Both Graves' hyperthyroidism (GH) and Graves' orbitopathy (GO) are associated with significant adverse health consequences. All conventional treatment options have limitations regarding efficacy and safety. Most importantly, they do not specifically address the underlying immunological mechanisms. We aim to review the latest development of treatment approaches in these two closely related disorders.
Immunotherapies of GH have recently demonstrated clinical efficacy in preliminary studies. They include ATX-GD-59, an antigen-specific immunotherapy which restores immune tolerance to the thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 costimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor-blocking monoclonal antibody. Novel treatment strategies have also become available in GO. Mycophenolate significantly increased the overall response rate combined with standard glucocorticoid (GC) treatment compared to GC monotherapy. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, displayed strong anti-inflammatory action in GC-resistant cases. Teprotumumab, an anti-insulin-like growth factor 1 receptor monoclonal antibody, resulted in remarkable improvement in terms of disease activity, proptosis, and diplopia. Further, rituximab appears to be useful in active disease of recent onset without impending dysthyroid optic neuropathy.
Therapeutic advances will continue to optimize our management of GH and associated orbitopathy in an effective and safe manner.
Therapeutic advances will continue to optimize our management of GH and associated orbitopathy in an effective and safe manner.Standardization of treatment outcomes in randomized clinical trials (RCTs) for active, moderate-to-severe Graves' orbitopathy (GO) is needed to make results of different RCTs comparable and to draw sound conclusions on the efficacy of a given treatment. Both subjective patient-reported outcome (PRO) and objective clinician-reported outcome (CRO) are important in this regard. In this paper, it is proposed that primary PRO should be the evaluation of treatment-related changes in the quality of life by the use of a validated and disease-specific questionnaire (GO-QoL). The proposed primary CRO is a revised composite index, which includes only objective items and provides an overall assessment of the effects of treatment. Secondary outcomes should also be provided in RCTs to show the effects of treatment on individual features of GO, as well on persistence of activity (by the 7-item Clinical Activity Score), safety, relapses of GO, need for subsequent medical and/or surgical treatments, and other indicators (orbital volume, cytokines, TSH receptor antibody levels). Assessment of the overall response to treatment by primary and secondary outcomes should be made 3 months after treatment completion.[This corrects the article .].Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to develop and combat EBV. If this is not effective, approaches include immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells. Immune checkpoint inhibition (ICI) to treat EBV+ PTLD was not established clinically due to the risks of organ rejection and graft-versus-host disease. https://www.selleckchem.com/products/borussertib.html Previously, blockade of the programmed death receptor (PD)-1 by a monoclonal antibody (mAb) during ex vivo infection of mononuclear cells with the EBV/M81+ strain showed lower xenografted lymphoma development in ****. Subsequently, fully humanized **** infected with the EBV/B95-8 strain and treated in vivo with a PD-1 blocking mAb showed aggravation of PTLD and lymphoma development. Here, we evaluated vis-a-vis in fudensities of FoxP3+ regulatory CD4+ and CD8+ T cells in the tumor microenvironment. We conclude that PD-1 blockade during acute EBV infections driving strong CD8+ T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV+ PTLD.
We aimed to investigate whether
F-FDG PET metabolic heterogeneity reflects the heterogeneity of estrogen receptor (ER) and progesterone receptor (PR) expressions within luminal non-metastatic breast tumors and if it could help in identifying patients with worst event-free survival (EFS).
On 38 PET high-resolution breast bed positions, a single physician drew volumes of interest encompassing the breast tumors to extract SUV
, histogram parameters and textural features. High-resolution immunochemistry (IHC) scans were analyzed to extract Haralick parameters and descriptors of the distribution shape. Correlation between IHC and PET parameters were explored using Spearman tests. Variables of interest to predict the EFS status at 8 years (EFS-8y) were sought by means of a random forest classification. EFS-8y analyses were then performed using univariable Kaplan-Meier analyses and Cox regression analysis. When appropriate, Mann-Whitney tests and Spearman correlations were used to explore the relationship bet skewness_
was significantly higher in youngest patients (ρ = -0.351, p = 0.031) and in clinical stage III tumors (p = 0.023).
A heterogeneous distribution of ER within the tumor in IHC appeared as an EFS-8y prognosticator in luminal non-metastatic breast cancers. Interestingly, it appeared to be correlated with PET histogram parameters which could therefore become potential non-invasive prognosticator tools, provided these results are confirmed by further larger and prospective studies.
A heterogeneous distribution of ER within the tumor in IHC appeared as an EFS-8y prognosticator in luminal non-metastatic breast cancers. Interestingly, it appeared to be correlated with PET histogram parameters which could therefore become potential non-invasive prognosticator tools, provided these results are confirmed by further larger and prospective studies.
