). The IHBRs increased significantly with increasing screening adherence rates and slightly with lower age at screening initiation, with a reduction in HPV incidence or with lower Pap-test sensitivity. Depending on the accepted IHBR threshold, biennial or triennial HPV-based screening in women as of age 30 and biennial cytology in younger women may be considered in opportunistic screening settings with low or moderate adherence such as in Austria. In organized settings with high screening adherence and in postvaccination settings with lower HPV prevalence, the interval may be prolonged.
Assuntos
Detecção Precoce de Câncer/métodos , Programas de Rastreamento/métodos , Infecções por Papillomavirus/diagnóstico , Displasia do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Alphapapillomavirus/fisiologia , Áustria , Inibidor p16 de Quinase Dependente de Ciclina/análise , Feminino , Humanos , Antígeno Ki-67/análise , Cadeias de Markov , Uso Excessivo dos Serviços de Saúde/prevenção & controle , Pessoa de Meia-Idade , Teste de Papanicolaou/métodos , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/virologia , Esfregaço Vaginal/métodos , Adulto Jovem , Displasia do Colo do Útero/virologiaRESUMO
AIMS: Proliferation assessment by the use of Ki67 is a crucial component in intrinsic subtyping of luminal breast cancers (BCs), but suffers from variability between laboratories, observers, and methods. MammaTyper is a quantitative molecular tool that measures mRNA levels of ERBB2, ESR1, PGR and MKI67 in BC, and interprets the results according to the St Gallen 2013 consensus recommendations. We compared MammaTyper with immunohistochemistry (IHC)-based subtypes, with a focus on standardised proliferation assessment. METHODS AND RESULTS: We analysed the agreement in assigning subtypes between MammaTyper and receptor IHC in 101 unifocal luminal HER2-negative early BCs of no special type. Two Ki67 counting protocols, Ki67-Global (Ki67-G) and Ki67-HotSpot (Ki67-H), recommended by the International Ki67 in BC Working Group, and the mitotic activity index (MAI) were used for proliferation assessment. The proportions of BCs identified as luminal A and as luminal B were 55% and 45% for MammaTyper, 55% and 45% for IHC + Ki67-G, 36% and 64% for IHC + Ki67-H, and 56% and 44% for IHC + MAI. The levels of agreement between MammaTyper-based and IHC-based subtyping were 84% (κ = 0.679) for IHC + Ki67-G, 72% (κ = 0.462) for IHC + Ki67-H, and 89% (κ = 0.779) for IHC + MAI. CONCLUSIONS: High rates of agreement between mRNA-based and IHC-based intrinsic subtyping of luminal HER2-negative BC can be achieved. However, the agreement between IHC-based and MammaTyper-based luminal subtypes depends on the proliferation assessment method, and was highest when the MAI was used. Further comparative clinical studies are needed to determine which method is to be preferred, including analysis of cost-effectiveness.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Índice Mitótico/métodos , RNA Mensageiro/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Antígeno Ki-67/metabolismo , Pessoa de Meia-IdadeRESUMO
Background & objectives: Breast cancer is the most common cancer of women. Inferior prognosis in some patients has been attributed to the higher proliferative capability of the tumour. Immunohistochemistry (IHC) for Ki-67, despite being a simple and cost-effective method, has not become a valid tool to evaluate this biomarker. This is ascribed to variation in pre-analytical and analytical techniques, variable expression, hotspot distribution and inter-and intra-observer inconsistency. This study was aimed at defining the analytical and clinical validity of real-time quantitative polymerase chain reaction (RT-qPCR) as an alternative to IHC evaluation. Methods: This study included a total of 109 patients with invasive breast cancers. Ki-67 IHC visual assessment was compared with the mRNA value determined by RT-qPCR. Concordance between both the methods was assessed. Receiver operating characteristic (ROC) curve analysis and Cohen's kappa value with intraclass correlation were performed. Results: The threshold value for Ki-67 by RT-qPCR obtained by ROC curve was 22.23 per cent, which was used to divide breast cancer cases into high proliferative and low proliferative groups. A significant correlation was observed between both the breast cancer groups formed using RT-qPCR threshold as well as median laboratory value of Ki-67 labelling index by IHC. Interpretation & conclusions: The study results showed a significant correlation between the two methods. While IHC is subject to technical and interpretative variability, RT-qPCR may offer a more objective alternative.
