Pub Date : 2023-03-01DOI: 10.1080/17446651.2023.2183840
Eckhard Klieser, Bettina Neumayer, Pietro Di Fazio, Christian Mayr, Daniel Neureiter, Tobias Kiesslich
Introduction: The pathogenic role of deregulated histone (de-)acetylation by histone deacetyles (HDACs) has been demonstrated in several human cancers. While some HDAC inhibitors (HDACi) have been approved for individual entities, for endocrine tumors such translation into clinical practice has not yet been achieved.
Areas covered: Relevant results identified by structured searches in PubMed as well as in reference lists are summarized in a narrative review to discuss the current knowledge of HDAC involvement and their therapeutic relevance in endocrine tumors. For thyroid, neuroendocrine, and adrenal tumors, various oncogenic mechanisms of HDAC deregulation and effects of HDAC inhibitors (HDACi) have been identified in preclinical studies including direct cancer cell toxicity and modification of differentiation status.
Expert opinion: Based on positive pre-clinical results, the research on HDAC (inhibition) in the various endocrine tumors should be intensified - yet, it needs to be considered that i) HDACs' oncogenic actions might constitute only a part of epigenetic mechanisms driving cancer, ii) individual HDAC has different roles in different endocrine tumor entities, iii) inhibition of HDACs might be especially attractive in combination with conventional or other targeted therapies, and iv) new HDAC-inhibiting drugs with improved specificity or functionally modified HDACi might further improve their efficacy.
{"title":"HDACs as an emerging target in endocrine tumors: a comprehensive review.","authors":"Eckhard Klieser, Bettina Neumayer, Pietro Di Fazio, Christian Mayr, Daniel Neureiter, Tobias Kiesslich","doi":"10.1080/17446651.2023.2183840","DOIUrl":"https://doi.org/10.1080/17446651.2023.2183840","url":null,"abstract":"<p><strong>Introduction: </strong>The pathogenic role of deregulated histone (de-)acetylation by histone deacetyles (HDACs) has been demonstrated in several human cancers. While some HDAC inhibitors (HDACi) have been approved for individual entities, for endocrine tumors such translation into clinical practice has not yet been achieved.</p><p><strong>Areas covered: </strong>Relevant results identified by structured searches in PubMed as well as in reference lists are summarized in a narrative review to discuss the current knowledge of HDAC involvement and their therapeutic relevance in endocrine tumors. For thyroid, neuroendocrine, and adrenal tumors, various oncogenic mechanisms of HDAC deregulation and effects of HDAC inhibitors (HDACi) have been identified in preclinical studies including direct cancer cell toxicity and modification of differentiation status.</p><p><strong>Expert opinion: </strong>Based on positive pre-clinical results, the research on HDAC (inhibition) in the various endocrine tumors should be intensified - yet, it needs to be considered that i) HDACs' oncogenic actions might constitute only a part of epigenetic mechanisms driving cancer, ii) individual HDAC has different roles in different endocrine tumor entities, iii) inhibition of HDACs might be especially attractive in combination with conventional or other targeted therapies, and iv) new HDAC-inhibiting drugs with improved specificity or functionally modified HDACi might further improve their efficacy.</p>","PeriodicalId":12107,"journal":{"name":"Expert Review of Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9285524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-03-01Epub Date: 2023-03-07DOI: 10.1080/17446651.2023.2187779
Jennifer N Clements, Rachel Franks, Diana Isaacs, Kevin Malloy, Lisa T Meade, Sara Mandy Reece, Debra J Reid, Eileen D Ward
Introduction: The most significant articles on diabetes pharmacotherapy and technology in the peer-reviewed literature from 2020, as determined by a panel of pharmacists with expertise in diabetes care and education, are summarized.
Areas covered: Members of the Association of Diabetes Care and Education Specialists Pharmacy Community of Interest were selected to review articles published in prominent peer-reviewed journals in 2020 that most impacted diabetes pharmacotherapy and technology. A list of 37 nominated articles were compiled (22 in diabetes pharmacotherapy and 15 in diabetes technology). Based on discussion among the authors, the articles were ranked based on significant contribution, impact, and diversity to diabetes pharmacotherapy and technology. The top 10 highest ranked publications (n = 6 for diabetes pharmacotherapy and n = 4 in diabetes technology) are summarized in this article.
