Catherine Skefos, Pamela L Brock, Erica L Blouch, Samantha Greenberg
This commentary explores the complexities faced by clinicians when encountering a secondary SDHA pathogenic variant (PV) in patients without a personal or family history of SDHA-related tumors. The increasing use of germline multi-gene panel testing has led to a rise in such secondary findings, necessitating a nuanced approach to counseling, surveillance, and decision-making. We aim to discuss the current data surrounding the penetrance of SDHA PVs, the spectrum of screening guidelines, recommendations for educating individuals and families about their secondary findings, and the need for future research to optimize care for these individuals. Practical recommendations for clinicians dealing with patients with secondary SDHA findings include acknowledging the limitations of existing guidelines, fostering shared decision-making, and considering specialist referrals. Overall, the evolving landscape of SDHA penetrance data warrants ongoing reassessment of surveillance approaches.
{"title":"SDHA secondary findings in germline testing: counseling and surveillance considerations","authors":"Catherine Skefos, Pamela L Brock, Erica L Blouch, Samantha Greenberg","doi":"10.1530/eo-23-0043","DOIUrl":"https://doi.org/10.1530/eo-23-0043","url":null,"abstract":"This commentary explores the complexities faced by clinicians when encountering a secondary SDHA pathogenic variant (PV) in patients without a personal or family history of SDHA-related tumors. The increasing use of germline multi-gene panel testing has led to a rise in such secondary findings, necessitating a nuanced approach to counseling, surveillance, and decision-making. We aim to discuss the current data surrounding the penetrance of SDHA PVs, the spectrum of screening guidelines, recommendations for educating individuals and families about their secondary findings, and the need for future research to optimize care for these individuals. Practical recommendations for clinicians dealing with patients with secondary SDHA findings include acknowledging the limitations of existing guidelines, fostering shared decision-making, and considering specialist referrals. Overall, the evolving landscape of SDHA penetrance data warrants ongoing reassessment of surveillance approaches.","PeriodicalId":508879,"journal":{"name":"Endocrine Oncology","volume":"306 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140781849","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}
D. Siripongsatian, Quido G de Lussanet de la Sablonière, F. A. Verburg, T. Brabander
The field of nuclear theranostic clinical trials is continuously expanding as an increasing number of novel agents and treatment combinations are explored for treating advanced and metastatic cancers. Moving from ‘bench-to-bedside’ is oftentimes a complex and lengthy process. The objective of this overview is to explore the basic elements involved in designing clinical trials with a special focus on theranostics in nuclear medicine. The 'bench-to-bedside' journey involves translating basic scientific research into patient-effective treatments. Preclinical studies, a crucial initial step, are a complex process encompassing in vitro experiments, in vivo studies, and animal models to explore hypotheses in humans. Clinical trials follow, with predefined phases assessing safety, effectiveness, and comparisons to existing treatments. This process demands investments in data management, statistics, Good Clinical Practice (GCP) accreditations, and collaborative efforts for funding and sustainable pricing. Theranostics, merging diagnostics and personalized treatment, is at the forefront. Continuous efforts to enhance existing agents involve reducing adverse effects, exploring new indications, and incorporating advanced imaging modalities. Radionuclide therapy, unique with non-uniform distribution and complex radiobiology, plays a distinct role. This article explores trends and challenges in each clinical trial phase in light of the emerging field of theranostics in nuclear medicine, emphasizing meticulous trial design, dosimetry optimization, and the necessity of collaborative stakeholder efforts for successful implementation.
