Difference In Ki-67 Expression Research Articles

Baseline breast tissue characteristics determine the effect of tamoxifen on mammographic density change.

Tamoxifen prevents recurrence of breast cancer and is also approved for preventive, risk-reducing, therapy. Tamoxifen alters the breast tissue composition and decreases the mammographic density. We aimed to test if baseline breast tissue composition influences tamoxifen-associated density change. This biopsy-based study included 83 participants randomised to 6 months daily intake of placebo, 20, 10, 5, 2.5, or 1 mg tamoxifen. The study is nested within the double-blinded tamoxifen dose-determination trial Karolinska Mammography Project for Risk Prediction of Breast Cancer Intervention (KARISMA) Study. Ultrasound-guided core-needle breast biopsies were collected at baseline before starting treatment. Biopsies were quantified for epithelial, stromal, and adipose distributions, and epithelial and stromal expression of proliferation marker Ki67, oestrogen receptor (ER) and progesterone receptor (PR). Mammographic density was measured using STRATUS. We found that greater mammographic density at baseline was positively associated with stromal area and inversely associated with adipose area and stromal expression of ER. Premenopausal women had greater mammographic density and epithelial tissue, and expressed more epithelial Ki67, PR, and stromal PR, compared to postmenopausal women. In women treated with tamoxifen (1-20 mg), greater density decrease was associated with higher baseline density, epithelial Ki67, and stromal PR. Women who responded to tamoxifen with a density decrease had on average 17% higher baseline density and a 2.2-fold higher PR expression compared to non-responders. Our results indicate that features in the normal breast tissue before tamoxifen exposure influences the tamoxifen-associated density decrease, and that the age-associated difference in density change may be related to age-dependant differences in expression of Ki67 and PR.

Effects of Sambiloto (Andrographis paniculata) Extract and Spirulina (Spirulina platensis) Administration on Ki-67 Protein Expression in the Colon Epithelial Cells of Plasmodium berghei-infected Mice

BACKGROUND: Malaria remains a global health concern and an endemic disease in Indonesia. Sambiloto (Andrographis paniculata) and spirulina (Spirulina platensis) are two potential antimalarial agents which act as antioxidants and antiinflammatories that can suppress morbidities during chronic inflammation in malaria, such as proliferation in the colon. This study aims to investigate the effects of A. paniculata extract and S. platensis administration on Ki-67 expression in medial colon epithelial cells of Plasmodium berghei-infected mice measured by H-score.METHODS: Thirty P. berghei-infected male Swiss-Webster mice were divided into five groups: negative controls (carboxymethyl cellulose/CMC); positive controls (dihydroartemisinin-piperaquine/DHP); A. paniculata extract alone (AP); A. paniculata extract in combination with S. platensis extract (AP+ES); and with S. platensis powder (AP+PS). All mice were infected with P. berghei on day 0. The treatment for each group were given 3 days before infection (D-3) until the day of infection (D0) for 28 days after infection. Colon tissues were processed with immunohistochemistry to detect Ki-67.RESULTS: A difference in Ki-67 expression was observed among the groups (p<0.01). The mean H-score for the CMC control group is 135.503±6.723. The lowest level of Ki-67 expression was observed in the AP+PS group (H-score= 110.941±7.079). AP group did not show a significant difference from the CMC group (p=0.514) and neither did the AP+ES group (p=0.234).CONCLUSION: In conclusion, administration of A. paniculata extract and S. platensis powder lowers Ki-67 expression in medial colon epithelial cells of P. berghei-infected mice.KEYWORDS: malaria, spirulina, Ki-67, Andrographis paniculata, Spirulina platensis

Abstract P4-05-01: Results from the first UK NEQAS ICC & ISH external quality assessment for Ki-67 demonstration in breast cancer

