Pathological and Genetic Stratification for Management of Adrenocortical Carcinoma

2021 ◽  
Author(s):  
Michael R Clay ◽  
Emilia M Pinto ◽  
Lauren Fishbein ◽  
Tobias Else ◽  
Katja Kiseljak-Vassiliades
Keyword(s):  
Adrenocortical Carcinoma ◽  
Therapeutic Approach ◽  
Evidence Synthesis ◽  
Critical Role ◽  
Tumor Stage ◽  
Significant Heterogeneity ◽  
Clinical Predictors ◽  
Comprehensive Genomic Profiling ◽  
Pubmed Search ◽  
Genetic Stratification

Abstract Context Adrenocortical carcinoma (ACC) is a rare endocrine malignancy that affects patients across the age spectrum. Although the overall survival in patients with ACC is poor, there is significant heterogeneity in terms of outcomes, presentation, and underlying genetic drivers. Evidence Acquisition This review is based on the evidence collected from primary research studies, expert reviews, and published guidelines. The studies were identified through PubMed search with key words “adrenocortical carcinoma”, “prognosis”, “pathology” and “genetics”. The PubMed search was complemented by authors’ expertise, research, and clinical experience in the field of ACC. Evidence Synthesis Identification of biomarkers has been critical to gain better insight into tumor behavior and to guide therapeutic approach to patients. Tumor stage, resection status and Ki67 are pathological tumor characteristics that have been identified as prognosticators in patients with ACC. Cortisol excess also correlates with worse prognosis. Clinical and histopathological characteristics help stratify patient outcomes, yet still up to 25% of patients have a different outcome than predicted. To bridge this gap, comprehensive genomic profiling studies have characterized additional profiles that correlate with clinical outcomes. In addition, studies of clinically applicable molecular markers are underway to further stratify outcomes in patients with ACC tumors. Conclusions Clinical predictors in combination with pathological markers play a critical role in the approach to patients with ACC. Recent advances in genetic prognosticators will help extend the stratification of these tumors and contribute to a personalized therapeutic approach to patients with ACC.

Antioxidant pathway targeting as a therapeutic approach in adrenocortical carcinoma

2017 ◽  
Author(s):  
Vasileios Chortis ◽  
Angela E. Taylor ◽  
Craig L. Doig ◽  
Eirini Meimaridou ◽  
Mark Walsh ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Therapeutic Approach

scholarly journals Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies

2014 ◽  
Vol 67 (11) ◽  
pp. 968-973 ◽  
Author(s):  
J S Ross ◽  
K Wang ◽  
J V Rand ◽  
L Gay ◽  
M J Presta ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Adrenocortical Carcinoma ◽  
Single Case ◽  
Next Generation ◽  
Illumina Hiseq ◽  
Modest Improvement ◽  
Aggressive Form ◽  
Comprehensive Genomic Profiling ◽  
Cytotoxic Therapies ◽  
Generation Sequencing

AimsAdrenocortical carcinoma (ACC) carries a poor prognosis and current systemic cytotoxic therapies result in only modest improvement in overall survival. In this retrospective study, we performed a comprehensive genomic profiling of 29 consecutive ACC samples to identify potential targets of therapy not currently searched for in routine clinical practice.MethodsDNA from 29 ACC was sequenced to high, uniform coverage (Illumina HiSeq) and analysed for genomic alterations (GAs).ResultsAt least one GA was found in 22 (76%) ACC (mean 2.6 alterations per ACC). The most frequent GAs were in TP53 (34%), NF1 (14%), CDKN2A (14%), MEN1 (14%), CTNNB1 (10%) and ATM (10%). APC, CCND2, CDK4, DAXX, DNMT3A, KDM5C, LRP1B, MSH2 and RB1 were each altered in two cases (7%) and EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN and PTCH1 were each altered in a single case (3%). In 17 (59%) of ACC, at least one GA was associated with an available therapeutic or a mechanism-based clinical trial.ConclusionsNext-generation sequencing can discover targets of therapy for relapsed and metastatic ACC and shows promise to improve outcomes for this aggressive form of cancer.

