Visual Counting and Automated Image-analytic Assessment of Ki-67 and their Prognostic Value in Synovial Sarcoma

Background: Ki-67 is a widely used proliferation marker reflecting prognosis in various tumors. However, visual assessment and scoring of Ki-67 suffers from marked inter-observer and intra-observer variability. We aimed to assess the concordance of manual counting and automated image-analytic scoring methods for Ki-67 in synovial sarcoma. Patients and Methods: Tissue microarrays from 34 patients with synovial sarcoma were immunostained for Ki-67 and scored both visually and with 3DHistech QuantCenter. Results: The automated assessment of Ki-67 expression was in good agreement with the visually counted Ki-67 (rPearson=0.96, p<0.001). In a Cox regression model automated [hazard ratio (HR)=1.047, p=0.024], but not visual (HR=1.063, p=0.053) assessment method associated high Ki-67 scores with worse overall survival. Conclusion: The automated Ki-67 assessment method appears to be comparable to the visual method in synovial sarcoma and had a significant association to overall survival.

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Nomogram Predicting Overall Survival After Surgical Resection For Retroperitoneal Leiomyosarcoma Patients

10.21203/rs.3.rs-1009507/v1 ◽

2021 ◽

Author(s):

Aobo Zhuang ◽

Hanxing Tong ◽

Yuan Fang ◽

Lijie Ma ◽

Weiqi Lu ◽

...

Keyword(s):

Public Health ◽

Overall Survival ◽

Surgical Resection ◽

General Surgery ◽

Cox Regression ◽

Concordance Index ◽

Clinical Center ◽

Surgery Department ◽

Actual Survival ◽

Good Agreement

Abstract Aim: To develop a survival nomogram for patients with retroperitoneal leiomyosarcoma (RLMS) after surgery.Methods: 118 patients with RLMS after surgical resection at the General Surgery Department, Shanghai Public Health Clinical Center, Fudan University were retrospectively analyzed. The nomogram was constructed based on COX regression model and discrimination was assessed using the concordance index (c-index). The predicted and actual survival was evaluated through calibration plots.Results: The c-index of the nomogram was 0.779 (95% CI, 0.659-0.898). The predicted and actual survival probabilities are in good agreement in all calibration curve.Conclusion: This study built the first survival nomogram for patients with surgical resected RLMS.

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Clinical Characteristics, Pathology and Outcome of 237 Patients With Synovial Sarcoma: Single Center Experience

International Journal of Surgical Pathology ◽

10.1177/10668969211056013 ◽

2021 ◽

pp. 106689692110560

Author(s):

Hao Cheng ◽

Chi Yihebali ◽

Hongtu Zhang ◽

Lei Guo ◽

Susheng Shi

Keyword(s):

