Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Ryuichi Sakamoto Last modified date:2022.06.14

Lecturer / Department of Endocrine and Metabolic Diseases / Diabetes Mellitus / Kyushu University Hospital


Papers
1. A case of mediastinal pancreatic pseudocysts conservatively treated with somatostatin analogue.
2. Yasuaki Koga, Kenji Ohe, Shigeki Gondo, Tetsuhiro Watanabe, Ryuichi Sakamoto, Masatoshi Nomura, Taijiro Okabe, Nobuyuki Kawazoe, Kiminobu Sasano, Toshihiko Yanase, MEN type I presenting hypokalemia and hypertension, complicated with acromegaly, adrenal cortical tumor and rectal carcinoid tumor, Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, 10.2169/naika.95.2298, 95, 11, 2298-2301, 2006.01.
3. MEN type I presenting hypokalemia and hypertension, complicated with acromegaly, adrenal cortical tumor and rectal carcinoid tumor.
4. Ichiro Abe, Masatoshi Nomura, Ryuichi Sakamoto, Tetsuhiro Watanabe, Sigeki Gondo, Kenji Ohe, Taijiro Okabe, Toshihiko Yanase, Ryoiti Takayanagi, Two cases of pheochromocytoma associated with single ventricle syndrome, Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, 10.2169/naika.96.994, 96, 5, 994-996, 2007.01.
5. Masatoshi Nomura, Hironobu Sasano, Yasuyo Okada, Tetsuhiro Watanabe, Shohei Sakamoto, Yumiko Sakiyama, Ryuichi Sakamoto, Ichiro Abe, Toshihiro Horiuchi, Toshihiko Yanase, Ryoichi Takayanagi, Adrenal failure caused by a retroperitoneal malignant mesothelioma, Internal Medicine, 10.2169/internalmedicine.48.2438, 48, 24, 2109-2114, 2009.12, A 62-year-old man presented with clinical signs of acute abdominal pain and adrenal insufficiency. Computerized tomographic scans revealed bilateral adrenal tumors and the left adrenal tumor was surgically resected. The patient was found to have retroperitoneal mesothelioma presenting as bilateral metastatic adrenal tumors, which were well controlled by systemic chemotherapy with CDDP and 5-FU. This case appears to be the first reported case in the literature of adrenal failure due to bilateral adrenal infiltration caused by retroperitoneal malignant mesothelioma..
6. Guangchun Chen, Yutaka Goto, Ryuichi Sakamoto, Kimitaka Tanaka, Eri Matsubara, Masafumi Nakamura, Hong Zheng, Jian Lu, Ryoichi Takayanagi, Masatoshi Nomura, GLI1, a crucial mediator of sonic hedgehog signaling in prostate cancer, functions as a negative modulator for androgen receptor, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2010.12.065, 404, 3, 809-815, 2011.01, Sonic hedgehog (SHH) signaling, acting in a combinatorial manner with androgen signaling, is essential for prostate patterning and development. Recently, elevated activation of SHH signaling has been shown to play important roles in proliferation, progression and metastasis of prostate cancer. In this report, we demonstrate for the first time, that GLI1, which has been shown to play a central role in SHH signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor (AR)-mediated transactivation, at least in part, by directly interacting with AR. Our observations suggest that the SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from an. androgen-dependent to an androgen-independent state by compensating, or even superseding androgen signaling..
7. Hisaya Kawate, Akinobu Taketomi, Tetsuhiro Watanabe, Masatoshi Nomura, Masaki Kato, Ryuichi Sakamoto, Toru Ikegami, Yuji Soejima, Yoshihiko Maehara, Ryoichi Takayanagi, Hypophosphatemic osteomalacia as a long-term complication after liver transplantation, Transplantation, 10.1097/TP.0b013e3181fc4b55, 91, 1, 2011.01.
8. Guangchun Chen, Yutaka Goto, Ryuichi Sakamoto, Kimitaka Tanaka, Eri Matsubara, Masafumi Nakamura, Hong Zheng, Jian Lu, Ryoichi Takayanagi, Masatoshi Nomura, GLI1, a crucial mediator of sonic hedgehog signaling in prostate cancer, functions as a negative modulator for androgen receptor., Biochemical and biophysical research communications, 10.1016/j.bbrc.2010.12.065, 404, 3, 809-15, 2011.01, Sonic hedgehog (SHH) signaling, acting in a combinatorial manner with androgen signaling, is essential for prostate patterning and development. Recently, elevated activation of SHH signaling has been shown to play important roles in proliferation, progression and metastasis of prostate cancer. In this report, we demonstrate for the first time, that GLI1, which has been shown to play a central role in SHH signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor (AR)-mediated transactivation, at least in part, by directly interacting with AR. Our observations suggest that the SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from anandrogen-dependent to an androgen-independent state by compensating, or even superseding androgen signaling..
9. Lixiang Wang, Masatoshi Nomura, Yutaka Goto, Kimitaka Tanaka, Ryuichi Sakamoto, Ichiro Abe, Shohei Sakamoto, Atsushi Shibata, Patricio L.M. Enciso, Masahiro Adachi, Ohnaka Keizo, Hisaya Kawate, Ryoichi Takayanagi, Smad2 protein disruption in the central nervous system leads to aberrant cerebellar development and early postnatal ataxia in mice, Journal of Biological Chemistry, 10.1074/jbc.M111.223271, 286, 21, 18766-18774, 2011.05, Smad2 is a critical mediator of TGF-β signals that are known to play an important role in a wide range of biological processes in various cell types. Its role in the development of the CNS, however, is largely unknown. Mice lacking Smad2 in the CNS (Smad2-CNS-KO) were generated by a Cre-loxP approach. These mice exhibited behavioral abnormalities in motor coordination from an early postnatal stage and mortality at approximately 3 weeks of age, suggestive of severe cerebellar dysfunction. Gross observation of Smad2-CNS-KO cerebella demonstrated aberrant foliations in lobule IX and X. Further analyses revealed increased apoptotic cell death, delayed migration and maturation of granule cells, and retardation of dendritic arborization of Purkinje cells. These findings indicate that Smad2 plays a key role in cerebellar development and motor function control..
10. Lixiang Wang, Masatoshi Nomura, Yutaka Goto, Kimitaka Tanaka, Ryuichi Sakamoto, Ichiro Abe, Shohei Sakamoto, Atsushi Shibata, Patricio L. M. Enciso, Masahiro Adachi, Keizo Ohnaka, Hisaya Kawate, Ryoichi Takayanagi, Smad2 Protein Disruption in the Central Nervous System Leads to Aberrant Cerebellar Development and Early Postnatal Ataxia in Mice, JOURNAL OF BIOLOGICAL CHEMISTRY, 10.1074/jbc.M111.223271, 286, 21, 18766-18774, 2011.05, Smad2 is a critical mediator of TGF-beta signals that are known to play an important role in a wide range of biological processes in various cell types. Its role in the development of the CNS, however, is largely unknown. Mice lacking Smad2 in the CNS (Smad2-CNS-KO) were generated by a Cre-loxP approach. These mice exhibited behavioral abnormalities in motor coordination from an early postnatal stage and mortality at approximately 3 weeks of age, suggestive of severe cerebellar dysfunction. Gross observation of Smad2-CNS-KO cerebella demonstrated aberrant foliations in lobule IX and X. Further analyses revealed increased apoptotic cell death, delayed migration and maturation of granule cells, and retardation of dendritic arborization of Purkinje cells. These findings indicate that Smad2 plays a key role in cerebellar development and motor function control..
11. yayoi matsuda, Hisaya Kawate, Chitose Matsuzaki, Ryuichi Sakamoto, Ichiro Abe, Kimitaka Shibue, Michiko Kohno, Masahiro Adachi, Ohnaka Keizo, Masatoshi Nomura, Ryoichi Takayanagi, Reduced arterial stiffness in patients with acromegaly
Noninvasive assessment by the cardio-ankle vascular index (CAVI), Endocrine Journal, 10.1507/endocrj.EJ12-0189, 60, 1, 29-36, 2013.02, In patients with acromegaly, cardiovascular diseases are the most common cause of death. Arterial stiffness is increasingly recognized as a valuable surrogate marker for predicting cardiovascular events. To evaluate the vascular status of acromegalic patients, we used the cardio-ankle vascular index (CAVI) to reflect the arterial stiffness from the heart to the ankles. We analyzed 21 acromegalic patients, comprising five patients with untreated active acromegaly, one patient treated with medication and 15 patients who underwent transsphenoidal surgery. Among the 15 patients with surgery, 10 received additional therapies with dopamine agonists and/or somatostatin analogs. All patients with acromegaly unexpectedly showed significant reductions in the CAVI, indicating reduced arterial stiffness, compared with age- and sex-matchedcontrols, regardless of whether they underwent surgery. There was a significant negative correlation between the CAVI and the serum insulin-like growth factor (IGF)-I level in these patients. Active acromegalic patients were associated with lower CAVI than controlled patients. Sequential measurements of the CAVI and serum IGF-I before and after treatment with octreotide and transsphenoidal surgery revealed that a reduced IGF-I level after treatment was accompanied by CAVI elevation. The present findings indicate that the CAVI is negatively correlated with the serum IGF-I level in acromegaly. These findings are consistent with previous reports indicating that the GH/IGF-I axis reduces peripheral vascular resistance. This non-invasive assessment can reflect the present vascular status and would be a useful marker for evaluation of therapeutic effects in patients with acromegaly..