scholarly journals The Emerging Role of Glucagon-like Peptide-1 Receptor Agonists for the Management of NAFLD

2021 ◽  
Author(s):  
Chandani Patel Chavez ◽  
Kenneth Cusi ◽  
Sushma Kadiyala
Keyword(s):  
Evidence Synthesis ◽  
Clinical Care ◽  
Treatment Options ◽  
Critical Role ◽  
Risk Groups ◽  
The United States ◽  
Multidisciplinary Teams ◽  
Consensus Statements ◽  
Meta Analyses

Abstract Context The burden of cirrhosis from NAFLD is reaching epidemic proportions in the United States. This calls for greater awareness among endocrinologists, who often see but may miss the diagnosis in adults with obesity or type 2 diabetes mellitus (T2D) who are at the highest risk. At the same time, recent studies suggest that GLP-1RAs are beneficial versus steatohepatitis (NASH) in this population. This minireview aims to assist endocrinologists to recognize the condition and recent work on the role of GLP-1RAs in NAFLD/NASH. Evidence acquisition Evidence from observational studies, randomized controlled trials, and meta-analyses. Evidence Synthesis Endocrinologists should lead multidisciplinary teams to implement recent consensus statements on NAFLD that call for screening and treatment of clinically significant fibrosis to prevent cirrhosis, especially in the high-risk groups (i.e., people with obesity, prediabetes or T2D). With no FDA-approved agents, weight loss is central to their successful management, with pharmacological treatment options limited today to vitamin E (in people without T2D) and diabetes medications that reverse steatohepatitis, such as pioglitazone or GLP-1RA. Recently the benefit of GLP-1RAs in NAFLD, suggested from earlier trials, has been confirmed in adults with biopsy-proven NASH. In 2021, the FDA also approved semaglutide for obesity management. Conclusion A paradigm change is developing between the endocrinologist’s greater awareness about their critical role to curve the epidemic of NAFLD and new clinical care pathways that include a broader use of GLP-1RAs in the management of these complex patients.

Abstract 345: Syzygium Jambos: A Potential Therapeutic Approach to Treat the Vascular and Hematological Complications of Sickle Cell Disease

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Analaura Santiago-Perez ◽  
Yaritza Inostroza-Nieves ◽  
Daniel Gil de la Madrid ◽  
Isamar Alicea ◽  
Christopher Vega ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Therapeutic Approach ◽  
Thrombus Formation ◽  
Critical Role ◽  
Antioxidant Properties ◽  
Cell Disease ◽  
Syzygium Jambos ◽  
Promising Therapeutic Approach

Protein disulfide isomerase (PDI) is an oxidoreductase that mediates thiol/disulfide interchange reactions and has been reported to play a critical role in thrombus formation following vascular injury. PDI has also been shown to regulate leukocyte adherence to the endothelium and nitric oxide delivery. We recently reported that PDI is present at high levels and regulates erythrocyte homeostasis and Gardos Channel activity in humans with Sickle Cell Disease (SCD). Thus, PDI inhibition has been proposed as a promising therapeutic approach to ameliorate both the vascular and hematological complications of SCD. Syzygium jambos (S. jambos) is purported to have anti-inflammatory and antioxidant properties. However, the regulation of PDI activity by S. jambos has not been studied. We studied in vitro PDI activity in the presence of the S. jambos aqueous leaf extract using a PDI insulin turbidity assay. We observed significant reductions in PDI activity at 25 μg/mL (66.0 ± 9.7%, p<0.01, n=3), 50 μg/mL (83.3 ± 6.0%, p<0.01, n=3), and 100 μg/mL (91.6 ± 11.5%, p<0.01, n=3). S. jambos extract showed a dose-dependent anti-PDI activity with an IC50 of 14.40 μg/mL. We then tested the effects of S. jambos on endothelin-1 (ET-1)-stimulated PDI activity in human endothelial cells. Using a fluorescence based PDI activity assay, we observed that ET-1 increased PDI activity (1.7 ± 0.7 folds, n=3) that was dose-dependently blocked by S. jambos extract. In addition, we observed that ET-1 stimulated ex vivo human polymorphic nucleated (PMN) leukocyte migration toward the endothelial cells that was likewise dose-dependently blocked by S. jambos extract. (p<0.01, n=3). We also quantified the levels of reactive oxygen species (ROS) production in ET-1 treated endothelial cells. ET-1 stimulation significantly increased ROS levels [3 fold] when compared to vehicle treatment (p<0.05, n=3). S. jambos extract reduced ET-1 stimulated ROS to baseline levels (p<0.05, n=3). Our results suggest that S. Jambos may represent a novel pharmacological approach to treat complications of SCD.