Overall Survival ◽

Synovial Sarcoma ◽

Tumor Size ◽

Clinical Characteristics ◽

Cox Regression ◽

Survival Outcomes ◽

Tumor Diameter ◽

Single Center ◽

Primary Tumors ◽

Cox Regression Analysis

Background Synovial sarcoma (SS) is a rare soft tissue sarcoma. Available data regarding survival outcomes of patients with SS still remains limited. In this study, a single center retrospective analysis was performed to investigate the clinical characteristics, pathology and survival outcomes in patients with SS in China. Methods Patient data were systematically reviewed at the National Cancer Center from January 2015 to December 2020. The general information and treatment condition of patients were collected. Overall survival (OS) was evaluated using the Kaplan-Meier and Cox regression method. Results A total of 237 consecutive patients were included in this study (follow-up cut-off date: December, 2020). The median age of patients involved was 35 years (ranging from 5 to 83 years) and the mean tumor diameter was 5.3 cm (ranging from .2 to 26.0 cm). The main findings of the immunohistochemical staining analyses were EMA (111/156) (71%), keratin (32/64) (50.0%), keratin (12/20) (60%), keratin (42/70) (60%), S-100 (18/160) (11%), BCL-2 (128/134) (96%), CD99 (137/148) (93%) and TLE1 (23/26) (88%). It was found that 109 patients (66%) were presented with monophasic subtype and 55 (34%) with biphasic subtype. A total of 137 patients were tested by FISH method and 119 patients (87%) demonstrated SS18 rearrangement, whereas 18 patients (13%) did not show SS18 rearrangement. Generally, it was found that the 3-year OS rate was 86% and the 3-year DFS was 55%. Results of univariate analysis revealed that age, tumor size, tumor site, radiotherapy and targeted therapy were significantly correlated with the overall survival ( P < .05). Further, multivariate Cox regression analysis revealed that age, tumor size and radiotherapy were significantly associated with OS ( P < .05). Conclusions In conclusion, this study shows that the outcomes of patients with SS significantly decrease with age and tumor size. It was evident that radiotherapy is an independent and positive prognostic factor for patients with SS. In addition, it was shown that the prognosis of SS varies with tumor location. For instance, primary tumors in lower extremities have a higher prognosis, whereas tumors located in thorax have a lower prognosis.

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526 MICROSATELLITE INSTABILITY IN GASTRO-ESOPHAGEAL ADENOCARCINOMAS

Diseases of the Esophagus ◽

10.1093/dote/doaa087.140 ◽

2020 ◽

Vol 33 (Supplement_1) ◽

Author(s):

A Katz ◽

G Evaristo ◽

M Issac ◽

J Ramirez-GraciaLuna ◽

M Park ◽

...

Keyword(s):

Overall Survival ◽

Microsatellite Instability ◽

Cox Regression ◽

Significant Proportion ◽

Genomic Analysis ◽

Poor Response ◽

Tissue Microarrays ◽

Braf V600e ◽

Chi Square ◽

Response To Chemotherapy

Abstract Microsatellite instability (MSI) in gastro-esophageal adenocarcinomas (GEAs) is associated with poor response to chemotherapy; however, this association is poorly understood. The aim of this study is to better understand the clinical relevance and mutational landscape of MSI in GEA. Methods In order to assess the status of mismatch repair (MMR) proteins, we performed immunohistochemistry for MLH1, MSH2, MSH6, PMS2 and BRAF V600E on tissue microarrays constructed from 161 patients with esophageal adenocarcinoma and 65 patients with gastric adenocarcinoma, operated between 2011 to 2019. MMR- deficient (MMR-D) status was confirmed using full sections of tumors. Demographics, tumor, and treatment details, operative variable and overall survival were evaluated. Genomic characterization of 3 MSI-H and 10 MSS patients was performed using deep targeted sequencing of 234 potential oncogenic genes. Statistical analysis was performed using Cox regression, logistic regression, ANOVA or Chi-square tests. Results Among the 28 (12%) MMR-D immunophenotype patients identified: 25 showed a combined MLH1/PMS2 loss, one case with MSH2/MSH6 loss and two cases with isolated MSH6 or MSH2 loss. Patients in the MMR-D were older (74 ± 14 vs 67 ± 11 years, p = 0.01) and with more Siewert-III and sub-cardia tumors [64%(18) vs 40%(79), p = 0.002] compared to MMR-Stable patients. All other variables including sex, stage and grade were not significantly different. MMR-D immunophenotype was associated with better overall survival (Median survival of 5.7vs2.3 years, p < 0.04) (Figure 1A). Genomic analysis linked patients with D-MMR with a higher mutational burden with some potentially targetable mutations (Figure 1B). Conclusion The significant proportion of MMR-D immunophenotype identified in this gastroesophageal cohort and the different pattern of overall survival and genetic mutations associated with this phenotype, highlight the importance of further characterization and understanding the mechanisms and role of MMR status in GEAs.