Expert opinion: With the significant number of publications in diabetes care and education, it can be challenging and overwhelming to remain current with published literature. This review article may be helpful in identifying key articles in diabetes pharmacotherapy and technology from the year 2020.
{"title":"Significant publications in diabetes pharmacotherapy and technology in 2020.","authors":"Jennifer N Clements, Rachel Franks, Diana Isaacs, Kevin Malloy, Lisa T Meade, Sara Mandy Reece, Debra J Reid, Eileen D Ward","doi":"10.1080/17446651.2023.2187779","DOIUrl":"10.1080/17446651.2023.2187779","url":null,"abstract":"<p><strong>Introduction: </strong>The most significant articles on diabetes pharmacotherapy and technology in the peer-reviewed literature from 2020, as determined by a panel of pharmacists with expertise in diabetes care and education, are summarized.</p><p><strong>Areas covered: </strong>Members of the Association of Diabetes Care and Education Specialists Pharmacy Community of Interest were selected to review articles published in prominent peer-reviewed journals in 2020 that most impacted diabetes pharmacotherapy and technology. A list of 37 nominated articles were compiled (22 in diabetes pharmacotherapy and 15 in diabetes technology). Based on discussion among the authors, the articles were ranked based on significant contribution, impact, and diversity to diabetes pharmacotherapy and technology. The top 10 highest ranked publications (n = 6 for diabetes pharmacotherapy and n = 4 in diabetes technology) are summarized in this article.</p><p><strong>Expert opinion: </strong>With the significant number of publications in diabetes care and education, it can be challenging and overwhelming to remain current with published literature. This review article may be helpful in identifying key articles in diabetes pharmacotherapy and technology from the year 2020.</p>","PeriodicalId":12107,"journal":{"name":"Expert Review of Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9661306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-03-01DOI: 10.1080/17446651.2023.2185221
Marta Padovan, Giulia Cerretti, Mario Caccese, Mattia Barbot, Eleonora Bergo, Gianluca Occhi, Carla Scaroni, Giuseppe Lombardi, Filippo Ceccato
Introduction: Pituitary adenomas can show a tendency to grow, despite multimodal treatment. Temozolomide (TMZ) has been used in the last 15 years in patients with aggressive pituitary tumors. TMZ requires a careful balance of different expertise, especially for selection criteria.
Areas covered: We conducted: (1) a systematic review of the published literature from 2006 to 2022, collecting only cases with a complete description of patient follow-up after TMZ discontinuation; (2) a description of all patients with aggressive pituitary adenoma or carcinoma treated in Padua (Italy).
Expert opinion: There is considerable heterogeneity in the literature: TMZ cycles duration ranged from 3 to 47 months; the follow-up time after TMZ discontinuation ranged from 4 to 91 months (mean 24 months, median 18 months), at least a stable disease has been reported in 75% of patients after a mean 13 months (range 3-47 months, median 10 months). The Padua (Italy) cohort reflects the literature. Future directions to explore are to understand the pathophysiological mechanism of TMZ resistance escape, to develop predicting factors to TMZ treatment (especially through the delineation of the underlying transformation processes), and to further expand the therapeutic applications of TMZ (as neoadjuvant, combined with radiotherapy).