12. Masatoshi Nomura, Ryuichi Sakamoto, Hidetaka Morinaga, Lixiang Wang, Chizu Mukasa, Ryoichi Takayanagi, Activin stimulates CYP19A gene expression in human ovarian granulosa cell-like KGN cells via the Smad2 signaling pathway, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2013.05.124, 436, 3, 443-448, 2013.07, Activin, a transforming growth factor β family member, has a wide range of physiological roles during embryonic development and organogenesis. In the ovary, activin, secreted from ovarian granulosa cells, not only acts on the pituitary gland to regulate the gonadotropin secretion from the pituitary gland in an endocrine manner but also acts on granulosa cells in a paracrine/autocrine manner to regulate folliculogenesis. Previously, we showed that activin signals through activin type IB receptor (ActRIB) and up-regulates follicle-stimulating hormone receptor expression and P450 aromatase activity in human ovarian granulose cell-like KGN cells. In the current study, we demonstrate the direct involvement of Smad2 as a downstream signal mediator of ActRIB in the transcriptional regulation of the P450 aromatase gene (CYP19A) in KGN cells. Upon activin stimulation, Smad2 activation and an increase in P450 aromatase messenger RNA (mRNA) were observed in KGN cells. Interestingly, Smad2 phosphorylation correlated well with the increase in P450 aromatase mRNA. Reciprocally, knockdown of Smad2 mRNA in KGN cells led to a decrease in the P450 aromatase mRNA expression, suggesting that Smad2 regulates CYP19A gene expression. Further analysis of CYP19A promoter activity revealed that the 5' upstream region between -2069 and -1271. bp is required for the activation by Smad2. Finally, we provide compelling evidence that Smad2 shows follicular stage-specific expression, which is high in granulosa cells of preantral or early antral follicles in mice. Our results suggest that activin signaling through the ActRIB-Smad2 pathway plays a pivotal role in CYP19A expression and thus in follicular development..
13. Masatoshi Nomura, Ryuichi Sakamoto, Hidetaka Morinaga, Lixiang Wang, Chizu Mukasa, Ryoichi Takayanagi, Activin stimulates CYP19A gene expression in human ovarian granulosa cell-like KGN cells via the Smad2 signaling pathway., Biochemical and biophysical research communications, 10.1016/j.bbrc.2013.05.124, 436, 3, 443-8, 2013.07, Activin, a transforming growth factor β family member, has a wide range of physiological roles during embryonic development and organogenesis. In the ovary, activin, secreted from ovarian granulosa cells, not only acts on the pituitary gland to regulate the gonadotropin secretion from the pituitary gland in an endocrine manner but also acts on granulosa cells in a paracrine/autocrine manner to regulate folliculogenesis. Previously, we showed that activin signals through activin type IB receptor (ActRIB) and up-regulates follicle-stimulating hormone receptor expression and P450 aromatase activity in human ovarian granulose cell-like KGN cells. In the current study, we demonstrate the direct involvement of Smad2 as a downstream signal mediator of ActRIB in the transcriptional regulation of the P450 aromatase gene (CYP19A) in KGN cells. Upon activin stimulation, Smad2 activation and an increase in P450 aromatase messenger RNA (mRNA) were observed in KGN cells. Interestingly, Smad2 phosphorylation correlated well with the increase in P450 aromatase mRNA. Reciprocally, knockdown of Smad2 mRNA in KGN cells led to a decrease in the P450 aromatase mRNA expression, suggesting that Smad2 regulates CYP19A gene expression. Further analysis of CYP19A promoter activity revealed that the 5' upstream region between -2069 and -1271bp is required for the activation by Smad2. Finally, we provide compelling evidence that Smad2 shows follicular stage-specific expression, which is high in granulosa cells of preantral or early antral follicles in mice. Our results suggest that activin signaling through the ActRIB-Smad2 pathway plays a pivotal role in CYP19A expression and thus in follicular development..
14. Ryuichi Sakamoto, Eri Matsubara, Masatoshi Nomura, Lixiang Wang, Yuta Kawahara, Toshihiko Yanase, Hajime Nawata, Ryoichi Takayanagi, Roles for corticotropin-releasing factor receptor type 1 in energy homeostasis in mice, Metabolism: Clinical and Experimental, 10.1016/j.metabol.2013.08.005, 62, 12, 1739-1748, 2013.12, Objective Expression of corticotropin-releasing factor type 1 receptor (CRFR1) has been shown on pancreatic β cells, and its activation potentiates glucose-stimulated insulin secretion (GSIS). However, the roles of CRFR1 in energy metabolism beyond insulin release remain elusive. Materials/Methods We characterized the metabolic phenotypes of mice lacking CRFR1 (CRFR1KO mice) under conditions of energy excess. Results When fed a normal diet, the glucose profile of CRFR1KO mice in response to a glucose tolerance test was similar to that of wild-type (WT) mice, while serum insulin levels were significantly lower in CRFR1KO mice, reflecting high insulin sensitivity in part due to very low glucocorticoid levels. Histology of the pancreas revealed islet hypoplasia in CRFR1KO mice, suggesting a role of CRFR1 in maintaining the β cell mass in a manner similar to incretins. In response to a high-fat diet, CRFR1KO mice showed insulin resistance, but serum insulin levels during glucose challenge remained at a low level, indicating defective GSIS. In addition, CRFR1KO mice showed resistance to diet-induced obesity and hepatic steatosis. Although total food intake was not different between CRFR1KO and WT mice, oxygen consumption was significantly increased in CRFR1KO mice. The increased energy expenditure may explain the lean phenotype of CRFR1KO mice under conditions of energy excess. Conclusions Our results suggest that CRFR1 plays important roles in whole body energy homeostasis, providing compelling evidence of the close relationship between energy homeostasis and the function of the hypothalamic-pituitary-adrenal axis..
15. Ryuichi Sakamoto, Eri Matsubara, Masatoshi Nomura, Lixiang Wang, Yuta Kawahara, Toshihiko Yanase, Hajime Nawata, Ryoichi Takayanagi, Roles for corticotropin-releasing factor receptor type 1 in energy homeostasis in mice., Metabolism: clinical and experimental, 10.1016/j.metabol.2013.08.005, 62, 12, 1739-48, 2013.12, OBJECTIVE: Expression of corticotropin-releasing factor type 1 receptor (CRFR1) has been shown on pancreatic β cells, and its activation potentiates glucose-stimulated insulin secretion (GSIS). However, the roles of CRFR1 in energy metabolism beyond insulin release remain elusive. MATERIALS/METHODS: We characterized the metabolic phenotypes of mice lacking CRFR1 (CRFR1KO mice) under conditions of energy excess. RESULTS: When fed a normal diet, the glucose profile of CRFR1KO mice in response to a glucose tolerance test was similar to that of wild-type (WT) mice, while serum insulin levels were significantly lower in CRFR1KO mice, reflecting high insulin sensitivity in part due to very low glucocorticoid levels. Histology of the pancreas revealed islet hypoplasia in CRFR1KO mice, suggesting a role of CRFR1 in maintaining the β cell mass in a manner similar to incretins. In response to a high-fat diet, CRFR1KO mice showed insulin resistance, but serum insulin levels during glucose challenge remained at a low level, indicating defective GSIS. In addition, CRFR1KO mice showed resistance to diet-induced obesity and hepatic steatosis. Although total food intake was not different between CRFR1KO and WT mice, oxygen consumption was significantly increased in CRFR1KO mice. The increased energy expenditure may explain the lean phenotype of CRFR1KO mice under conditions of energy excess. CONCLUSIONS: Our results suggest that CRFR1 plays important roles in whole body energy homeostasis, providing compelling evidence of the close relationship between energy homeostasis and the function of the hypothalamic-pituitary-adrenal axis..