Abstract AIMS: We previously described use of digital image analysis (DIA) to improve objectivity and reproducibility in external quality assessment (EQA) for immunocytochemical (ICC) staining in pathology [1]. Here we extend the work and report on: (1) use in EQA of the proliferation marker, Ki-67 in breast cancer, (2) use of a commercial prototype cell-line microarray (CLMA). MATERIALS AND METHODS: 34 laboratories stained slides provided by UK NEQAS using their routine ICC methods and returned them for central review and analysis. Slides were provided in duplicate; 29 laboratories returned both and 5 one slide (N = 63). Centrally performed DIA used the Cognition Master Professional Suite (CogM, VMscope GmbH) to quantify Ki67 labelling index (LI) [2]. Qualitative assessment aimed to separate submissions that were not useful from those which could be reported. This followed UK NEQAS standard methods. Materials assessed comprised two different breast cancer samples and a Ki-67 CLMA (Karpas Prototype, Array Science). RESULTS: Descriptive statistics on Ki-67 scores for each sample are presented in Table 1. Analysis of individual sample types for difference in Ki-67 expression associated with primary antibody showed the following: mean Ki-67 LI on breast cancer A had a range of 13.6% (K2, Leica Biosystems) to 17.6% (30-9, Ventana Medical Systems), but no significant difference was found for any primary antibody clone. For breast cancer sample B, the range was 2.0% (MIB-1, Dako Agilent) to 3.2% (30-9), and the difference was significant at P<0.05. In contrast, the CLMA showed no significant difference in expression for either MIB-1 or 30-9 (K2 could not be reported).The Ki-67-positive Karpas cell line in the CLMA had a small nuclear size compared to that of ‘standard’ breast cancer, which led to undercalling by CogM and potentially other DIA software; it also demonstrated a restricted dynamic range of high staining intensity, which reduced its ability to demonstrate differential staining in response to methodological variations.When assessed qualitatively 11.1% of submissions were not reportable (fail), 12.7% were sub-optimal but were scoreable (borderline), 23.8% had minor defects (adequate) and 52.4% were optimally stained (good). For both breast cancer samples, but not for the CLMA these qualitative categories were associated with increasing Ki-67 LI scores. For breast cancer A the mean Ki-67 LI score for the non-reportable group was significantly different from all other categories, which were not significantly different from each other; for breast cancer B, significant differences were seen between the non-reportable group and the adequate and good groups only (all at P<0.05). CONCLUSIONS: Centrally performed DIA of Ki-67 LI on breast cancer tissue samples produces additional information that allows the identification of statistically significant differences between primary antibodies (MIB-1 and 30-9). It also validates qualitative assessment by demonstrating significant differences between qualitative categories and is likely to be useful to identify lab-specific differences in staining performance in future rounds of EQA.The prototype CLMA produced using the Karpas cell-line did not demonstrate statistically significant differences between primary antibody clones or qualitative categories and is not a useful tool for use in EQA.REFERENCES: 1. Warrick N, et al. UK IBCS 2020. Breast Cancer Res Treat 180, 527-596 (2020)2. http://vmscope.com/index BC_ABC_BCLMA_0%CLMA_5%CLMA_10%CLMA_20%CLMA_30%Number of values124125164165110165165Minimum0.30.00.00.01.93.30.025% Percentile11.31.00.01.74.07.613.5Median15.22.20.02.35.09.416.375% Percentile20.03.50.23.26.111.519.8Maximum32.212.112.09.111.721.335.995% CI of medianActual confidence level96.2%95.1%96.5%95.7%95.5%95.7%95.7%Lower confidence limit14.01.80.02.04.99.115.5Upper confidence limit16.62.60.02.65.59.817.1Mean15.72.50.42.65.510.017.1Std. Deviation6.52.11.71.42.23.35.7Std. Error of Mean0.60.20.10.10.20.30.4Lower 95% CI of mean14.52.20.22.45.09.516.2Upper 95% CI of mean16.82.90.72.85.910.518.0 Citation Format: Andrew Dodson, Dawn Wilkinson, Mitch Dowsett, Suzanne Parry. Results from the first UK NEQAS ICC & ISH external quality assessment for Ki-67 demonstration in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-05-01.

Malignant Progression Contributes to the Failure of Combination Therapy for Atypical Meningiomas.

ObjectiveTo investigate the independent risk factors for recurrence in intracranial atypical meningiomas (AMs) treated with gross total resection (GTR) and early external beam radiotherapy (EBRT).MethodsClinical, radiological, and pathological data of intracranial AMs treated with GTR-plus-early-EBRT between January 2008 and July 2016 were reviewed. Immunohistochemical staining for Ki-67 was performed. Kaplan–Meier curves and univariate and multivariate Cox proportional hazards regression analyses were used to explore independent predictors of tumor recurrence. Chi square test was performed to compare variables between subgroups.ResultsForty-six patients with intracranial AMs underwent GTR and early EBRT. Ten (21.7%) recurred and three (6.5%) died during a median follow-up of 76.00 months. Univariate and multivariate Cox analyses revealed that malignant progression (MP) (P = 0.009) was the only independent predictor for recurrence, while Ki-67 was of minor value in this aspect (P = 0.362). MP-AMs had a significantly higher recurrence rate (P = 0.008), a higher proportion of irregularly shaped tumors (P = 0.013) and significantly lower preoperative Karnofsky Performance Scale (KPS) scores (P = 0.040) than primary (Pri) AMs. No significant difference in Ki-67 expression was detected between these subgroups (P = 0.713).ConclusionsMP was significantly correlated with an increased incidence of recurrence in GTR-plus-early-EBRT-treated intracranial AMs. Significantly higher frequencies of tumor relapse and irregularly shaped tumors and lower preoperative KPS scores were observed in MP-AMs compared with Pri-AMs. Ki-67 expression is of minor value in predicting tumor recurrence or distinguishing tumor origins in AMs.