Both Graves' hyperthyroidism (GH) and Graves' orbitopathy (GO) are associated with significant adverse health consequences. All conventional treatment options have limitations regarding efficacy and safety. Most importantly, they do not specifically address the underlying immunological mechanisms. We aim to review the latest development of treatment approaches in these two closely related disorders.
Immunotherapies of GH have recently demonstrated clinical efficacy in preliminary studies. They include ATX-GD-59, an antigen-specific immunotherapy which restores immune tolerance to the thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 costimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor-blocking monoclonal antibody. Novel treatment strategies have also become available in GO. Mycophenolate significantly increased the overall response rate combined with standard glucocorticoid (GC) treatment compared to GC monotherapy. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, displayed strong anti-inflammatory action in GC-resistant cases. Teprotumumab, an anti-insulin-like growth factor 1 receptor monoclonal antibody, resulted in remarkable improvement in terms of disease activity, proptosis, and diplopia. Further, rituximab appears to be useful in active disease of recent onset without impending dysthyroid optic neuropathy.
Therapeutic advances will continue to optimize our management of GH and associated orbitopathy in an effective and safe manner.
Therapeutic advances will continue to optimize our management of GH and associated orbitopathy in an effective and safe manner.Standardization of treatment outcomes in randomized clinical trials (RCTs) for active, moderate-to-severe Graves' orbitopathy (GO) is needed to make results of different RCTs comparable and to draw sound conclusions on the efficacy of a given treatment. Both subjective patient-reported outcome (PRO) and objective clinician-reported outcome (CRO) are important in this regard. In this paper, it is proposed that primary PRO should be the evaluation of treatment-related changes in the quality of life by the use of a validated and disease-specific questionnaire (GO-QoL). The proposed primary CRO is a revised composite index, which includes only objective items and provides an overall assessment of the effects of treatment. Secondary outcomes should also be provided in RCTs to show the effects of treatment on individual features of GO, as well on persistence of activity (by the 7-item Clinical Activity Score), safety, relapses of GO, need for subsequent medical and/or surgical treatments, and other indicators (orbital volume, cytokines, TSH receptor antibody levels). Assessment of the overall response to treatment by primary and secondary outcomes should be made 3 months after treatment completion.[This corrects the article .].Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to develop and combat EBV. If this is not effective, approaches include immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells. Immune checkpoint inhibition (ICI) to treat EBV+ PTLD was not established clinically due to the risks of organ rejection and graft-versus-host disease. https://www.selleckchem.com/products/borussertib.html Previously, blockade of the programmed death receptor (PD)-1 by a monoclonal antibody (mAb) during ex vivo infection of mononuclear cells with the EBV/M81+ strain showed lower xenografted lymphoma development in mice. Subsequently, fully humanized mice infected with the EBV/B95-8 strain and treated in vivo with a PD-1 blocking mAb showed aggravation of PTLD and lymphoma development. Here, we evaluated vis-a-vis in fudensities of FoxP3+ regulatory CD4+ and CD8+ T cells in the tumor microenvironment. We conclude that PD-1 blockade during acute EBV infections driving strong CD8+ T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV+ PTLD.
We aimed to investigate whether
F-FDG PET metabolic heterogeneity reflects the heterogeneity of estrogen receptor (ER) and progesterone receptor (PR) expressions within luminal non-metastatic breast tumors and if it could help in identifying patients with worst event-free survival (EFS).
On 38 PET high-resolution breast bed positions, a single physician drew volumes of interest encompassing the breast tumors to extract SUV
, histogram parameters and textural features. High-resolution immunochemistry (IHC) scans were analyzed to extract Haralick parameters and descriptors of the distribution shape. Correlation between IHC and PET parameters were explored using Spearman tests. Variables of interest to predict the EFS status at 8 years (EFS-8y) were sought by means of a random forest classification. EFS-8y analyses were then performed using univariable Kaplan-Meier analyses and Cox regression analysis. When appropriate, Mann-Whitney tests and Spearman correlations were used to explore the relationship bet skewness_
was significantly higher in youngest patients (ρ = -0.351, p = 0.031) and in clinical stage III tumors (p = 0.023).
A heterogeneous distribution of ER within the tumor in IHC appeared as an EFS-8y prognosticator in luminal non-metastatic breast cancers. Interestingly, it appeared to be correlated with PET histogram parameters which could therefore become potential non-invasive prognosticator tools, provided these results are confirmed by further larger and prospective studies.
A heterogeneous distribution of ER within the tumor in IHC appeared as an EFS-8y prognosticator in luminal non-metastatic breast cancers. Interestingly, it appeared to be correlated with PET histogram parameters which could therefore become potential non-invasive prognosticator tools, provided these results are confirmed by further larger and prospective studies.
0 Comments
0 Shares
23 Views
0 Reviews