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Skp2 Protein Expression in Soft Tissue Sarcomas

Journal of Clinical Oncology ◽

10.1200/jco.2003.05.112 ◽

2003 ◽

Vol 21 (4) ◽

pp. 722-727 ◽

Cited By ~ 33

Author(s):

Andre M. Oliveira ◽

Scott H. Okuno ◽

Antonio G. Nascimento ◽

Ricardo V. Lloyd

Keyword(s):

Overall Survival ◽

Soft Tissue ◽

Cox Regression ◽

Univariate Analysis ◽

Soft Tissue Sarcomas ◽

Inverse Correlation ◽

Ki 67 ◽

Female Ratio ◽

Skp2 Expression ◽

Disease Free

Background: p45 S phase kinase-associated protein-2 (p45skp2), a member of the F-box family of proteins, is an important component of the Skp1-Cullin-F-box protein (SCF) ubiquitin-ligase complex (SCFskp2). The latter has been implicated in the ubiquitination and degradation of p27kip1 (p27) and G1-S cell cycle progression. The expression and prognostic role of Skp2 in a large series of soft tissue sarcomas has not been previously investigated. Methods: Clinicopathologic features and immunohistochemical expression of Skp2, p27, and Ki-67 proteins were studied in 182 cases of soft tissue sarcomas (American Joint Committee on Cancer stages II and III). Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. Results: The male to female ratio was 1.2:1, and the median age at the diagnosis was 53 years. The tumors were predominantly located in the lower extremities (n = 163; 90%) and had a median size of 9 cm. High Skp2 expression (≥ 10% of the cells) was identified in 68 tumors (37%), and was correlated with high grade histology (P = .002) and Ki-67 proliferative index (r = 0.44; P < .0001), but not with p27 expression (r = −0.02; P = .80). By univariate analysis, high Skp2 expression was associated with decreased metastasis-free, disease-free, and overall survival. In a multivariate model, high Skp2 expression was an independent predictor for decreased local recurrence-free, disease-free, and overall survival. Conclusion: These results indicate that Skp2 expression is associated with cell proliferation and a worse prognosis in soft tissue sarcomas. The lack of an inverse correlation between Skp2 and p27 suggests that additional molecular events associated with either Skp2 expression or p27 proteolysis may be operating in these tumors.

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Protein Analysis of Glioblastoma Primary and Posttreatment Pairs Suggests a Mesenchymal Shift at Recurrence

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlw068 ◽

2016 ◽

Vol 75 (10) ◽

pp. 925-935 ◽

Cited By ~ 16

Author(s):

Matthew D Wood ◽

Gerald F Reis ◽

David E Reuss ◽

Joanna J Phillips

Keyword(s):

Gene Expression ◽

Overall Survival ◽

Gene Expression Pattern ◽

Tissue Microarrays ◽

Poor Correlation ◽

Ki 67 ◽

Mesenchymal Phenotype ◽

Idh1 R132h ◽

Recurrent Tumors ◽

Phosphorylated Stat3

Abstract Glioblastomas (GBM) are aggressive brain tumors that inevitably recur despite surgical resection, chemotherapy, and radiation. The degree to which recurrent GBM retains its initial immunophenotype is incompletely understood. We generated tissue microarrays of paired initial and posttreatment GBM (3 pairs positive and 17 negative for IDH1 R132H ) from the same patients and made comparisons in the IDH1 R132H -negative group for immunohistochemical and gene expression differences between primary and recurrent tumors. In initial tumors, immunopositivity for Ki-67 in > 20% of tumor cells was associated with shorter progression-free and overall survival. Recurrent tumors showed decreased staining for CD34 suggesting lower vessel density. A subset of tumors showed increased staining for markers associated with the mesenchymal gene expression pattern, including CD44, phosphorylated STAT3, and YKL40. Recurrent tumors with the greatest increase in mesenchymal marker expression had rapid clinical progression, but no difference in overall survival after second surgery. Comparison of protein and gene expression data from the same samples revealed a poor correlation. A subset of tumors (15%) showed loss of neurofibromin protein in both initial and recurrent tumors. These data support the notion that GBM progression is associated with a shift toward a mesenchymal phenotype in a subset of tumors and this may portend a more aggressive behavior.