{"title":"How to design a theranostic trial?","authors":"D. Siripongsatian, Quido G de Lussanet de la Sablonière, F. A. Verburg, T. Brabander","doi":"10.1530/eo-23-0045","DOIUrl":"https://doi.org/10.1530/eo-23-0045","url":null,"abstract":"The field of nuclear theranostic clinical trials is continuously expanding as an increasing number of novel agents and treatment combinations are explored for treating advanced and metastatic cancers. Moving from ‘bench-to-bedside’ is oftentimes a complex and lengthy process. The objective of this overview is to explore the basic elements involved in designing clinical trials with a special focus on theranostics in nuclear medicine. The 'bench-to-bedside' journey involves translating basic scientific research into patient-effective treatments. Preclinical studies, a crucial initial step, are a complex process encompassing in vitro experiments, in vivo studies, and animal models to explore hypotheses in humans. Clinical trials follow, with predefined phases assessing safety, effectiveness, and comparisons to existing treatments. This process demands investments in data management, statistics, Good Clinical Practice (GCP) accreditations, and collaborative efforts for funding and sustainable pricing. Theranostics, merging diagnostics and personalized treatment, is at the forefront. Continuous efforts to enhance existing agents involve reducing adverse effects, exploring new indications, and incorporating advanced imaging modalities. Radionuclide therapy, unique with non-uniform distribution and complex radiobiology, plays a distinct role. This article explores trends and challenges in each clinical trial phase in light of the emerging field of theranostics in nuclear medicine, emphasizing meticulous trial design, dosimetry optimization, and the necessity of collaborative stakeholder efforts for successful implementation.","PeriodicalId":508879,"journal":{"name":"Endocrine Oncology","volume":"266 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140767512","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}
V. Venetsanaki, Eleana Zisimopoulou, Chrysanthi Zouli, M. Boudina, Konstantinos Gkiouras, P. Xirou, Aimilia Fotiadou, M. Stamati, E. Argyropoulou, Alexandra Chrisoulidou
Background: Mönckeberg sclerosis is a form of calcification of the tunica media of small and medium size arteries. It occurs more often in the peripheral arteries of the lower limbs and it has been associated with diabetes and renal disease. Although there are a few reports of Mönckeberg sclerosis in thyroid vessels, there are no data regarding its significance in thyroid disease. Objective: To investigate the possible prognostic value of Mönckeberg sclerosis in thyroid vessels of patients with diagnosed thyroid cancer. Methods: We retrospectively studied patients with papillary thyroid cancer treated at the Theagenio Hospital of Thessaloniki from 2005 to 2021. The patients were divided in two groups based on the presence, or not, of histopathological findings of Mönckeberg sclerosis in the thyroid vessels-along with papillary thyroid cancer. Patient characteristics, histopathological details, personal history of thyroid disease and metabolic parameters were compared between the two groups. Results: Thirty-three patients with papillary thyroid carcinoma and Mönckeberg sclerosis were identified and matched to thirty-three controls with papillary thyroid cancer, without evidence of Mönckeberg sclerosis. The metabolic profile of patients with Mönckeberg sclerosis was not significantly different from those who did not have Mönckeberg sclerosis. Moreover, the comparison between the two groups did not reveal any remarkable differences in terms of the aggressiveness of the disease. Conclusions: The presence of Mönckeberg sclerosis does not seem to impact on histological characteristics of patients with papillary thyroid cancer.
{"title":"Mönckeberg sclerosis in patients with thyroid papillary carcinoma","authors":"V. Venetsanaki, Eleana Zisimopoulou, Chrysanthi Zouli, M. Boudina, Konstantinos Gkiouras, P. Xirou, Aimilia Fotiadou, M. Stamati, E. Argyropoulou, Alexandra Chrisoulidou","doi":"10.1530/eo-23-0047","DOIUrl":"https://doi.org/10.1530/eo-23-0047","url":null,"abstract":"Background: Mönckeberg sclerosis is a form of calcification of the tunica media of small and medium size arteries. It occurs more often in the peripheral arteries of the lower limbs and it has been associated with diabetes and renal disease. Although there are a few reports of Mönckeberg sclerosis in thyroid vessels, there are no data regarding its significance in thyroid disease.\u0000\u0000Objective: To investigate the possible prognostic value of Mönckeberg sclerosis in thyroid vessels of patients with diagnosed thyroid cancer.