Assuntos
Neoplasias da Mama/diagnóstico , Imuno-Histoquímica/métodos , Antígeno Ki-67/análise , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biópsia , Neoplasias da Mama/metabolismo , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Prospectivos , RNA Mensageiro/metabolismo , Curva ROC , Reprodutibilidade dos TestesRESUMO
Invasive lobular carcinoma (ILC) is almost always classified as Nottingham histological grade 2. Despite this, prognosis is markedly varied, with some ILCs behaving more akin to grade 3 invasive ductal carcinoma (IDC). Methods to separate these aggressive ILCs are needed. Digital image analysis (DIA) of the Ki-67 biomarker has potential in this regard; thus, we sought to determine the feasibility of its use for automated evaluation of ILC. An initial pilot study demonstrated no ILC specific changes were required to our Ki-67 DIA algorithm for reproducible results. Subsequently, 42 consecutive cases of ILC were evaluated by visual mitosis counting in H&E stained sections and by DIA on Ki-67 stained sections. Ki-67 proliferative index (PI) DIA showed significant correlation with visual mitosis counting on H&E stained sections (rs=0.63; p<0.05), significant strong correlation (rs=0.78; p<0.05) and substantial agreement (κ=0.62) with manual/visual Ki-67 assessment and significant positive associations with grade, nodal status and 'pleomorphic' ILC subtype, and a wide stratification of values in classical/grade 2 ILC. In conclusion, DIA of Ki-67 PI in ILC is feasible, correlates with mitotic index, manual/visual Ki-67 PI and clinico-pathological variables. The broad stratification of Ki-67 PI in classical/grade 2 ILC supports its practicability as a biomarker with prognostic and predictive potential, although large studies with outcome data are required for validation.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Lobular/diagnóstico por imagem , Antígeno Ki-67/análise , Adulto , Idoso , Algoritmos , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Carcinoma Lobular/classificação , Carcinoma Lobular/patologia , Proliferação de Células , Estudos de Coortes , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Projetos Piloto , PrognósticoRESUMO
BACKGROUND: Proliferation rate is a major determinant of the biologic behavior of the tumor and provides information that can be used to guide treatment decisions. METHODS: This ring study included 27 pathologists from 14 Institutions, in order to assess inter-observer concordance between pathologists in Croatia. We analyzed Ki-67 proliferative index on ten randomly selected breast cancer samples comparing consistency between visual assessment using light microscopy compared to digital image analyses results from one central laboratory as a referral value. RESULTS: When we analyzed Ki-67 as numeric value high concordance rate was found between Ki-67 score visually assessed in all participating Institutions compared to referral value assessed by digital image analysis (ICC 0.76, 95% CI 0.58-0.91), and Krippendorff's alpha was 0.79 (95% CI 0.58-1.00). Concordance was better in slides with higher Ki-67 values. When we categorized Ki-67 values according to generally accepted 20% cut-off value we noticed the lower concordance rate among participants in our study. CONCLUSION: Proliferation remains one of the most important parameters for tumor characterization helpful in making clinical decisions, but it should be used with great caution. Standardization of the Ki-67 assessment is essential and proliferating index should be expressed as exact numeric value. For patients with proliferative index near the cut-off value, other factors must be considered in making clinical decisions.