{"title":"Knowing when to discontinue Temozolomide therapy in responding aggressive pituitary tumors and carcinomas: a systematic review and Padua (Italy) case series.","authors":"Marta Padovan, Giulia Cerretti, Mario Caccese, Mattia Barbot, Eleonora Bergo, Gianluca Occhi, Carla Scaroni, Giuseppe Lombardi, Filippo Ceccato","doi":"10.1080/17446651.2023.2185221","DOIUrl":"https://doi.org/10.1080/17446651.2023.2185221","url":null,"abstract":"<p><strong>Introduction: </strong>Pituitary adenomas can show a tendency to grow, despite multimodal treatment. Temozolomide (TMZ) has been used in the last 15 years in patients with aggressive pituitary tumors. TMZ requires a careful balance of different expertise, especially for selection criteria.</p><p><strong>Areas covered: </strong>We conducted: (1) a systematic review of the published literature from 2006 to 2022, collecting only cases with a complete description of patient follow-up after TMZ discontinuation; (2) a description of all patients with aggressive pituitary adenoma or carcinoma treated in Padua (Italy).</p><p><strong>Expert opinion: </strong>There is considerable heterogeneity in the literature: TMZ cycles duration ranged from 3 to 47 months; the follow-up time after TMZ discontinuation ranged from 4 to 91 months (mean 24 months, median 18 months), at least a stable disease has been reported in 75% of patients after a mean 13 months (range 3-47 months, median 10 months). The Padua (Italy) cohort reflects the literature. Future directions to explore are to understand the pathophysiological mechanism of TMZ resistance escape, to develop predicting factors to TMZ treatment (especially through the delineation of the underlying transformation processes), and to further expand the therapeutic applications of TMZ (as neoadjuvant, combined with radiotherapy).</p>","PeriodicalId":12107,"journal":{"name":"Expert Review of Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9285523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-03-01DOI: 10.1080/17446651.2023.2179985
Bhavik P Shah, Patrick M Sleiman, Jessica Mc Donald, Ida H Moeller, Patrick Kleyn
Objective: Hyperphagia and early-onset, severe obesity are clinical characteristics of rare melanocortin-4 receptor (MC4R) pathway diseases due to loss-of-function (LOF) variants in genes comprising the MC4R pathway. In vitro functional characterization of 12,879 possible exonic missense variants from single-nucleotide variants (SNVs) of LEPR, POMC, and PCSK1 was performed to determine the impact of these variants on protein function.
Methods: SNVs of the three genes were transiently transfected into cell lines, and each variant was subsequently classified according to functional impact. We validated three assays by comparing classifications against functional characterization of 29 previously published variants.
Results: Our results significantly correlated with previously published pathogenic categories (r = 0.623; P = 3.03 × 10-4) of all potential missense variants arising from SNVs. Of all observed variants identified through available databases and a tested cohort of 16,061 patients with obesity, 8.6% of LEPR, 63.2% of PCSK1, and 10.6% of POMC variants exhibited LOF, including variants currently classified as a variant of uncertain significance (VUS).
Conclusions: The functional data provided here can assist in the reclassification of several VUS in LEPR, PCSK1, and POMC and highlight their impact in MC4R pathway diseases.
{"title":"Functional characterization of all missense variants in <i>LEPR, PCSK1</i>, and <i>POMC</i> genes arising from single-nucleotide variants.","authors":"Bhavik P Shah, Patrick M Sleiman, Jessica Mc Donald, Ida H Moeller, Patrick Kleyn","doi":"10.1080/17446651.2023.2179985","DOIUrl":"https://doi.org/10.1080/17446651.2023.2179985","url":null,"abstract":"<p><strong>Objective: </strong>Hyperphagia and early-onset, severe obesity are clinical characteristics of rare melanocortin-4 receptor (MC4R) pathway diseases due to loss-of-function (LOF) variants in genes comprising the MC4R pathway. In vitro functional characterization of 12,879 possible exonic missense variants from single-nucleotide variants (SNVs) of <i>LEPR, POMC</i>, and <i>PCSK1</i> was performed to determine the impact of these variants on protein function.</p><p><strong>Methods: </strong>SNVs of the three genes were transiently transfected into cell lines, and each variant was subsequently classified according to functional impact. We validated three assays by comparing classifications against functional characterization of 29 previously published variants.</p><p><strong>Results: </strong>Our results significantly correlated with previously published pathogenic categories (r = 0.623; <i>P</i> = 3.03 × 10<sup>-4</sup>) of all potential missense variants arising from SNVs. Of all observed variants identified through available databases and a tested cohort of 16,061 patients with obesity, 8.6% of <i>LEPR</i>, 63.2% of <i>PCSK1</i>, and 10.6% of <i>POMC</i> variants exhibited LOF, including variants currently classified as a variant of uncertain significance (VUS).</p><p><strong>Conclusions: </strong>The functional data provided here can assist in the reclassification of several VUS in <i>LEPR, PCSK1</i>, and <i>POMC</i> and highlight their impact in MC4R pathway diseases.</p>","PeriodicalId":12107,"journal":{"name":"Expert Review of Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9292341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-03-01DOI: 10.1080/17446651.2023.2184796
Juan Pablo Frías
Introduction: Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA), received regulatory approval from the U.S. Food and Drug Administration (13 May 2022) and marketing authorization from the European Commission (25 September 2022) for the improvement of glycemic control in adults with type 2 diabetes (T2D). In the phase 3 clinical development program (SURPASS), tirzepatide demonstrated superior glycemic and body weight control compared with placebo and active comparators across a spectrum of patients with T2D.
