Sodium Fluorescein Facilitates Guided Sampling of Diagnostic Tumor Tissue in Nonenhancing Gliomas

Neurosurgery ◽  
2017 ◽  
Vol 82 (5) ◽  
pp. 719-727 ◽  
Author(s):  
Stephen G Bowden ◽  
Justin A Neira ◽  
Brian J A Gill ◽  
Timothy H Ung ◽  
Zachary K Englander ◽  
...  
Keyword(s):  
Contrast Enhancement ◽  
Cell Density ◽  
Predictive Value ◽  
Tumor Tissue ◽  
Sodium Fluorescein ◽  
Ki 67 ◽  
Tissue Samples ◽  
Tumor Identification ◽  
Fluid Attenuated Inversion Recovery ◽  
Histological Heterogeneity

Abstract BACKGROUND Accurate tissue sampling in nonenhancing (NE) gliomas is a unique surgical challenge due to their intratumoral histological heterogeneity and absence of contrast enhancement as a guide for intraoperative stereotactic guidance. Instead, T2/fluid-attenuated inversion-recovery (FLAIR) hyperintensity on MRI is commonly used as an imaging surrogate for pathological tissue, but sampling from this region can yield nondiagnostic or underdiagnostic brain tissue. Sodium fluorescein is an intraoperative fluorescent dye that has a high predictive value for tumor identification in areas of contrast enhancement and NE in glioblastomas. However, the underlying histopathological alterations in fluorescent regions of NE gliomas remain undefined. OBJECTIVE To evaluate whether fluorescein can identify diagnostic tissue and differentiate regions with higher malignant potential during surgery for NE gliomas, thus improving sampling accuracy. METHODS Thirteen patients who presented with NE, T2/FLAIR hyperintense lesions suspicious for glioma received fluorescein (10%, 3 mg/kg intravenously) during surgical resection. RESULTS Patchy fluorescence was identified within the T2/FLAIR hyperintense area in 10 of 13 (77%) patients. Samples taken from fluorescent regions were more likely to demonstrate diagnostic glioma tissue and cytologic atypia (P < .05). Fluorescein demonstrated a 95% positive predictive value for the presence of diagnostic tissue. Samples from areas of fluorescence also demonstrated greater total cell density and higher Ki-67 labeling than nonfluorescent biopsies (P < .05). CONCLUSION Fluorescence in NE gliomas is highly predictive of diagnostic tumor tissue and regions of higher cell density and proliferative activity.

A randomized, placebo-controlled trial of celecoxib in men prior to receiving prostatectomy for clinically localized adenocarcinoma of the prostate: Evaluation of drug-specific biomarker modulation

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5001-5001 ◽  
Author(s):  
M. A. Carducci ◽  
J. R. Walczak ◽  
E. Heath ◽  
W. G. Nelson ◽  
A. M. DeMarzo ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Controlled Trial ◽  
Clinical Stage ◽  
Double Blind Study ◽  
Mrna Levels ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Ki 67 ◽  
Tissue Samples ◽  
Cox 2

5001 Background: Cyclooxygenase-2 (COX-2) has been postulated as a pharmacological target for preventing a variety of epithelial malignancies including prostate cancer (PCa). We conducted a randomized, double-blind study evaluating celecoxib (C) on biomarkers in normal and PCa tissue at prostatectomy (RRP). Methods: Patients with Gleason sum ≥ 7, pre-study PSA ≥ 15 ng/ml, clinical stage T2b, T2c, or any combination of PSA, Stage, or two or more cores positive for PCa received either C at 400 mg po bid or placebo for 4–6 wks pre-RRP. The primary endpoint was to compare and correlate tissue PG levels with histologic and secondary endpoints performed on prostate tissue and serum from the two comparable groups. Outcomes included PG levels, quantitative RT-PCR for mRNA levels of COX-1 and COX-2, oxidized DNA bases; measurement of apoptosis, proliferation, angiogenic-potential assays and histologic comparison of treated/untreated tissue specimens; PSA levels; and tissue levels of C. Estimates of change in endpoints required 30 patients per arm. Results: Seventy three subjects consented with 64 randomized and included in the intent to treat analysis; 2 had missing data for primary endpoints. Age, baseline PSA, race and Gleason score were comparable across treatment groups. The regimen was well tolerated with no serious adverse events. There was no treatment effect observed in the PG, COX mRNA levels or oxidized DNA base levels in the RRP specimens. Tumor tissue contained significantly less COX-2 mRNA levels than benign tissue (p=<0.0001). Of the markers of apoptosis and proliferation assessed, Ki-67 was higher in tumor samples, and p21 was less in C treated samples. Celecoxib was present in tumor tissue demonstrating that it reached the target, but there were no observed effects in the study endpoints. There was no toxicity greater grade 1 except hepatic toxicity in a placebo group subject. Conclusions: Our results show a lack of effect of C on PCa despite demonstrating that C was present in tissue samples. At this time, we cannot recommend further studies of C as a PCa preventative agent when dosed at 400 mg PO BID. The study was supported by a grant from the NCI, DCP (#NO1-CN-95000–46) and Pfizer, Inc. No significant financial relationships to disclose.

