Value Of Ki-67 Labeling Index Research Articles

Retracted: Intravoxel Incoherent Motion Diffusion-Weighted Imaging and 3D-ASL to Assess the Value of Ki-67 Labeling Index and Grade in Glioma.

[This retracts the article DOI: 10.1155/2022/8429659.].

Adult IDH Wild-Type Glioblastoma Ultrastructural Investigation Suggests a Possible Correlation between Morphological Biomarkers and Ki-67 Index.

Glioblastoma is an aggressive brain tumor with an average life expectancy between 14 and 16 months after diagnosis. The Ki-67 labeling index (LI), a measure of cellular proliferation, is emerging as a prognostic marker in GBM. In this study, we investigated the ultrastructure of glioblastoma tissue from 9 patients with the same molecular profile (adult IDH wild-type glioblastoma, wild-type ATRX, and positive for TP53 expression, GFAP expression, and EGFR overexpression) to find possible ultrastructural features to be used as biomarkers and correlated with the only parameter that differs among our samples, the Ki-67 LI. Our main results were the visualization of the anatomical basis of astrocyte-endothelial cells crosstalk; the ultrastructural in situ imaging of clusters of hyperactivated microglia cells (MsEVs); the ultrastructural in situ imaging of microglia cells storing lipid vesicles (MsLVs); the ultrastructural in situ imaging of neoplastic cells mitophagy (NCsM). The statistical analysis of our data indicated that MsEVs and MsLVs correlate with the Ki-67 LI value. We can thus assume they are good candidates to be considered morphological biomarkers correlating to Ki-67 LI. The role of NCsM instead must be further evaluated. Our study findings demonstrate that by combining ultrastructural characteristics with molecular information, we can discover biomarkers that have the potential to enhance diagnostic precision, aid in treatment decision-making, identify targets for therapy, and enable personalized treatment plans tailored to each patient. However, further research with larger sample sizes is needed to validate these findings and fully utilize the potential of ultrastructural analysis in managing glioblastoma.

The Value of Ki-67 Labeling Index in Central Lymph Node Metastasis and Survival of Papillary Thyroid Carcinoma: Evidence From the Clinical and Molecular Analyses.

Recent evidence suggests that the Ki-67 labeling index is associated with lymph node metastasis and the prognosis of papillary thyroid carcinoma (PTC). We retrospectively evaluated the clinicopathological features of consecutive PTC patients between Jan 2019 and Oct 2020 in our medical center. The molecular analysis was also conducted by using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) program. The Chi-square test was performed for the comparison of variables between patients with central lymph node metastasis (CLNM) and not. Besides, univariate and stepwise multivariate logistic regression analyses were further used to determine the risk factors for CLNM in PTC. Our results showed that male gender (odd ratio (OR) = 3.02; 95% CI: 1.81-5.04), tumor size >1cm (OR = 2.81; 95% CI: 1.84-4.29), multifocality (OR = 2.08; 95% CI: 1.31-3.30, and Ki-67 labeling index (>3% and ≤5%: OR = 1.20; 95% CI: .73-1.97; >5%: OR = 3.85; 95% CI: 1.62-9.14) were independent risk factors for CLNM. After excluding the patients with harvested central lymph nodes <3, increased Ki-67 labeling index was still associated with the number of CLNM and the lymph node ratio. Additionally, the expression level of Ki-67 was significantly correlated with a higher N stage and worse disease-free survival in TCGA and validated GSE60542 datasets. Higher Ki-67 labeling index (>5%) is significantly associated with the CLNM in PTC patients, like other indicators of the male gender, larger tumor size, and multifocality. Besides, the Ki-67 was also determined to be associated with CLNM and DFS in PTC patients, which may act as an important molecular marker in PTC.

Expression of Apurinic/Apyrimidinic Endonuclease 1 in Colorectal Cancer and its Relation to Tumor Progression and Prognosis.