16. Atsushi Ogo, Yuka Sakaki, Ryoko Saito, Ryuichi Sakamoto, Yuka Matoba, A pilot study to examine the management of asymptomatic hyperparathyroidism in Japanese patients in accordance with the guidelines for asymptomatic PHPT proposed at the Third International Workshop in 2008, Internal Medicine, 10.2169/internalmedicine.53.2133, 53, 16, 1749-1754, 2014.01, Objective The treatment for asymptomatic primary hyperparathyroidism (PHPT) remains controversial. In 2008, the Third International Workshop on the Management of Asymptomatic PHPT proposed a set of guidelines for the management of asymptomatic PHPT. We therefore evaluated the application of the Workshop recommendations in Japanese patients with asymptomatic PHPT.
Methods We analyzed each parameter of the guidelines in 87 Japanese patients with asymptomatic PHPT who underwent methoxy-isobutyl-isonitrile (MIBI) scintigraphy.
Results Fewer than 10% of the patients were less than 50 years of age. The bone mineral density T-score was below -2.5 SD in 20 women (46.5% of all women analyzed) and in none of the men. The eGFR was <60 mL/min/1.73 m2 in 17 patients. A majority of patients (43) satisfied only one parameter, while 25 patients satisfied none of the parameters. Furthermore, the MIBI-positive and surgically treated patients tended to satisfy a larger number of the parameters. The Workshop criteria and levels of PTH, daily Ca excretion, serum ALP and 1,25(OH)2 Vitamin D were further analyzed in relation to the findings of MIBI scans, and almost all of the parameters were found to be significantly correlated with the results of the MIBI studies.
Conclusion Our results suggest the need to reassess the Workshop guidelines for the treatment of hyperparathyroidism in Japanese patients. It is desirable that MIBI scintigraphy be performed whenever possible, as this modality is anticipated to play an important role in determining whether or not surgery is appropriate..
17. Atsushi Ogo, Nao Hasuzawa, Yuka Sakaki, Ryuichi Sakamoto, Yuka Matoba, Pneumatosis cystoides intestinalis related to α-glucosidase inhibitor treatment in a polymyalgia rheumatica patient with diabetes mellitus, Diabetology International, 10.1007/s13340-014-0158-y, 5, 4, 244-248, 2014.01, The patient presented in this case was an 83-year-old female who was referred to our department for a detailed examination and treatment of a diabetic foot. She had history of treatment with continuous oral steroid therapy (8 mg/day) for polymyalgia rheumatica (PMR), insulin therapy (NovoRapid 30 Mix: 8 units in the morning and 2 units in the evening), and oral treatment with acarbose (100 mg, 3T) for diabetes. Although she did not complain of abdominal fullness or pain, a routine abdominal X-ray revealed free air below the diaphragm and noticeable gaseous distention in the ascending and transverse colon. Abdominal CT demonstrated dilatation, mesenteric edema, and diffuse pneumatosis intestinalis throughout the ascending and transverse colon. A diagnosis of pneumatosis cystoides intestinalis (PCI) was made based on these findings. As the α-glucosidase inhibitor (α-GI) was suspected to be the cause of the PCI, we administered conservative treatment, discontinuing acarbose with fasting and fluid supplementation. The patient progressed well, and 3 weeks later, an abdominal X-ray and CT scan confirmed the disappearance of the pneumocystis lesions in the colon. With the recent rise in the number of elderly individuals and increased awareness of PMR, the number of reported patients with PMR receiving steroid therapy in Japan has increased. Therefore, the incidence of PMR among elderly patients with diabetes mellitus receiving α-GI and steroid therapy is anticipated to increase in the future. Hence, PCI should be carefully assessed as a possible complication and the gastrointestinal tract should be investigated in such patients..
18. Hironobu Umakoshi, Kanako Tanase-Nakao, Norio Wada, Takamasa Ichijo, Masakatsu Sone, Nobuya Inagaki, Takuyuki Katabami, Kohei Kamemura, Yuichi Matsuda, Yuichi Fujii, Tatsuya Kai, Tomikazu Fukuoka, Ryuichi Sakamoto, Atsushi Ogo, Tomoko Suzuki, Mika Tsuiki, Akira Shimatsu, Mitsuhide Naruse, Importance of contralateral aldosterone suppression during adrenal vein sampling in the subtype evaluation of primary aldosteronism, Clinical Endocrinology, 10.1111/cen.12761, 83, 4, 462-467, 2015.01, Objectives Adrenal vein sampling (AVS) is the standard criterion for the subtype diagnosis in primary aldosteronism (PA). Although lateralized index (LI) ≥4 after cosyntropin stimulation is the commonly recommended cut-off for unilateral aldosterone hypersecretion, many of the referral centres in the world use LI cut-off of <4 without sufficient evidence for its diagnostic accuracy. Aim The aim of the study was to establish the diagnostic significance of contralateral (CL) aldosterone suppression for the subtype diagnosis in patients with LI <4 in AVS. Design and patients A retrospective multicentre study was conducted in Japan. Of 124 PA patients subjected to unilateral adrenalectomy after successful AVS with cosyntropin administration, 29 patients with LI < 4 were included in the study. The patients were divided into Group A with CL suppression (n = 16) and Group B (n = 13) without CL suppression. Three outcome indices were assessed after 6 months postoperatively: normalization/significant improvement of hypertension, normalization of the aldosterone to renin ratio (ARR) and normalization of hypokalaemia. Results The normalization/significant improvement of hypertension was 81% in Group A and 54% in Group B (P = 0·2). The normalization of ARR was 100% in Group A and 46% in Group B (P = 0·004). Hypokalaemia was normalized in all patients of both groups. The overall cure rate of PA based on meeting all the three criteria was 81% in Group A and 31% in Group B (P = 0·01). Conclusions In patients with PA, where the LI is <4 on AVS, CL suppression of aldosterone is an accurate predictor of a unilateral source of aldosterone excess. CL suppression data should be interpreted in conjunction with computed tomographic adrenal imaging findings to guide surgical management..
19. Hironobu Umakoshi, Kanako Tanase-Nakao, Norio Wada, Takamasa Ichijo, Masakatsu Sone, Nobuya Inagaki, Takuyuki Katabami, Kohei Kamemura, Yuichi Matsuda, Yuichi Fujii, Tatsuya Kai, Tomikazu Fukuoka, Ryuichi Sakamoto, Atsushi Ogo, Tomoko Suzuki, Mika Tsuiki, Akira Shimatsu, Mitsuhide Naruse, Importance of contralateral aldosterone suppression during adrenal vein sampling in the subtype evaluation of primary aldosteronism, CLINICAL ENDOCRINOLOGY, 10.1111/cen.12761, 83, 4, 462-467, 2015.10, Objectives Adrenal vein sampling (AVS) is the standard criterion for the subtype diagnosis in primary aldosteronism (PA). Although lateralized index (LI) >= 4 after cosyntropin stimulation is the commonly recommended cut-off for unilateral aldosterone hypersecretion, many of the referral centres in the world use LI cut-off of <4 without sufficient evidence for its diagnostic accuracy.Aim The aim of the study was to establish the diagnostic significance of contralateral (CL) aldosterone suppression for the subtype diagnosis in patients with LI <4 in AVS.Design and patients A retrospective multicentre study was conducted in Japan. Of 124 PA patients subjected to unilateral adrenalectomy after successful AVS with cosyntropin administration, 29 patients with LI < 4 were included in the study. The patients were divided into Group A with CL suppression (n = 16) and Group B (n = 13) without CL suppression. Three outcome indices were assessed after 6 months postoperatively: normalization/significant improvement of hypertension, normalization of the aldosterone to renin ratio (ARR) and normalization of hypokalaemia.Results The normalization/significant improvement of hypertension was 81% in Group A and 54% in Group B (P = 0.2). The normalization of ARR was 100% in Group A and 46% in Group B (P = 0.004). Hypokalaemia was normalized in all patients of both groups. The overall cure rate of PA based on meeting all the three criteria was 81% in Group A and 31% in Group B (P = 0.01).Conclusions In patients with PA, where the LI is < 4 on AVS, CL suppression of aldosterone is an accurate predictor of a unilateral source of aldosterone excess. CL suppression data should be interpreted in conjunction with computed tomographic adrenal imaging findings to guide surgical management..