Changes in ki-67 and cleaved caspase-3 (CC3) with short term androgen deprivation therapy (ADT) prior to prostatectomy as part of a trial in intermediate and high-risk prostate cancer (PC).

e17502 Background: Ki-67 and CC3 are markers of cellular proliferation and apoptosis and have been associated with prognosis in localized PC. Testosterone suppression promotes a time-dependent modulation of these indices. We explored changes in Ki-67 and CC3 at different timepoints in a pilot trial using short-term ADT prior to radical prostatectomy (RP). Methods: Pts with intermediate and high-risk localized PC were randomized to receive a single dose of neoadjuvant degarelix (240 mg SC) either 4 ± 1 days (Cohort A) or 7 ± 1 days (Cohort B) prior to RP. Anatomically matched tumor foci from the pre-treatment diagnostic biopsy and the prostatectomy specimens were assessed by immunohistochemistry (IHC) for Ki-67, CC3, and PTEN expression. Results: 32 pts were randomized: 15 to Cohort A and 17 to Cohort B. Ki-67 and CC3 expression in the pre- and post-treatment samples for both cohorts are summarized in the table. A significant reduction in Ki-67 and increase in CC3 expression occurred in both cohorts (all p-values < 0.05). No difference was found when the absolute difference of Ki-67 expression was compared between Cohort A and Cohort B (p = 0.7). A significant reduction of Ki-67 and increase in CC3 expression occurred in pts independent of PTEN status. Conclusions: A reduction of Ki-67 and an increase in CC3 expression was achieved in both cohorts following a single dose of degarelix within 1 week of RP. Although loss of PTEN has been associated with androgen-independent progression, reduction of proliferation and increase in apoptosis levels were achieved independent of PTEN status in this small cohort. Further analyses are ongoing to correlate the pathologic findings with clinical outcomes. Clinical trial information: NCT01542021 . [Table: see text]

Effect of the Ileum and Colon on Liver Regeneration

Purpose The colon and ileum play significant roles on liver physiology. Studies about simultaneous hepatectomy and colectomy or enterectomy are scarce and controversial. We investigated and compared the effects of ileum and colon resection on liver regeneration. Materials and Methods Twenty four Wistar rats were allocated in group I-(sham), group II-70% hepatectomy; group III-70% hepatectomy + ileal resection, and group IV-70% hepatectomy + partial colectomy. On the sixth day, serum hepatic enzymes, albumin, hepatocyte growth-factor (HGF) and transforming growth factor-alpha (TGF-α) were measured. The hepatic regeneration rate was estimated. Ki-67 immunohistochemical analysis was done in remnant liver. Results Hepatic enzymes levels were significantly higher in group III rats comparing to the other groups (p < 0.001). In group IV, the levels were significantly lower than in groups II and III (p < 0.001). Albuminemia was significantly lower in group III rats comparing with the other groups (p < 0.001). Albuminemia was not different comparing groups I and IV (p > 0.05). Cytokines HGF and TGF-α levels in group IV were significantly higher than in the other groups (p < 0.001). Liver regeneration rate was higher group IV than in groups II and III, and the difference was statistically significant (p = 0.002). The hepatocytes expression of Ki-67 was significantly higher in the remnant liver of group IV than in group III (p = 0.002). There was no difference in Ki-67 expression between groups II and IV (p > 0.05). Conclusion Ileum and colon resection have different effects on liver regeneration. Colon resection positively influences liver regeneration, while ileum resection negatively influences the regenerative process, in a rat model.

Cerebral cavernomas in adults and children express relaxin.