\u0000\u0000Methods: We retrospectively studied patients with papillary thyroid cancer treated at the Theagenio Hospital of Thessaloniki from 2005 to 2021. The patients were divided in two groups based on the presence, or not, of histopathological findings of Mönckeberg sclerosis in the thyroid vessels-along with papillary thyroid cancer. Patient characteristics, histopathological details, personal history of thyroid disease and metabolic parameters were compared between the two groups.\u0000\u0000Results: Thirty-three patients with papillary thyroid carcinoma and Mönckeberg sclerosis were identified and matched to thirty-three controls with papillary thyroid cancer, without evidence of Mönckeberg sclerosis. The metabolic profile of patients with Mönckeberg sclerosis was not significantly different from those who did not have Mönckeberg sclerosis. Moreover, the comparison between the two groups did not reveal any remarkable differences in terms of the aggressiveness of the disease.\u0000\u0000Conclusions: The presence of Mönckeberg sclerosis does not seem to impact on histological characteristics of patients with papillary thyroid cancer.","PeriodicalId":508879,"journal":{"name":"Endocrine Oncology","volume":"32 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140796700","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}
P. Khatiwada, Ujjwal Rimal, Zhengyang Han, L. Shemshedini
Androgen Receptor (AR) and its constitutively active splice variant AR Variant 7 (AR-V7) regulate genes essential for the development and progression of prostate cancer. Degradation of AR and AR-V7 by ubiquitination proteasomal pathway is important for the regulation of both their protein stability. Our published results demonstrated that interaction of TM4SF3 with either AR or AR-V7 leads to mutual stabilization due to reduction in their ubiquitination and proteasomal degradation. These results led us to search for a common E3 ligase for AR, AR-V7, and TM4SF3. Depletion by siRNA of several E3 ligases identified MDM2 as the common E3 ligase. MDM2 inhibition by siRNA depletion or using a pharmacological inhibitor (MDM2i) of its E3 ligase activity led to elevated levels of endogenous AR, AR-V7, and TM4SF3 in prostate cancer cells. MDM2 knockdown in PC-3 cells, which do not express AR, also increased TM4SF3, demonstrating that MDM2 affects the TM4SF3 protein independent of AR. We further demonstrate that MDM2i treatment reduced the ubiquitination of AR and TM4SF3, suggesting that MDM2 can induce the ubiquitination of these proteins. Increased AR and AR-V7 protein levels induced by MDM2i treatment resulted in the expected increased expression of AR-regulated genes and enhanced proliferation and migration of both LNCaP and Enzalutamide-resistant CWR-22Rv1 prostate cancer cells. Thus, our study expands the known roles of MDM2 in prostate cancer to include its potential involvement in the important mutual stabilization that TM4SF3 exhibits when interacting with either AR or AR-V7.
雄激素受体（AR）及其组成型活性剪接变体 AR 变体 7（AR-V7）调控前列腺癌发生和发展所必需的基因。通过泛素化蛋白酶体途径降解 AR 和 AR-V7，对调节这两种蛋白的稳定性非常重要。我们已发表的研究结果表明，TM4SF3 与 AR 或 AR-V7 的相互作用会降低它们的泛素化和蛋白酶体降解，从而导致它们的相互稳定。这些结果促使我们寻找AR、AR-V7和TM4SF3的共同E3连接酶。通过 siRNA 清除几种 E3 连接酶，我们发现 MDM2 是共同的 E3 连接酶。通过 siRNA 去除或使用药理抑制剂（MDM2i）抑制 MDM2 的 E3 连接酶活性会导致前列腺癌细胞中的内源性 AR、AR-V7 和 TM4SF3 水平升高。在不表达 AR 的 PC-3 细胞中敲除 MDM2 也会增加 TM4SF3，这表明 MDM2 对 TM4SF3 蛋白的影响与 AR 无关。我们进一步证明，MDM2i 处理可减少 AR 和 TM4SF3 的泛素化，这表明 MDM2 可诱导这些蛋白的泛素化。MDM2i处理诱导的AR和AR-V7蛋白水平的增加导致了预期的AR调控基因表达的增加，并增强了LNCaP和耐恩扎鲁胺的CWR-22Rv1前列腺癌细胞的增殖和迁移。因此，我们的研究扩展了 MDM2 在前列腺癌中的已知作用，包括它可能参与 TM4SF3 与 AR 或 AR-V7 相互作用时表现出的重要的相互稳定作用。
{"title":"MDM2 regulates the stability of AR, AR-V7, and TM4SF3 proteins in prostate cancer","authors":"P. Khatiwada, Ujjwal Rimal, Zhengyang Han, L. Shemshedini","doi":"10.1530/eo-23-0017","DOIUrl":"https://doi.org/10.1530/eo-23-0017","url":null,"abstract":"Androgen Receptor (AR) and its constitutively active splice variant AR Variant 7 (AR-V7) regulate genes essential for the development and progression of prostate cancer. Degradation of AR and AR-V7 by ubiquitination proteasomal pathway is important for the regulation of both their protein stability. Our published results demonstrated that interaction of TM4SF3 with either AR or AR-V7 leads to mutual stabilization due to reduction in their ubiquitination and proteasomal degradation. These results led us to search for a common E3 ligase for AR, AR-V7, and TM4SF3. Depletion by siRNA of several E3 ligases identified MDM2 as the common E3 ligase. MDM2 inhibition by siRNA depletion or using a pharmacological inhibitor (MDM2i) of its E3 ligase activity led to elevated levels of endogenous AR, AR-V7, and TM4SF3 in prostate cancer cells. MDM2 knockdown in PC-3 cells, which do not express AR, also increased TM4SF3, demonstrating that MDM2 affects the TM4SF3 protein independent of AR. We further demonstrate that MDM2i treatment