MIB-1 Expression Research Articles

Proximity interactions of the ubiquitin ligase Mind bomb 1 reveal a role in regulation of epithelial polarity complex proteins

MIB1 belongs to the RING domain containing family of E3 ubiquitin ligases. In vertebrates, MIB1 plays an essential role in activation of Notch signaling during development, through the ubiquitination and endocytosis of Notch ligands. More recently, Notch independent functions for MIB1 have been described in centriole homeostasis, dendritic spine outgrowth and directional cell migration. Here we use proximity-dependent biotin identification (BioID) to define the MIB1 interactome that included 163 high confidence interactions with polypeptides linked to centrosomes and cilia, endosomal trafficking, RNA and DNA processing, the ubiquitin system, and cell adhesion. Biochemical analysis identified several proteins within these groups including CCDC14 and EPS15 that were ubiquitinated but not degraded when co-expressed with MIB1. The MIB1 interactome included the epithelial cell polarity protein, EPB41L5. MIB1 binds to and ubiquitinates EPB41L5 resulting in its degradation. Furthermore, MIB1 ubiquitinates the EPB41L5-associated polarity protein CRB1, an important determinant of the apical membrane. In polarized cells, MIB1 localized to the lateral membrane with EPB41L5 and to the tight junction with CRB1, CRB3 and ZO1. Furthermore, over expression of MIB1 resulted in altered epithelial cell morphology and apical membrane expansion. These results support a role for MIB1 in regulation of polarized epithelial cell morphology.

COX2 expression is associated with proliferation and tumor extension in vestibular schwannoma but is not influenced by acetylsalicylic acid intake

Acetylsalicylic acid has been linked to a lower risk for different cancer types, presumably through its inhibitory effect on cyclooxygenase 2. This has also been investigated in vestibular schwannomas with promising results suggesting an antiproliferative effect and recently the intake has been recommended for vestibular schwannomas as a conservative treatment option. We constructed tissue microarrays from paraffin-embedded tissue samples of 1048 vestibular schwannomas and analyzed the expression of cyclooxygenase 2 and the proliferation marker MIB1 (Molecular Immunology Borstel) via immunohistochemistry together with clinical data (age, gender, tumor extension, prior radiotherapy, neurofibromatosis type 2, tumor recurrence, cyclooxygenase 2 responsive medication). Univariate analysis showed that cyclooxygenase 2 expression was increased with age, female gender, prior radiotherapy and larger tumor extension. MIB1 expression was also associated with higher cyclooxygenase 2 expression. Schwannomas of neurofibromatosis type 2 patients had lower cyclooxygenase 2 levels. Use of acetylsalicylic acid, non-steroidal anti-inflammatory drugs, glucocorticoids or other immunosuppressants did not show differences in cyclooxygenase 2 or MIB1 expression. Instead, cyclooxygenase 2 expression increases with tumor extension while MIB1 expression is not associated with tumor size. Overall, cyclooxygenase 2 expression is associated with proliferation but not influenced by regular intake of acetylsalicylic acid or other cyclooxygenase 2-responsive medications. Acetylsalicylic acid intake does not alter cyclooxygenase 2 expression and has no antiproliferative effect in vestibular.

Recurrence of spinal meningiomas: analysis of the risk factors

Objective: Spinal meningiomas are slow-growing tumors with low recurrence rate after complete resection. The aim of this study is to investigate the risk factors correlated to the recurrence.Material and Methods: Six patients with spinal WHO grade I meningiomas which recurred after complete resection were reviewed and compared to 50 patients with no recurrence; the data were also compared with those of 50 intracranial meningiomas which recurred and 50 which did not recur after complete resection. The investigated factors included age and sex, tumor location and size, type of arachnoid interface, entity of resection (Simpson I or II), tumor consistency and vascularity, histological type, Ki-67 MIB-1, progesterone receptor (PR) and estrogen receptor (ER) expression. The data were statistically analyzed with the Kaplan-Meier method.Results: The statistical analysis showed that the presence of arachnoidal invasion (p = 0.023) and higher Ki-67 LI (p < 0.0001) were the only two significant risk factors for recurrence for both spinal and intracranial meningiomas. Large tumor size (p = 0.012), Simpson grade II resection (p = 0.03) and the absence of PR expression (p < 0.0001) were significant risk factors for recurrence of intracranial but not spinal meningiomas. Finally, age and sex, tumor location, consistency and vascularity, histological type, and ER expression were not correlated to recurrence for both localizations.Conclusions: The proliferation index Ki-67 and the arachnoid invasion are the risk factors for recurrence of spinal meningiomas, whereas tumor size, dural resection and PR expression are not significant. The small tumor size and the limited dural invasion may contribute to explain the lower recurrence rate.

