Diagnostic and prognostic accuracy of miR-21 in renal cell carcinoma: A systematic review protocol

Introduction: Renal cell carcinoma (RCC) is the most common neoplasm in adult kidneys. One of the most important unmet medical needs in RCC is a prognostic biomarker to enable identification of patients at high risk of relapse after nephrectomy. New biomarkers can help improve diagnosis and hence the management of patients with renal cancer. Thus, this systematic review aims to clarify the prognostic and diagnostic accuracy of miR-21 in patients with RCC. Methods and analysis: We will include observational studies evaluating the diagnostic and prognostic roles of miR-21 in patients with renal cancer. The index test and reference standards should ideally be performed on all patients. We will search PubMed, SCOPUS and ISI Web of Science with no restriction of language. The outcome will be survival measures in adult patients with RCC. Study selection and data extraction will be performed by two independent reviewers. QUADAS-1 will be used to assess study quality. Publication bias and data synthesis will be assessed by funnel plots and Begg's and Egger's tests using Stata software V.11.1. Ethics and dissemination: No ethical issues are predicted. These findings will be published in a peerreviewed journal and presented at national and international conferences. Trail registration number: This systematic review protocol is registered in the PROSPERO International Prospective Register of Systematic Reviews, registration number CRD42015025001

Monosomy 3 by chromogenic in situ hybridization (CISH) in Iranian patients with uveal melanoma

Purpose: The aim of this study was to investigate the rate of monosomy 3 by CISH technique in Iranian patients with uveal melanoma (UM) and its correlation with clinical and histopathological features. Method: Archival formalin fixed, paraffin-embedded material from 50 patients who had undergone enucleation for large uveal melanomas was obtained. Monosomy of chromosome 3 alteration by chromogenic in situ hybridization (CISH) was investigated. Clinical and histopathological features of tumors were collected. Results: The patients had a mean age of 56.6±7.6 years. Mean basal diameter and thickness of tumors were 14.1 mm and 10.2 mm, respectively. Four patients (8) were identified to harbor monosomy of chromosome 3. In the mean follow-up of 5.3 years (range, 3.2-9.5 y), only one case with monosomy 3 died of UM metastasis. The most common type of cellularity was mixed cell (86).There was not any statistically significant correlation between monosomy of chromosome 3 and type of cellularity, ciliary body involvement, and largest basal diameter. Conclusion: The low rate of monosomy chromosome 3 and the consequent low rate of mortality may be indicative of good prognosis in Iranian patients with uveal melanoma. © 2015 Iranian Society of Ophthalmology

Chromogenic in situ hybridisation test for breast cancer patients with equivocal IHC results - A study from Iran

Background: HER2/neu overexpression on cell membranes of breast cancer cells is due to HER2/neu gene amplification and it is important to identify potential candidates for anti HER2 therapy with trastuzumab. IHC, FISH and CISH are standard FDA approved assays currently used to determine HER2 status in routine practice. The aim of this study was to determine HER2 gene amplification, using the CISH method in breast carcinoma samples which had IHC +2 reactions. Materials and Methods: This study was conducted from 2008-2010 using 334 consecutive breast carcinoma samples referred from local laboratories to Mehr Hospital. CISH assays were performed for all cases, and IHC tests were also done for determining efficacy and accuracy of local labs. HER2 status in local IHC tests was compared with central IHC and CISH results. Results: Of 334 breast cancer patients, 16 were negative for HER2 IHC (0, +1), 201 cases were equivocal (+2), and 31 positive (+3). Of 334 referral cases, 88 were CISH positive (26.3) and 246 were CISH negative (73.7). Of 201 IHC +2 cases, HER2 gene amplification was observed in 42 cases (kappa: 0.42). A 29.9 concordance was found between local IHC and central IHC. Sensitivity and specificity of local IHC were 90 and 53.8, respectively. Conclusions: Low accuracy of IHC results in local labs was associated with the following factors: using former FDA-approved criteria for HER2 interpretation, utilizing non-validated kits, and lack of any quality assurance program. Therefore, following the new 2014 ASCO/CAP guideline and comprehensive quality assurance should be implemented to ensure accuracy of HER2 testing

Clinicopathological significance of tumor stem cell markers aldh1 and CD133 in colorectal carcinoma