20. Hironobu Umakoshi, Norio Wada, Takamasa Ichijo, Kohei Kamemura, Yuichi Matsuda, Yuichi Fuji, Tatsuya Kai, Tomikazu Fukuoka, Ryuichi Sakamoto, Atsushi Ogo, Tomoko Suzuki, Mika Tsuiki, Mitsuhide Naruse, Optimum position of left adrenal vein sampling for subtype diagnosis in primary aldosteronism, Clinical Endocrinology, 10.1111/cen.12847, 83, 6, 768-773, 2015.12, Context Although adrenal vein sampling (AVS) is the standard method for subtype diagnosis in primary aldosteronism (PA), protocol details including the sampling position in the adrenal vein are not standardized. Objective To establish the optimum sampling position in the left adrenal vein based on postoperative outcome in PA patients. Design and Setting Retrospective study in nine referral centres. Participants Of 496 consecutive PA patients who underwent AVS between 2006 and 2013, 217 with successful AVS under cosyntropin stimulation, and with concomitant data from two positions: proximal (common trunk) and distal (central vein) to the junction with the inferior phrenic vein, were included. Main outcome measures Discordant rate of subtype diagnosis between common trunk and central vein, and postoperative outcomes in patients with discordant results. Results Subtype diagnosis using common trunk and central vein was discordant in 10 (4·6%) of the 217 patients (κ = 0·87, P < 0·05). Of these 10 patients, eight with left unilateral subtype and two with bilateral subtype using common trunk data showed bilateral subtype and unilateral subtype, respectively, using central vein data. Five patients with left unilateral subtype and one with bilateral subtype by common trunk data underwent unilateral adrenalectomy. All six patients were cured of PA after adrenalectomy, resulting in false-negative rates of 17% (1/6) by common trunk data, and 83% (5/6) by central vein data. Conclusion In view of its better potential diagnostic accuracy, technical ease, lower cost and lower risk of vein rupture, blood sampling from the common trunk of the left adrenal vein may be preferable as the standard method of AVS in patients with PA, although additional studies in a larger number of cases are required..
21. Hironobu Umakoshi, Norio Wada, Takamasa Ichijo, Kohei Kamemura, Yuichi Matsuda, Yuichi Fuji, Tatsuya Kai, Tomikazu Fukuoka, Ryuichi Sakamoto, Atsushi Ogo, Tomoko Suzuki, Mika Tsuiki, Mitsuhide Naruse, Optimum position of left adrenal vein sampling for subtype diagnosis in primary aldosteronism, CLINICAL ENDOCRINOLOGY, 10.1111/cen.12847, 83, 6, 768-773, 2015.12, Context Although adrenal vein sampling (AVS) is the standard method for subtype diagnosis in primary aldosteronism (PA), protocol details including the sampling position in the adrenal vein are not standardized.Objective To establish the optimum sampling position in the left adrenal vein based on postoperative outcome in PA patients.Design and Setting Retrospective study in nine referral centres.Participants Of 496 consecutive PA patients who underwent AVS between 2006 and 2013, 217 with successful AVS under cosyntropin stimulation, and with concomitant data from two positions: proximal (common trunk) and distal (central vein) to the junction with the inferior phrenic vein, were included.Main outcome measures Discordant rate of subtype diagnosis between common trunk and central vein, and postoperative outcomes in patients with discordant results.Results Subtype diagnosis using common trunk and central vein was discordant in 10 (4.6%) of the 217 patients (kappa = 0.87, P < 0.05). Of these 10 patients, eight with left unilateral subtype and two with bilateral subtype using common trunk data showed bilateral subtype and unilateral subtype, respectively, using central vein data. Five patients with left unilateral subtype and one with bilateral subtype by common trunk data underwent unilateral adrenalectomy. All six patients were cured of PA after adrenalectomy, resulting in false-negative rates of 17% (1/6) by common trunk data, and 83% (5/6) by central vein data.Conclusion In view of its better potential diagnostic accuracy, technical ease, lower cost and lower risk of vein rupture, blood sampling from the common trunk of the left adrenal vein may be preferable as the standard method of AVS in patients with PA, although additional studies in a larger number of cases are required..
22. yayoi matsuda, Hisaya Kawate, Chitose Matsuzaki, Ryuichi Sakamoto, Kimitaka Shibue, Ohnaka Keizo, Keizo Anzai, Masatoshi Nomura, Ryoichi Takayanagi, Eplerenone improves carotid intima-media thickness (IMT) in patients with primary aldosteronism, Endocrine Journal, 10.1507/endocrj.EJ15-0362, 63, 3, 249-255, 2016.03, Primary aldosteronism (PA) is associated with a higher rate of cardiovascular events than essential hypertension. Although adrenalectomy has been reported to reduce carotid intima-media thickness (IMT) in patients with PA, the effects of the selective aldosterone blocker, eplerenone, on vascular damage in these patients remains unclear. To evaluate the effects of eplerenone on vascular status in PA patients, we sequentially measured carotid IMT (using computer software to calculate an average IMT for accurate and reproducible evaluation) in 22 patients including 8 patients treated by unilateral adrenalectomy and 14 patients treated with eplerenone for 12 months. Patients who underwent adrenalectomy showed significant reductions in aldosterone concentration (from 345 ± 176 pg/mL to 67 ± 34 pg/mL; P<0.01) and IMT (from 0.67 ± 0.07 mm to 0.63 ± 0.09 mm; P<0.05) 6 months after surgery. Patients treated with eplerenone showed significant reductions in IMT from baseline (0.75 ± 0.10 mm) to 6 (0.71 ± 0.11 mm; P<0.05) and 12 (0.65 ± 0.09 mm; P<0.01) months, although plasma aldosterone level increased significantly, from 141 ± 105 pg/mL to 207 ± 98 pg/mL (P<0.05). Eplerenone treatment of patients with PA reduces blood pressure, increases serum potassium level, and improves vascular status. Carotid IMT may be a useful marker for evaluating the effectiveness of eplerenone in patients with PA..
23. Hironobu Umakoshi, Mitsuhide Naruse, Norio Wada, Takamasa Ichijo, Kohei Kamemura, Yuichi Matsuda, Yuichi Fujii, Tatsuya Kai, Tomikazu Fukuoka, Ryuichi Sakamoto, Atsushi Ogo, Tomoko Suzuki, Kazutaka Nanba, Mika Tsuiki, Adrenal venous sampling in patients with positive screening but negative confirmatory testing for primary aldosteronism, Hypertension, 10.1161/HYPERTENSIONAHA.115.06607, 67, 5, 1014-1019, 2016.05, Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to investigate aldosterone concentration and its gradient in the adrenal vein of non-PA hypertensive patients. We retrospectively studied the results of cosyntropin-stimulated adrenal venous sampling in 40 hypertensive patients who showed positive screening testing but negative results in 2 confirmatory tests/captopril challenge test and saline infusion test. Plasma aldosterone concentration, aldosterone/cortisol ratio, its higher/lower ratio (lateralization index) in the adrenal vein with cosyntropin stimulation were measured. Median plasma aldosterone concentration in the adrenal vein was 25 819 pg/mL (range, 5154-69 920) in the higher side and 12 953 (range, 1866-36 190) pg/mL in the lower side (P<0.001). There was a significant gradient in aldosterone/cortisol ratio between the higher and the lower sides (27.2 [5.4-66.0] versus 17.3 [4.0-59.0] pg/mL per μg/dL; P<0.001) with lateralization index ranging from 1.01 to 3.87. The aldosterone lateralization gradient was between 1 to 2 in 32 patients and 2 to 4 in 8 patients. None of the patients showed lateralization index ≥4. The present study demonstrated that plasma aldosterone concentration in the adrenal veins showed significant variation and lateralization gradient even in non-PA hypertensive patients. Adrenal venous sampling aldosterone lateralization gradients between 2 and 4 should be interpreted with caution in patients with PA because these gradients can be found even in patients with negative confirmatory testing for PA..