Prognostic Value of Ki-67/MIB-1 Expression in Meningioma Patients: A Meta-Analysis.

Ki-67/MIB-1 is the most widely used immumohistochemical marker to measure cell proliferation in recent years, and its high expression is significantly related to high malignancy and short survival cycle. This meta-analysis was conducted to confirm the prognostic value of Ki-67/MIB-1 in meningioma patients. A comprehensive search was carried out of mainstream electronic databases including Pubmed, EMBASE, Google Scholar, Web of Science, and Cochrane Library, and finally 10 studies containing 1,414 meningioma patients were included in the meta-analysis. The combined hazard ratio (HR) and its 95% confident intervals (CIs) were used to evaluate the association between Ki-67/MIB-1 expression and survival. High expression of Ki-67/MIB-1 was found to be significantly associated with low RFS (HR 3.31, 95% CI 1.62-6.78, P = 0.001, random effect) and PFS(HR 3.14, 95% CI 1.64-6.00, P = 0.001, fixed effect). Subgroup analysis was conducted to explore the potential heterogeneity. Results of the meta-analysis indicated that high expression of Ki-67/MIB-1 may serve as a useful biomarker for poor prognosis in meningioma patients.

Prognostic Value of Ki-67/MIB-1 Expression in Bladder Cancer: A Systematic Review and Meta-Analysis

Prognostic Value of Ki-67/MIB-1 Expression in Bladder Cancer: A Systematic Review and Meta-Analysis

Green tea extract inhibits early oncogenic responses in mice with nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) increases hepatocellular carcinoma (HCC) risk. We hypothesized that the hepatoprotective anti-inflammatory benefits of catechin-rich green tea extract (GTE) would protect against HCC progression by inhibiting NASH-associated liver injury and pro-oncogenic responses. We used an HCC model in high-fat (HF)-fed mice that mimics early oncogenic events during NASH without inducing tumorigenesis and premature mortality. Male C57BL/6J mice (4-weeks old) were fed a HF diet containing GTE at 0% or 2%. Mice were administered saline or diethylnitrosamine (DEN; 60 mg kg-1, i.p.) at 5-weeks and 7-weeks of age. NASH, inflammation, fibrosis, and oncogenic responses were assessed at 25-weeks of age. Saline-treated mice showed prominent histopathological signs of steatosis and hepatocellular ballooning. Although DEN did not impact adiposity, steatosis, ballooning and hepatic lipid accumulation, these parameters were attenuated by GTE regardless of DEN. Hepatic lipid peroxidation and fibrosis that were increased by DEN were attenuated by GTE. Hepatic TLR4, MCP1 and TNFα mRNA levels were unaffected by DEN, whereas iNOS was increased by DEN. These transcripts were lowered by GTE. GTE attenuated the frequency of PCNA+ hepatocytes and mRNA expression of cyclin D1, MIB1 and Ki-67 that were otherwise increased by DEN. GTE increase APAF1 mRNA that was otherwise lowered by DEN. Relative to saline-treated mice, DEN increased mRNA levels of oncostatin M, gp130, c-Fos, c-Myc and survivin; each was lowered by GTE in DEN-treated mice. These findings indicate that GTE may protect against hepatic oncogenesis by limiting early steps in the carcinogenic cascade related to NASH-associated HCC.

Effects of supplemental vitamin D and calcium on markers of proliferation, differentiation, and apoptosis in the normal colorectal mucosa of colorectal adenoma patients.

