Somatostatin receptor 1(SSTR1)is a crucial therapeutic target for various neuroendocrine and oncological disorders.Current SSTR1-targeted treatments,including the first-generation somatostatin analog lanreotide(Lan)an...Somatostatin receptor 1(SSTR1)is a crucial therapeutic target for various neuroendocrine and oncological disorders.Current SSTR1-targeted treatments,including the first-generation somatostatin analog lanreotide(Lan)and the second-generation analog pasireotide(Pas),show promise but encounter challenges related to selectivity and efficacy.This study presents high-resolution cryo-electron microscopy structures of SSTR1 complexed with Lan or Pas,revealing the distinct mechanisms of ligand-binding and activation.These structures illustrate unique conformational changes in the SSTR1 orthosteric pocket induced by each ligand,which are critical for receptor activation and ligand selectivity.Combined with the biochemical assays and molecular dynamics simulations,our results provide a comparative analysis of binding characteristics within the SSTR family,highlighting subtle differences in SSTR1 activation by Lan and Pas.These insights pave the way for designing next-generation therapies with enhanced efficacy and reduced side effects through improved receptor subtype selectivity.展开更多
Gastric carcinoids(GCs) are classified as: type Ⅰ,related to hypergastrinemia due to chronic atrophic gastritis(CAG), type Ⅱ, associated with Zollinger-Ellison syndrome in multiple endocrine neoplasia type 1, and ty...Gastric carcinoids(GCs) are classified as: type Ⅰ,related to hypergastrinemia due to chronic atrophic gastritis(CAG), type Ⅱ, associated with Zollinger-Ellison syndrome in multiple endocrine neoplasia type 1, and type Ⅲ, which is normogastrinemic. The management of type-Ⅰ gastric carcinoids(GC1s) is still debated,because of their relatively benign course. According to the European Neuroendocrine Tumor Society guidelines endoscopic resection is indicated whenever possible;however, it is not often feasible because of the presence of a multifocal disease, large lesions, submucosal invasion or, rarely, lymph node involvement. Therefore,somatostatin analogs(SSAs) have been proposed as treatment for GC1 s in view of their antisecretive,antiproliferative and antiangiogenic effects. However,in view of the high cost of this therapy, its possible side effects and the relatively benign course of the disease,SSAs should be reserved to specific subsets of "high risk patients", i.e., those patients with multifocal or recurrent GCs. Indeed, it is reasonable that, after the development of a gastric neuroendocrine neoplasm in patients with a chronic predisposing condition(such as CAG), other enterochromaffin-like cells can undergo neoplastic proliferation, being chronically stimulated by hypergastrinemia. Therefore, definite indications to SSAs treatment should be established in order to avoid the undertreatment or overtreatment of GCs.展开更多
BACKGROUND Primary testicular neuroendocrine tumors(TNETs)are sporadic,accounting for only 0.23%of all testicular tumors.Few cases have been reported in the literature,and no uniform treatment protocol exists.We repor...BACKGROUND Primary testicular neuroendocrine tumors(TNETs)are sporadic,accounting for only 0.23%of all testicular tumors.Few cases have been reported in the literature,and no uniform treatment protocol exists.We report a case of a primary TNET with liver lymph node metastasis diagnosed at the age of 24 years and discuss its clinicopathological features,diagnosis,differential diagnosis,treatment,and prognosis.CASE SUMMARY We report the case of a 24-year-old patient with a primary TNET with liver lymph node metastasis.The patient was found to have a right testicular swelling of about 3 cm×4 cm in size with unclear borders and no testicular pressure pain seven years ago without any examination or treatment.One month ago,an ultrasound examination was performed for persistent enlargement of the right testis,which showed an occupying lesion of the right testis approximately 110 mm×102 mm×82 mm in size.Magnetic resonance imaging scan of the testis(plain scan)showed that the right testis was an occupying lesion with inhomogeneous density and mixed signal,the boundary was still clear,and the possibility of seminoma was considered;chest X-ray and computed tomography did not show any apparent abnormalities.The patient underwent radical orchiectomy,and the pathological examination suggested a right TNET with a typical carcinoid tumor histological type.One month after the surgery,the patient received nine cycles of lanreotide chemotherapy at a dose of 90 mg/mo without adverse effects.No distant lymph node or other organ metastases were detected at follow-up.He is in good physical condition and attends regular follow-up visits.CONCLUSION Neuroendocrine tumors are rare in clinical practice,and the diagnosis mainly relies on the characteristics of microscopic tumor cells and immunohistochemical features.Treatment involves radical orchiectomy.If it is accompanied by distant lymph node metastasis and the metastatic lesion can be resected,it should be surgically removed;if it cannot be resected,growth inhibitor analog octreotide or lanreotide chemotherapy can be administered to obtain good results,with close postoperative follow-up to prevent recurrence and metastasis.展开更多