To shed light on the role of relaxin in cerebral cavernous malformations (CCMs) in adults and children, the authors investigated endothelial cell (EC) expression of relaxin 1, 2, and 3; vascular endothelial growth factor receptor-1 and -2 (VEGFR-1 and -2); Ki-67; vascular geometry; and hemorrhage, as well as the clinical presentation of 32 patients with surgically resected lesions. Paraffin-embedded sections of 32 CCMs and 5 normal nonvascular lesion control (NVLC) brain tissue samples were immunohistochemically stained with antibodies to relaxin 1, 2, and 3; angiogenesis growth factor receptors Flt-1 (VEGFR-1) and Flk-1 (VEGFR-2); and proliferation marker Ki-67. For morphometric analysis, Elastica van Gieson stain was used, and for hemorrhage demonstration, Turnbull stain was used. Data from the pediatric and adult CCMs were compared with each other and with those obtained from the NVLCs. Statistical analyses were performed with Fisher's exact test, the chi-square test, the phi correlation coefficient, and the Student t-test. A p value < 0.05 was considered significant. Pediatric and adult cavernoma vessels did not significantly differ in diameter. Hemorrhage was observed in CCMs but not in NVLC samples (p < 0.05). There was no difference in expression of Ki-67, VEGFR-1 and -2, and relaxin 1, 2, and 3 in the ECs of pediatric and adult CCMs. The ECs of CCMs were largely negative for relaxin 3 compared to NVLCs (p < 0.05), whereas CCMs, compared to control brain tissue samples, more frequently expressed Flt-1 and relaxin 2 (p < 0.05). Ki-67 was not expressed in the NVLCs, but the difference was not statistically significant. Relaxin 1 and 2 expression and increased expression of VEGFR-1 were associated with a supra- versus infratentorial location (p < 0.05). Relaxin 1 and 2 and VEGFR-1 play a role in supratentorial cavernomas. Relaxin 3 may play a physiological role in normal brain vasculature. Relaxin 1 and 3 are also found in normal cerebral vasculature. Relaxin 1, 2, and 3 are associated with increased VEGFR-1 expression.

The therapeutic potential of epigallocatechin‑3‑gallate against human oral squamous cell carcinoma through inhibition of cell proliferation and induction of apoptosis: Invitro and invivo murine xenograft study.

Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors in the oral region. Despite current therapeutic strategies, the survival rate has not been improved for several decades. Thus, it is important to develop a novel approach for the treatment of OSCC. Epigallocatechin-3-gallate (EGCG) is a major constituent of green tea and has previously been demonstrated to inhibit the growth of several types of cancer cells. However, few studies have investigated the effect of EGCG on human OSCC cells, especially in experimental animal models. The aim of the present study was to evaluate the therapeutic potential of EGCG for targeting human OSCC in vitro and in vivo. In the in vitro experiments, EGCG suppressed HSC-3 cell viability in a time- and dose-dependent manner. Cell cycle analysis revealed that EGCG induced G1 phase arrest of the tumor cells. Apoptosis was examined by Annexin V and propidium iodide staining, assays of caspase-3 and −7 activity and TdT-mediated dUTP nick end labeling (TUNEL) staining. Treatment with EGCG significantly increased caspase-3 and −7 activities, and the percentage of apoptotic cells when compared with control cells. In the in vivo xenograft experiment on mice, EGCG treatment resulted in a 45.2% reduction in tumor size as compared with the control group without weight loss. In vivo cell proliferation and apoptosis were assessed by immunohistochemical Ki-67 staining and the TUNEL staining. There were significant differences in Ki-67 expression between the EGCG treatment group and control group, and the percentage of apoptotic cells in the EGCG treatment group was significantly greater than that in the control group. These results indicated that EGCG significantly inhibited cell proliferation by affecting the cell cycle progression and apoptosis in vitro and in vivo. These findings suggest that EGCG may have clinical applications as a novel approach to oral-cancer therapy.

Cell proliferation proteins and aggressiveness of histological variants of ameloblastoma and keratocystic odontogenic tumor

ABSTRACTTumors that originate from the epithelium of the odontogenic apparatus are classified as benign or malignant. The proliferative activity could provide a basis for differences in the biologic behavior among the histological variants of ameloblastoma (AM) and keratocystic odontogenic tumor (KCOT). We examined 32 solid AM and 18 KCOT cases. The AM sample comprised 16 cases of follicular AM, six cases of unicystic AM, eight cases of plexiform AM and two cases of acanthomatous AM. Sections were stained with the Ki-67 antibody. Ten representative fields were selected randomly in each section. For AM, peripheral tall columnar cells of tumor islands/nests/cords were selected. For KCOT, fields were selected in the basal and the suprabasal region of the epithelial lining. We counted the average number of Ki-67 positive cells/field for AM and KCOT. AM exhibited Ki-67 expression in peripheral tall columnar cells, whereas KCOT exhibited Ki-67 expression in the basal and suprabasal layer. No significant difference between AM and KCOT was observed; the cellular proliferative activity varied among the subtypes. No significant difference in Ki-67 expression in acanthomatous, cystic and follicular types of AM was observed, although the plexiform type exhibited significantly higher levels than the other three types. High expression of Ki-67 could be a useful prognostic marker for proliferative activity and a prognostic indicator for recurrence rate of AM and KCOT.

The impact of the immune microenvironment in patients with GEP-NETs.