To clarify the roles of vitamin D and calcium as potential chemopreventive agents against colorectal cancer in humans, and to develop “treatable”, pre-neoplastic, phenotypic biomarkers of risk for colorectal neoplasms, we estimated the effects of supplemental vitamin D3 (1,000 IU/day [25 μg/day]) and calcium (1,200 mg/day), alone and in combination, on biomarkers of proliferation (mib-1), differentiation (p21), and apoptosis (bax [apoptosis-promoting] and bcl-2 [apoptosis-inhibiting]), in the normal-appearing rectal mucosa in a subsample of participants (n = 104) in a larger randomized, double-blind, placebo-controlled clinical trial among colorectal adenoma patients. The biomarkers were measured in rectal biopsies at baseline and after one year of follow up, using automated immunohistochemistry and quantitative image analysis. In the vitamin D plus calcium group relative to control, in the crypt differentiation zone (upper 40% of crypts), mib-1 expression decreased 24% (P = 0.28); p21 expression alone and relative to mib-1 expression increased 29% (P = 0.06) and 73% (P = 0.06), respectively; and bax expression relative to mib-1 expression increased 58% (P = 0.21). The estimated vitamin D alone treatment effects were similar but of lesser magnitudes, and those for calcium alone were mixed. All estimated treatment effects on bcl-2 expression were close to the null. These pilot study results support further investigation of whether 1) vitamin D and calcium promote colorectal epithelial cell differentiation, reduce proliferation, and promote apoptosis in the normal-appearing human colorectal mucosa, 2) vitamin D and calcium act as chemopreventive agents against colorectal neoplasms, and 3) mib-1, p21, and bax are potential “treatable”, pre-neoplastic, biomarkers of risk for colorectal neoplasms.

Pancreatic Cell Fate Determination Relies on Notch Ligand Trafficking by NFIA

Notch is activated globally in pancreatic progenitors; however, for progenitors to differentiate into endocrine cells, they must escape Notch activation to express Neurogenin-3. Here, we find that the transcription factor nuclear factor I/A (NFIA) promotes endocrine development by regulating Notch ligand Dll1 trafficking. Pancreatic deletion of NFIA leads to cell fate defects, with increased duct and decreased endocrine formation, while ectopic expression promotes endocrine formation in mice and human pancreatic progenitors. NFIA-deficient mice exhibit dysregulation of trafficking-related genes including increased expression of Mib1, which acts to target Dll1 for endocytosis. We find that NFIA binds to the Mib1 promoter, with loss of NFIA leading to an increase in Dll1 internalization and enhanced Notch activation with rescue of the cell fate defects after Mib1 knockdown. This study reveals NFIA as a pro-endocrine factor in the pancreas, acting to repress Mib1, inhibit Dll1 endocytosis and thus promote escape from Notch activation.

Serous ovarian tumors: Immunohistochemical profiling as an aid to grading and understanding tumorigenesis

BackgroundThe aim of this study was to evaluate the expression of p53, p16, Wilms tumor gene (WT1), and Mindbomb E3 Ubiquitin Protein Ligase 1 (MIB-1) index by immunohistochemical (IHC) staining in benign, low-grade, and high-grade serous ovarian tumors. MethodsForty-one cases of ovarian serous tumors were included in the study (benign serous tumor [n = 10], low-grade ovarian serous carcinoma [n = 8], and high-grade ovarian serous carcinoma [n = 23]). Expression of p53, p16, WT1, and MIB-1 by IHC was evaluated statistically with the grade of tumor. Semiquantitative scoring system for percentage (0–5) and intensity (1–3) of staining pattern was used to bring about objectivity. Resultsp53, p16, and WT1 showed significantly higher staining scores in ovarian serous carcinoma group than in the benign group (p < 0.05). However, p16 score was not significant in benign versus low-grade tumors. In the carcinoma group, the high-grade serous tumors showed significantly higher staining scores of p53, p16, and WT1 than the low-grade serous tumors (p < 0.05). Papillary serous tumors had comparatively lower p53 and WT1 scores for the same grade of tumor. MIB-1 scores were not significant. Conclusionp53, p16, and WT1 are helpful for the subtyping of serous ovarian tumors as low grade and high grade. WT1 is helpful in establishing primary ovarian serous tumors. The combination of moderate-to-high p53 and WT1 scores provides a robust way of confirming high-grade tumors.