Background: Somatostatin analogues have shown to be effective in controlling the levels of growth hormone and are recommended for the treatment of acromegaly. These treatments have high costs of acquisition and their ...Background: Somatostatin analogues have shown to be effective in controlling the levels of growth hormone and are recommended for the treatment of acromegaly. These treatments have high costs of acquisition and their use might be restricted in limited resource settings. Objective: To evaluate the cost-effectiveness of somatostatin analogues for acromegaly in Colombia. Setting/Subjects/Intervention: A decision model was developed using a hypothetical cohort of patients with Acromegaly. Patients were treated according to the clinical practice of the country. Response to treatment and transition probabilities were derived from published literature. Costs and resource utilization were extracted from public and private sources in Colombia. Main Outcome Measure(s): Cost-effectiveness ratio, measured in Colombian pesos in a 2 year time-horizon. Results: The total medical treatment costs for the octreotide group were (Colombian Pesos) COP$ 53,807,616, compared to the total costs for the lanreotide group of COP$ 83,126,567. In the octreotide arm 65.30% of the patients and in the lanreotide arm 59.50% of the patients were successfully controlled. The number of deaths was 295 (13.1%) and 302 (13.4%) for octreotide and lanreotide, respectively. Because the costs are lower and the effectiveness is higher for octreotide in comparison with lanreotide, octreotide is more cost-effective than lanreotide. Probabilistic sensitivity analyses were consistent showing octreotide as the most cost-effective option. Conclusions: Costs and effects of octreotide compare favorably to those of lanreotide in the treatment of acromegaly in Colombia. Sensitivity analysis showed that despite the uncertainty in cost-effectiveness ratio this result is robust.展开更多
基金supported by funds from the Ganghong Young Scholar Development Fund(China)and the Shenzhen-Hong Kong Cooperation Zone for Technology and Innovation(No.HZQB-KCZYB-2020056,China)Thiansze Wong is supported by research fundings from Shenzhen Pengcheng Peacock Plan(Nos.2021TC0059 and 2024TC0153,China)+7 种基金Yang Du is supported by grants from the National Natural Science Foundation of China(No.32271263)Shenzhen Sci.&Tech Innovation Bureau(Nos.JCYJ 20220818103009018 and JCYJ 20240813113521028,China)and the Shenzhen-Hong Kong Cooperation Zone for Technology and Innovation(No.HZQB-KCZYB-2020056,China)Richard Ye is supported by Shenzhen Medical Research Fund(No.SMRFD2403009,China)Joint Research Fund of the Second Affiliated Hospital-School of Medicine,the Chinese University of Hong Kong,Shenzhen(No.YXLH13,China)Ganghong Young Scholar Development Fund(No.2019E0020)and Fund from Shenzhen-Hong Kong Cooperation Zone for Technology and Innovation(No.HZQB-KCZYB-2020056,China)Jing Chen is supported by the National Natural Science Foundation of China(No.31271243)。
文摘Somatostatin receptor 1(SSTR1)is a crucial therapeutic target for various neuroendocrine and oncological disorders.Current SSTR1-targeted treatments,including the first-generation somatostatin analog lanreotide(Lan)and the second-generation analog pasireotide(Pas),show promise but encounter challenges related to selectivity and efficacy.This study presents high-resolution cryo-electron microscopy structures of SSTR1 complexed with Lan or Pas,revealing the distinct mechanisms of ligand-binding and activation.These structures illustrate unique conformational changes in the SSTR1 orthosteric pocket induced by each ligand,which are critical for receptor activation and ligand selectivity.Combined with the biochemical assays and molecular dynamics simulations,our results provide a comparative analysis of binding characteristics within the SSTR family,highlighting subtle differences in SSTR1 activation by Lan and Pas.These insights pave the way for designing next-generation therapies with enhanced efficacy and reduced side effects through improved receptor subtype selectivity.
