scholarly journals Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications

2021 ◽  
Vol 12 ◽  
Author(s):  
Iuliu Sbiera ◽  
Stefan Kircher ◽  
Barbara Altieri ◽  
Kerstin Lenz ◽  
Constanze Hantel ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Kinase Inhibitors ◽  
Univariate Analysis ◽  
Tumor Stage ◽  
Adrenal Tumors ◽  
Ki 67 ◽  
Fgf Receptor ◽  
Therapeutic Implications ◽  
Adrenocortical Tumors

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 – 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 – 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials.

scholarly journals Fascin-1 Is a Novel Prognostic Biomarker Associated With Tumor Invasiveness in Adrenocortical Carcinoma

2018 ◽  
Vol 104 (5) ◽  
pp. 1712-1724 ◽  
Author(s):  
Giada Poli ◽  
Carmen Ruggiero ◽  
Giulia Cantini ◽  
Letizia Canu ◽  
Gianna Baroni ◽  
...  
Keyword(s):  
Disease Free Survival ◽  
Tumor Stage ◽  
Labeling Index ◽  
University Hospital ◽  
Adrenal Tumors ◽  
Adrenocortical Cancer ◽  
Tumor Spread ◽  
Adrenocortical Tumors ◽  
Tumor Invasiveness ◽  
Ki67 Labeling Index

Abstract Context Novel tumor markers are urgently needed to better stratify adrenocortical cancer (ACC) patients and improve therapies for this aggressive neoplasm. Objective To assess the diagnostic and prognostic value of the actin-bundling protein fascin-1 (FSCN1) in adrenocortical tumors. Design, Setting and Participants A local series of 37 malignant/37 benign adrenocortical tumors at Careggi University Hospital and two independent validation ACC cohorts (Cochin, TCGA) from the European Network for the Study of Adrenal Tumors were studied. Main Outcome Measures FSCN1 expression was quantified by immunohistochemistry, Western blot and quantitative RT-PCR in ACC specimens; overall and disease-free survival associated with FSCN1 expression were assessed by Kaplan-Meier analysis and compared with that of Ki67 labeling index and tumor stage. Results Despite the low diagnostic power, in the Florence ACC series, FSCN1 immunohistochemical detection appeared as an independent prognostic factor, also refining results obtained with staging and Ki67 labeling index. The robust prognostic power of FSCN1 levels was further confirmed in two independent ACC cohorts. A positive correlation was found between FSCN1 and steroidogenic factor-1 (SF-1), with a substantially higher expression of both factors in ACCs at advanced stages and with at least one of the three Weiss score parameters associated with invasiveness. Moreover, we demonstrated FSCN1 role in promoting cell invasion in a human ACC cell line only in the case of increased SF-1 dosage. Conclusions These findings show that FSCN1 is a novel independent prognostic marker in ACC and may serve as a potential therapeutic target to block tumor spread.

scholarly journals Molecular Profiling and Novel Therapeutic Strategies for Mucosal Melanoma: A Comprehensive Review

2021 ◽  
Vol 23 (1) ◽  
pp. 147
Author(s):  
Alice Indini ◽  
Fausto Roila ◽  
Francesco Grossi ◽  
Daniela Massi ◽  
Mario Mandalà
Keyword(s):  
Clinical Trials ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Poor Response ◽  
Pooled Analysis ◽  
Therapeutic Strategies ◽  
Mucosal Melanoma ◽  
Driver Mutations ◽  
Therapeutic Implications

Mucosal melanoma is a rare and aggressive subtype of melanoma. Unlike its cutaneous counterpart, mucosal melanoma has only gained limited benefit from novel treatment approaches due to the lack of actionable driver mutations and poor response to immunotherapy. Over the last years, whole-genome and exome sequencing techniques have led to increased knowledge on the molecular landscape of mucosal melanoma. Molecular studies have underlined noteworthy findings with potential therapeutic implications, including the presence of KIT mutations, which are potential targets of tyrosine kinase inhibitors currently in use in the clinic (imatinib), but also SF3B1 mutation, CDK4 amplifications, and CDKN2A gene deletions, which are presently under investigation in clinical trials. Recent results from a pooled analysis of patients with mucosal melanoma treated with immunotherapy have suggested that the combination of immune checkpoint inhibitors might improve survival outcomes in this subset of patients, as compared with single-agent immunotherapy. However, these results are not confirmed across different studies, and combo-immunotherapy correlates with a higher rate of adverse events. In this review, we describe the clinical, biological, and genetic features of mucosal melanoma. We also provide an update on the results of approved systemic treatment in this setting and overview the therapeutic strategies currently under investigation in clinical trials.

scholarly journals The emerging role of the molecular marker p27 in the differential diagnosis of adrenocortical tumors