High proliferation rate and TNM stage but not histomorphological subtype are independent prognostic markers for overall survival in papillary renal cell carcinoma

Papillary renal cell carcinoma (PRCC) is currently divided in 2 subtypes. We reviewed a large cohort of PRCC and correlated subtype, morphological features and diagnostic marker expression with overall survival (OS) to uncover differences between the 2 subtypes. Three hundred seventy-six renal tumors initially diagnosed as PRCC with clinical and survival data were collected from the participating centers. Two hundred forty-six tumors were classified as PRCC1 (65.4%) and 130 as PRCC2 (34.6%) and graded according to the 2016 World Health Organization/International Society of Urological Pathology grading system. Morphological features (abundant cytoplasm, necrosis, fibrous stroma, foamy macrophages and psammoma bodies) were noted. Immunohistochemical stains (MIB1, p53, Racemase, EMA, CK7, CK20, E-Cadherin) were performed using tissue microarrays. χ2-Tests, log-rank tests and uni- and multivariate Cox regression analysis were performed. Both subtypes displayed different morphological features and immunohistochemical profiles: abundant cytoplasm was more frequent in PRCC2, while foamy macrophages were more common in PRCC1. Abundant cytoplasm and presence of psammoma bodies were associated with poorer OS. PRCC1 showed more frequent CK7 expression, PRCC2 more frequent E-Cadherin, p53 and higher MIB1 expression (>15%). Expression of Racemase and CK7 was associated with better OS, while high MIB1 (>15%) was associated with poorer OS. In multivariate analysis, the only independent predictors of OS were proliferation (MIB1), tumor stage, metastasis and age at surgery. Subtype was not an independent prognostic factor. Therefore, PRCC subtype on its own is not suitable for estimating survival. More data focusing on PRCC tumor biology is needed to define prognostic subgroups, especially in PRCC2.

AAA+ ATPases Reptin and Pontin as potential diagnostic and prognostic biomarkers in salivary gland cancer - a short report.

Salivary gland cancer (SGC) is a rare and heterogeneous disease with significant differences in recurrence and metastasis characteristics. As yet, little is known about the mechanisms underlying the initiation and/or progression of these diverse tumors. In recent years, the AAA+ ATPase family members Pontin (RuvBL1, Tip49a) and Reptin (RuvBL2, Tip49b) have been implicated in various processes, including transcription regulation, chromatin remodeling and DNA damage repair, that are frequently deregulated in cancer. The aim of this study was to assess the clinical and functional significance of Reptin and Pontin expression in SGC. Immunohistochemical staining of Pontin, Reptin, β-catenin, Cyclin D1, TP53 and MIB-1 was performed on a collection of 94 SGC tumor samples comprising 13 different histological subtypes using tissue microarrays. We found that Reptin and Pontin were expressed in the majority of SGC samples across all histological subtypes. Patients with a high Reptin expression showed a significantly inferior 5-year overall survival rate compared to patients with a low Reptin expression (47.7% versus 78.3%; p = 0.033), whereas no such difference was observed for Pontin. A high Reptin expression strongly correlated with a high expression of the proliferation marker MIB-1 (p = 0.003), the cell cycle regulator Cyclin D1 (p = 0.006), accumulation of TP53 as a surrogate p53 mutation marker (p = 0.042) and cytoplasmic β-catenin expression (p = 0.002). Increased Pontin expression was found to significantly correlate with both cytoplasmic and nuclear β-catenin expression (p = 0.037 and p = 0.018, respectively), which is indicative for its oncogenic function. Our results suggest a role of Reptin and Pontin in SGC tumor progression and/orpatient survival. Therefore, SGC patients exhibiting a high Reptin expression may benefit from more aggressive therapeutic regimens. Future studies should clarify whether such patients may be considered for more radical surgery, extended adjuvant therapy and/or targeted therapy.