文摘Gastric carcinoids(GCs) are classified as: type Ⅰ,related to hypergastrinemia due to chronic atrophic gastritis(CAG), type Ⅱ, associated with Zollinger-Ellison syndrome in multiple endocrine neoplasia type 1, and type Ⅲ, which is normogastrinemic. The management of type-Ⅰ gastric carcinoids(GC1s) is still debated,because of their relatively benign course. According to the European Neuroendocrine Tumor Society guidelines endoscopic resection is indicated whenever possible;however, it is not often feasible because of the presence of a multifocal disease, large lesions, submucosal invasion or, rarely, lymph node involvement. Therefore,somatostatin analogs(SSAs) have been proposed as treatment for GC1 s in view of their antisecretive,antiproliferative and antiangiogenic effects. However,in view of the high cost of this therapy, its possible side effects and the relatively benign course of the disease,SSAs should be reserved to specific subsets of "high risk patients", i.e., those patients with multifocal or recurrent GCs. Indeed, it is reasonable that, after the development of a gastric neuroendocrine neoplasm in patients with a chronic predisposing condition(such as CAG), other enterochromaffin-like cells can undergo neoplastic proliferation, being chronically stimulated by hypergastrinemia. Therefore, definite indications to SSAs treatment should be established in order to avoid the undertreatment or overtreatment of GCs.
基金Supported by Support Plan of Jiangxi Provincial Department of Science and Technology,China,No.20133BBG70062.
文摘BACKGROUND Primary testicular neuroendocrine tumors(TNETs)are sporadic,accounting for only 0.23%of all testicular tumors.Few cases have been reported in the literature,and no uniform treatment protocol exists.We report a case of a primary TNET with liver lymph node metastasis diagnosed at the age of 24 years and discuss its clinicopathological features,diagnosis,differential diagnosis,treatment,and prognosis.CASE SUMMARY We report the case of a 24-year-old patient with a primary TNET with liver lymph node metastasis.The patient was found to have a right testicular swelling of about 3 cm×4 cm in size with unclear borders and no testicular pressure pain seven years ago without any examination or treatment.One month ago,an ultrasound examination was performed for persistent enlargement of the right testis,which showed an occupying lesion of the right testis approximately 110 mm×102 mm×82 mm in size.Magnetic resonance imaging scan of the testis(plain scan)showed that the right testis was an occupying lesion with inhomogeneous density and mixed signal,the boundary was still clear,and the possibility of seminoma was considered;chest X-ray and computed tomography did not show any apparent abnormalities.The patient underwent radical orchiectomy,and the pathological examination suggested a right TNET with a typical carcinoid tumor histological type.One month after the surgery,the patient received nine cycles of lanreotide chemotherapy at a dose of 90 mg/mo without adverse effects.No distant lymph node or other organ metastases were detected at follow-up.He is in good physical condition and attends regular follow-up visits.CONCLUSION Neuroendocrine tumors are rare in clinical practice,and the diagnosis mainly relies on the characteristics of microscopic tumor cells and immunohistochemical features.Treatment involves radical orchiectomy.If it is accompanied by distant lymph node metastasis and the metastatic lesion can be resected,it should be surgically removed;if it cannot be resected,growth inhibitor analog octreotide or lanreotide chemotherapy can be administered to obtain good results,with close postoperative follow-up to prevent recurrence and metastasis.
文摘Background: Somatostatin analogues have shown to be effective in controlling the levels of growth hormone and are recommended for the treatment of acromegaly. These treatments have high costs of acquisition and their use might be restricted in limited resource settings. Objective: To evaluate the cost-effectiveness of somatostatin analogues for acromegaly in Colombia. Setting/Subjects/Intervention: A decision model was developed using a hypothetical cohort of patients with Acromegaly. Patients were treated according to the clinical practice of the country. Response to treatment and transition probabilities were derived from published literature. Costs and resource utilization were extracted from public and private sources in Colombia. Main Outcome Measure(s): Cost-effectiveness ratio, measured in Colombian pesos in a 2 year time-horizon. Results: The total medical treatment costs for the octreotide group were (Colombian Pesos) COP$ 53,807,616, compared to the total costs for the lanreotide group of COP$ 83,126,567. In the octreotide arm 65.30% of the patients and in the lanreotide arm 59.50% of the patients were successfully controlled. The number of deaths was 295 (13.1%) and 302 (13.4%) for octreotide and lanreotide, respectively. Because the costs are lower and the effectiveness is higher for octreotide in comparison with lanreotide, octreotide is more cost-effective than lanreotide. Probabilistic sensitivity analyses were consistent showing octreotide as the most cost-effective option. Conclusions: Costs and effects of octreotide compare favorably to those of lanreotide in the treatment of acromegaly in Colombia. Sensitivity analysis showed that despite the uncertainty in cost-effectiveness ratio this result is robust.