Areas covered: This review summarizes efficacy and safety results of the tirzepatide T2D phase 3 clinical trials that supported regulatory approvals. Additionally, it discusses a meta-analysis assessing tirzepatide cardiovascular (CV) safety, and provides a brief overview of ongoing late-stage clinical trials in patients with T2D. Information in this review was acquired from peer-reviewed published trials, ClinicalTrials.gov, and the manufacturer's website.
Expert opinion: Based on phase 3 clinical trial data, tirzepatide is the most potent glucose and body weight lowering agent available for the management of T2D. The potential for tirzepatide to improve CV outcomes is currently being assessed in a CV outcomes trial (SURPASS CVOT). Results of this trial are highly anticipated and expected in 2024.
{"title":"An update on tirzepatide for the management of type 2 diabetes: a focus on the phase 3 clinical development program.","authors":"Juan Pablo Frías","doi":"10.1080/17446651.2023.2184796","DOIUrl":"https://doi.org/10.1080/17446651.2023.2184796","url":null,"abstract":"<p><strong>Introduction: </strong>Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA), received regulatory approval from the U.S. Food and Drug Administration (13 May 2022) and marketing authorization from the European Commission (25 September 2022) for the improvement of glycemic control in adults with type 2 diabetes (T2D). In the phase 3 clinical development program (SURPASS), tirzepatide demonstrated superior glycemic and body weight control compared with placebo and active comparators across a spectrum of patients with T2D.</p><p><strong>Areas covered: </strong>This review summarizes efficacy and safety results of the tirzepatide T2D phase 3 clinical trials that supported regulatory approvals. Additionally, it discusses a meta-analysis assessing tirzepatide cardiovascular (CV) safety, and provides a brief overview of ongoing late-stage clinical trials in patients with T2D. Information in this review was acquired from peer-reviewed published trials, ClinicalTrials.gov, and the manufacturer's website.</p><p><strong>Expert opinion: </strong>Based on phase 3 clinical trial data, tirzepatide is the most potent glucose and body weight lowering agent available for the management of T2D. The potential for tirzepatide to improve CV outcomes is currently being assessed in a CV outcomes trial (SURPASS CVOT). Results of this trial are highly anticipated and expected in 2024.</p>","PeriodicalId":12107,"journal":{"name":"Expert Review of Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9345336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1080/17446651.2023.2168644
Ahmed H Abdelhafiz
Introduction: The prevalence of diabetes is increasing in older people. With increasing age, frailty emerges as a new complication leading to disability. Frailty does not only include physical dysfunction but also involves negative impact on cognition and mood. Triad of impairments (TOI) is a new concept that includes physical frailty, dementia and depression to reflect the wider spectrum of frailty.
Areas covered: Little is known about effects of hypoglycaemic agents on frailty syndrome. A literature search was performed on studies, which reported effects of hypoglycaemic agents on the component of the TOI.
Expert opinion: It appears that most hypoglycaemic agents have some effects on frailty, although the results of clinical studies are inconsistent. Metformin seems to have a consistent and a positive effect on physical frailty. Its effects on cognitive function, however, are inconclusive but tend to be positive. Metformin appeared to improve depressive symptoms. Other agents such as incretins, thiazolidinediones, and sodium glucose transporter-2 inhibitors have some positive effects on cognition and depression. Sulfonylureas, glinides, or insulin have either negative or neutral effects on TOI components. The negative effects of insulin could be partially explained by the negative psychological factors and the frequent episodes of hypoglycemia associated with such therapy.