267 Background: The immune microenvironment in neuroendocrine tumors (NETs) remains largely unexplored with very limited data evaluating its impact on survival. We aimed to characterize the immune microenvironment and lymphocytic infiltrate in patients with gastroenteropancreatic (GEP) NET. Methods: We performed comprehensive immune profiling for CD3, CD8, PD-1, IDO, and PD-L1 expression in two cohorts of patients with primary GEP-NET: patients who had short progression free survival (PFS) ≤ 4 years (n = 12) or long PFS &gt; 4 years (n = 14) following surgical resection. Tumor associated immune infiltrates in the tumor, inner and outer invasive front were recorded and quantified. The percentage of PD-L1 membranous expression was manually counted in tumor, stroma and invasive front. To account for the correlation among multiple samples within the same patient, generalized estimating equations (GEE) were used for model estimation and hypothesis testing. Results: Patients with shorter PFS had larger primary tumor size compared to patients with longer PFS (Wilcoxon p value = 0.02), with no statistically significant differences in Ki-67 expression. For all patients univariate GEE results showed a higher mean expression of CD3+, CD8+, and PD-1+ cells at the interface (inner and outer) as compared to the tumor region: 1.28 (95% CI: 0.98, 1.58, p &lt; 0.0001), 0.99 (95% CI: 0.67, 1.32, p = 0.0005) and 1.38 (95% CI: 0.90, 1.38, p &lt; 0.0001) respectively. Comparison between the two groups showed that tumors from patients with a longer PFS had higher intratumoral CD3+ TILs densities than did those from patients who had a shortened PFS (0.88, 95% CI: 0.44, 1.31, p = 0.004). Intratumoral expression of CD8+TILs, and IDO+ cells tended to be higher in the long PFS group (p = 0.143 and 0.29 respectively). While the probability of positive PD-L1 expression did not differ according to location, it was higher in patients with shortened PFS (odds ratio = 1.96; 95% CI: 0.64, 5.93), though not significant. Conclusions: Higher intratumoral T cell infiltrate (CD3+) is associated with a favorable outcome and longer PFS following resection for GEP-NETs. Immune escape is a potential mechanism for disease progression and warrants further investigation as a therapeutic strategy for this disease.

Follicular Regulatory T Cells Are Highly Permissive to R5-Tropic HIV-1.

Follicular regulatory T (TFR) cells are a subset of CD4+ T cells in secondary lymphoid follicles. TFR cells were previously included in the follicular helper T (TFH) cell subset, which consists of cells that are highly permissive to HIV-1. The permissivity of TFR cells to HIV-1 is unknown. We find that TFR cells are more permissive than TFH cells to R5-tropic HIV-1 ex vivo TFR cells expressed more CCR5 and CD4 and supported higher frequencies of viral fusion. Differences in Ki67 expression correlated with HIV-1 replication. Inhibiting cellular proliferation reduced Ki67 expression and HIV-1 replication. Lymph node cells from untreated HIV-infected individuals revealed that TFR cells harbored the highest concentrations of HIV-1 RNA and highest levels of Ki67 expression. These data demonstrate that TFR cells are highly permissive to R5-tropic HIV-1 both ex vivo and in vivo This is likely related to elevated CCR5 levels combined with a heightened proliferative state and suggests that TFR cells contribute to persistent R5-tropic HIV-1 replication in vivoIMPORTANCE In chronic, untreated HIV-1 infection, viral replication is concentrated in secondary lymphoid follicles. Within secondary lymphoid follicles, follicular helper T (TFH) cells have previously been shown to be highly permissive to HIV-1. Recently, another subset of T cells in secondary lymphoid follicles was described, follicular regulatory T (TFR) cells. These cells share some phenotypic characteristics with TFH cells, and studies that showed that TFH cells are highly permissive to HIV-1 included TFR cells in their definition of TFH cells. The permissivity of TFR cells to HIV-1 has not previously been described. Here, we show that TFR cells are highly permissive to HIV-1 both ex vivo and in vivo The expression of Ki67, a marker of proliferative capacity, is predictive of expression of viral proteins, and downregulating Ki67 leads to concurrent decreases in expression of viral proteins. Our study provides new insight into HIV-1 replication and a potential new cell type to target for future treatment.

Differences in Ki67 expressions between pre- and post-neoadjuvant chemotherapy specimens might predict early recurrence of breast cancer