Background & Objective: Colorectal cancer (CRC) is the third most common cancer worldwide with a high mortality rate. The main causes of death in patients are recurrence and metastasis which are mainly attributed to the small subpopulation of cells within tumors called cancer stem cells (CSCs). This study aimed to evaluate the correlation between the expression of ALDH1 and CD133 as CSC associated markers and clinicopathological characteristics in CRC. Methods: In this cross-sectional study, a total of 483 CRC tumor samples were immunohistochemically stained for detection of CD133 and ALDH1 markers. Correlations of marker expression with clinicopathological factors were also evaluated. Results: There was a significant correlation between the luminal intensity of CD133 and neural invasion (P=0.05) and between the cytoplasmic intensity of CD133 and metastasis (P=0.05). In terms of H-score, a positive significant relation was observed between cytoplasmic expression of CD133 and lymph node (P=0.02), neural (P=0.04) and vascular invasion (P=0.02). The ALDH1 cytoplasmic expression showed a significant correlation with tumor size (P=0.001). Conclusion: Our findings showed that increased expression of CD133 and ALDH1 is associated with tumor progression and worse outcomes in CRC patients. These markers can be good candidates for localized targeting of CSCs using antibodies. Future researches need to be improved approaches for early detection of CRC, and treatment monitoring for CRC and other cancers. © 2021, Iranian Society of Pathology. All rights reserved

Bilateral maxillary, sphenoid sinuses and lumbosacral spinal cord extramedullary relapse of CML following allogeneic stem cell transplant

Isolated extramedullary relapse of chronic myelogenous leukemia (CML) after allogeneic stem cell transplant is rare. There is a case report of a child who developed a granulocytic sarcoma of the maxillary and sphenoid sinuses and lumbosacral spinal cord mass 18 months after allogeneic bone marrow transplant for CML. He was presented with per orbital edema and neurological deficit of lower extremities and a mass lesion was found on spinal cord imaging. No evidence of hematologic relapse was identified at that time by bone marrow histology or cytogenetic. The patient died 1 month later with a picture of pneumonia, left ventricular dysfunction and a cardiopulmonary arrest on a presumed underlying sepsis with infectious etiology. Granulocytic sarcoma should be considered in the differential diagnosis of mass lesions presenting after allogeneic bone marrow transplantation for CML, even if there is no evidence of bone marrow involvement. © 2016, Tehran University of Medical Sciences (TUMS). All Rights Reserved

Common bile duct stone associated with hemolytic uremic syndrome

Cholelithiasis is an unusual complication of hemolytic uremic syndrome. A 12-year-old boy with hemolytic uremic syndrome, established by renal biopsy, who developed cholestatic jaundice is presented here. Laboratory results for secondary causes of hemolytic uremic syndrome were normal. Abdominal ultrasonography and magnetic resonance cholangiopancreatography revealed extrahepatic obstruction. A common bile duct stone, discovered by retrograde cholanglopancreatography was extracted by sphincterotomy. In conclusion, cholelithiasis should be considered as a cause of abdominal pain and cholestasis in patients who are diagnosed as having hemolytic uremic syndrome

SMAD4 Expression in Renal Cell Carcinomas Correlates With a Stem-Cell Phenotype and Poor Clinical Outcomes

Renal cell carcinoma (RCC) is the most lethal neoplasm of common urologic cancers with poor prognoses. SMAD4 has a principal role in TGF-β (Transformis growth factorβ)-induced epithelial to mesenchymal transition (EMT) as a key factor in gaining cancer stem cell (CSC) features and tumor aggressiveness. This study aimed to evaluate the expression patterns and clinical significance of SMAD4 in RCC and the impact of its targeting on stem cell/mesenchymal cells and EMT characteristics in renal spheroid derived cells (SDCs) compared to parental cells (PCs) in RCC. The expression pattern and clinical significance of SMAD4 was evaluated in RCC. SDCs were enriched using a sphere culture system. Then SDCs and their PCs were compared with respect to their sphere and colony formation, expression of putative CSC markers, invasiveness as well as expression of genes, including stemness/mesenchymal, SMAD4 and TGFβ1genes. Finally, the effect of SMAD4 knockdown on SDCs was analyzed. We demonstrated that SMAD4 is positively correlated with decreased disease specific survival (DSS) in RCC patients and clear cell RCC (ccRCC) subtype and associates with poor DSS in patients with RCC, especially in ccRCC as the most metastatic RCC subtype. SDCs exhibited higher stem cell/mesenchymal properties. Inhibition of SMAD4 in PCs accelerated the dissociation of SDCs and decreased their clonogenicity, invasiveness, expression of mesenchymal markers and expression of SMAD4 and TGFβ1 genes compared to SDCs before transfection. We suggest that targeting SMAD4 may be useful against renal CSCs and may improve RCC prognosis. © Copyright © 2021 Rasti, Madjd, Saeednejad Zanjani, Babashah, Abolhasani, Asgari and Mehrazma