The use of gamification and incentives in mobile health apps to improve medication adherence: a systematic scoping review (Preprint)

2021 ◽  
Author(s):  
Steven Tran ◽  
Lorraine Smith ◽  
Sarira El-Den ◽  
Stephen Carter
Keyword(s):  
Medication Adherence ◽  
Scoping Review ◽  
Computer Games ◽  
Financial Incentives ◽  
Mobile Apps ◽  
Evidence Synthesis ◽  
Significant Heterogeneity ◽  
Improve Medication Adherence ◽  
Screening Process ◽  
Published Evidence

BACKGROUND Emerging healthcare strategies to address medication adherence include the use of direct-to-patient incentives or elements adapted from computer games. However, there is currently no published evidence synthesis on the use of gamification and/or financial incentives in mobile applications (apps) to improve medication adherence. OBJECTIVE To explore the use of gamification and/or financial incentives in mobile apps to improve medication adherence. METHODS The following databases were searched for relevant articles published in English up to 24th of September: Embase, MEDLINE, PsycINFO, CINAHL and Web of Science. Arksey and O’Malley’s framework and the PRISMA-ScR checklist guided this systematic scoping review. Using a systematic screening process, studies were included if incentives and/or game features were used in mobile apps to address medication adherence. RESULTS An initial 691 potentially relevant articles were retrieved. Using a systematic process, 11 studies were included in this review. Across the studies, gamification alone (n=9) was used more than financial incentives (n=1) alone or a combination of the two (n=1). There was great variability in the development of the apps and underpinning theories. Patient involvement and contributions were not commonly seen in predevelopment but were evident in evaluations of feasibility, acceptance and effectiveness. The studies generally reported improved or sustained optimal medication adherence outcomes with gamification and financial incentives; however, there were significant heterogeneity in the patient population, methodology such as outcome measures and reporting of these studies. CONCLUSIONS To address medication adherence via gamified and incentivised mobile apps, an evidence-based co-design approach and agile methodology should be used during development. Further research in a generalised cohort of patients living with chronic conditions would facilitate the identification of barriers and potential opportunities for the use of gamification and financial incentives in mobile apps for medication adherence.

scholarly journals Contemporary Thyroid Nodule Evaluation and Management

2020 ◽  
Vol 105 (9) ◽  
pp. 2869-2883 ◽  
Author(s):  
Giorgio Grani ◽  
Marialuisa Sponziello ◽  
Valeria Pecce ◽  
Valeria Ramundo ◽  
Cosimo Durante
Keyword(s):  
Thyroid Nodule ◽  
Access To Health Care ◽  
English Language ◽  
Evidence Synthesis ◽  
Low Frequency ◽  
Initial Assessment ◽  
Molecular Testing ◽  
Data Systems ◽  
Sonographic Examination ◽  
Pubmed Search