2013 ◽  
Vol 2 (3) ◽  
pp. 137-145 ◽  
Author(s):  
Sofia S Pereira ◽  
Tiago Morais ◽  
Madalena M Costa ◽  
Mariana P Monteiro ◽  
Duarte Pignatelli
Keyword(s):  
Differential Diagnosis ◽  
Cyclin D1 ◽  
Adrenal Glands ◽  
Malignant Tumors ◽  
Molecular Profile ◽  
Benign Tumors ◽  
Ki 67 ◽  
Adrenocortical Tumors ◽  
Percentage Area

Malignant adrenocortical tumors (ACTs) are rare and highly aggressive; conversely, benign tumors are common and frequently found incidentally (the so-called incidentalomas). Currently, the use of molecular markers in the diagnosis of ACTs is still controversial. The aim of this study was to analyze the molecular profile of different ACTs with the purpose of identifying markers useful for differentiating between these tumors. The ACTs that were studied (n=31) included nonfunctioning adenomas (ACAn)/incidentalomas (n=13), functioning adenomas with Cushing's syndrome (ACAc) (n=7), and carcinomas (n=11); normal adrenal glands (n=12) were used as controls. For each sample, the percentage area stained for the markers StAR, IGF2, IGF1R, p53, MDM2, p21, p27, cyclin D1, Ki-67, β-catenin, and E-cadherin was quantified using a morphometric computerized tool. IGF2, p27, cyclin D1, and Ki-67 were the markers for which the percentage of stained area was significantly higher in carcinoma samples than in adenoma samples. Ki-67 and p27 were the markers that exhibited the highest discriminative power for differential diagnosis between carcinomas and all type of adenomas, while IGF2 and StAR were only found to be useful for differentiating between carcinomas and ACAn and between carcinomas and ACAc respectively. The usefulness of Ki-67 has been recognized before in the differential diagnosis of malignant tumors. The additional use of p27 as an elective marker to distinguish benign ACTs from malignant ACTs should be considered.

scholarly journals Luteinizing Hormone and GATA4 Action in the Adrenocortical Tumorigenesis of Gonadectomized Female Mice

2017 ◽  
Vol 43 (3) ◽  
pp. 1064-1076 ◽  
Author(s):  
Milena Doroszko ◽  
Marcin Chrusciel ◽  
Joanna Stelmaszewska ◽  
Tomasz Slezak ◽  
Adolfo Rivero-Muller ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Physiological Role ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Adrenal Tumors ◽  
Zona Fasciculata ◽  
Adrenocortical Tumors ◽  
Topmost Layer

Background/Aims: Physiological role of luteinizing hormone (LH) and its receptor (LHCGR) in adrenal remains unknown. In inhibin-α/Simian Virus 40 T antigen (SV40Tag) (inhα/Tag) mice, gonadectomy-induced (OVX) elevated LH triggers the growth of transcription factor GATA4 (GATA4)-positive adrenocortical tumors in a hyperplasia-adenoma-adenocarcinoma sequence. Methods: We investigated the role of LHCGR in tumor induction, by crossbreeding inhα/Tag with Lhcgr knockout (LuRKO) mice. By knocking out Lhcgr and Gata4 in Cα1 adrenocortical cells (Lhcgr-ko, Gata4-ko) we tested their role in tumor progression. Results: Adrenal tumors of OVX inhα/Tag mice develop from the hyperplastic cells localized in the topmost layer of zona fasciculata. OVX inhα/Tag/LuRKO only developed SV40Tag positive hyperplastic cells that were GATA4 negative, cleaved caspase-3 positive and did not progress into adenoma. In contrast to Lhcgr-ko, Gata4-ko Cα1 cells presented decreased proliferation, increased apoptosis, decreased expression of Inha, SV40Tag and Lhcgr tumor markers, as well as up-regulated adrenal- and down-regulated sex steroid gene expression. Both Gata4-ko and Lhcgr-ko Cα1 cells had decreased expression of steroidogenic genes resulting in decreased basal progesterone production. Conclusion: Our data indicate that LH/LHCGR signaling is critical for the adrenal cell reprogramming by GATA4 induction prompting adenoma formation and gonadal-like phenotype of the adrenocortical tumors in inhα/Tag mice.

scholarly journals A review on immunohistochemical and histopathologic validation in PET-CT findings with consideration to microRNAs

2019 ◽  
Author(s):  
Marius-Ioan Bădan ◽  
Eduard-Alexandru Bonci ◽  
Doina Piciu
Keyword(s):  
Clinical Trials ◽  
Future Research ◽  
Ki 67 ◽  
Extensive Search ◽  
Mesh Terms ◽  
Positron Emission ◽  
Time Period ◽  
Pet Ct ◽  
Further Development