Over-expression of apurinic/apyrimidinic endonuclease 1 (APE1) has been demonstrated to be associated with cancer progression, chemo- and radioresistance in various cancers. This study examined the expression of APE1 and its relation to tumor progression and prognosis in patients with colorectal cancer (CRC). We investigated 193 patients with CRC who received curative surgery for whom formalin-fixed and paraffin-embedded blocks were available, and long-term tumor-specific survival rate analysis was possible. The expression of APE1 was investigated by reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry in CRC and lymph node tissues. The apoptosis, proliferation, and angiogenesis of CRC cells were determined using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and immunohistochemical staining for Ki-67 and CD34 antibodies. APE1 was over-expressed in CRC and metastatic lymph node tissues compared with normal colorectal mucosa and non-metastatic lymph node tissues. Over-expression of APE1 was significantly associated with advanced stage, lymphovascular invasion, perineural invasion, deeper tumor invasion, lymph node metastasis, distant metastasis, and poor survival. Multivariate analysis demonstrated that APE1, perineural invasion, and lymph node metastasis were the independent prognostic factors associated with overall survival. The mean Ki-67 labeling index value of APE1-positive tumors was significantly higher than that of APE1-negative tumors. However, there was no significant association between APE1 expression and the apoptotic index or microvessel density. Over-expression of APE1 is significantly associated with tumor progression and poor survival in patients with CRC. Therefore, APE1 may be a novel biomarker and present a potential prognostic factor for CRC.

The prognostic value of S-100 protein and Ki-67 index in olfactory neuroblastoma.

To evaluate the prognostic value of S-100 protein and Ki-67 labeling index in olfactory neuroblastomas. A retrospective study was conducted on a cohort of 85 patients with olfactory neuroblastomas. The immunohistochemical expression of S-100 and Ki-67 was assessed, and the predictive value of S-100 and Ki-67 was further evaluated. The optimal cutoff value of Ki-67 labeling index was determined using time-dependent receiver operating characteristic curve analysis. Overall survival and progression-free survival were assessed using the Kaplan-Meier method. A cut-off Ki-67 labeling index value of 67.5% was determined for prognosis in patients with olfactory neuroblastomas. There was a significant correlation between Ki-67 expression and cervical lymph node metastasis (P=0.049). Compared with S-100 (+), S-100 (-) was associated with a higher rate of lymph node metastasis and a higher level of Ki-67 (P=0.007,<0.001, respectively), as well as an advanced Kadish stage (P=0.037). Survival analyses showed that patients with S-100 (+) had better 5-year overall survival than those with S-100 (-) (P=0.028), and patients with both S-100 (+) and Ki-67 (<67.5%) had superior 5-year overall survival compared with all the other patients (P=0.0225). Our findings suggest that S-100 combined with Ki-67 labeling index are reliable prognostic factors in patients with olfactory neuroblastomas.

Immunohistochemical Study of Ki-67 Labelling Index in Neoplasms of Central Nervous System