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Correlation Between Digital and Manual Determinations of Ki-67/MIB-1 Proliferative Indices in Human Meningiomas

International Journal of Surgical Pathology ◽

10.1177/1066896919889148 ◽

2019 ◽

Vol 28 (3) ◽

pp. 273-279 ◽

Cited By ~ 1

Author(s):

Duc-Tien Pham ◽

Ivar Skaland ◽

Theo L. Winther ◽

Øyvind Salvesen ◽

Sverre H. Torp

Keyword(s):

Cox Regression ◽

Rank Correlation ◽

Tissue Microarrays ◽

World Health ◽

Daily Routine ◽

Ki 67 ◽

Human Meningiomas ◽

Health Organization ◽

Proliferative Indices ◽

Mib 1

Objective. Proliferative activity in tumor tissues is assessed as the percentage of Ki-67/MIB-1-positive cells, or the proliferative index (PI). The PI is routinely assessed manually. However, the subjectivity of manual assessments might result in poor reproducibility. We hypothesized that digital assessments might reduce the error. Method. In our study, we assessed Ki-67/MIB-1 PIs, both manually and digitally, with tissue microarrays constructed from 141 human meningioma samples. Spearman-rank correlation and κ statistics were applied for correlation and agreement analyses, respectively. Mann-Whitney U tests were used to compare MIB-1 PIs between groups. Prognostic ability was assessed with Kaplan-Meier and Cox regression analyses. Results. We found a significant, high correlation (Spearman ρ = 0.832, P < .01) and moderate agreement (κ coefficient = 0.617, observed agreement = 80.9%) between the 2 methods. Both methods found significantly different Ki-67/MIB-1 PIs for different World Health Organization grades ( P < .05). Neither method showed significant prognostic value. Conclusion. Digital determinations of Ki-67/MIB-1 PIs in human meningiomas are feasible for the daily routine.

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GATA3 as an Adjunct Prognostic Factor in Breast Cancer Patients with Less Aggressive Disease: A Study with a Review of the Literature

Diagnostics ◽

10.3390/diagnostics11040604 ◽

2021 ◽

Vol 11 (4) ◽

pp. 604

Author(s):

Patrizia Querzoli ◽

Massimo Pedriali ◽

Rosa Rinaldi ◽

Paola Secchiero ◽

Paolo Giorgi Rossi ◽

...

Keyword(s):

Overall Survival ◽

Prognostic Value ◽

Tissue Microarrays ◽

Routine Practice ◽

Lower Grade ◽

Breast Cancer Patients ◽

Wild Type ◽

Ki 67 ◽

Luminal B

Background: GATA binding protein 3 (GATA3) expression is positively correlated with estrogen receptor (ER) expression, but its prognostic value as an independent factor remains unclear. Thus, we undertook the current study to evaluate the expression of GATA3 and its prognostic value in a large series of breast carcinomas (BCs) with long-term follow-up. Methods: A total of 702 consecutive primary invasive BCs resected between 1989 and 1993 in our institution were arranged in tissue microarrays, immunostained for ER, progesterone receptor (PR), ki-67, HER2, p53, and GATA3, and scored. Clinico-pathological data were retrospectively collected. Results: GATA3 was evaluable in 608 (87%) of the 702 cases; it was positive in 413 (68%) cases and negative in 195 (32%) cases. GATA3 positivity was significantly associated with lower grade (p < 0.0001), size (p = 0.0463), stage (p = 0.0049), ER+ (p < 0.0001), PR+ (p < 0.0001), HER2− (p = 0.0175), and p53 wild-type pattern (p < 0.0001). The median follow-up was 183 months, GATA3 positivity was associated with better overall survival (HR 0.70, p = 0.001), and its prognostic value was retained in a multivariate analysis. The association with better overall survival was stronger in patients with grade 1–2, pT1–2, pN0, stage I–II, ER+, PR+, ki-67 < 20%, HER2−, a wild-type p53 immunohistochemical pattern, and in luminal B BC. Conclusions: Our findings indicate that GATA3 is a positive prognostic marker in BC patients, especially in patients with biologically less aggressive BC. Incorporating GATA3 immunohistochemistry into routine practice could help further stratify BC patients for their risk.