{"title":"Effects of hypoglycaemic therapy on frailty: a multi-dimensional perspective.","authors":"Ahmed H Abdelhafiz","doi":"10.1080/17446651.2023.2168644","DOIUrl":"https://doi.org/10.1080/17446651.2023.2168644","url":null,"abstract":"<p><strong>Introduction: </strong>The prevalence of diabetes is increasing in older people. With increasing age, frailty emerges as a new complication leading to disability. Frailty does not only include physical dysfunction but also involves negative impact on cognition and mood. Triad of impairments (TOI) is a new concept that includes physical frailty, dementia and depression to reflect the wider spectrum of frailty.</p><p><strong>Areas covered: </strong>Little is known about effects of hypoglycaemic agents on frailty syndrome. A literature search was performed on studies, which reported effects of hypoglycaemic agents on the component of the TOI.</p><p><strong>Expert opinion: </strong>It appears that most hypoglycaemic agents have some effects on frailty, although the results of clinical studies are inconsistent. Metformin seems to have a consistent and a positive effect on physical frailty. Its effects on cognitive function, however, are inconclusive but tend to be positive. Metformin appeared to improve depressive symptoms. Other agents such as incretins, thiazolidinediones, and sodium glucose transporter-2 inhibitors have some positive effects on cognition and depression. Sulfonylureas, glinides, or insulin have either negative or neutral effects on TOI components. The negative effects of insulin could be partially explained by the negative psychological factors and the frequent episodes of hypoglycemia associated with such therapy.</p>","PeriodicalId":12107,"journal":{"name":"Expert Review of Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10711488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1080/17446651.2023.2168645
Marco Infante, Camillo Ricordi
Introduction: Diabetes of the exocrine pancreas (DEP; a.k.a. pancreatic diabetes or pancreatogenic diabetes or type 3c diabetes mellitus or T3cDM) refers to different diabetes types resulting from disorders of the exocrine pancreas. DEP is characterized by the structural and functional loss of glucose-normalizing insulin secretion in the context of exocrine pancreatic dysfunction. Among these forms, new-onset diabetes mellitus secondary to total pancreatectomy (TP) has unique pathophysiological and clinical features, for which we propose a new nomenclature such as post-total pancreatectomy diabetes mellitus (PTPDM).
Areas covered: TP results in the complete loss of pancreatic parenchyma, with subsequent absolute insulinopenia and lifelong need for exogenous insulin therapy. Patients with PTPDM also exhibit deficiency of glucagon, amylin and pancreatic polypeptide. These endocrine abnormalities, coupled with increased peripheral insulin sensitivity, deficiency of pancreatic enzymes and TP-related modifications of gastrointestinal anatomy, can lead to marked glucose variability and increased risk of iatrogenic (insulin-induced) severe hypoglycemic episodes ('brittle diabetes').
Expert opinion: We believe that diabetes mellitus secondary to TP should not be included in the DEP spectrum in light of its peculiar pathophysiological and clinical features. Therefore, we propose a new classification for this entity, that would likely provide more accurate prognosis and treatment strategies.
{"title":"The unique pathophysiological features of diabetes mellitus secondary to total pancreatectomy: proposal for a new classification distinct from diabetes of the exocrine pancreas.","authors":"Marco Infante, Camillo Ricordi","doi":"10.1080/17446651.2023.2168645","DOIUrl":"https://doi.org/10.1080/17446651.2023.2168645","url":null,"abstract":"<p><strong>Introduction: </strong>Diabetes of the exocrine pancreas (DEP; a.k.a. pancreatic diabetes or pancreatogenic diabetes or type 3c diabetes mellitus or T3cDM) refers to different diabetes types resulting from disorders of the exocrine pancreas. DEP is characterized by the structural and functional loss of glucose-normalizing insulin secretion in the context of exocrine pancreatic dysfunction. Among these forms, new-onset diabetes mellitus secondary to total pancreatectomy (TP) has unique pathophysiological and clinical features, for which we propose a new nomenclature such as post-total pancreatectomy diabetes mellitus (PTPDM).</p><p><strong>Areas covered: </strong>TP results in the complete loss of pancreatic parenchyma, with subsequent absolute insulinopenia and lifelong need for exogenous insulin therapy. Patients with PTPDM also exhibit deficiency of glucagon, amylin and pancreatic polypeptide. These endocrine abnormalities, coupled with increased peripheral insulin sensitivity, deficiency of pancreatic enzymes and TP-related modifications of gastrointestinal anatomy, can lead to marked glucose variability and increased risk of iatrogenic (insulin-induced) severe hypoglycemic episodes ('brittle diabetes').</p><p><strong>Expert opinion: </strong>We believe that diabetes mellitus secondary to TP should not be included in the DEP spectrum in light of its peculiar pathophysiological and clinical features. Therefore, we propose a new classification for this entity, that would likely provide more accurate prognosis and treatment strategies.</p>","PeriodicalId":12107,"journal":{"name":"Expert Review of Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9266494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1080/17446651.2023.2166489
Rami Aldafas, Thomas Crabtree, Yana Vinogradova, Jason P Gordon, Iskandar Idris
Objective: The aim of study is to re-evaluate the risk-benefits of intensive glycemic control in the context of multi-factorial intervention in adults with T2D.