Introduction: The central nervous system tumours show a varied histopathological spectrum. The cell proliferation index may provide an objective method for assessing tumour biology. The Ki-67 is considered to be the most reliable proliferative marker predicting the tumour behaviour of various systemic and intracranial neoplasms. As it reflects tumour proliferating potential, it helps in determining the grade and hence the likelihood of recurrence. This study was carried out considering that very few studies of Ki-67 Labelling Index (LI) is seen in Central Nervous System (CNS) neoplasms collectively. Aim: To study the Ki-67 LI in CNS neoplasms and the association of Ki-67 LI with different parameters like age, sex, World Health Organisation (WHO) grading and histological types. Materials and Methods: The present descriptive analytical study was conducted at Department of Pathology, Mahadevappa Rampure Medical College, Karnataka, India, attached to a tertiary care hospital, Kalaburagi, for a period of five years between 1st Aug 2013 to 31st July 2018 after approval from the Institutional Ethics Committee. The formalin-fixed and paraffin-embedded tissue sections were stained with haematoxylin and eosin. Immunohistochemistry (IHC) was carried out with Ki-67 antibody using standard protocol. The data was analysed using IBM SPSS software version 19.0. The descriptive statistics frequency and percentages were calculated. The morphological grading of CNS tumours was done and the distribution of Ki-67 LI values were analysed. Results: A total of 102 histopathologically diagnosed primary CNS tumours were included in the study. High incidence of CNS neoplasms was seen in 3rd to 4th decade with slight male preponderance. This study included 40 meningioma cases. Mean percentages of Ki-67 LI for grade I and grade II meningiomas were 3.3% and 4%, respectively. The Ki-67 mean value for Astrocytomas grade I was 5.6% and grade II was 8.7%. Grade IV Glioblastoma and Gliosarcoma showed mean value of 18% and 18.8%, respectively. It was observed that LI increased with increase in grade of the tumour. Schwannoma and Dysembryoplastic Neuroepethelial Tumour (DNET) showed Ki-67 LI of 2.9% and 2.6%, respectively. Mean value of Ki-67 LI of other primary CNS neoplasms were as follows: Medulloblastoma 53%, Atypical Teratoid/Rhabdoid Tumour (ATRT) 32%, Haemangiopericytoma 8%, Neurocytoma 4%, Malignant Peripheral Nerve Sheath Tumour (MPNST) 3%, Ganglioglioma 4% and Haemangioblastoma 4%. Conclusion: The Ki-67 LI is the simplest and the most reliable method for evaluating the cell proliferation. It has a great value in designating the exact grade of the tumour when used in combination with histopathological features. It can also be used for planning of adjuvant therapy in primary CNS neoplasms.

Expression of ADAM12 in Gastric Cancer and its Relation to Tumor Cell Behavior and Prognosis.

A disintegrin and metalloprotease (ADAM) 12 expression has been found up-regulated in various cancer types. The aim of the study was to evaluate whether ADAM12 affects oncogenic behavior of gastric cancer (GC) cells and investigate its prognostic value. The effect of ADAM12 on tumor cell behavior was examined using the small interfering RNA and pcDNA6-myc vector in human GC cell lines. Expression of ADAM12 in GC tissues was confirmed by immunohistochemistry. Apoptosis and proliferation were determined by a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and immunohistochemical staining for Ki-67. ADAM12 overexpression enhanced tumor cell migration and invasion in AGS and SNU638 cells. Down-regulation of caspase-3 and PARP activity due to ADAM12 overexpression enhanced tumor cell proliferation and inhibited apoptosis. The expression of Snail and Vimentin increased and that of E-cadherin decreased following ADAM12 overexpression. In contrast, ADAM12 knockdown reversed these effects. ADAM12 overexpression increased the phosphorylation of Akt and GSK-3β. The mean Ki-67 labeling index value of ADAM12-positive tumors was significantly higher compared to that of ADAM12-negative tumors. ADAM12 expression was associated with age, tumor size, cancer stage, depth of invasion, lymph node metastasis, and poor survival. ADAM12 enhances tumor progression by increasing cell mobility, enhancing cell proliferation, and inhibiting apoptosis in GC cells. Also, ADAM12 is associated with adverse clinicopathological features and poor survival. It may be used as a molecular marker for the prediction of clinical outcomes of patients with GC.

Axillary management based on American college of surgeons oncology group Z0011 criteria makes it possible to omit intraoperative diagnosis of sentinel lymph nodes in early breast cancer patients.

The ACOSOG Z0011 trial has resulted in the omission of axillary lymph node dissection (ALND) in early breast cancer patients with one or two metastatic sentinel lymph nodes (SLNs). There has been increasing interest in the necessity of intraoperative assessment of SLNs in patients treated based on the Z0011 criteria. We evaluated the utility of intraoperative assessment in these eligible patients. A total of 1396 patients were treated following the Z0011 criteria from April 2012 to December 2019. We examined the proportion and clinicopathological features of patients who underwent ALND due to three or more metastatic SLNs and the sensitivity of intraoperative assessment. Only 16 (1.1%) patients had three or more metastatic SLNs diagnosed by intraoperative assessment, and they immediately underwent ALND. Of the clinicopathological factors, high clinical tumor stage (p=0.002) and high Ki-67 labeling index value (p=0.056) were more likely to be associated with the presence of three or more metastatic SLNs. The major independent risk factor for three or more metastatic SLNs was high clinical tumor stage (OR 3.94 [95% CI 1.42-11.0]; p=0.009). Intraoperative assessment had low sensitivity (70.5%) and a high false-negative rate (29.5%) in detecting SLN metastases. The main finding of our study was the small proportion of patients who required ALND due to three or more metastatic SLNs according to the Z0011 criteria. The Z0011 strategy enables intraoperative assessment of SLNs to be omitted in early breast cancer patients.