Purpose. This review provides an overview of some of the most recent clinical trials which investigated various types of cancer and other diseases, through the use of PET-CT imaging, highlighting the use of immunohistochemical stains or conventional histopathology for the validation or contradiction of their hypothesis. Furthermore, we investigate a potential new direction of research by analyzing the upcoming role of microRNAs in disease confirmation. Methods. An extensive search of MEDLINE/ PubMed and SCOPUS electronic databases was made, using the MeSH terms "positron emission tomography computed tomography" and "immunohistochemistry" as well as ”SUV” and ”immunohistochemistry”, restricting the search by clinical trials and time period. Further searches were made for articles regarding Ki-67 and microRNAs in correlation with metabolic PET-CT uptake. Results. Out of all 389 initial search results, 27 original articles were found relevant to the topic. Their contents were synthesized and discussed regarding the matter at hand. No relevant clinical trials involving microRNAs were found. Conclusions. Immunohistochemical and histopathologic results remain widely used and indispensable in modern research, concerning PET-CT validation. Possible candidates for diagnosis confirmation, in future research, may reside in the further development of microRNAs.

scholarly journals Is there a role for anti-CD20 antibodies in CLL?

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 68-75
Author(s):  
Harsh R. Shah ◽  
Deborah M. Stephens
Keyword(s):  
Clinical Trials ◽  
Kinase Inhibitors ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Antagonistic Effect ◽  
Lymphocytic Leukemia ◽  
Treatment Naïve ◽  
Anti Cd20 ◽  
Cd20 Antibodies

Abstract Anti-CD20 monoclonal antibodies (mAbs) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) by improving survival of patients with CLL in conjunction with chemotherapy. However, the novel targeted agents such as Bruton tyrosine kinase inhibitors (BTKis) and venetoclax have now mostly replaced chemotherapy in frontline treatment of CLL. Several clinical trials have been conducted to examine the role of anti-CD20 mAbs in combination with BTK inhibitors and venetoclax. Addition of rituximab to ibrutinib does not improve progression-free survival (PFS) of treatment-naive patients with CLL, possibly related to ibrutinib's antagonistic effect on anti-CD20 antibodies. Alternatively, addition of a glycoengineered anti-CD20 mAb obinutuzumab to a more selective BTKi acalabrutinib may improve PFS but does not improve overall survival of patients with CLL in the frontline setting, pending long-term follow-up. Thus, we suggest that the addition of an anti-CD20 mAb to a BTKi is of most benefit to patients with autoimmune cytopenia or rapidly progressive disease. In contrast to BTKis, combination of fixed-duration venetoclax and anti-CD20 mAb can induce deep remission with high rates of undetectable minimal residual disease, correlating with improved survival of patients with CLL in both frontline and relapsed/refractory settings. In this review, we discuss clinical trials of BTKis and venetoclax that have investigated the role of anti-CD20 mAbs in frontline and relapsed settings of CLL treatment. We also provide an algorithm suggesting how anti-CD20 mAbs may be incorporated in the treatment of patients with CLL, including specific scenarios.

Anti-Proliferative Role of the Tyrosine Kinase Inhibitors TKI-258 on Oral Squamous Cell Carcinoma In Vitro

2020 ◽  
Vol 20 (6) ◽  
pp. 751-755
Author(s):  
Isadora C. Silveira ◽  
Anna Cecília D.M. Carneiro ◽  
Lorraine S. Hiss ◽  
Virgínia O. Crema
Keyword(s):  
Squamous Cell Carcinoma ◽  
Growth Factor ◽  
Oral Squamous Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Ki 67 ◽  
Pi3k Inhibition

Background: Identification of the antitumor role of tyrosine kinase inhibitors, such as TKI-258, may lead to novel therapeutics for Oral Squamous Cell Carcinoma (OSCC), which has high mortality rates. TKI-258 blocks Fibroblast Growth Factor Receptors (FGFRs), Platelet-Derived Growth Factor Receptors (PDGFRs), and Endothelial Growth Factor Receptor (VEGFRs). Objective: This study aimed to evaluate the effect of TKI-258 treatment on cell proliferation in SCC-4 cells of OSCC. Methods: BrdU and KI-67 assays were performed by using SCC-4 cells. Control was compared to 1, 5 and 10μM TKI-258 treatment. Control vehicle was compared to: 60μM LY294002 (LY), 2μM Wortmannin (WTN) and LY+WNT. Moreover, TKI 5μM treatment was compared to: TKI 5μM+LY; TKI 5 μM+WTN; TKI 5μM+LY+WTN. After 6h of treatments, immunofluorescence stained BrdU and KI-67 positive cells. Morphometry of proliferative cells was analyzed considering significance of p<0.05. Results: BrdU and KI-67 assays results were similar for all experiments. TKI-258 treatment leads to an important reduction in proliferation rate in SCC-4 cells in a concentration dependent manner. As expected, there was a significant reduction in the percentage of proliferative cells that had PI3K inhibited. When compared with TKI 5 treatment, proliferating cells were significantly lower with simultaneous PI3K inhibition. Conclusion: This study demonstrated that TKI-258 plays an anti-proliferative role on SCC-4 cells of OSCC. It could be interesting to block multiples pathways such as FGFRs, PDGFRs and VEGFRs. Therefore, TKI-258 is a promising option for novel therapeutics for OSCC, especially if associated with PI3K inhibition.