The prognosis of breast cancer patients not obtaining a pathological complete response (pCR) with neoadjuvant chemotherapy (NAC) is poorer than that of pCR patients. Identifying new prognostic factors for non-pCR patients is important because fractions of this population might benefit from novel adjuvant treatments currently under development. High Ki67 expression in remnant disease after NAC has been described as a poor prognostic factor. Studies have shown that a reduction in Ki67 expression is more often observed in good responders to chemotherapy. We hypothesized that the change in Ki67 expression might be useful for predicting patient outcomes and thus retrospectively examined pairs of biopsy and surgical specimens of breast tissue from individual patients. One hundred sixteen patients with remnant invasive disease in the breast, who received NAC and underwent surgery at our institution, were retrospectively examined. Differences in Ki67 expression between pre- and post-NAC specimens were analyzed in relation to patient outcomes. The mean Ki67 expression value after NAC was higher in patients who developed metastasis than in those without metastasis (P<.01). Tumors showing higher Ki67 expression in the surgical than in the biopsy specimen were more frequent in patients with metastasis (P<.01). This trend was more obvious in patients who developed metastasis within 1 year after surgery. Our results indicate that a difference in Ki67 expressions after versus before NAC might be an important predictor of early metastasis. Evaluating not only absolute Ki67 values, but also any changes in response to NAC, may improve the prediction of patient outcomes.

Abstract 10: Concordance of BAP1, PBRM1, Ki-67, and TOPOIIa protein expression in primary clear cell renal cell carcinoma tumors and patient-matched metastatic tumors

Abstract Introduction: Efforts to improve clear cell renal cell carcinoma (ccRCC) mortality have focused primarily on evaluating prognostic biomarkers in primary tumors in order to identify indicators of response to treatment and targets for novel therapies. To date little attention has been paid to the status of these biomarkers in the more therapeutically-relevant metastatic tumor. Thus, we evaluated concordance of expression of four key prognostic ccRCC biomarkers (BAP1, PBRM1, Ki-67 and TOPOIIa) in a large cohort of patient-matched primary ccRCC and metastatic tumors. Methods: We identified 114 patients treated surgically for ccRCC between 1990 and 2005 who had synchronous (M1) or metachronous (M0) metastases, underwent metastasectomy for at least one metastatic lesion and had archived tissue available from the primary and at least one metastatic tumor. We performed IHC on all primary and metastatic tumors for BAP1, PBRM1, Ki-67, and TOPOIIa using previously-published protocols. BAP1 and PBRM1 expression was categorized as positive or negative and Ki-67 and TOPOIIa was quantified as the number of positive cells per mm2. For BAP1 and PBRM1, we calculated the concordance between patient-matched primary and metastatic tumors as the percentage of pairs where the primary and metastatic tumor had the same designation (i.e., positive or negative). For TOPOIIa and Ki-67, we assessed concordance using Spearman correlation coefficient. Analysis of variance was used to evaluate if concordance between primary-metastatic tumor pairs for TOPOIIa and Ki-67 was associated with metastatic site, metastatic timing (M0/M1), metastatic tumor grade, metastatic tumor necrosis, and metastatic tumor sarcomatoid differentiation. Results: There were a total of 161 patient-matched metastatic tumors available for the 114 patients: 78 patients had only a single metastasis while 36 patients had two or more metastases. While sites of metastases varied, pulmonary metastases were the most common (44% of all metastases). Loss of BAP1 expression was observed in19% of the primary ccRCC and 98.6% of the tumor pairs had concordant BAP1 status between the paired primary and metastatic tumors. Loss of PBRM1 was observed in 56% of the primary ccRCC tumors and 89.3% of tumor pairs showed concordant PBRM1 status. By comparison, median expression of Ki-67 was 65.0mm2 in the primary ccRCC tumors and the Pearson correlation with the patient-matched metastatic tumors was 0.43. The difference in Ki-67 expression between primary-metastatic tumor pairs was associated with necrosis in the metastatic tumor (p=0.014). Median expression of TOPOIIa was 2.6mm2 in the primary ccRCC tumors and the Pearson correlation with the patient-matched metastatic tumors was 0.25. The difference in TOPOIIa expression between primary-metastatic tumor pairs was associated with metastatic site (p=0.0006) and metastases to the heart were significantly different than pulmonary metastases (p&amp;lt;0.0001). Additionally, synchronous metastases had larger differences from their patient-matched primary tumors in comparison to metachronous metastases (p=0.012), as did necrotic metastases (p=0.028). Conclusion: We observed high concordance for loss of BAP1 and PBRM1 expression between primary ccRCC and metastatic tumors in the same patient. Conversely, we noted high discordance in protein expression of Ki-67 and TOPOIIa between patient-matched primary-metastatic tumor pairs. Moreover, this discordance varied by key pathological features. Our results suggest that using the status of a biomarker in primary ccRCC as a guide for the status in metastatic tumors is not always appropriate and needs to be evaluated on a marker-by-marker basis. Citation Format: Jeanette E. Eckel-Passow, Daniel J. Serie, John C. Cheville, Thai H. Ho, Sue M. Harrington, Tracy Hilton, Christine Lohse, Amanda Shreders, Payal Kapur, James Brugarolas, R Houston Thompson, Bradley C. Leibovich, Eugene D. Kwon, Richard W. Joseph, Alexander S. Parker. Concordance of BAP1, PBRM1, Ki-67, and TOPOIIa protein expression in primary clear cell renal cell carcinoma tumors and patient-matched metastatic tumors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 10.