Abstract Context Approximately 60% of adults harbor 1 or more thyroid nodules. The possibility of cancer is the overriding concern, but only about 5% prove to be malignant. The widespread use of diagnostic imaging and improved access to health care favor the discovery of small, subclinical nodules and small papillary cancers. Overdiagnosis and overtreatment is associated with potentially excessive costs and nonnegligible morbidity for patients. Evidence Acquisition We conducted a PubMed search for the recent English-language articles dealing with thyroid nodule management. Evidence Synthesis The initial assessment includes an evaluation of clinical risk factors and sonographic examination of the neck. Sonographic risk-stratification systems (e.g., Thyroid Imaging Reporting and Data Systems) can be used to estimate the risk of malignancy and the need for biopsy based on nodule features and size. When cytology findings are indeterminate, molecular analysis of the aspirate may obviate the need for diagnostic surgery. Many nodules will not require biopsy. These nodules and those that are cytologically benign can be managed with long-term follow-up alone. If malignancy is suspected, options include surgery (increasingly less extensive), active surveillance or, in selected cases, minimally invasive techniques. Conclusion Thyroid nodule evaluation is no longer a 1-size-fits-all proposition. For most nodules, the likelihood of malignancy can be confidently estimated without resorting to cytology or molecular testing, and low-frequency surveillance is sufficient for most patients. When there are multiple options for diagnosis and/or treatment, they should be discussed with patients as frankly as possible to identify an approach that best meets their needs.

A Critical Role for the Bcl-2 Pathway in Notch-Mediated B Cell Apoptosis, Where Growth Arrest Is Independent of the E2A, IL-3 and p21Waf1/p27Kip1 Pathways.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 237-237 ◽  
Author(s):  
Patrick A. Zweidler-McKay ◽  
Julian J. Lum ◽  
Craig B. Thompson ◽  
Warren S. Pear
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Notch Signaling ◽  
Cell Apoptosis ◽  
Therapeutic Approach ◽  
Critical Role ◽  
Growth Arrest ◽  
Model System ◽  
B Cell Malignancies ◽  
Induce Growth Arrest

Abstract The Notch receptor pathway regulates critical cell fate decisions in multiple developmental systems, including hematopoiesis. We have previously demonstrated that Notch signaling induces growth arrest and apoptosis in a wide range of human B cell malignancies and has potential as a B cell-specific therapeutic approach. In order to identify the mechanisms of growth arrest and apoptosis we analyzed an immortalized murine progenitor B cell line derived from Bax/Bak double knockout mice. These cells are unable to undergo apoptosis since they lack the pro-apoptotic effectors of the Bcl-2 pathway, and have been shown to be resistant to multiple apoptotic stimuli. Here we report that induction of Notch signaling through expression of several family members (Notch1, Notch4, Hes1) leads to rapid growth arrest, but not apoptosis, within 48 hours in these Bax-/Bak- progenitor B cells. These findings provide the first evidence for a critical role of the Bcl-2 pathway in Notch-mediated B cell apoptosis, and establish a mitochondrial-dependent mechanism for this effect. Importantly, the kinetics of growth arrest are accelerated with the expression of the Notch downstream target Hes1 as compared to the Notch receptors 1 and 4. These results extend our observation that Hes1 is sufficient to reproduce Notch-mediated B cell death, by demonstrating that Hes1 is more proximal to the critical growth inhibiting events, and may therefore provide a therapeutic target. In this model system we can isolate growth arrest from the effects on the apoptotic cascade. This provides a unique opportunity to explore the mechanism of Notch-mediated growth arrest. Prior studies have suggested that Notch signaling may induce growth arrest through inhibition of the E2A pathway, or through upregulation of the cell cycle regulators p21Waf1 and p27Kip1. In this model system, inhibition of the E2A pathway is not sufficient to induce growth arrest. Similarly, Hes1 does not upregulate either p21Waf1 or p27Kip1, suggesting that this is not the mechanism of growth arrest. To explore whether Notch/Hes1 induce growth arrest through inhibition of the IL-3 pathway, we compared phenotypic and functional aspects of Hes1 expression and IL-3 withdrawal. Although the timing and phenotypic effects (cell size, cell cycle and metabolic studies) were quite similar, Hes1 growth arrested cells lose their ability to migrate in response to the pan-B chemo-attractant SDF1a compared to IL-3 withdrawn cells. In summary, these results demonstrate that Notch/Hes1-mediated B cell apoptosis relies critically on pro-apoptotic members of the Bcl-2 pathway, Bax/Bak. Furthermore, growth arrest when isolated from apoptosis does not rely on inhibition of the E2A or IL-3 pathways, nor upregulation of p21Waf1/ p27Kip1. These findings provide the first insight into the mechanisms of Notch/Hes1-mediated B cell growth arrest and apoptosis and will help guide the development of Notch/Hes1 signaling as a cell-type specific therapeutic approach for B cell malignancies.