scholarly journals Metadherin (MTDH) Overexpression Significantly Correlates with Advanced Tumor Grade and Stages among Colorectal Cancer Patients

2021 ◽  
Author(s):  
Aimen Sultan ◽  
Namood-e Sahar ◽  
Syeda Kiran Riaz ◽  
Javeria Qadir ◽  
Shahzad Hussain Waqar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Tumor Tissue ◽  
Tumor Grade ◽  
Ki 67 ◽  
Core Element ◽  
Age And Gender ◽  
Tissue Samples ◽  
Advanced Tumor ◽  
And Gender

Abstract BackgroundColorectal cancer is the 4th leading cause of cancer related deaths affecting both men and women worldwide. In the present study, any probable role of MTDH mRNA expression in CRC tumorigenesis was explored using both discovery and validation cohorts. Methods and resultsAfter prior ethical and biosafety approvals, tumor tissue samples along with their adjacent controls were collected for this study from Pakistani patients diagnosed with colorectal cancer. RNA was isolated using Trizol reagent, followed by cDNA synthesis. Transcript analysis of MTDH was performed by using qPCR. Moreover, genome-wide expression of MTDH was also determined through micro-array data analysis using BRB- Array Tools software. MTDH expression was significantly high in tumor tissue samples (p<0.05) compared to their respective controls. Likewise, results of microarray analysis also revealed overamplification of MTDH in tumor samples as compared to controls. Expression of MTDH was also found to be positively correlated with KI-67 index (p<0.05) and were observed to be significantly upregulated in advance tumor grade (p< 0.05) and stage (p< 0.05). However, no association of MTDH overexpression with age and gender could be established. ConclusionHence, it can be concluded that MTDH is a core element that plays a pivotal role in colorectal tumorigenesis irrespective of patient’s age and gender. Molecular insight into the tumor microenvironment revealed MTDH as a niche, representing distinctive framework for cancer progression, thus, making it an innovative target strategy for colorectal cancer treatment.

Measurement of treatment dependent glioblastoma cell density in T1- weighted contrast enhancement at autopsy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14035-e14035
Author(s):  
Allison Lowman ◽  
Samuel Bobholz ◽  
Jennifer Marie Connelly ◽  
Elizabeth Cochran ◽  
Wade Mueller ◽  
...  
Keyword(s):  
Overall Survival ◽  
Contrast Enhancement ◽  
Cell Density ◽  
Control Point ◽  
Tumor Burden ◽  
Mixed Effect ◽  
Post Contrast ◽  
Tissue Samples ◽  
Treatment Groups ◽  
Death Time

e14035 Background: With an average overall survival of 12-18 months, glioblastoma has a particularly grim diagnosis. Standard treatment of glioblastoma, following detection on MRI, is surgical resection followed by radiation therapy and chemotherapy and is monitored through MR imaging. Glioblastoma has a unique heterogenous nature that complicates visualization of subtly enhancing tumor. This study used autopsy tissue samples taken from glioblastoma patients with varying treatment, to examine the effects of treatment on cell density within regions of contrast enhancement, using T1-weighted subtraction maps (T1S) from the last MR images to death. Methods: Eight patients diagnosed with glioblastoma at autopsy were recruited for this study. Two patients had no treatment and six received a combination of chemo-radiation and other treatments, including but not limited to bevacizumab (Bev) and TTFields therapy. At autopsy, whole brain samples were sliced axially aligned to the patient’s final MRI to death. Time between last MRI and death ranged from 4-27 days (mean 16 days). Overall survival (OS) ranged from 4-538 days (mean 307 days). Large tissue samples were taken from regions of suspected tumor or treatment effect, for a total of 18 tissue samples. Tissue samples were processed, H&E stained, and digitized at 40X resolution (Huron Slide Scanner). Cell density (cells/mm2) was calculated using digital histology. T1S were created for each patient by subtracting intensity normalized T1 weighted images from T1 post contrast images (T1C). Digital histology was aligned and resampled into MRI space using manual control point registration. Mixed effect models were used to compare differences in cell density across contrast enhancement (T1SE vs. NE) as well as across treatment groups (treatment vs. no treatment). Results: Cellularity was compared across regions of T1S enhancement (T1SE) and non-enhancement (NE) within manually selected regions of interest. Cell density compared between regions of T1SE and NE was not different (p=0.219). Total cell density was increased in patients who had received treatment compared to no treatment in both regions of T1SE and NE (p=0.014). Conclusions: Overall, cell density was increased in patients who had received treatment after diagnosis of glioblastoma. Additional research is needed to examine the extent of treatment’s effect on cellularity of glioblastoma. This work begins to characterize the use of T1S in evaluating glioblastoma tumor burden in patients with varying treatment histories.[Table: see text]