Ki-67 expression as a diagnostic biomarker in odontogenic cysts and tumors: A systematic review and meta-analysis.

Ki-67 is a marker of cell proliferation, used as an important diagnostic marker in the pathologic differentiation of various lesions. It is also relevant for developing targeted molecular therapies. We carried out a systematic review to assess the Ki-67 labeling index (LI) in odontogenic cysts and tumors. Databases were searched, including PubMed (MEDLINE), Scopus, CINHAL, PsycoInfo, the Cochrane Library, and Proquest. The meta-analysis was carried out based on the data of 608 lesions. When a 5% cut-off point was set, ki-67 LI of all benign odontogenic tumors dropped below this point. All the malignant tumors demonstrated an LI of over 15.3%; a significantly higher Ki-67 LI in malignant odontogenic lesions (17.59±2.80) was observed. Among benign tumors, the largest and the smallest Ki-67 LIs were seen in ameloblastoma (4.39±0.47) and adenomatoid odontogenic tumor (0.91±1.71). The mean values of Ki-67 LI in tumors and cysts were 4.23 (0.38) and 1.04 (0.07), respectively. Among odontogenic cysts, the highest Ki-67 LI was found in odontogenic keratocyst (OKC) (3.58±0.51), and the lowest in the radicular cyst (1.29±0.62%). Ki-67 LIs in all odontogenic cysts were <3%, except for OKC. This controversial lesion seems to have a profile more similar to a tumor, and a treatment plan similar to tumors might be suggested. We found that odontogenic lesions have diverse proliferative activities that help differentiate between various lesions and suggest therapeutic plans.

Concomitant use of 18F-FDG PET-CT SUVmax is useful in the assessment of Ki67 labeling index in core-needle biopsy specimens of breast cancer.

Ki67 is a recognized proliferative and predictive marker in invasive breast cancer. However, results of Ki67 evaluation are affected by the method employed for sample fixation or biopsy, as well as by intratumor heterogeneity. Here, we aimed to compare the Ki67 labeling index (Ki67LI) between core-needle biopsy specimens (CNBSs) and surgically resected specimens (SRSs) of invasive breast cancer, and verify whether the discordance in Ki67LI can be reduced by analyzing the maximum standardized uptake value (SUVmax) obtained from pretreatment whole-body positron emission tomography/computed tomography (PET/CT) in combination with Ki67LI. Tumor tissues were obtained from 118 patients with invasive breast cancer. Ki67LI was evaluated in CNBSs and SRSs by immunohistochemistry. First, we directly compared Ki67LI between CNBS and SRS, "allowing a tolerance margin of 5%." We divided the Ki67LI values into three groups (Low: 0≤ Ki67LI ≤10, Intermediate: 10< Ki67LI <30, and High: 30≤ Ki67LI) and the SUVmax into three groups (SUVmax ≤4, 4< SUVmax <8, and 8≤ SUVmax). We then verified the concordance rate between CNBS and SRS in each group in combination with the SUVmax obtained by PET/CT. The median Ki67LI was 17.8% (0.5-75.9%) and 17.0% (1.0-75.7%) in CNBS and SRS, respectively. The overall Ki67LI concordance rate between CNBS and SRS was 37.3% (44/118). The concordance was improved in the Low and High Ki67LI groups by applying SUVmax thresholds of 4 [82.6% (19/23), P=0.033 and 8 (92.3% (12/13), P=0.009], respectively. Our results indicated that CNBS Ki67LI alone was not able to reflect SRS Ki67LI with sufficient accuracy. By dividing CNBS Ki67LI into three classes in combination with SUVmax, tumor proliferation could be predicted with higher accuracy in patients with invasive breast carcinoma.