Study on the overexpression of succinate dehydrogenase B and MIB-1 in pheochromocytoma/paraganglioma tissue

Objective We aimed to investigate the overexpression of succinic dehydrogenase (SDH)B and MIB-1 in patients with pheochromocytoma/paraganglioma(PHEO/PGLs) and its significance for predicting the clinical malignant behavior. Methods From August 2008 to April 2016, the clinical characteristics of 93 patients with PHEO/PGLs were analyzed retrospectively. There were 57 males and 36 females. with an average of 34 years, ranging 8-73 years old. There were 68 cases of adrenal pheochromocytoma and 25 cases of paraganglioma. There were 79 cases with hypertension and 14 cases of adrenal accidental tumors. Sixty-six cases with typical hyper-catecholamine secretion symptoms and 27 cases with non-functional PHEO/PGL. Benign PHEO/PGLs were 77 cases and malignant 16 cases. The tumor was located on the left side in 39 cases, on the right side in 32 cases and multiple lesions in 22 cases. The diameter of the PHEO/PGL tumor was (6.8±2.7) cm. The 24 h urine catecholamine was measured before operation, which showed epinephrine was(42.6±5.1)μg/24 h, norepinephrine was(167.5±13.5)μg/24h and dopamine was (246.4±71.2)μg/24h. Six cases wihtout hereditary diseases of urinary system were selected as normal control group. SDHB, SDHAF2, SDHC, SDHD, VHL and RET gene mutations were detected in all patients. Immunohistochemical panel has been performed to detect the expression of SDHB, MIB-1, EPAS1, VEGF-1 receptor (VEGF-1R), and chromain A (CgA) in 93 specimens of PHEO/PGL tissue. The positive granular cytoplasm staining >50% was strongly positive (+ + + ), 11% to 50% was moderately positive (+ + ), 1% to 10% was weak positive (+ ) and the negative was compared with the known positive internal reference, that is, there was less than 1% or no stain completely. Results SDHB, SDHAF2, SDHC, SDHD, VHL and RET gene mutations in 27 cases (29.5%). Nine patients with SDHB gene mutation (9.7%). RET proto-oncogene mutations in 8 cases (8.6%). 3 cases had VHL mutation (3.2%). Immunohistochemical staining showed that MIB-1 positive expression was found in 7 of 9 patients with SDHB gene mutation. Six cases in the control group were negative for gene detection and MIB-1, EPAS1, CgA and VEGF-1R immunohistochemical results. EPAS1 showed moderately positive in patients with PHEO/PGL and strong positive in patients with malignant PHEO/PGL. In 9 cases with SDHM mutation, EPAS1 was noticed positive in seven cases, which showed the relationship with CgA, MIB-1 and VEGF-1R. Conclusions The SDHB gene mutation is usually shown as a paraganglioma focus outside the adrenal gland. And 9.8% of the paragangliomas were associated with a mutation of the SDHB gene with an increase in malignant risk. The SDHB mutation caused over-expression of MIB-1 and the positive expression of EPAS1 and VEGF-1R in PHEO/PGL tissues, which was associated with invasion and metastasis of malignant PHEO/PGL. Key words: Pheochromocytoma; Paraganglioma; Succinate dehydrogenase B

Contribution of chromosome 9p deletion and Bcl1, Myc and p16 immunohistochemistry to the characterization of oligodendrogliomas

Molecular studies suggest that anaplastic oligodendrogliomas (OIII) can be subdivided into clinically relevant subgroups. We analyzed a retrospective series of 40 consecutive OIII operated at our institution and compared them to 10 grade II oligodendrogliomas (OII). Chromosome 9p status was compared to Bcl1, Myc and p16 expression by immunohistochemistry, clinical and histological data, and to event free survival (EFS) and overall survival (OS).Chromosome 9p deletion was observed in 55 % of OIII (22/40) but not in OII, and correlated with both OS and EFS. Bcl1 expression was significantly higher in OIII (45 % versus 14% for OII) and correlated with MIB-1 expression, vascular proliferation, tumour necrosis and a shorter EFS. Myc expression was correlated with histologic grade (27% in OII, 35% in OIII) and to a shorter EFS in chromosome 9p non-deleted OIII. p16 expression was not correlated with grade but revealed two distinct expression profiles according to chromosome 9p status. In 9p non-deleted oligodendrogliomas, p16 hyperexpression was correlated with shorter OS in both OII and OIII whereas absence of p16 expression was correlated with shorter OS and EFS in 9p deleted OIII.