scholarly journals Histological investigation of the effects of western diet on pressure wound healing period

2021 ◽  
Vol 8 (9) ◽  
pp. 556-562
Author(s):  
Özcan Budak ◽  
Hüseyin Çakıroğlu
Keyword(s):  
Wound Healing ◽  
Cell Density ◽  
Western Diet ◽  
P Value ◽  
Standard Diet ◽  
Sprague Dawley ◽  
Skin Wound Healing ◽  
Ki 67 ◽  
Tissue Samples ◽  
Healing Period

Objective: The stages of skin wound healing are a dynamic process and it is thought to be related to nutrition. Carbohydrates, proteins and fats have particular importance in different periods of recovery process.  Our study has aimed to examine the effects of a western diet with high protein, fat, and carbohydrate content on pressure ulcer healing. Material and Methods: In this study, we used 22 healthy male Sprague Dawley rats weighing 100-185 g. We randomly divided the rats into two groups. The rats were fed according to the indicated diets (standard diet and western diet). On the first day of the fourth week, ischemia skin by histopathological examinations of the wound tissue samples on the 7th and 14th days of the wound healing period. Results: Statistically significant differences were observed in histological and immunohistochemical parameters in the tissue samples on the 7th and 14th days. On the 7th day, there were re-epithelialization (P=0.003), granulation cell density (P=0.004), inflammation (P=0.004), and angiogenesis (P= 0.003). We found re-epithelialization (P=0.001), granulation cell density (P=0.002), inflammation (P=0.002), and angiogenesis (P=0.001) on the 14th day. On the 7th and 14th days, we found the p-value between Ki-67 immunohistochemical staining percentages as P= 0.003 and the p-value for VEGF as P=0.002. Conclusion: We determined that in short-term wound healing, the western type diet was more effective on pressure wound healing than the standard diet.

A Novel Method for Microsatellite Instability Detection by Liquid Biopsy Based on Next- Generation Sequencing

2020 ◽  
Vol 15 ◽  
Author(s):  
Zheng Jiang ◽  
Hui Liu ◽  
Siwen Zhang ◽  
Jia Liu ◽  
Weitao Wang ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Microsatellite Instability ◽  
Liquid Biopsy ◽  
Tumor Tissue ◽  
High Sensitivity ◽  
Next Generation ◽  
Tissue Samples ◽  
Next Generation Sequencing Technology ◽  
Medication Selection ◽  
Generation Sequencing

Background: Microsatellite instability (MSI) is a prognostic biomarker used to guide medication selection in multiple cancers, such as colorectal cancer. Traditional PCR with capillary electrophoresis and next-generation sequencing using paired tumor tissue and leukocyte samples are the main approaches for MSI detection due to their high sensitivity and specificity. Currently, patient tissue samples are obtained through puncture or surgery, which causes injury and risk of concurrent disease, further illustrating the need for MSI detection by liquid biopsy. Methods: We propose an analytic method using paired plasma/leukocyte samples and MSI detection using next-generation sequencing technology. Based on the theoretical progress of oncogenesis, we hypothesized that the microsatellite site length in plasma equals the combination of the distribution of tumor tissue and leukocytes. Thus, we defined a window-judgement method to identify whether biomarkers were stable. Results: Compared to traditional PCR as the standard, we evaluated three methods in 20 samples (MSI-H:3/MSS:17): peak shifting method using tissue vs. leukocytes, peak shifting method using plasma vs. leukocytes, and our method using plasma vs. leukocytes. Compared to traditional PCR, we observed a sensitivity of 100%, 0%, and 100%, and a specificity of 100.00%, 94.12%, and 88.24%, respectively. Conclusion: Our method has the advantage of possibly detecting MSI in a liquid biopsy and provides a novel direction for future studies to increase the specificity of the method.