24. Hironobu Umakoshi, Mitsuhide Naruse, Norio Wada, Takamasa Ichijo, Kohei Kamemura, Yuichi Matsuda, Yuichi Fujii, Tatsuya Kai, Tomikazu Fukuoka, Ryuichi Sakamoto, Atsushi Ogo, Tomoko Suzuki, Kazutaka Nanba, Mika Tsuiki, Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism, HYPERTENSION, 10.1161/HYPERTENSIONAHA.115.06607, 67, 5, 1014-1019, 2016.05, Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to investigate aldosterone concentration and its gradient in the adrenal vein of non-PA hypertensive patients. We retrospectively studied the results of cosyntropin-stimulated adrenal venous sampling in 40 hypertensive patients who showed positive screening testing but negative results in 2 confirmatory tests/captopril challenge test and saline infusion test. Plasma aldosterone concentration, aldosterone/cortisol ratio, its higher/lower ratio (lateralization index) in the adrenal vein with cosyntropin stimulation were measured. Median plasma aldosterone concentration in the adrenal vein was 25 819 pg/mL (range, 5154-69 920) in the higher side and 12 953 (range, 1866-36 190) pg/mL in the lower side (P<0.001). There was a significant gradient in aldosterone/cortisol ratio between the higher and the lower sides (27.2 [5.4-66.0] versus 17.3 [4.0-59.0] pg/mL per mu g/dL; P<0.001) with lateralization index ranging from 1.01 to 3.87. The aldosterone lateralization gradient was between 1 to 2 in 32 patients and 2 to 4 in 8 patients. None of the patients showed lateralization index >= 4. The present study demonstrated that plasma aldosterone concentration in the adrenal veins showed significant variation and lateralization gradient even in non-PA hypertensive patients. Adrenal venous sampling aldosterone lateralization gradients between 2 and 4 should be interpreted with caution in patients with PA because these gradients can be found even in patients with negative confirmatory testing for PA..
25. Yui Shibayama, Norio Wada, Hironobu Umakoshi, Takamasa Ichijo, Yuichi Fujii, Kohei Kamemura, Tatsuya Kai, Ryuichi Sakamoto, Atsushi Ogo, Yuichi Matsuda, Tomikazu Fukuoka, Mika Tsuiki, Tomoko Suzuki, Mitsuhide Naruse, Bilateral aldosterone suppression and its resolution in adrenal vein sampling of patients with primary aldosteronism
analysis of data from the WAVES-J study, Clinical Endocrinology, 10.1111/cen.13090, 85, 5, 696-702, 2016.11, Context: In adrenal vein sampling (AVS) for patients with primary aldosteronism, the contralateral ratio of aldosterone/cortisol (A/C) between the nondominant adrenal vein and the inferior vena cava is one of the best criteria for determining lateralized aldosterone secretion. Despite successful cannulation in some patients, the A/C ratios in the adrenal veins are bilaterally lower than that in the inferior vena cava (bilateral aldosterone suppression; BAS). Objectives: To investigate the prevalence of BAS in AVS and how to resolve this condition. Design and setting: Retrospective study involving nine referral centres. Patients: Four hundred and ninety-one patients who were confirmed as having primary aldosteronism and had an AVS between January 2006 and December 2013. Measurements: The prevalence of BAS before and after ACTH stimulation was compared. In addition, we investigated other methods for overcoming BAS. Results: In 304 patients with successful AVS before ACTH stimulation, BAS was observed in 29 (9·5%). BAS was resolved after ACTH stimulation in 22 patients. In 276 patients with successful AVS both before and after ACTH stimulation, the frequency of BAS was significantly reduced after ACTH (8·7% vs 2·5%, P < 0·01). In a few patients, BAS was also resolved by adding a sampling point at the common trunk of the left adrenal vein and by an alternative drainage vein from the adrenal tumour. Conclusions: BAS sometimes occurs in AVS without ACTH stimulation. ACTH stimulation significantly reduces BAS with a single AVS procedure..
26. Yui Shibayama, Norio Wada, Hironobu Umakoshi, Takamasa Ichijo, Yuichi Fujii, Kohei Kamemura, Tatsuya Kai, Ryuichi Sakamoto, Atsushi Ogo, Yuichi Matsuda, Tomikazu Fukuoka, Mika Tsuiki, Tomoko Suzuki, Mitsuhide Naruse, Bilateral aldosterone suppression and its resolution in adrenal vein sampling of patients with primary aldosteronism: analysis of data from the WAVES-J study., Clinical endocrinology, 10.1111/cen.13090, 85, 5, 696-702, 2016.11, CONTEXT: In adrenal vein sampling (AVS) for patients with primary aldosteronism, the contralateral ratio of aldosterone/cortisol (A/C) between the nondominant adrenal vein and the inferior vena cava is one of the best criteria for determining lateralized aldosterone secretion. Despite successful cannulation in some patients, the A/C ratios in the adrenal veins are bilaterally lower than that in the inferior vena cava (bilateral aldosterone suppression; BAS). OBJECTIVES: To investigate the prevalence of BAS in AVS and how to resolve this condition. DESIGN AND SETTING: Retrospective study involving nine referral centres. PATIENTS: Four hundred and ninety-one patients who were confirmed as having primary aldosteronism and had an AVS between January 2006 and December 2013. MEASUREMENTS: The prevalence of BAS before and after ACTH stimulation was compared. In addition, we investigated other methods for overcoming BAS. RESULTS: In 304 patients with successful AVS before ACTH stimulation, BAS was observed in 29 (9·5%). BAS was resolved after ACTH stimulation in 22 patients. In 276 patients with successful AVS both before and after ACTH stimulation, the frequency of BAS was significantly reduced after ACTH (8·7% vs 2·5%, P < 0·01). In a few patients, BAS was also resolved by adding a sampling point at the common trunk of the left adrenal vein and by an alternative drainage vein from the adrenal tumour. CONCLUSIONS: BAS sometimes occurs in AVS without ACTH stimulation. ACTH stimulation significantly reduces BAS with a single AVS procedure..
27. , Hironobu Umakoshi, Yang Xiaomei, Takamasa Ichijo, Kohei Kamemura, Yuichi Matsuda, Yuichi Fujii, Tatsuya Kai, Tomikazu Fukuoka, Ryuichi Sakamoto, Atsushi Ogo, Tomoko Suzuki, Tatsuki Ogasawara, Mika Tsuiki, Mitsuhide Naruse, Reassessment of the cosyntropin stimulation test in the confirmatory diagnosis and subtype classification of primary aldosteronism, Clinical Endocrinology, 10.1111/cen.13167, 86, 2, 170-176, 2017.02, Objective: Although corticotropin is a representative secretagogue of aldosterone, the utility of the cosyntropin stimulation test (C-ST) in diagnosing primary aldosteronism (PA) has not been elucidated. Aim of the study was to evaluate the clinical utility of C-ST for confirmatory testing and subtype classification of PA. Design, Setting and Patients: In this retrospective study, we identified patients with hypertension and positive case-detection results for PA who underwent C-ST and saline infusion testing (SIT) between 2006 and 2013 at eight referral centres in Japan. PA and essential hypertension (EH) were distinguished based on SIT results. PA subtype classification was determined by adrenal venous sampling (AVS). Plasma aldosterone concentration (PAC) was measured before and 30 and 60 min after intravenous cosyntropin administration. The ability of C-ST to distinguish PA from EH and to distinguish unilateral from bilateral disease was assessed by the area under the receiver operating characteristic curve. Results: Of 205 patients with hypertension and positive case-detection results, 139 (68%) had PA based on SIT results. Eighteen patients in whom AVS was unsuccessful were excluded from analysis. The baseline PAC before C-ST was significantly higher (P < 0·01) in patients with PA than in those with EH. However, the degree of difference in PAC between patients with PA and EH was not enhanced by the administration of cosyntropin. In addition, the administration of cosyntropin did not improve the distinction between bilateral and unilateral PA subtypes. Conclusions: C-ST has no utility as a confirmatory and subtype testing of PA when the diagnosis of PA is based on the positive results in SIT..
28. Hironobu Umakoshi, Yang Xiaomei, Takamasa Ichijo, Kohei Kamemura, Yuichi Matsuda, Yuichi Fujii, Tatsuya Kai, Tomikazu Fukuoka, Ryuichi Sakamoto, Atsushi Ogo, Tomoko Suzuki, Tatsuki Ogasawara, Mika Tsuiki, Mitsuhide Naruse, Reassessment of the cosyntropin stimulation test in the confirmatory diagnosis and subtype classification of primary aldosteronism, CLINICAL ENDOCRINOLOGY, 10.1111/cen.13167, 86, 2, 170-176, 2017.02, ObjectiveAlthough corticotropin is a representative secretagogue of aldosterone, the utility of the cosyntropin stimulation test (C-ST) in diagnosing primary aldosteronism (PA) has not been elucidated. Aim of the study was to evaluate the clinical utility of C-ST for confirmatory testing and subtype classification of PA.Design, Setting and PatientsIn this retrospective study, we identified patients with hypertension and positive case-detection results for PA who underwent C-ST and saline infusion testing (SIT) between 2006 and 2013 at eight referral centres in Japan. PA and essential hypertension (EH) were distinguished based on SIT results. PA subtype classification was determined by adrenal venous sampling (AVS). Plasma aldosterone concentration (PAC) was measured before and 30 and 60 min after intravenous cosyntropin administration. The ability of C-ST to distinguish PA from EH and to distinguish unilateral from bilateral disease was assessed by the area under the receiver operating characteristic curve.ResultsOf 205 patients with hypertension and positive case-detection results, 139 (68%) had PA based on SIT results. Eighteen patients in whom AVS was unsuccessful were excluded from analysis. The baseline PAC before C-ST was significantly higher (P < 001) in patients with PA than in those with EH. However, the degree of difference in PAC between patients with PA and EH was not enhanced by the administration of cosyntropin. In addition, the administration of cosyntropin did not improve the distinction between bilateral and unilateral PA subtypes.ConclusionsC-ST has no utility as a confirmatory and subtype testing of PA when the diagnosis of PA is based on the positive results in SIT..