MIB-1 Is Required for Spermatogenesis and Facilitates LIN-12 and GLP-1 Activity in Caenorhabditis elegans.

Covalent attachment of ubiquitin to substrate proteins changes their function or marks them for proteolysis, and the specificity of ubiquitin attachment is mediated by the numerous E3 ligases encoded by animals. Mind Bomb is an essential E3 ligase during Notch pathway signaling in insects and vertebrates. While Caenorhabditis elegans encodes a Mind Bomb homolog (mib-1), it has never been recovered in the extensive Notch suppressor/enhancer screens that have identified numerous pathway components. Here, we show that C. elegans mib-1 null mutants have a spermatogenesis-defective phenotype that results in a heterogeneous mixture of arrested spermatocytes, defective spermatids, and motility-impaired spermatozoa. mib-1 mutants also have chromosome segregation defects during meiosis, molecular null mutants are intrinsically temperature-sensitive, and many mib-1 spermatids contain large amounts of tubulin. These phenotypic features are similar to the endogenous RNA intereference (RNAi) mutants, but mib-1 mutants do not affect RNAi. MIB-1 protein is expressed throughout the germ line with peak expression in spermatocytes followed by segregation into the residual body during spermatid formation. C. elegans mib-1 expression, while upregulated during spermatogenesis, also occurs somatically, including in vulva precursor cells. Here, we show that mib-1 mutants suppress both lin-12 and glp-1 (C. elegans Notch) gain-of-function mutants, restoring anchor cell formation and a functional vulva to the former and partly restoring oocyte production to the latter. However, suppressed hermaphrodites are only observed when grown at 25°, and they are self-sterile. This probably explains why mib-1 was not previously recovered as a Notch pathway component in suppressor/enhancer selection experiments.

Immunohistochemical Profiles of Endometrioid Endometrial Carcinomas With and Without Metastatic Disease.

A minority of endometrial carcinomas present at an advanced stage with a poor prognosis, and should be identified to individualize treatment. Immunohistochemical markers have been studied, but most have not been directly linked to metastasis. This study analyzes the immunohistochemical profile of endometrioid endometrial carcinomas (EECs) with and without metastases, and corresponding metastases. Tissue microarray slides from stage I EECs, stage III-IV EECs, and corresponding metastases were stained and scored for expression of β-catenin, E-cadherin, ER, PR, PTEN, p16, MLH1, PMS2, L1CAM, p53, p21, and MIB1. Scores were compared between primary stage I and III-IV EECs, stage III-IV EECs, and the corresponding metastases, and between intra-abdominal and distant metastases. Primary tumors with distant metastases had a significantly lower ER expression than those without metastases or with intra-abdominal metastases. Distant metastases had a significantly lower PR expression than the corresponding primary tumor and intra-abdominal metastases. In contrast, p16 and PTEN expression was significantly higher in intra-abdominal metastases compared with corresponding primary tumors. Immunohistochemistry predicts both presence and location of EEC metastases. Loss of ER and PR was related to distant spread, and increased expression of PTEN and p16 was related to intra-abdominal spread. Additional research should assess the use of these markers in the diagnostic workup as well as the possibility to target metastases through these markers.

Impact of 9p deletion and p16, Cyclin D1, and Myc hyperexpression on the outcome of anaplastic oligodendrogliomas.