scholarly journals Expression and clinical significance of miR-3615 in hepatocellular carcinoma

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098154
Author(s):  
Xin Yuan ◽  
Yize Zhang ◽  
Zujiang Yu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Survival Curve ◽  
Clinicopathological Characteristics ◽  
The Cancer Genome Atlas ◽  
Prognostic Information ◽  
Ki 67 ◽  
Tissue Samples ◽  
Expression Levels ◽  
Kaplan Meier ◽  
Serum Alpha Fetoprotein

Objective To investigate the association between microRNA-3615 (miR-3615) expression and the prognosis and clinicopathological features in patients with hepatocellular carcinoma (HCC). Methods We obtained clinicopathological and genomic data and prognostic information on HCC patients from The Cancer Genome Atlas (TCGA) database. We then analyzed differences in miR-3615 expression levels between HCC and adjacent tissues using SPSS software, and examined the relationships between miR-3615 expression levels and clinicopathological characteristics. We also explored the influence of miR-3615 expression levels on the prognosis of HCC patients using Kaplan–Meier survival curve analysis. Results Based on data for 345 HCC and 50 adjacent normal tissue samples, expression levels of miR-3615 were significantly higher in HCC tissues compared with adjacent tissues. MiR-3615 expression levels in HCC patients were negatively correlated with overall survival time and positively correlated with high TNM stage, serum Ki-67 expression level, and serum alpha-fetoprotein level. There were no significant correlations between miR-3615 expression and age, sex, and pathological grade. Conclusion MiR-3615 may be a promising new biomarker and prognostic factor for HCC.

scholarly journals Possible Role of IRS-4 in the Origin of Multifocal Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2560
Author(s):  
Luis G. Guijarro ◽  
Patricia Sanmartin-Salinas ◽  
Eva Pérez-Cuevas ◽  
M. Val Toledo-Lobo ◽  
Jorge Monserrat ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Hepg2 Cells ◽  
Cellular Polarity ◽  
Ki 67 ◽  
Tissue Samples ◽  
Vitro Analysis ◽  
Tumoral Cells

New evidence suggests that insulin receptor substrate 4 (IRS-4) may play an important role in the promotion of tumoral growth. In this investigation, we have evaluated the role of IRS-4 in a pilot study performed on patients with liver cancer. We used immunohistochemistry to examine IRS-4 expression in biopsies of tumoral tissue from a cohort of 31 patient suffering of hepatocellular carcinoma (HCC). We simultaneously analyzed the expression of the cancer biomarkers PCNA, Ki-67, and pH3 in the same tissue samples. The in vitro analysis was conducted by studying the behavior of HepG2 cells following IRS-4 overexpression/silencing. IRS-4 was expressed mainly in the nuclei of tumoral cells from HCC patients. In contrast, in healthy cells involved in portal triads, canaliculi, and parenchymal tissue, IRS-4 was observed in the cytosol and the membrane. Nuclear IRS-4 in the tumoral region was found in 69.9 ± 3.2%, whereas in the surrounding healthy hepatocytes, nuclear IRS-4 was rarely observed. The percentage of tumoral cells that exhibited nuclear PCNA and Ki-67 were 52.1 ± 7%, 6.1 ± 1.1% and 1.3 ± 0.2%, respectively. Furthermore, we observed a significant positive linear correlation between nuclear IRS-4 and PCNA (r = 0.989; p < 0.001). However, when we correlated the nuclear expression of IRS-4 and Ki-67, we observed a significant positive curvilinear correlation (r = 0.758; p < 0.010). This allowed us to define two populations, (IRS-4 + Ki-67 ≤ 69%) and (IRS-4 + Ki-67 > 70%). The population with lower levels of IRS-4 and Ki-67 had a higher risk of suffering from multifocal liver cancer (OR = 16.66; CI = 1.68–164.8 (95%); p < 0.05). Immunoblot analyses showed that IRS-4 in normal human liver biopsies was lower than in HepG2, Huh7, and Chang cells. Treatment of HepG2 with IGF-1 and EGF induced IRS-4 translocation to the nucleus. Regulation of IRS-4 levels via HepG2 transfection experiments revealed the protein’s role in proliferation, cell migration, and cell-collagen adhesion. Nuclear IRS-4 is increased in the tumoral region of HCC. IRS-4 and Ki-67 levels are significantly correlated with the presence of multifocal HCC. Moreover, upregulation of IRS-4 in HepG2 cells induced proliferation by a β-catenin/Rb/cyclin D mechanism, whereas downregulation of IRS-4 caused a loss in cellular polarity and in its adherence to collagen as well as a gain in migratory and invasive capacities, probably via an integrin α2 and focal adhesion cascade (FAK) mechanism.