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Identification of Clinical and Biologic Correlates Associated With Outcome in Children With Adrenocortical Tumors Without Germline TP53 Mutations: A St Jude Adrenocortical Tumor Registry and Children’s Oncology Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2017.74.2460 ◽

2017 ◽

Vol 35 (35) ◽

pp. 3956-3963 ◽

Cited By ~ 17

Author(s):

Emilia Modolo Pinto ◽

Carlos Rodriguez-Galindo ◽

Stanley B. Pounds ◽

Lei Wang ◽

Michael R. Clay ◽

...

Keyword(s):

Overall Survival ◽

Cox Regression ◽

Prognostic Indicator ◽

Disease Stage ◽

Ki 67 ◽

Chromosome 11P15 ◽

Cox Regression Analysis ◽

Tumor Weight ◽

Tp53 Mutations ◽

Adrenocortical Tumors

Purpose The clinical features, pathogenesis, and outcomes in children with adrenocortical tumors (ACTs) without germline TP53 mutations have not been systematically studied. Herein, we describe these correlates and analyze their association with outcome. Patients and Methods Genomic DNA was analyzed for TP53, CTNNB1, CDKN1C, ATRX, and chromosome 11p15 abnormalities. β-catenin expression and Ki-67 labeling index (LI) were evaluated by immunostaining. Primary end points were progression-free (PFS) and overall survival. Results Median age of 42 girls and 18 boys was 3.3 years (range, 0.25 to 21.7 years). Complete resection (stages I and II) was achieved in 32 patients, and 28 patients had stage III or IV disease. Constitutional abnormalities of chromosome 11p15 occurred in nine of 40 patients, with six patients not showing phenotype of Beckwith-Wiedemann syndrome. Three-year PFS and overall survival for all patients were 71.4% and 80.5%, respectively. In single-predictor Cox regression analysis, age, disease stage, tumor weight, somatic TP53 mutations, and Ki-67 LI were associated with prognosis. Ki-67 LI and age remained significantly associated with PFS after adjusting for stage and tumor weight. Three-year PFS for 27 patients with Ki-67 LI ≥ 15% was 48.5% compared with 96.2% for 29 patients with Ki-67 LI < 15% (log-rank P = .002), and the rate of relapse increased by 24% with each 1-year increase in age at diagnosis (hazard ratio, 1.24; P = .0057). Conclusion Clinicopathologic features and outcomes of children with ACTs without germline TP53 mutations overlapped those reported for children with germline TP53 mutations. Our findings highlight the central role of genetic or epigenetic alterations on chromosome 11p15 in pediatric ACTs. Ki-67 LI is a strong prognostic indicator and should be investigated to improve the histologic classification of pediatric ACTs.

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Association of positive Ki-67 and PD-L1 expressions in post neoadjvuant chemotherapy (NAC) radical cystectomy samples with lack of tumor downstaging (TD) and shorter overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.554 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 554-554

Author(s):

Selene Rubino ◽

Wade J. Sexton ◽

Youngchul Kim ◽

Junmin Zhou ◽

Jasreman Dhilon ◽

...