Clinicopathological characteristics of dysplastic teratomous neuroglia with anti-N-methyl-d-aspartate receptor encephalitis

In this study, we investigated whether unique pathological characteristics exist in teratomas that can trigger autoimmune anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. We compared a case of retroperitoneal teratoma associated with anti-NMDAR encephalitis and four control cases. The encephalitis-positive case showed that (i) more dysplastic neuroglia with higher Ki-67 labeling index values than the control cases, which met the diagnostic criteria of astrocytoma, (ii) the NMDAR subunit NR1 was expressed more abundantly in neuroglial tissue where many neuroglial cells co-expressed glial fibrillary acidic protein (GFAP) and NR1 and formed abnormally large cellular masses, (iii) intense NR1 expression occurs in squamous epithelium near neuroglial tissue and lymphocyte infiltration. This study showed that dysplastic neuroglial tissue resembling central nervous system tumors, which might promote autoimmunity, distinguished the case with NMDAR encephalitis from the controls. Additionally, abnormal expression of NR1 occurs in non-neural tissues and could be triggered by inflammation and participate in autoimmunity.

Cut-off value of Ki-67 labeling index in the pathologic grading of follicular lymphoma

Objective: To determine the cut-off values of Ki-67 labeling index (LI) in the histological grading of follicular lymphoma (FL). Methods: Clinicopathological data of 350 FL patients diagnosed at Beijing Friendship Hospital from June 2014 to January 2016 were analyzed retrospectively by quantitative evaluation and statistical analysis of Ki-67 LI. Results: Of the 350 patients with FL, the male and female ratio was 1.1 and the average age was (50.2±14.0) years with a median age of 51 years (range 4 to 82 years). The tumors were graded as grade Ⅰ-Ⅱ in 215 cases (61.4%), grade Ⅲ A in 105 cases (30.0%), and grade Ⅲ B in 30 cases (8.6%). The average Ki-67 values were (22.8%±8.3%) for the FL low (grade Ⅰ-Ⅱ) and (50.4%±10.7%) for high grade (Ⅲ A and Ⅲ B) and were statistically significant by Mann Whitney U test (P<0.01). Receiver operated characteristic curve analysis showed that the best diagnostic cut-off value of low grade FL was 35% (sensitivity of 96.3% and specificity of 93.3%) with the largest area under curve (AUC=0.990, P<0.01, 95%CI for 0.982-0.998). According to the analysis of four lattice diagnostic tests, Ki-67 LI >40% was an important factor (χ2=230.733, P<0.01) in predicting high grade FL. When the cut-off value of Ki-67 LI was set at 40%, high grade LF could be diagnosed with the greatest sensitivity (98.1%) and specificity (87.7%). Moreover, a significant correlation between the Ki-67 LI and the pathological grade of FL (r=0.836, P<0.01) was observed. Conclusions: Ki-67 LI of below a cut-off value of 35% is a reliable indicator of low grade FL.Ki-67 over 40% is consistent with high grade FL. These Ki-67 cut-off values may serveas an important auxiliary indicator in the grading of FL.

Value of K i -67 Labeling Index in Predicting Recurrence of WHO Grade I Cranial Base Meningiomas.