Menstrual cycle could affect Ki67 expression in estrogen receptor-positive breast cancer patients

BackgroundKi67 is a potent prognostic marker for determining systemic treatment of patients with hormone receptor-positive breast cancer. However, evaluation of Ki67 expression can be difficult, due mostly to its heterogeneity....

Abstract 3887: The association between expression of ALDH1, KI67 and grading system in breast adenocarcinoma

Abstract Introduction: Many studies have shown that the ALDH1 and Ki67 markers can accurately identify different types of cells in the breast. ALDH1 has proven to be a biomarker of breast cancer stem-like cells, while Ki67 has considered a proliferative marker. However, although Ki67 has been correlated with breast cancer grading, little attention has been given to the relationship between ALDH1 and histological grading. On the other hand, although ALDH1 has been correlated with intrinsic molecular subtype of breast cancer, there is an absence of literature between Ki67 and breast cancer subtypes. Thus, the goals of this study are to address the relationship between ALDH, Ki67 and histological grading in breast cancer. Methods and Material: Immunohistochemistry staining (IHC) for ALDH1 was performed on tissue micro array (TMA) of 200 patient samples with different histological grades of breast cancer. Similarly, IHC was used to identify and assess the expression of Ki67 on TMA of 66 patient samples of various breast cancer subtypes (40 Luminal and 26 TNBC). Both biomarkers were compared to respective normal breast tissue using t-test statistical analysis. Results: results showed that 51/129 (39.5%) of cancerous breast tissues were ALDH1 positive. ALDH1 positivity differed significantly between different grades cancerous breast tissues and normal tissue (p=0.0007). In addition, a direct relationship exists between increasing grade and increasing ALDH1 positivity, with grade 3 having the highest frequency and intensity of ALDH1 positivity (p=0.005). In normal tissue, 6/25 (24%) cores on the tissue microarray showed presence of Ki67. The average percentage of cells containing in Ki67 positive cores for normal tissue was 2.54%. In luminal subtypes, 30/38 (78.9%) patients on the tissue microarray showed presence of Ki67. The average percentage of cells containing Ki67 in luminal breast cancer, for patients with Ki67 positive cores was 3.93%, with a median of 2.5%. Ki67 was also present in 24/26 (92.3%) patients with triple negative breast cancer. Among the 24 patients with Ki67 present, an average of 6.91% of cells exhibited Ki67 in each core, with a median of 4.25%. A one-tailed student's T-test was used to determine statistical significance of the difference in Ki67 expression (including the patients with no Ki67 expression) between Luminal and Triple Negative subtypes of breast cancer with a p-value of 0.026 Conclusion: Our findings suggest that higher grades of breast cancer may contain higher quantities of breast cancer stem like cells. Given the role of Ki67 in cell proliferation, the increased presence of Ki67 in triple negative breast cancer, when compared to Luminal subtypes of breast cancer, may suggest a correlation with a worse prognosis. Identification of Ki67 positivity in breast cancer cells may aid in the development of prognosis and novel treatment techniques. Citation Format: Yahya I. Elshimali, Pierre Tamer, Sami Dwabe, Yanyuan Wu, Marianna Sarkissyan, Jaydutt V. Vadgama. The association between expression of ALDH1, KI67 and grading system in breast adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3887. doi:10.1158/1538-7445.AM2014-3887

Expression of hormone receptors, Bcl-2, Cox-2 and Ki67 in benign endometrial polyps and their association with obesity

The present study examined the immunoexpression of the estrogen receptor (ER), the progesterone receptor (PR), B‑cell lymphoma 2 (Bcl‑2), cyclooxygenase‑2 (Cox‑2) and Ki67 in endometrial polyps and their association with obesity. In total, 515 premenopausal and postmenopausal females undergoing hysteroscopy with histological diagnosis of benign polyps were included. The immunohistochemical expression of the ER, PR, Bcl‑2, Cox‑2 and Ki67 was compared between obese and non‑obese females. The median final score demonstrated a higher PR expression in the stromal and glandular compartments of postmenopausal obese females as compared with no‑obese females. However, in this group, there was no difference in regard to the ER. No difference in hormone receptor expression was identified among premenopausal females. In postmenopausal females, the immunoexpression of Cox‑2 and Bcl‑2 in the glandular epithelium was higher in obese than in non‑obese females. Among premenopausal females, obese females demonstrated a higher Bcl‑2 expression in the glandular epithelium than non‑obese females. There were no differences in Ki67 expression between obese and non‑obese females. Polyps from obese females had a higher PR expression in the glandular and stromal compartments. The expression of Cox‑2 and Bcl‑2 was higher in the glandular compartment. These data suggested that the etiology and pathogenesis of polyps in obese females appear to be associated with the PR, the inhibition of apoptosis and cellular mechanisms linked with inflammation.