29. K. Kamemura, N. Wada, T. Ichijo, Y. Matsuda, Y. Fujii, T. Kai, T. Fukuoka, Ryuichi Sakamoto, A. Ogo, T. Suzuki, H. Umakoshi, M. Tsuiki, M. Naruse, Significance of adrenal computed tomography in predicting laterality and indicating adrenal vein sampling in primary aldosteronism, Journal of Human Hypertension, 10.1038/jhh.2016.61, 31, 3, 195-199, 2017.03, Although laterality assessed by computed tomography (CT) in primary aldosteronism (PA) is not always concordant with that assessed by adrenal vein sampling (AVS), it is unclear whether all patients diagnosed with PA should undergo AVS for subtype classification. The aim of the current study was to investigate the accuracy of CT in subtype classification and to develop a prediction score for bilateral subtype in patients without adrenal tumour. As part of the WAVES-J study, 393 patients with PA were analysed. Subtyping using CT was concordant with that using AVS in 68% (269/393) of patients in the total sample, and in 38% (68/156) of patients with unilateral tumours, 56% (5/9) of patients with bilateral tumours and 89% (204/228) of patients without tumour. In patients without tumour, female gender, plasma aldosterone concentration (pg ml-1) to plasma renin activity ratio ≤550 and serum potassium ≥3.8 mEq l-1 were shown to be independent predictors for bilateral subtype. A prediction score based on these three variables was constructed with one point attributed to each variable. A score of three points had 29% sensitivity and 96% specificity in a receiver operating characteristic curve analysis. The results suggest that although CT is not sufficiently accurate for subtype classification in patients with adrenal tumours, it is sufficient to determine bilateral subtype in patients without tumour. Moreover, using our clinical prediction score in patients without tumour could be useful in determining the necessity of AVS for subtype classification..
30. N. Wada, Y. Shibayama, H. Umakoshi, T. Ichijo, Y. Fujii, K. Kamemura, T. Kai, Ryuichi Sakamoto, A. Ogo, Y. Matsuda, T. Fukuoka, M. Tsuiki, T. Suzuki, M. Naruse, Hyperkalemia in both surgically and medically treated patients with primary aldosteronism, Journal of Human Hypertension, 10.1038/jhh.2017.38, 31, 10, 627-632, 2017.10, Hyperkalemia is an important complication of adrenalectomy for patients with primary aldosteronism (PA). The frequency of hyperkalemia after medication using mineralocorticoid receptor antagonists (MRAs) for PA is unclear. The aim of this study is to investigate the frequency and the risk factors of hyperkalemia after surgery and medication for PA. The data of 376 patients with PA registered in a multicentre-collaborative study in Japan, including surgically treated patients (group A; n=142) and medically treated patients with MRAs (group B; n=234) were studied. The prevalence of hyperkalemic patients (serum potassium >5.0 mEq l -1) after treatment was higher in group A than group B (9.9 vs 3.8%, P<0.01). At diagnosis, the hyperkalemic patients were older and had a poorer renal function than the non-hyperkalemic patients in both groups (P<0.05). The hyperkalemic patients had severer PA in group A and milder PA in group B. The independent risk factor by a logistic regression analysis was only age in both groups. After treatment, the percentages of patients withdrawing antihypertensive drugs and the normalization of aldosterone renin ratio were not different between hyperkalemic and non-hyperkalemic patients in group A. The type and dose of MRAs and the combination of other antihypertensive drugs were not different between hyperkalemic and non-hyperkalemic patients in group B. In conclusion, the potential occurrence of hyperkalemia should be considered after medical as well as surgical treatment for PA, especially in patients with older age (>60 years) and impaired renal function (estimated glomerular filtration rate <70 ml min -1 per 1.73 m 2) at diagnosis..
31. Yuichi Fujii, Hironobu Umakoshi, Norio Wada, Takamasa Ichijo, Kohei Kamemura, Yuichi Matsuda, Tatsuya Kai, Tomikazu Fukuoka, Ryuichi Sakamoto, Atsushi Ogo, Tomoko Suzuki, Kazutaka Nanba, Mika Tsuiki, Mitsuhide Naruse, Subtype prediction of primary aldosteronism by combining aldosterone concentrations in the left adrenal vein and inferior vena cava
A multicenter collaborative study on adrenal venous sampling, Journal of Human Hypertension, 10.1038/s41371-017-0015-0, 32, 1, 12-19, 2017.12, Subtype diagnosis of primary aldosteronism (PA) by adrenal vein sampling (AVS) is recommended as a mandatory step for indicating adrenal surgery. It is a technically demanding procedure, especially in the right adrenal vein. The aim of the study was to predict the subtype diagnosis in the absence of values from the right AVS. From the databases of nine centers (WAVES-J), 308 patients with PA who underwent successful AVS were studied. Based on the ipsilateral ratio (IR) (aldosterone/cortisol ratio of the left adrenal vein [A/Cleft AV] / aldosterone/cortisol ratio of the inferior vena cava [A/CIVC]), the patients were divided into two groups: the patients with IR ≥ 1.0 (n = 262) and those with IR < 1.0 (n = 46). In patients with IR > 1.0, the A/Cleft AV was significantly higher in patients with the left unilateral subtype than in patients with the bilateral subtype. Receiver operating characteristic (ROC) curve analysis revealed that an A/Cleft AV cutoff >68 showed 70.8% sensitivity and 93.5% specificity for the left unilateral subtype. On the other hand, in patients with IR < 1.0, the A/Cleft AV was significantly lower in patients with the right unilateral subtype. ROC analysis revealed that an A/Cleft AV cutoff <9 showed 86.7% sensitivity and 75.0% specificity for the right unilateral subtype. Hence, the combination of the IR and A/C ratio in the left adrenal vein is useful for predicting the subtype. The present results provide important information for patients with PA in whom AVS was unsuccessful in the right adrenal vein..
32. Seiichi Yano, Kenji Ashida, Hiromi Nagata, Kenji Ohe, Naoko Wada, Yukina Takeichi, Yuki Hanada, Yuta Ibayashi, Lixiang Wang, Shohei Sakamoto, Ryuichi Sakamoto, Uchi Hiroshi, Motoaki Shiratsuchi, Masutaka Furue, Masatoshi Nomura, Yoshihiro Ogawa, Nivolumab-induced thyroid dysfunction lacking antithyroid antibody is frequently evoked in Japanese patients with malignant melanoma, BMC Endocrine Disorders, 10.1186/s12902-018-0267-x, 18, 1, 2018.06, Background: Nivolumab, an anti-programmed cell death-1 monoclonal antibody, has improved the survival of patients with malignant melanoma. Despite its efficacy, nivolumab inconsistently induces thyroid dysfunction as an immune-related adverse event (irAE). This study aimed to evaluate nivolumab-induced thyroid dysfunction to determine the risks and mechanisms of thyroid irAEs. Methods: After excluding 10 patients, data of 24 patients with malignant melanoma (aged 17-85years; 54% female) were retrospectively analyzed. Results: Thyroid irAEs were observed in seven patients (29%). Three patients had hypothyroidism after preceding transient thyrotoxicosis, and the other four patients had hypothyroidism without thyrotoxicosis. Levothyroxine-Na replacement was required in three patients. Antithyroid antibody (ATA) titer was elevated in one of four assessable patients. The average (±SD) time to onset of thyroid irAE was 33.6 (±21.9) weeks. The administration period of nivolumab was longer in patients with thyroid irAEs than in those without thyroid irAEs (P<0.01). There were no significant differences between patients with and without thyroid irAEs regarding age, sex, tumor stage, response to nivolumab therapy, baseline thyroid function, antithyroid peroxidase antibody (anti-TPO Ab) and antithyroglobulin antibody (anti-Tg Ab). Conclusions: Thyroid dysfunction was a common irAE of nivolumab in malignant melanoma. Neither anti-TPO Ab nor anti-Tg Ab was associated with the risk for nivolumab-induced thyroid dysfunction. A conventional ATA-independent mechanism might be involved in thyroid irAEs. Further studies are required to clarify the mechanism and identify the predictive factors of thyroid irAEs..