Objectives Assess impact of K i -67 labeling index (LI; K i -67 LI) on risk of recurrence or progression of WHO grade I meningiomas. Study Design Retrospective study of adult patients who underwent resection of cranial base meningioma between 2004 and 2016. Results 272 patients fulfilled criteria for inclusion in the study. Average age was 61.8 years; 196 (72%) were females. Simpson's grade 1 resection was noted in 77 patients (32%), grade 2 in 39 (16%), grade 3 in 36 (15%), and grade 4 in 88 (37%). The K i -67 LI was low (1-4%) in 214 (78.7%), intermediate (5-9%) in 44 (16.2%), and high (>10%) in 14 (5.2%). Median follow-up was 39 months (IQR: 16-71 months); 221 (87.1%) tumors remained stable or did not recur, 19 (7.4%) recurred, and 14 (5.5%) progressed. Compared with tumors with low K i -67 LI, those with intermediate K i -67 LI had 2.47 times (2.47 [1.09-5.59], p = 0.03), and those with high K i -67 LI had 3.38 times (3.38 [1.16-9.89], p = 0.03) higher risk of recurrence or progression. Tumors with K i -67 LI > 4% had a shorter time to recurrence or progression ( p = 0.01). Recurrence or progression-free survival rates at 3, 5, and 10 years for tumors with low K i -67 LI were 95%, 89%, and 75%, respectively; tumors with intermediate K i -67 LI, 87%, 69%, and 52%, respectively; tumors with high K i -67 LI, 78%, 49%, and 49%, respectively. Conclusions Following surgical resection of a WHO grade I cranial base meningioma, K i -67 LI > 4% may predict an increased risk of recurrence or progression of residual tumor.

Prognostic Value of Ki-67 Labeling Index and Postoperative Radiotherapy in WHO Grade II Meningioma.

This study was performed to determine the clinical significance of the Ki-67 labeling index (LI) for local control (LC) in patients with World Health Organization (WHO) grade II meningioma. We also tried to discern the effect of postoperative radiotherapy (PORT) on LC depending upon the Ki-67 LI value. The medical records and values of Ki-67 LIs were retrospectively reviewed for 50 patients who underwent surgical resection of intracranial WHO grade II meningiomas at Samsung Medical Center from May 2001 to December 2012. Forty-three patients (86%) were treated with immediate PORT. The median total radiation dose was 60 Gy (range, 54 to 60 Gy). The median follow-up was 47.4 months. The mean Ki-67 LI was 13% (range, 1% to 47%). Twelve patients (24.0%) showed local failure, and 8 patients (16.0%) experienced local failure even after PORT. The mean Ki-67 LI was 15% in patients with local failure (n=12) and 12% in patients without local failure (n=38). The 3-year actuarial LC was 80.5%. The 3-year overall survival was 89.5%. Ki-67 LI>13% and PORT were significant prognostic factors for LC (P=0.015 and 0.009, respectively). In patients with Ki-67 LI>13% (n=17), PORT (n=14) improved LC (P<0.001). However, PORT (n=29) did not affect LC (P=0.412) for patients with Ki-67 LI≤13% (n=33). Ki-67 LI can be a useful prognostic factor for LC in WHO grade II meningioma. In patients with Ki-67 LI>13%, PORT should be recommended to improve LC.

Ki-67 labeling index may be a promising indicator to identify “very high-risk” gastrointestinal stromal tumor: a multicenter retrospective study of 1022 patients

We sought to determine whether Ki-67 labeling index (LI) was an independent prognostic factor for gastrointestinal stromal tumor (GIST). A multicenter cohort of 1022 patients undergoing surgical resection of primary GIST between August 2004 and October 2015 was retrospectively analyzed. Immunohistochemical analysis was performed to evaluate expression of Ki-67 in their paraffin-embedded tissue samples. The optimal cutoff value of Ki-67 LI was determined as 6% by receiver operating characteristics curve analysis. Multivariate analysis showed that Ki-67 LI was a significant predictor of overall survival (OS) (hazard ratio: 1.793; 95% confidence interval, 1.240-2.593; P=.002). When stratified by modified National Institutes of Health classification, it was still independently associated with OS in high-risk and non-high-risk patients (P=.001 and P=.055, respectively). Of note, the prognostic significance of Ki-67 LI was also maintained when stratified by tumor size, mitotic index, tumor site, and histological subtype (all Ps<.05). In addition, high-risk patients with Ki-67 LI >6% exhibited a significantly poorer OS rate than those with Ki-67 LI ≤6% (53.6% versus 88.7%, respectively; P=.001). The area under the receiver operating characteristics curve for Ki-67 LI was higher than that of modified National Institutes of Health classification component in high-risk patients (P=.029). Therefore, Ki-67 LI is a promising predictor of outcome in GIST, especially in high-risk patients, and it may have important clinical utility in identifying "very high-risk" patients for rational targeted therapy.