THE IMPACT OF TUMOR STAGE ON PROGNOSIS IN CHILDREN WITH ADRENOCORTICAL CARCINOMA

2005 ◽  
Vol 174 (6) ◽  
pp. 2338-2342 ◽  
Author(s):  
SILVIO TUCCI ◽  
ANTONIO C.P. MARTINS ◽  
HAYLTON J. SUAID ◽  
ADAUTO J. COLOGNA ◽  
RODOLFO B. REIS
Keyword(s):  
Adrenocortical Carcinoma ◽  
Tumor Stage ◽  
The Impact

scholarly journals Association Between Gut Microbiota and Bone Health: Potential Mechanisms and Prospective

2017 ◽  
Vol 102 (10) ◽  
pp. 3635-3646 ◽  
Author(s):  
Yuan-Cheng Chen ◽  
Jonathan Greenbaum ◽  
Hui Shen ◽  
Hong-Wen Deng
Keyword(s):  
Gut Microbiota ◽  
Bone Metabolism ◽  
Bone Health ◽  
Association Studies ◽  
Evidence Synthesis ◽  
Critical Role ◽  
Mucosal Barrier ◽  
Biological Processes ◽  
The Relationship

Abstract Context It has been well established that the human gut microbiome plays a critical role in the regulation of important biological processes and the mechanisms underlying numerous complex diseases. Although researchers have only recently begun to study the relationship between the gut microbiota and bone metabolism, early efforts have provided increased evidence to suggest an important association. Evidence Acquisition In this study, we attempt to comprehensively summarize the relationship between the gut microbiota and bone metabolism by detailing the regulatory effects of the microbiome on various biological processes, including nutrient absorption and the intestinal mucosal barrier, immune system functionality, the gut–brain axis, and excretion of functional byproducts. In this review, we incorporate evidence from various types of studies, including observational, in vitro and in vivo animal experiments, as well as small efficacy clinic trails. Evidence Synthesis We review the various potential mechanisms of influence for the gut microbiota on the regulation of bone metabolism and discuss the importance of further examining the potential effects of the gut microbiota on the risk of osteoporosis in humans. Furthermore, we outline some useful tools/approaches for metagenomics research and present some prominent examples of metagenomics association studies in humans. Conclusion Current research efforts, although limited, clearly indicate that the gut microbiota may be implicated in bone metabolism, and therefore, further exploration of this relationship is a promising area of focus in bone health and osteoporosis research. Although most existing studies investigate this relationship using animal models, human studies are both needed and on the horizon.

scholarly journals Role of Angiopoietin-2 in Regulating Growth and Vascularity of Astrocytomas

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Gelareh Zadeh ◽  
Keyvan Koushan ◽  
Qian Baoping ◽  
Patrick Shannon ◽  
Abhijit Guha
Keyword(s):  
Tumor Angiogenesis ◽  
Cancer Biology ◽  
Critical Role ◽  
Tumor Stage ◽  
Growth Stages ◽  
Vascular Growth ◽  
Malignant Astrocytomas ◽  
Significant Research ◽  
Angiopoietin 2

Angiopoietins and Tie2 are angiogenic-specific ligand and receptor complex that have been shown to play a critical role in tumor angiogenesis. Angiopoietin-2 (Ang2) is one of four ligands for receptor Tie2 and it is the naturally occurring antagonist to Tie2, inhibiting the action of Angiopoietin-1 (Ang1). Over the last decade, significant research has focused on elucidating the role of Ang2 in cancer biology and its exact role in tumor angiogenesis remains elusive. In this study we have focused on establishing the role of Ang2 in angiogenesis of malignant astrocytomas. We have demonstrated that Ang2 significantly enhances the vascular growth of malignant astrocytomas and constant upregulation of Ang2 throughout all phases of tumor growth generates abnormal vascular structures that are not typically seen in human astrocytomas, suggesting that Ang2 plays a tumor stage-dependent role and is not a consistently elevated throughout all growth stages of malignant astroctyomas.

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