ObjectiveTo study the presence of 9p deletion and p16, cyclin D1 and Myc expression and their respective diagnostic and prognostic interest in oligodendrogliomas.MethodsWe analyzed a retrospective series of 40 consecutive anaplastic oligodendrogliomas (OIII) from a single institution and compared them to a control series of 10 low grade oligodendrogliomas (OII). Automated FISH analysis of chromosome 9p status and immunohistochemistry for p16, cyclin D1 and Myc was performed for all cases and correlated with clinical and histological data, event free survival (EFS) and overall survival (OS).ResultsChromosome 9p deletion was observed in 55% of OIII (22/40) but not in OII. Deletion was highly correlated to EFS (median = 29 versus 53 months, p<0.0001) and OS (median = 48 versus 83 months, p<0.0001) in both the total cohort and the OIII population. In 9p non-deleted oligodendrogliomas, p16 hyperexpression correlated with a shorter OS (p = 0.02 in OII and p = 0.0001 in OIII) whereas lack of p16 expression was correlated to a shorter EFS and OS in 9p deleted OIII (p = 0.001 and p = 0.0002 respectively). Expression of Cyclin D1 was significantly higher in OIII (median expression 45% versus 14% for OII, p = 0.0006) and was correlated with MIB-1 expression (p<0.0001), vascular proliferation (p = 0.002), tumor necrosis (p = 0.04) and a shorter EFS in the total cohort (p = 0.05). Hyperexpression of Myc was correlated to grade (median expression 27% in OII versus 35% in OIII, p = 0.03), and to a shorter EFS in 9p non-deleted OIII (p = 0.01).ConclusionChromosome 9p deletion identifies a subset of OIII with significantly worse prognosis. The combination of 9p status and p16 expression level identifies two distinct OIII populations with divergent prognosis. Hyperexpression of Bcl1 and Myc appears highly linked to anaplasia but the prognostic value is unclear and should be investigated further.

The Combination Of Weak Expression Of PRDX4 And Very High MIB-1 Labelling Index Independently Predicts Shorter Disease-free Survival In Stage I Lung Adenocarcinoma.

Background:Oxidative stress plays pivotal roles in the progression of lung adenocarcinoma (LUAD) through cell signaling related closely to cancer growth. We previously reported that peroxiredoxin 4 (PRDX4), a secretory-type antioxidant enzyme, can protect against the development of various diseases, including potential malignancies. Since many patients with early-stage LUAD develop recurrence, even after curative complete resection, we investigated the association of the PRDX4 expression with the clinicopathological features and recurrence/prognosis using post-surgical samples of stage I-LUAD.Methods: The expression of PRDX4 and MIB-1, a widely accepted Ki67 protein, was immunohistochemically analysed in 206 paraffin-embedded tumour specimens of patients with stage I-LUAD. The PRDX4 expression was considered to be weak when less than 25% of the adenocarcinoma cells showed positive staining.Results: A weak PRDX4+ expression demonstrated a significantly close relationship with pathologically poor differentiation, highly invasive characteristics and recurrence. The decrease in PRDX4-positivity potentially induced cell growth in LUAD, which was correlated significantly with a very high MIB-1 labelling index (≥17.3%). Univariate/multivariate analyses revealed that the subjects with both weak PRDX4+ expression and a very high MIB-1 index had significantly worse disease-free survival rates than other subjects.Conclusions: The combination of weak PRDX4 expression and a very high MIB-1 index can predict high proliferating activity and recurrence with a potential poor prognosis, especially in post-operative stage I-LUAD patients.

Prognostic and clinicopathological value of Ki-67/MIB-1 expression in renal cell carcinoma: a meta-analysis based on 4579 individuals.

BackgroundPrevious studies have investigated the prognostic significance of Ki-67/MIB-1 expression in renal cell carcinoma (RCC), however, the reports are controversial and inconsistent. This study aimed to investigate Ki-67/MIB-1 expression in RCC and its correlation with prognosis and clinicopathological features.MethodsWe searched relevant studies that reported associations between Ki-67/MIB-1 expression and prognosis in RCC from PubMed, Embase, Web of Science, and Cochrane Library studies published until April 14, 2017. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted from eligible studies. Fixed and random effects models were used to calculate pooled HRs and 95% CIs according to heterogeneity.ResultsA total of 4579 participants from 23 eligible studies were included in this analysis. The results showed that Ki-67/MIB-1 expression was associated with poor overall survival (HR=2.06, 95% CI: 1.64–2.57) and cancer specific survival (HR=2.01, 95% CI: 1.66–2.44). In addition, Ki-67/MIB-1 expression was also correlated with TNM stage (III/IV vs I/II: OR=1.92, 95% CI: 1.61–2.28), pathological T stage (pT3/pT4 vs pT1/pT2: OR=1.56, 95% CI: 1.21–2.02), distant metastasis (M1 vs M0: OR=1.81, 95% CI: 1.34–2.43), and Fuhrman grade (III/IV vs I/II: OR=1.94, 95% CI: 1.21–3.10).ConclusionOur study demonstrates that the presence of high Ki-67/MIB-1 expression and advanced clinicopathological features were correlated with poor prognosis in RCC patients.