reduced the ubiquitination of AR and TM4SF3, suggesting that MDM2 can induce the ubiquitination of these proteins. Increased AR and AR-V7 protein levels induced by MDM2i treatment resulted in the expected increased expression of AR-regulated genes and enhanced proliferation and migration of both LNCaP and Enzalutamide-resistant CWR-22Rv1 prostate cancer cells. Thus, our study expands the known roles of MDM2 in prostate cancer to include its potential involvement in the important mutual stabilization that TM4SF3 exhibits when interacting with either AR or AR-V7.","PeriodicalId":508879,"journal":{"name":"Endocrine Oncology","volume":"88 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139635281","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}
Mark Stein, Victor Kalff, Scott Williams, Declan G. Murphy, Peter G Colman, M. Hofman
OBJECTIVES: The glucagon-like peptide 1 (GLP-1) receptor agonist, Liraglutide, reduces human prostate cancer incidence and similar GLP-1 receptor agonists reduce in vitro proliferation and in vivo growth of prostate cancer cell lines. Primary human prostate cancer expresses the GLP-1 receptor (GLP-1R) in vitro. Cancer evolves with stage and whether advanced stage human prostate cancer expresses GLP-1R is unknown. We hypothesised and aimed to prove, that human metastatic castrate resistant prostate cancer (mCRPC) expresses the GLP-1R in vivo. We hypothesised mCRPC would thus be detectable by positron emission tomography/computed tomography (PET/CT) using radiotracer bound to a GLP-1R ligand, as in Exendin PET/CT. DESIGN AND METHODS: Men with mCRPC, with more than one prostate specific membrane antigen (PSMA)-avid lesion on PET/CT scanning (pathognomic in that setting for prostate cancer lesions), were approached to undergo PET/CT with Gallium68-Dota-Exendin-4. We documented PET/CT PSMA-avid lesions which were also PET/CT Exendin-avid as evidence of in vivo GLP-1R expression. RESULTS: Of 24 men referred, three did not meet inclusion criteria. Seventeen declined, largely because the study offered them no therapeutic benefit. Of four men imaged, three had no Exendin-avid lesions, one had six osseous PSMA-avid lesions, three of which were also Exendin-avid. CONCLUSIONS: We demonstrated in vivo GLP-1R expression by human mCPRC, detecting PET/CT lesions avid for both PSMA and Exendin, in one of four participants. GLP-1R expression may thus occur even in advanced stage prostate cancer. Our data contribute to growing evidence supporting the testing of GLP-1 receptor agonists for therapeutic benefit in prostate cancer.
{"title":"The GLP-1 receptor is expressed in vivo by human metastatic prostate cancer","authors":"Mark Stein, Victor Kalff, Scott Williams, Declan G. Murphy, Peter G Colman, M. Hofman","doi":"10.1530/eo-23-0015","DOIUrl":"https://doi.org/10.1530/eo-23-0015","url":null,"abstract":"OBJECTIVES: The glucagon-like peptide 1 (GLP-1) receptor agonist, Liraglutide, reduces human prostate cancer incidence and similar GLP-1 receptor agonists reduce in vitro proliferation and in vivo growth of prostate cancer cell lines. Primary human prostate cancer expresses the GLP-1 receptor (GLP-1R) in vitro. Cancer evolves with stage and whether advanced stage human prostate cancer expresses GLP-1R is unknown. We hypothesised and aimed to prove, that human metastatic castrate resistant prostate cancer (mCRPC) expresses the GLP-1R in vivo. We hypothesised mCRPC would thus be detectable by positron emission tomography/computed tomography (PET/CT) using radiotracer bound to a GLP-1R ligand, as in Exendin PET/CT. DESIGN AND METHODS: Men with mCRPC, with more than one prostate specific membrane antigen (PSMA)-avid lesion on PET/CT scanning (pathognomic in that setting for prostate cancer lesions), were approached to undergo PET/CT with Gallium68-Dota-Exendin-4. We documented PET/CT PSMA-avid lesions which were also PET/CT Exendin-avid as evidence of in vivo GLP-1R expression. RESULTS: Of 24 men referred, three did not meet inclusion criteria. Seventeen declined, largely because the study offered them no therapeutic benefit. Of four men imaged, three had no Exendin-avid lesions, one had six osseous PSMA-avid lesions, three of which were also Exendin-avid. CONCLUSIONS: We demonstrated in vivo GLP-1R expression by human mCPRC, detecting PET/CT lesions avid for both PSMA and Exendin, in one of four participants. GLP-1R expression may thus occur even in advanced stage prostate cancer. Our data contribute to growing evidence supporting the testing of GLP-1 receptor agonists for therapeutic benefit in prostate cancer.","PeriodicalId":508879,"journal":{"name":"Endocrine Oncology","volume":"12 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139196446","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}
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