Suitability/Unsuitability of Cell Proliferation as an Indicator of Malignant Potential in Oral Lichen Planus: an Immunohistochemical Study

Oral lichen planus (OLP) is categorized as premalignant lesion although its malignant potential is a matter of controversy. The objective of this study was to investigate Ki67 expression in OLP, oral epithelial dysplasia and oral squamous cell carcinoma (OSCC). Expression of Ki67 was evaluated through immunohistochemistry (IHC) in groups of A (17 cases of epithelial hyperplasia), B (16 cases of OLP), C1 (10 cases of mild epithelial dysplasia), C2 (10 cases of severe epithelial dysplasia), D1 (10 cases of well-differentiated OSCC), and D2 (10 cases of poorly-differentiated OSCC). There was a significant difference in Ki67 expression based on quantitative analysis among the six studied groups as well as group B compared bilaterally with groups C2, D1 and D2 (p< 0.0001). However, there was no significant difference between groups B and C1 or between groups D1 and D2 (p> 0.05). Based on the results of the present study it may not be possible to definitely consider malignant transformation potential for OLP. However, expression of Ki67 was significantly higher in OLP than that of epithelial hyperplasia with no significant difference from that of mild epithelial dysplasia. This should be considered by clinicians to carefully and regularly follow up OLP lesions to detect potential subtle changes at an early stage.

Ki-67 expression and significance of different molecular subtypes of breast invasive ductal carcinoma

To analyze Ki-67 expression and explore its significance in different molecular subtypes of breast invasive ductal carcinoma (IDC). The expressions of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2) and Ki-67 were detected in 126 cases of IDC by immunohistochemical staining. Then the molecular subtype of each case of IDC was determined.Statistical analysis was performed to determine the relationship between Ki-67 expression and the molecular subtypes with clinicopathological features of IDC. There was no statistically significant difference of Ki-67 expression in age and tumor size (P > 0.05).However, significant difference existed in histological grading and lymph node metastasis (P < 0.05). The expression level of Ki-67 was negatively correlated with ER expression (r = -0.273, P = 0.002) and PR expression (r = -0.242, P = 0.007) and positively with HER-2 expression (r = 0.245, P = 0.006) . A low expression of Ki-67 was in LumianlA subtype (17/17) and high expression in other molecular subtypes. Moreover, the rate of high expression (Ki-67 LI>50%) in each subtype progressively increased with the degree of molecular typing and Ki-67 expression in different molecular subtypes showed significant difference (P < 0.05). The expression level of Ki-67 is correlated with histological grading and molecular type of IDC. High expression of Ki-67 carries poor prognosis. Thus it is necessary to perform a variety of routine clinicopathological examinations, such as Ki-67, ER, PR and HER-2.

Assessment of Cellular Proliferation in Oral Verrucous Carcinoma and Well-Differentiated Oral Squamous Cell Carcinoma Using Ki67: A Non-Reliable Factor for Differential Diagnosis?

Non-invasive oral verrucous carcinoma (OVC) and invasive well-differentiated oral squamous cell carcinoma (OSCC) have similar histopathologic findings but different biological behavior. These two malignancies must be correctly differentiated by pathologists. The aim of this study was to determine immunohistochemical (IHC) expression of Ki67 in OVC and well-differentiated OSCC. Expression of Ki67 was evaluated by IHC in 15 cases of epithelial hyperplasia with no dysplasia (A group), 15 cases of OVC (B group), 12 cases of microinvasive OSCC(C group) and 15 cases of well-differentiated OSCC (D group). There was a significant difference in Ki67 expression based on pattern distribution of immunostaining positive cells, with quantitative and semi-quantitative analyses, among the four groups ; also, between A group and each of the other three groups (P=0.0001). But there was no significant difference between B and C, C and D, and B and D groups (P>0.05). The three evaluation methods of Ki67 expression showed Ki67 (Mib-1) is not a good immunohistochemical marker to assess invasion status and differentiate OVC from well-differentiated OSCC; also, it cannot be used as a diagnostic tool to distinguish between variants of OSCC with similar grade.

The prognostic value of Ki-67 expression in penile squamous cell carcinoma

AimsTo determine whether Ki-67 immunoexpression in penile squamous cell carcinoma (PSCC) has a prognostic value and correlates with lymph node metastasis, human papillomavirus (HPV) infection and patient survival.Methods148 formalin-fixed paraffin-embedded...