33. Seiichi Yano, Kenji Ashida, Hiromi Nagata, Kenji Ohe, Naoko Wada, Yukina Takeichi, Yuki Hanada, Yuta Ibayashi, Lixiang Wang, Shohei Sakamoto, Ryuichi Sakamoto, Hiroshi Uchi, Motoaki Shiratsuchi, Masutaka Furue, Masatoshi Nomura, Yoshihiro Ogawa, Nivolumab-induced thyroid dysfunction lacking antithyroid antibody is frequently evoked in Japanese patients with malignant melanoma, BMC Endocrine Disorders, 10.1186/s12902-018-0267-x, 18, 1, 36-36, 2018.06, © 2018 The Author(s). Background: Nivolumab, an anti-programmed cell death-1 monoclonal antibody, has improved the survival of patients with malignant melanoma. Despite its efficacy, nivolumab inconsistently induces thyroid dysfunction as an immune-related adverse event (irAE). This study aimed to evaluate nivolumab-induced thyroid dysfunction to determine the risks and mechanisms of thyroid irAEs. Methods: After excluding 10 patients, data of 24 patients with malignant melanoma (aged 17-85years; 54% female) were retrospectively analyzed. Results: Thyroid irAEs were observed in seven patients (29%). Three patients had hypothyroidism after preceding transient thyrotoxicosis, and the other four patients had hypothyroidism without thyrotoxicosis. Levothyroxine-Na replacement was required in three patients. Antithyroid antibody (ATA) titer was elevated in one of four assessable patients. The average (±SD) time to onset of thyroid irAE was 33.6 (±21.9) weeks. The administration period of nivolumab was longer in patients with thyroid irAEs than in those without thyroid irAEs (P<0.01). There were no significant differences between patients with and without thyroid irAEs regarding age, sex, tumor stage, response to nivolumab therapy, baseline thyroid function, antithyroid peroxidase antibody (anti-TPO Ab) and antithyroglobulin antibody (anti-Tg Ab). Conclusions: Thyroid dysfunction was a common irAE of nivolumab in malignant melanoma. Neither anti-TPO Ab nor anti-Tg Ab was associated with the risk for nivolumab-induced thyroid dysfunction. A conventional ATA-independent mechanism might be involved in thyroid irAEs. Further studies are required to clarify the mechanism and identify the predictive factors of thyroid irAEs..
34. Hitomi Umeguchi, Hiromasa Takenoshita, Hiroshi Inoue, Yuki Kurihara, Chihiro Sakaguchi, Seiichi Yano, Nao Hasuzawa, Shohei Sakamoto, Ryuichi Sakamoto, Kenji Ashida, Autoimmune-related primary hypoparathyroidism possibly induced by the administration of pembrolizumab
A case report, Journal of Oncology Practice, 10.1200/JOP.18.00076, 14, 7, 449-451, 2018.07.
35. Hitomi Umeguchi, Hiromasa Takenoshita, Hiroshi Inoue, Yuki Kurihara, Chihiro Sakaguchi, Seiichi Yano, Nao Hasuzawa, Shohei Sakamoto, Ryuichi Sakamoto, Kenji Ashida, Autoimmune-related primary hypoparathyroidism possibly induced by the administration of pembrolizumab: A case report, Journal of Oncology Practice, 10.1200/JOP.18.00076, 14, 7, 449-451, 2018.07.
36. Chihiro Sakaguchi, Seiichi Yano, Kenji Ashida, Naoko Wada, Kenji Ohe, Hiromi Nagata, yayoi matsuda, Shohei Sakamoto, Ryuichi Sakamoto, Ohnaka Keizo, Uchi Hiroshi, Masutaka Furue, Masatoshi Nomura, Yoshihiro Ogawa, A case of acute exacerbation of chronic adrenal insufficiency due to ipilimumab treatment for advanced melanoma, American Journal of Case Reports, 10.12659/AJCR.913021, 20, 106-110, 2019.01, Objective: Unusual clinical course Background: Ipilimumab is a therapeutic human monoclonal antibody that targets the T-cell inhibitory molecule, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and is classified as an immune checkpoint inhibitor that has been shown to improve prognosis in patients with advanced melanoma. However, several immune-related adverse events have been reported to be associated with ipilimumab Treatment. A case of acute exacerbation of chronic adrenal insufficiency is presented that highlights that glucocorticoid dosage for patients undergoing steroid treatment at the time of ipilimumab treatment has yet to be established. Case Report: A 50-year-old Japanese woman was diagnosed with malignant melanoma on the sole of her right foot. During her second course of ipilimumab treatment, she developed acute adrenal insufficiency caused by isolated adrenocorticotropic hormone (ACTH) deficiency, which required treatment with oral hydrocortisone. However, the symptoms of her adrenal insufficiency worsened, and she commenced treatment with 12 courses of nivolumab, a therapeutic human monoclonal antibody that blocks programmed cell death protein 1 (PD-1) on the surface of T-cells. She did not require corticosteroid support during nivolumab treatment. Conclusions: This case report highlights the risk of exacerbating adrenal insufficiency during treatment with ipilimumab. The differences in clinical outcome in this patient between ipilimumab and nivolumab treatment might be explained by the different mechanisms between ipilimumab and nivolumab on immune function..
37. Chihiro Sakaguchi, Kenji Ashida, Kenichi Kouhashi, Kenji Ohe, Yoichi Fujii, Seiichi Yano, yayoi matsuda, Shohei Sakamoto, Ryuichi Sakamoto, Yoshinao Oda, Masatoshi Nomura, Yoshihiro Ogawa, A case of autonomous cortisol secretion in a patient with subclinical Cushing's syndrome, GNAS mutation, and paradoxical cortisol response to dexamethasone, BMC Endocrine Disorders, 10.1186/s12902-019-0345-8, 19, 1, 2019.01, Background: Increased urinary free cortisol in response to the oral administration of dexamethasone is a paradoxical reaction mainly reported in patients with primary pigmented nodular adrenocortical disease. Here, we describe the first case of subclinical Cushing's syndrome represented by autonomous cortisol secretion and paradoxical response to oral dexamethasone administration, harboring an activating mutation in the α subunit of the stimulatory G protein (GNAS). Case presentation: A 65-year-old woman was diagnosed with subclinical Cushing's syndrome during an evaluation for bilateral adrenal masses. Tumors of unknown origin were found in the heart, brain, thyroid gland, colon, pancreas, and both adrenal glands. Adenocarcinoma of the sigmoid colon and systemic brown-patchy skin pigmentation were also present. Her urinary cortisol levels increased in response to oral dexamethasone, while serum dehydroepiandrosterone-sulfate was not suppressed. After right adrenalectomy, genetic analysis of the resected tumor revealed the somatic GNAS activating mutation, p.R201H. Paradoxical urinary cortisol response persisted even after unilateral adrenal resection, although serum and urinary cortisol levels were attenuated. Conclusions: This patient harbored a GNAS activating mutation, and presented with a mild cortisol- and androgen-producing adrenal adenoma. Administration of oral dexamethasone paradoxically increased cortisol levels, possibly via the stimulation of the cyclic adenosine monophosphate-dependent protein kinase A signaling pathway, which is seen in patients with pigmented nodular adrenocortical disease or Carney complex. GNAS mutations may provide clues to the mechanisms of hyper-function and tumorigenesis in the adrenal cortex, especially in bilateral adrenal masses accompanied by multiple systemic tumors. Examining GNAS mutations could help physicians detect extra-adrenal malignancies, which may contribute to an improved prognosis for patients with this type of Cushing's syndrome..