Methods: We searched Ovid MEDLINE, Embase, Cochrane, and CINHAL for randomized control trials comparing standard glucose targets to intensive glucose targets with pre-specified HbA1clevels. Subgroup analysis was also performed to account for the inclusion of glucose only versus multi-factorial intervention trials. Results are reported as risk ratio (RR) and 95% confidence interval (CI).
Results: Fifty-seven publications including 19 trials were included. Compared to conventional glycemic control, intensive glycemic control decreased the risk of non-fatal myocardial infarction (0.8, 0.7-0.91), macroalbuminuria (0.72, 0.5--0.87), microalbuminuria (0.67, 0.52-0.85), major amputation (0.6, 0.38-0.96), retinopathy (0.75 ,0.63-0.9), and nephropathy (0.78, 0.63-0.97). The risk of hypoglycemia increased with intensive glycemic control than conventional treatment (2.04, 1.34-3.1). No reduction in all-cause or cardiovascular mortality was observed. However, in the context of multifactorial intervention, intensive glucose control was associated with a significant reduction in all-cause mortality (0.74, 0.57-0.95).
Conclusion: Targeting HbA1c levels should be individualized based on the clinical status, balancing risks and benefits and potential risk for developing these complications among people with T2D.
{"title":"Efficacy and safety of intensive versus conventional glucose targets in people with type 2 diabetes: a systematic review and meta-analysis.","authors":"Rami Aldafas, Thomas Crabtree, Yana Vinogradova, Jason P Gordon, Iskandar Idris","doi":"10.1080/17446651.2023.2166489","DOIUrl":"https://doi.org/10.1080/17446651.2023.2166489","url":null,"abstract":"<p><strong>Objective: </strong>The aim of study is to re-evaluate the risk-benefits of intensive glycemic control in the context of multi-factorial intervention in adults with T2D.</p><p><strong>Methods: </strong>We searched Ovid MEDLINE, Embase, Cochrane, and CINHAL for randomized control trials comparing standard glucose targets to intensive glucose targets with pre-specified HbA<sub>1c</sub>levels. Subgroup analysis was also performed to account for the inclusion of glucose only versus multi-factorial intervention trials. Results are reported as risk ratio (RR) and 95% confidence interval (CI).</p><p><strong>Results: </strong>Fifty-seven publications including 19 trials were included. Compared to conventional glycemic control, intensive glycemic control decreased the risk of non-fatal myocardial infarction (0.8, 0.7-0.91), macroalbuminuria (0.72, 0.5--0.87), microalbuminuria (0.67, 0.52-0.85), major amputation (0.6, 0.38-0.96), retinopathy (0.75 ,0.63-0.9), and nephropathy (0.78, 0.63-0.97). The risk of hypoglycemia increased with intensive glycemic control than conventional treatment (2.04, 1.34-3.1). No reduction in all-cause or cardiovascular mortality was observed. However, in the context of multifactorial intervention, intensive glucose control was associated with a significant reduction in all-cause mortality (0.74, 0.57-0.95).</p><p><strong>Conclusion: </strong>Targeting HbA<sub>1c</sub> levels should be individualized based on the clinical status, balancing risks and benefits and potential risk for developing these complications among people with T2D.</p>","PeriodicalId":12107,"journal":{"name":"Expert Review of Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10772315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1080/17446651.2023.2166487
Jerome H Check, Diane L Check
Introduction: Patients with various advanced cancers devoid of nuclear progesterone receptors (nPR) have demonstrated increased quality and length of life when treated with the PR modulator mifepristone, which likely works by interacting with membrane PRs (mPR).