Role of Ki-67, MRE11, and PD-L1 As Predictive Biomarkers for Recurrence Pattern in Muscle Invasive Bladder Cancer Following Radical Cystectomy

2021 ◽  
Author(s):  
Croix C. Fossum ◽  
Yin Xiong ◽  
Anthony Magliocco ◽  
Siamak Daneshmand ◽  
Manju Aron ◽  
...  
Keyword(s):  
Local Recurrence ◽  
Radical Cystectomy ◽  
Univariate Analysis ◽  
Predictive Biomarkers ◽  
Molecular Signature ◽  
Recurrence Pattern ◽  
Ki 67 ◽  
Normal Bladder ◽  
Muscle Invasive

Abstract Background Muscle invasive bladder (MIBC) cancer is an aggressive disease with high rates of local recurrence following radical cystectomy (RC). Currently, there are no clinically validated biomarkers to predict local only recurrence (LOR) and guide adjuvant treatment decisions. This pilot study evaluated the role of Ki-67, MRE11 and PD-L1 as predictive biomarkers for recurrence patterns in patients undergoing RC for MIBC. Methods: Our institutional cystectomy database containing cases of urothelial MIBC from 1992–2014 was queried for patients with LOR and case-matched with patients who had distant recurrence (DR) and no recurrence (NR). Clinical and histopathological data were collected from selected patients and a tissue microarray was built and analyzed for presence of Ki-67, MRE11 and PD-L1 using immunofluorescence (IF) and immunohistochemistry (IHC). Univariate, multivariate, and principal component analyses (PCA) were performed to evaluate association of these biomarkers with recurrence pattern. Results: Pathologic specimens from 42 patients (18 NR, 16 LOR and 8 DR) were reviewed. Compared to adjacent normal bladder tissue, tumors had increased expression of PD-L1 on both IHC and IF (p < 0.05) and higher Ki-67 H-score on IHC (33 vs 0, p < 0.01). A high Ki-67 was associated with recurrence pattern (local vs distant) on univariate analysis (p < 0.05) and on multivariate regression, having positive surgical margins was associated with local recurrence (p = 0.04). Ki-67 cell density varied by recurrence type: LR (1354 cells/mm2), DR (557 cells/mm2) and NR (1111 cells/mm2) p = 0.034. Several PCAs were unable to identify a signature associated with recurrence pattern. Conclusion: The biomarkers used in this study were helpful in distinguishing tumor from normal tissue and high Ki-67 may be associated with LOR, however, a useful molecular signature for recurrence pattern could not be identified.

Role of melatonin in regulating neurogenesis: Implications for the neurodegenerative pathology and analogous therapeutics for Alzheimer’s disease

2020 ◽  
Vol 3 (2) ◽  
pp. 216-242 ◽  
Author(s):  
Mayuri Shukla ◽  
Areechun Sotthibundhu ◽  
Piyarat Govitrapong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adult Neurogenesis ◽  
Adult Brain ◽  
Therapeutic Approaches ◽  
Therapeutic Implications ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Progenitor Cell Proliferation

The revelation of adult brain exhibiting neurogenesis has established that the brain possesses great plasticity and that neurons could be spawned in the neurogenic zones where hippocampal adult neurogenesis attributes to learning and memory processes. With strong implications in brain functional homeostasis, aging and cognition, various aspects of adult neurogenesis reveal exuberant mechanistic associations thereby further aiding in facilitating the therapeutic approaches regarding the development of neurodegenerative processes in Alzheimer’s Disease (AD). Impaired neurogenesis has been significantly evident in AD with compromised hippocampal function and cognitive deficits. Melatonin the pineal indolamine augments neurogenesis and has been linked to AD development as its levels are compromised with disease progression. Here, in this review, we discuss and appraise the mechanisms via which melatonin regulates neurogenesis in pathophysiological conditions which would unravel the molecular basis in such conditions and its role in endogenous brain repair. Also, its components as key regulators of neural stem and progenitor cell proliferation and differentiation in the embryonic and adult brain would aid in accentuating the therapeutic implications of this indoleamine in line of prevention and treatment of AD.   

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