Prognostic value of Ki-67 labeling index according to age in patients with non-metastasic triple-negative breast cancer.

e12118 Background: The prognostic value of Ki67 in triple negative breast cancer (TNBC) is yet unclear because the cut-off points employed differ widely and its predictive effect may vary according to age. The purpose of this study was to analyze the role of Ki-67 among patients with TNBC, and determined the optimal Ki-67 cut-off point to demonstrate its prognostic relevance associated with patient age and treatment strategy. Methods: 201 patients treated for primary TNBC from 1999 to 2014 were identified from the breast surgery database. Clinicopathologic characteristics and outcomes were compared between patients treated with neoadjuvant or adjuvant chemotherapy. We used time-dependent receiver operating characteristic (ROC) curve and time-dependent area under the ROC curve (AUC) to evaluate the discriminative ability of Ki-67 at 3 and 5 years of follow up. A Ki-67 cut-off point was set up to maximize sensitivity and specificity. Interaction effect between age and Ki-67 on disease-free survival (DFS) and overall survival (OS) was evaluated by stratified analysis. Results: There was a non-significant Ki-67 cut off value to predict OS and DFS at 3 and 5 years neither in the whole serie (201) nor in the adjuvant group (125), and only a slightly better threshold for DFS in the neoadjuvant one (N = 46) at 5 years (AUC = 0.697). According to the coordinates of the ROC curves, the best cut-off point for Ki-67 was 60%. In the multivariate analysis (COX proportional hazards regression), high Ki-67 ( &gt; 60%), was a poor prognostic factor for DFS in patients &gt; 40 yo. Among the patients &lt; 40 yo, high Ki-67 was a better prognosis factor. Conclusions: Our data suggest that a threshold of Ki-67 of 60% could provide a usefull tool to define patients with significantly different outcome in TNBC.

Comprehensive Analysis of the Association of Clinically Relevant Values of Ki-67 Labeling Index with Clinicopathologic and Immunohistochemical Criteria in Female Invasive Breast Carcinoma

Objective: Breast cancer aggressiveness is related to tumor cell proliferation. Despite this, the Ki-67 index is not recommended for routine use in newly diagnosed breast carcinomas. Material and Methods: A total of 164 invasive breast carcinomas were stratified into the intrinsic molecular subtypes based on estrogen receptor, progesterone receptor (PR), HER2, and Ki-67 immunostaining. We studied the distribution of Ki-67 among the molecular subtypes and correlated it with clinicopathologic parameters. Furthermore, the change in the Ki-67 index with tumor size, grade and lymph node (LN) status among the molecular subtypes was examined. Results: As a continuous variable, the median Ki-67 did not show significant differences with the clinicopathological variables. At a cutoff ≥14%, it correlated significantly with the mitotic index. At a cutoff ≥20%, it additionally correlated with the PR status. The median Ki-67 level varied significantly between luminal A and all other molecular subtypes. The median Ki-67 level in T1/T2 tumors compared to T3/T4 tumors was slightly higher in luminal B HER2+, slightly lower in HER2 enriched, and nearly similar among luminal A, triple negative and luminal B HER2-subtypes, yet without statistical significance. The median Ki-67 was lower in G1/G2 compared to G3 tumors in all-except luminal B HER2-positive subtype but without statistical significance. The Ki-67 distribution change between N0/N1 and N2/N3 cases among the molecular subtypes was significant. Conclusions: The impact of Ki-67 as a proliferation marker on the biological behavior of breast carcinomas is context dependent, and its clinical utility increases when interpreted in combination with other prognostic markers in the context of the molecular subtypes. Further studies, on larger sample sizes are recommended to unravel how the molecular types can affect the relation between Ki-67 and clinicopathological characteristics, particularly the LN status.