Co-expression of Cancer Stem Cell Markers OCT4 and NANOG Predicts Poor Prognosis in Renal Cell Carcinomas

Many renal cancer patients experience disease recurrence after combined treatments or immunotherapy due to permanence of cancer stem cells (CSCs). This study was conducted to evaluate the expression patterns and clinical significance of octamer-binding transcription factor 4 (OCT4) and NANOG as the key stem cell factors in renal cell carcinoma (RCC). A total of 186 RCC tissues were immunostained on a tissue microarray (TMA) for the putative CSC markers OCT4 and NANOG. Subsequently, the correlation among the expression of these markers, the clinicopathological variables and survival outcomes were determined. OCT4 and NANOG were expressed in both the nucleus and the cytoplasm of RCC cells. Coexpression of OCT4 and NANOG in renal cancer was significantly associated with RCC subtypes. A significant association was found among nuclear coexpression of OCT4 and NANOG, worse PFS in RCC, and the clear cell renal cell carcinomas (ccRCC) subtype. The OCT4-nuclear high/NANOG-nuclear high phenotype in RCC and ccRCC subtype indicated aggressive tumor behavior and predicted a worse clinical outcome, which may be a useful biomarker to identify patients at high risk of postoperative recurrence and metastasis. Cytoplasmic expression of NANOG could be considered as a novel independent prognostic predictor in patients with renal cancer. © 2018, The Author(s)

Human telomerase reverse transcriptase protein expression predicts tumour aggressiveness and survival in patients with clear cell renal cell carcinoma

Human telomerase reverse transcriptase (hTERT) is an active component of telomerase and responsible for its catalytic activity, associated with cell proliferation and differentiation. For the first time, the present study was conducted to evaluate the expression and prognostic significance of hTERT in different histological subtypes of renal cell carcinoma (RCC). Expression of hTERT was examined in 176 well-defined renal tumour samples including clear cell RCCs (ccRCCs), papillary and chromophobe RCCs using immunohistochemistry on tissue microarrays. The association between hTERT expression and clinicopathological parameters as well as survival outcomes were then analysed. There was a statistically significant difference in terms of hTERT expression among various RCC subtypes. In ccRCC, increased expression of hTERT was significantly associated with advanced stage, higher grade, presence of microvascular invasion, lymph node invasion, and metastasis. Moreover, in the multivariate analysis, tumour stage and tumour size were independent predictors of the disease-specific survival (DSS). Additionally, expression of hTERT was found to be a significant predictor of worse DSS (p = 0.012) in the univariate analysis. In papillary carcinoma samples (type I and II), significant association was detected between hTERT expression and the tumour stage (p = 0.010, p = 0.050), respectively. In chromophobe RCC, no significant association was detected between expression of hTERT and clinicopathological parameters and survival data. We showed that hTERT protein expression was associated with more aggressive tumour behaviour and more advanced disease in ccRCC patients. Also, hTERT may be a novel poor prognostic indicator of DSS, if the patients are followed for more prolonged time periods. © 2018 Royal College of Pathologists of Australasi

High expression of DNA damage-inducible transcript 4 (DDIT4) is associated with advanced pathological features in the patients with colorectal cancer

DNA damage-inducible transcript 4 (DDIT4) is induced in various cellular stress conditions. This study was conducted to investigate expression and prognostic significance of DDIT4 protein as a biomarker in the patients with colorectal cancer (CRC). PPI network and KEGG pathway analysis were applied to identify hub genes among obtained differentially expressed genes in CRC tissues from three GEO Series. In clinical, expression of DDIT4 as one of hub genes in three subcellular locations was evaluated in 198 CRC tissues using immunohistochemistry method on tissue microarrays. The association between DDIT4 expression and clinicopathological features as well as survival outcomes were analyzed. Results of bioinformatics analysis indicated 14 hub genes enriched in significant pathways according to KEGG pathways analysis among which DDIT4 was selected to evaluate CRC tissues. Overexpression of nuclear DDIT4 protein was found in CRC tissues compared to adjacent normal tissues (P = 0.003). Furthermore, higher nuclear expression of DDIT4 was found to be significantly associated with the reduced tumor differentiation and advanced TNM stages (all, P = 0.009). No significant association was observed between survival outcomes and nuclear expression of DDIT4 in CRC cases. Our findings indicated higher nuclear expression of DDIT4 was significantly associated with more aggressive tumor behavior and more advanced stage of disease in the patients with CRC. © 2021, The Author(s)