Areas covered: Two immunomodulatory proteins are discussed that seem to play a role in cancers that proliferate whether the malignant tumor is positive or negative for the nPR. These two proteins are the progesterone receptor membrane component-1 (PGRMC-1) and the progesterone-induced blocking factor (PIBF). Both PGRMC-1 and the parent form of PIBF foster increased tumor aggressiveness, whereas splice variants of the 90 kDa form of PIBF inhibit immune response against cancer cells.
Expert opinion: The marked clinical improvement following 200-300 mg of mifepristone is likely related to blocking PIBF. In the low dosage used, mifepristone likely acts as an agonist for PGRMC-1 protein. Mifepristone may be less effective for cancers positive for the nPR because the nPR may be protective and blocking it may have detrimental effects. Based on this hypothetical model, the development of other potential treatment options to provide even greater efficacy for treating cancer are discussed.
{"title":"The role of progesterone and the progesterone receptor in cancer: progress in the last 5 years.","authors":"Jerome H Check, Diane L Check","doi":"10.1080/17446651.2023.2166487","DOIUrl":"https://doi.org/10.1080/17446651.2023.2166487","url":null,"abstract":"<p><strong>Introduction: </strong>Patients with various advanced cancers devoid of nuclear progesterone receptors (nPR) have demonstrated increased quality and length of life when treated with the PR modulator mifepristone, which likely works by interacting with membrane PRs (mPR).</p><p><strong>Areas covered: </strong>Two immunomodulatory proteins are discussed that seem to play a role in cancers that proliferate whether the malignant tumor is positive or negative for the nPR. These two proteins are the progesterone receptor membrane component-1 (PGRMC-1) and the progesterone-induced blocking factor (PIBF). Both PGRMC-1 and the parent form of PIBF foster increased tumor aggressiveness, whereas splice variants of the 90 kDa form of PIBF inhibit immune response against cancer cells.</p><p><strong>Expert opinion: </strong>The marked clinical improvement following 200-300 mg of mifepristone is likely related to blocking PIBF. In the low dosage used, mifepristone likely acts as an agonist for PGRMC-1 protein. Mifepristone may be less effective for cancers positive for the nPR because the nPR may be protective and blocking it may have detrimental effects. Based on this hypothetical model, the development of other potential treatment options to provide even greater efficacy for treating cancer are discussed.</p>","PeriodicalId":12107,"journal":{"name":"Expert Review of Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9266033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1080/17446651.2023.2167710
Daniel Marrero-Rodríguez, Keiko Taniguchi-Ponciano, Moises Mercado
Pituitary adenomas (PA) are rather frequent, they constitute up to 25% of all intracranial tumors, with a prevalence varying from 70 to 115 cases per 100,000 persons and an incidence of 4 to 6 per 100,000 persons per year [1]. The prevalence among autopsy and radiological studies varies between 10% and 20%. Pituitary carcinomas (PC), on the other hand, are among the least frequent malignancies known to man, barely reaching 0.2–0.4% of all pituitary tumors [2]. In fact, most practicing endocrinologists worldwide do not get to see a single case of PC during their professional lifetime. Published information regarding PC mostly consists of isolated case reports, very few series, and a handful of reviews [3–5]. Over 70% of PC are functioning, usually ACTHor PRL-secreting tumors that arise from apparently benign, but usually invasive macroadenomas, with a latency period from adenoma to carcinoma that varies from 6 months to over 10 years [3–5]. Features associated with malignancy such as hypercellularity, nuclear pleomorphism, increased mitotic activity, dural, bone and vascular invasion, extracellular matrix degradation, neoangiogenesis, a high Ki-67 proliferative index, and p53 immunostaining are not always present in PC and can occasionally be found in nonmalignant pituitary tumors [4]. Thus, the documentation of craniospinal or distant metastasis (bone, lymph nodes, liver, and lung, being the most frequently reported sites) is a sine qua non criteria to establish the diagnosis [2–5]. Lying between PA and PC in the pathological spectrum of pituitary neoplasms, we found what used to be called ‘atypical pituitary adenomas’ and that are currently known as aggressive pituitary tumors (APT). According to the European Society of Endocrinology (ESE) 2018 guidelines, APT are