Keyword(s):

Bladder Cancer ◽

Radical Cystectomy ◽

Cox Regression ◽

Unmet Need ◽

Predictive Biomarker ◽

Complete Response ◽

Tissue Microarrays ◽

Rank Test ◽

Cancer Center ◽

Ki 67

554 Background: Previous chart review studies have reported that adjuvant chemotherapy after NAC did not clearly increase OS in MIBC cases characterized by a lack of TD. There is an unmet need to develop biomarkers to guide adjuvant therapy for this patient population. High levels of expression of cell proliferation marker Ki-67 are associated with poor outcome in chemotherapy naïve bladder cancer. Expression of PD-L1 has been studied as a potential predictive biomarker for anti-PD1 or PD-L1 therapies in metastatic MIBC. We therefore studied Ki-67 and PD-L1 expression in post NAC radical cystectomy samples at Moffitt Cancer Center and correlate them with TD and OS. Methods: Tissue microarrays (TMAs) were constructed from 116 post NAC cystectomy samples. The expressions of Ki-67 were evaluated with immunohistochemistry (IHC) and considered positive if any of the cores per sample were stained positive for Ki-67. The Dako 22C3 assay was used for PD-L1 IHC and the combined positive score of 10 or above was considered positive for PD-L1. Results: The median survival of this cohort of 116 patients was 33.4 months (range: 1.13 -127 months). 40 patients (35%) had TD and 21 patients (18%) achieved pathological complete response. Using Cox regression for OS, positive Ki-67 expression in post NAC radical cystectomy sample was associated with poorer OS (hazard ratio=2.412, 95% CI:1.076-5.408, p=0.033), independent of the pathological N stage. Patients with Ki67/PD-L1 double-negative tumors had a significantly longer median OS of 98.2 months versus 29.9 and 26.9 months in PD-L1-/Ki67+ and PD-L1+/Ki67+ tumors respectively (Log-rank test, p=0.0361). Lack of TD was significantly associated with positive Ki-67 (P<0.001) and positive PD-L1 (p=0.003) in the post NAC samples with a multi-variable logistic regression model. Conclusions: Positive Ki-67 and PD-L1 expressions in post NAC radical cystectomy samples were associated with inferior OS and absence of TD. Adjuvant anti-PD1 therapy either alone or in combination with chemotherapy would be indicated for this subset of patients.

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Clinical value evaluation of microRNA-324-3p and other available biomarkers in patients with HBV-infection-related hepatocellular carcinoma

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab108 ◽

2021 ◽

Author(s):

Li Zhao ◽

Qian Yang ◽

Jianbo Liu

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Hepatitis B ◽

Diagnostic Performance ◽

Cox Regression ◽

Hbv Infection ◽

Healthy Controls ◽

Survival Prognosis ◽

Diagnosis And Prognosis ◽

Hcc Cells

Abstract Background Patients with hepatitis B virus (HBV) infection are at high risk of hepatocellular carcinoma (HCC). This study aimed to evaluate the expression of microRNA-324-3p (miR-324-3p) in HBV-related HCC, and explore the clinical significance of serum miR-324-3p and other available biomarkers in the diagnosis and prognosis of HBV-related HCC. Methods Expression of miR-324-3p in HBV-infection-related cells and patients was estimated using quantitative real-time PCR. The receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic performance of serum miR-324-3p, AFP and PIVKA-II in the differentiation of HBV-related HCC from healthy controls and chronic hepatitis B (CHB). The relationship between serum miR-324-3p and patients’ clinical features was assessed using Chi-square test, and the value of miR-324-3p to predict overall survival prognosis was evaluated using Kaplan-Meier methods and Cox regression assay in patients with HBV-related HCC. Results HBV-related HCC cells had significantly increased miR-324-3p compared with normal and HBV-unrelated HCC cells, and serum miR-324-3p in HCC patients with HBV infection was also higher than that in healthy controls and CHB. Serum miR-324-3p had relatively high diagnostic accuracy for the screening of HCC case with HBV infection, and the combination of miR-324-3p, AFP and PIVKA-II showed the improved diagnostic performance. Additionally, high serum miR-324-2p in HBV-related HCC patients was associated with cirrhosis, tumor size, clinical stage and poor overall survival prognosis. Conclusion Serum increased miR-324-3p may be involved in the progression of HBV-related hepatitis to HCC, and may serve as a candidate biomarker for the diagnosis and prognosis of HBV-related HCC.

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