scholarly journals Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jun-Xian Du ◽  
Yi-Hong Luo ◽  
Si-Jia Zhang ◽  
Biao Wang ◽  
Cong Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
High Risk Group ◽  
Clinical Samples ◽  
Binding Motif ◽  
Ki 67 ◽  
Tissue Samples

Abstract Background Intensive evidence has highlighted the effect of aberrant alternative splicing (AS) events on cancer progression when triggered by dysregulation of the SR protein family. Nonetheless, the underlying mechanism in breast cancer (BRCA) remains elusive. Here we sought to explore the molecular function of SRSF1 and identify the key AS events regulated by SRSF1 in BRCA. Methods We conducted a comprehensive analysis of the expression and clinical correlation of SRSF1 in BRCA based on the TCGA dataset, Metabric database and clinical tissue samples. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and their binding motifs were identified by RNA-seq, RNA immunoprecipitation-PCR (RIP-PCR) and in vivo crosslinking followed by immunoprecipitation (CLIP), which was further validated by the minigene reporter assay. PTPMT1 exon 3 (E3) AS was identified to partially mediate the oncogenic role of SRSF1 by the P-AKT/C-MYC axis. Finally, the expression and clinical significance of these AS events were validated in clinical samples and using the TCGA database. Results SRSF1 expression was consistently upregulated in BRCA samples, positively associated with tumor grade and the Ki-67 index, and correlated with poor prognosis in a hormone receptor-positive (HR+) cohort, which facilitated proliferation, cell migration and inhibited apoptosis in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of splice switching of PTPMT1. Furthermore, PTPMT1 splice switching was regulated by SRSF1 by binding directly to its motif in E3 which partially mediated the oncogenic role of SRSF1 by the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients and using the TCGA database. The high-risk group, identified by AS of PTPMT1 and expression of SRSF1, possessed poorer prognosis in the stage I/II TCGA BRCA cohort. Conclusions SRSF1 exerts oncogenic roles in BRCA partially by regulating the AS of PTPMT1, which could be a therapeutic target candidate in BRCA and a prognostic factor in HR+ BRCA patient.

scholarly journals Combining tissue and circulating tumor DNA increases the detection rate of a CTNNB1 mutation in hepatocellular carcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Stine Karlsen Oversoe ◽  
Michelle Simone Clement ◽  
Britta Weber ◽  
Henning Grønbæk ◽  
Stephen Jacques Hamilton-Dutoit ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mutation Rate ◽  
Detection Rate ◽  
Tumor Tissue ◽  
Circulating Tumor Dna ◽  
Treatment Modalities ◽  
Advanced Hepatocellular Carcinoma ◽  
Tissue Samples ◽  
The Impact ◽  
Tumor Dna

Abstract Background and aims Studies suggest that mutations in the CTNNB1 gene are predictive of response to immunotherapy, an emerging therapy for advanced hepatocellular carcinoma (HCC). Analysis of circulating tumor DNA (ctDNA) offers the possibility of serial non-invasive mutational profiling of tumors. Combining tumor tissue and ctDNA analysis may increase the detection rate of mutations. This study aimed to evaluate the frequency of the CTNNB1 p.T41A mutation in ctDNA and tumor samples from HCC patients and to evaluate the concordance rates between plasma and tissue. We further evaluated changes in ctDNA after various HCC treatment modalities and the impact of the CTNNB1 p.T41A mutation on the clinical course of HCC. Methods We used droplet digital PCR to analyze plasma from 95 patients and the corresponding tumor samples from 37 patients during 3 years follow up. Results In tumor tissue samples, the mutation rate was 8.1% (3/37). In ctDNA from HCC patients, the CTNNB1 mutation rate was 9.5% (9/95) in the pre-treatment samples. Adding results from plasma analysis to the subgroup of patients with available tissue samples, the mutation detection rate increased to 13.5% (5/37). There was no difference in overall survival according to CTNNB1 mutational status. Serial testing of ctDNA suggested a possible clonal evolution of HCC or arising multicentric tumors with separate genetic profiles in individual patients. Conclusion Combining analysis of ctDNA and tumor tissue increased the detection rate of CTNNB1 mutation in HCC patients. A liquid biopsy approach may be useful in a tailored therapy of HCC.

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