defined as tumors with radiological evidence of invasiveness, particularly cavernous sinus invasion, with an unusually rapid growth rate and that is persistent despite multimodal therapy (surgery, radiation, pharmacological treatment) [6,7]. It is important to emphasize, however, that while an aggressive tumor is almost always invasive, an invasive lesion does not always behave aggressively. The latter is illustrated by some giant prolactinomas that may be quite sensitive to pharmacological treatment with dopamine agonists. Interestingly, the conversion of a nonfunctioning into a functioning tumor, or more specifically, of a silent corticotrope adenoma into a Cushing diseasecausing tumor is associated with an aggressive biological behavior and should warn us of the possibility of an eventual malignant transformation [8]. In an attempt to summarize the complex cellular and subcellular events that underlie malignant transformation, Hanahan and Weinberg published back in 2000 their seminal article ‘The Hallmarks of Cancer’ [9]. The original review is based on six biological processes that characterize carcinogenesis, namely, 1) self-sufficiency in growth signals, 2) insensitivity to anti-
{"title":"Why is pituitary carcinoma so rare?","authors":"Daniel Marrero-Rodríguez, Keiko Taniguchi-Ponciano, Moises Mercado","doi":"10.1080/17446651.2023.2167710","DOIUrl":"https://doi.org/10.1080/17446651.2023.2167710","url":null,"abstract":"Pituitary adenomas (PA) are rather frequent, they constitute up to 25% of all intracranial tumors, with a prevalence varying from 70 to 115 cases per 100,000 persons and an incidence of 4 to 6 per 100,000 persons per year [1]. The prevalence among autopsy and radiological studies varies between 10% and 20%. Pituitary carcinomas (PC), on the other hand, are among the least frequent malignancies known to man, barely reaching 0.2–0.4% of all pituitary tumors [2]. In fact, most practicing endocrinologists worldwide do not get to see a single case of PC during their professional lifetime. Published information regarding PC mostly consists of isolated case reports, very few series, and a handful of reviews [3–5]. Over 70% of PC are functioning, usually ACTHor PRL-secreting tumors that arise from apparently benign, but usually invasive macroadenomas, with a latency period from adenoma to carcinoma that varies from 6 months to over 10 years [3–5]. Features associated with malignancy such as hypercellularity, nuclear pleomorphism, increased mitotic activity, dural, bone and vascular invasion, extracellular matrix degradation, neoangiogenesis, a high Ki-67 proliferative index, and p53 immunostaining are not always present in PC and can occasionally be found in nonmalignant pituitary tumors [4]. Thus, the documentation of craniospinal or distant metastasis (bone, lymph nodes, liver, and lung, being the most frequently reported sites) is a sine qua non criteria to establish the diagnosis [2–5]. Lying between PA and PC in the pathological spectrum of pituitary neoplasms, we found what used to be called ‘atypical pituitary adenomas’ and that are currently known as aggressive pituitary tumors (APT). According to the European Society of Endocrinology (ESE) 2018 guidelines, APT are defined as tumors with radiological evidence of invasiveness, particularly cavernous sinus invasion, with an unusually rapid growth rate and that is persistent despite multimodal therapy (surgery, radiation, pharmacological treatment) [6,7]. It is important to emphasize, however, that while an aggressive tumor is almost always invasive, an invasive lesion does not always behave aggressively. The latter is illustrated by some giant prolactinomas that may be quite sensitive to pharmacological treatment with dopamine agonists. Interestingly, the conversion of a nonfunctioning into a functioning tumor, or more specifically, of a silent corticotrope adenoma into a Cushing diseasecausing tumor is associated with an aggressive biological behavior and should warn us of the possibility of an eventual malignant transformation [8]. In an attempt to summarize the complex cellular and subcellular events that underlie malignant transformation, Hanahan and Weinberg published back in 2000 their seminal article ‘The Hallmarks of Cancer’ [9]. The original review is based on six biological processes that characterize carcinogenesis, namely, 1) self-sufficiency in growth signals, 2) insensitivity to anti-","PeriodicalId":12107,"journal":{"name":"Expert Review of Endocrinology & Metabolism","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9266031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}