Parafibromin, APC, and MIB-1 Are Useful Markers for Distinguishing Parathyroid Carcinomas From Adenomas.

Differentiation of parathyroid carcinoma (PC) from parathyroid adenoma (PA) relies solely on the pathologic determination of invasion of surrounding structures and/or distant metastasis. Parathyroid lesions with atypical histologic features with no demonstration of invasion or metastasis present a diagnostic dilemma. Different authors report a parafibromin and adenomatous polyposis coli (APC) loss or reduction in PC cases. High proliferative activity of MIB-1 and increased galectin 3 expression are reported in PC. There is no clear cutoff for the sensitivity, specificity, or predictive value for all these markers. The immunohistochemical expression of parafibromin, APC, MIB-1, and galectin 3 was studied in 73 adenomas, 21 PCs, and 3 atypical adenomas. The presence or absence of each marker was identified through the use of a comprehensive scoring system based on multiplying the percentage of tumor cells stained (0 to 100) and the staining intensity (0 to 3) on each biopsy. The highest score that any slide could reach was 300. A cutoff of >100 was used to consider the specimen positive for parafibromin, APC, or galectin 3 staining. MIB-1 proliferation indices were calculated using image cytometry; proliferation indices >5% were considered positive. We identified parafibromin loss in 7/21 (33%) carcinomas and 1/73 (1%) adenomas. Loss of APC was seen in 20/21 (95%) carcinomas and 38/73 (52%) adenomas. MIB-1 indices were elevated in 18/21 (86%) carcinomas. MIB-1 indices were <5% in all (100%) adenomas. MIB-1 indices were elevated in 2/3 (67%) atypical adenomas. Our study presents a clear cutoff to determine the practicality of using parafibromin, APC, and MIB-1 as immunohistochemical markers to differentiate between PCs and PAs. Loss of parafibromin and a high MIB-1 index are both independently sensitive and specific markers for the diagnosis of PC. Loss of APC was only specific for PC. This panel of markers provides a novel, useful approach in the diagnosis and differentiation of PCs from PAs.

The anti-apoptotic protein survivin can improve the prognostication of meningioma patients.

BackgroundThe 2016 WHO histopathological grading includes a substantial within-variation in recurrence risk, and is thus insufficient to predict prognosis after initial surgery of patients suffering from meningiomas. The aim of this study was to compare the prognostic value of the histopathological grading and the conventional biomarker MIB-1 with expression of the anti-apoptotic protein survivin to see if this biomarker could complement recurrence prediction.MethodsUsing immunohistochemistry, the expression of MIB-1 and survivin were determined as labeling indices (LIs) in tissue micro arrays from 160 human meningiomas. The accuracy of prognostication was assessed with receiver operator characteristics analyses and standard survival analyses.ResultsThe expression of survivin was significantly associated with both histopathological grade (P = 0.022) and recurrence status (P = 0.035). A survivin LI of 1% was identified as the optimal cutoff value to predict recurrence (P = 0.003), and was proven as more reliable than the histopathological grading (P = 0.497) and MIB-1 expression (P = 0.091). This result was further strengthened in multivariate analyses where survivin expression was revealed as an independent predictor of recurrence-free survival, while the histopathological grading and MIB-1 expression did not reach significance (P ≥ 0.156).ConclusionsThese findings suggest that incorporation of survivin in the clinical practice might be useful as complement for the histopathological grading and should further be evaluated in independent prospective studies.