Comparison of visual assessment and image analysis in the evaluation of Ki-67 expression and their prognostic significance in immunohistochemically defined luminal breast carcinoma

To compare the Ki-67 labeling index value obtained through immunohistochemistry analysis by human examiners to that obtained from computer-assisted image analysis, and to establish a cut-off value for Ki-67 labeling index for each method in luminal B breast carcinoma. Immunohistochemistry analysis for Ki-67 was performed on the formalin-fixed, paraffin-embedded tissue samples from 403 patients with primary luminal breast cancers. Whole slide images were obtained using the NanoZoomer (Hamamatsu Photonics, Hamamatsu, Japan) and thoroughly analyzed using the Definiens Tissue Studio version 1.1 (Definiens AG, Munich, Germany) to detect the percentage of positively-stained nuclei of carcinoma cells. Although a significant correlation was found between the Ki-67 labeling index obtained by manual assessment and computer-assisted image analysis (Spearman rank correlation coefficient, P<0.01), the Ki-67 labeling index value obtained by manual assessment was significantly higher than that obtained by computer-assisted image analysis (Wilcoxon signed rank test, P<0.0001). Disease-free survival was significantly lower in 403 patients with tumors having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P<0.00001) and visual counting (cut-off value: 28.5%; P<0.00001). Disease-free survival was also significantly lower in 288 patients who received adjuvant endocrine therapy alone having high Ki-67labeling index values determined by automated analysis (cut-off value: 11.5%; P<0.0001) and visual counting (cut-off value: 19.7%, P<0. 0001). The Ki-67 labeling index values determined by automated analysis and visual counting could equally predict disease-free survival in patients with luminal B breast carcinoma, including those who received endocrine therapy.

New insights into the prognostic value of Ki-67 labeling index in patients with triple-negative breast cancer

The clinicopathological importance of the Ki-67 labeling index (LI) in breast cancer has been studied intensely; however, its prognostic significance in triple-negative breast cancer (TNBC) is unclear. We aimed to determine the optimal Ki-67 cut-off point to demonstrate its prognostic relevance for breast-cancer-specific survival (BCSS) in TNBC patients. A total of 571 female TNBC patients underwent diagnosis and surgery at our institution from January 2002 to June 2011. Clinicopathological information for all patients was available and categorized by Ki-67 LI and age at diagnosis. The cut-off values for Ki-67 LI and age were selected using the medians. A varying-coefficient Cox model was used to describe the effect of Ki-67 LI on BCSS outcomes changing with age after adjustment for disease characteristics. For survival analysis, the Kaplan–Meier method and the log-rank test were used. Cox proportional hazards models were applied to determine the association of Ki-67 LI and age with BCSS outcomes after adjustment for disease characteristics. Median age was 50 years, and median Ki-67 LI was 35% (range, 0 – 97.5%). There was no prognostic significance of stratification by Ki-67 LI in all patients. When analyzing age at diagnosis as a continuous variable, the log-transformed HRKi67 > 35% vs. ≤ 35% for BCSS increased in an S-shaped curve with increasing age up to about 50 years-old and remained higher-risk for high Ki-67 LI. After adjusting for clinicopathological risk factors, low Ki-67 LI was a poor prognostic factor for BCSS (HR: 0.36, 95% CI: 0.14–0.96, P = 0.042) in patients of ≤ 50 years, but not in patients diagnosed at > 50 years (hazard ratio [HR]: 1.57, 95% CI: 0.76–3.22, P = 0.241). In conclusion, lower Ki-67 LI has poor prognosis relevance in TNBC patients diagnosed at ≤ 50 years-old. Further validation of the clinical significance of Ki-67 LI in TNBC is required.

New insights into the prognostic value of Ki-67 labeling index in patients with triple-negative breast cancer.

e12031 Background: The clinical-pathological importance of Ki-67 labeling index (LI) in breast cancers has been intensely studied; however, the prognostic relevance in triple negative (TN) subtype ...