Assuntos
Neoplasias da Mama/patologia , Proliferação de Células , Processamento de Imagem Assistida por Computador/normas , Antígeno Ki-67/análise , Laboratórios Hospitalares/normas , Automação Laboratorial/normas , Automação Laboratorial/estatística & dados numéricos , Neoplasias da Mama/diagnóstico , Croácia , Estudos Transversais , Feminino , Humanos , Processamento de Imagem Assistida por Computador/estatística & dados numéricos , Imuno-Histoquímica , Laboratórios Hospitalares/estatística & dados numéricos , Inclusão em ParafinaRESUMO
PURPOSE: To determine the impact of three different regions of interests (ROIs) positioning methods for apparent diffusion coefficient (ADC) measurements on the assessment of the grade and recurrence and to examine the correlation between ADC value and histopathological grade/ Ki-67 labeling index (LI) in patients with bladder cancer. MATERIALS AND METHODS: Sixty-one patients with bladder cancer were retrospectively evaluated. Two observers measured mean ADC values using whole-volume-ROIs, single-section-ROI and three-ROIs methods. Interclass correlation coefficient was analyzed to assess interobserver variability. The grade and recurrence in patients with bladder cancer were assessed by calculating the areas under the receiver operating characteristic curves with Az values. Spearman's correlation was used to analyze the correlations of ADC value with grade and Ki-67 LI. RESULTS: For the mean ADC value, the interclass correlation coefficient were excellent with the whole-volume and the single-section method (0.90 [95% CI: 0.84, 0.94] and 0.89 [95% CI: 0.81, 0.93]) and was good with the three-ROIs method (0.72 [95% CI: 0.53, 0.83]). The Az value for determining histological grade and recurrence of bladder cancer were not significantly different from each positioning method (all p > 0.05). There's significant correlation between histological grade and ADC measuring by whole-volume-ROIs and single-section-ROI methods (râ¯=â¯0.31, pâ¯=â¯0.02; râ¯=â¯0.37, p < 0.05). The ADC measured by whole-volume-ROIs, single-section-ROI, and three-ROIs methods were significantly and inversely correlated with the Ki-67 LI (râ¯=â¯-0.3; râ¯=â¯-0.49; râ¯=â¯-0.40, all p < 0.05). CONCLUSION: There's no significant difference among any of the ROI positioning methods in evaluation of tumor grade and recurrence. There's significant correlation between histological grade and ADC measuring by whole-volume-ROIs and single-section-ROI methods. The ADC value obtained by either of three methods was significantly and inversely correlated with the Ki-67 LI.
Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/patologia , Idoso , Feminino , Humanos , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Variações Dependentes do Observador , Curva ROC , Estudos RetrospectivosRESUMO
BACKGROUND: Immunohistochemistry is a basic diagnostic technique. Immunohistochemical examination results reflect mainly qualitative and less quantitative characteristics of proteomic status of cells. A combined approach with complex quantitative evaluation of marker expression using colorimetric analysis and computer technologies can expand the diagnostic capabilities of immunohistochemistry. We studied such an approach developed by using expression of the proliferative marker Ki-67 in pituitary adenomas. METHODS: A retrospective, blind, randomized, comparative study was performed of Ki-67 expression activity in pituitary adenomas using the traditional Ki-67 labeling index and a simple immunohistochemical cytocolorimetric analysis developed by us with immunohistochemical cytocolorimetric index (ICI) estimation as predictors of relapse, assessing the relationships of these indicators with the time before relapse. RESULTS: Mean Ki-67 labeling index was 3.87% ± 0.29% in the relapse-free group and 4.01% ± 0.29% in the relapse group; the difference was not statistically significant. The average Ki-67 ICI was 24.16% ± 0.51% in the relapse-free group and 30.68% ± 0.64% in the relapse group; the difference was statistically significant. The correlation coefficient of ICI values and time before relapse was -0.302, indicating the presence of a weak negative correlation. CONCLUSIONS: We successfully tested an ICI estimation method developed by us to assess Ki-67 expression in pituitary adenomas. The ICI technique can be used both as a prognostic factor for relapse and, in combination with other modern proteomic and genetic methods, as the basis for creation of new multimodal analyzing systems for functional state assessment of cells and tissues.