38. Ryoko Takei, Tomoaki Inoue, Noriyuki Sonoda, Motoyuki Kohjima, Misato Okamoto, Ryuichi Sakamoto, Toyoshi Inoguchi, Yoshihiro Ogawa, Bilirubin reduces visceral obesity and insulin resistance by suppression of inflammatory cytokines, PloS one, 10.1371/journal.pone.0223302, 14, 10, 2019.01, Objective Although previous studies have reported a negative relationship between serum bilirubin concentration and the development of diabetes mellitus (DM), the relationship between bilirubin and insulin resistance has not been thoroughly assessed. This study was designed to determine the relationships between bilirubin, body fat distribution, and adipose tissue inflammation in patients with type 2 DM and the effect of bilirubin in an obese animal model. Method Body fat distribution was measured using an abdominal dual bioelectrical impedance analyzer in patients with type 2 DM. We also measured glycemic control, lipid profile, serum bilirubin concentration and other clinical characteristics, and determined their relationships with body fat distribution. In the animal study, biliverdin (20 mg/kg daily) was orally administered to high-fat diet (HFD)-induced obese (DIO) mice for 2 weeks, after which intraperitoneal insulin tolerance testing was performed. Then, adipocyte area, adipocytokine expression, and macrophage polarization were evaluated in epididymal adipose tissues. Results In the clinical study, univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower HDL-C. In multivariate analyses, bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area. However, there was no association between bilirubin concentration and subcutaneous fat area. In the animal study, DIO mice treated with biliverdin had smaller adipocytes than untreated DIO mice and biliverdin improved HFD-induced insulin resistance. Biliverdin treatment reversed the higher gene expression of Cd11c, encoding an M1 macrophage marker, and Tnfa, encoding the proinflammatory cytokine tumor necrosis factor-α, in the adipose tissues of DIO mice. These data suggest biliverdin administration alleviates insulin resistance by ameliorating inflammation and the dysregulation of adipocytokine expression in adipose tissues of DIO mice. Conclusions Bilirubin may protect against insulin resistance by ameliorating visceral obesity and adipose tissue inflammation..
39. Chihiro Sakaguchi, Kenji Ashida, Kenichi Kohashi, Kenji Ohe, Yoichi Fujii, Seiichi Yano, Yayoi Matsuda, Shohei Sakamoto, Ryuichi Sakamoto, Yoshinao Oda, Masatoshi Nomura, Yoshihiro Ogawa, A case of autonomous cortisol secretion in a patient with subclinical Cushing's syndrome, GNAS mutation, and paradoxical cortisol response to dexamethasone, BMC Endocrine Disorders, 10.1186/s12902-019-0345-8, 19, 1, 13-13, 2019.01, © 2019 The Author(s). Background: Increased urinary free cortisol in response to the oral administration of dexamethasone is a paradoxical reaction mainly reported in patients with primary pigmented nodular adrenocortical disease. Here, we describe the first case of subclinical Cushing's syndrome represented by autonomous cortisol secretion and paradoxical response to oral dexamethasone administration, harboring an activating mutation in the α subunit of the stimulatory G protein (GNAS). Case presentation: A 65-year-old woman was diagnosed with subclinical Cushing's syndrome during an evaluation for bilateral adrenal masses. Tumors of unknown origin were found in the heart, brain, thyroid gland, colon, pancreas, and both adrenal glands. Adenocarcinoma of the sigmoid colon and systemic brown-patchy skin pigmentation were also present. Her urinary cortisol levels increased in response to oral dexamethasone, while serum dehydroepiandrosterone-sulfate was not suppressed. After right adrenalectomy, genetic analysis of the resected tumor revealed the somatic GNAS activating mutation, p.R201H. Paradoxical urinary cortisol response persisted even after unilateral adrenal resection, although serum and urinary cortisol levels were attenuated. Conclusions: This patient harbored a GNAS activating mutation, and presented with a mild cortisol- and androgen-producing adrenal adenoma. Administration of oral dexamethasone paradoxically increased cortisol levels, possibly via the stimulation of the cyclic adenosine monophosphate-dependent protein kinase A signaling pathway, which is seen in patients with pigmented nodular adrenocortical disease or Carney complex. GNAS mutations may provide clues to the mechanisms of hyper-function and tumorigenesis in the adrenal cortex, especially in bilateral adrenal masses accompanied by multiple systemic tumors. Examining GNAS mutations could help physicians detect extra-adrenal malignancies, which may contribute to an improved prognosis for patients with this type of Cushing's syndrome..
40. C. Sakaguchi, K. Ashida, S. Yano, K. Ohe, Naoko Wada, N. Hasuzawa, yayoi matsuda, Shohei Sakamoto, Ryuichi Sakamoto, Uchi Hiroshi, Masutaka Furue, M. Nomura, Yoshihiro Ogawa, A case of nivolumab-induced acute-onset type 1 diabetes mellitus in melanoma, Current oncology (Toronto, Ont.), 10.3747/co.26.4130, 26, 1, e115-e118, 2019.02, Nivolumab, an anti-PD-1 antibody, is now considered an important therapeutic agent in several advanced malignancies. However, immune-related adverse events such as endocrinopathies have been reported with its use. Thyroid disorder and isolated adrenocorticotropic hormone deficiency have frequently been reported as nivolumab-induced immune-related adverse events. Another endocrinopathy is nivolumab-induced type 1 diabetes mellitus (t1dm), described as diabetes mellitus with rapid onset and complete insulin insufficiency, at times leading to fulminant t1dm. We report the case of a 68-year-old woman who developed pancreatic islet-related autoantibody-negative t1dm, possibly induced by nivolumab, under continuous glucocorticoid administration. She was treated with nivolumab for advanced malignant melanoma, concomitant with 10 mg prednisolone daily for thrombophlebitis tapered to 5 mg after 13 courses of nivolumab therapy. At approximately the 27th course of nivolumab therapy, she showed elevated plasma glucose levels despite preserved insulin secretion. A month later, she developed diabetic ketoacidosis. Her insulin secretion decreased and finally was exhausted. She was diagnosed with acute-onset rather than fulminant t1dm because of a rapidly progressive course to diabetic ketoacidosis during just more than 1 week. She is currently receiving insulin replacement. There has been no recurrence of the melanoma. Thus, nivolumab might induce autoimmune diabetes mellitus, with patients having t1dm-sensitive human leucocyte antigen being more susceptible even when receiving glucocorticoids. Physicians should be aware that nivolumab could potentially induce t1dm as a critical immune-related adverse event..
41. Mitsuhide Naruse, Yasuhiro Koike, Nozomu Kamei, Ryuichi Sakamoto, Yuko Yambe, Michinori Arimitsu, Effects of azilsartan compared with telmisartan on insulin resistance in patients with essential hypertension and type 2 diabetes mellitus
An open-label, randomized clinical trial, PloS one, 10.1371/journal.pone.0214727, 14, 4, 2019.04, Background Based on non-clinical data, it is expected that azilsartan, an angiotensin II receptor blocker, will help improve insulin resistance in addition to its hypotensive action. The present study is aimed to explore the effect of azilsartan compared to telmisartan on insulin sensitivity in hypertensive patients in the clinical setting. Methods This multicenter, randomized, open-label, parallel-group exploratory study was conducted in Japan. We randomized adult patients (20 years old) with grade I or II essential hypertension and coexisting type 2 diabetes (1:1) to receive either oral azilsartan (20 mg/day;17 patients) or telmisartan (40 mg/day;16 patients) for 12 weeks. The primary endpoint was the change in the homeostasis model assessment ratio of insulin resistance (HOMA-R) from the baseline at the end of the treatment period. We also evaluated its safety and efficacy on other diabetes-related variables and blood pressure. Findings The mean changes in HOMA-R at the end of treatment were 0.22 (95% CI, −1.09–1.52) in the azilsartan group and −0.23 (95% CI, −0.72–0.27) in the telmisartan group. We found no clinically remarkable changes between the groups in diabetes-related variables such as fasting blood glucose, fasting insulin, HbA1c (NGSP), HOMA-β, or 1,5-anhydroglucitol. Reductions in clinic systolic and diastolic blood pressure were observed at week 4 and the reduced levels were maintained throughout the treatment period in both groups. No serious treatment-emergent adverse events (TEAEs) were observed. Only one drug-related TEAE (mild decrease in blood pressure) was reported in one patient in the azilsartan group. Conclusion Neither azilsartan nor telmisartan had any clinically remarkable effects on insulin resistance parameters when administered for 12 weeks to patients with grade I or II essential hypertension and coexisting type 2 diabetes mellitus. Azilsartan (20 mg/day) and telmisartan (40 mg/ day) exerted comparable antihypertensive effects..
42. Mitsuhide Naruse, Yasuhiro Koike, Nozomu Kamei, Ryuichi Sakamoto, Yuko Yambe, Michinori Arimitsu, Effects of azilsartan compared with telmisartan on insulin resistance in patients with essential hypertension and type 2 diabetes mellitus: An open-label, randomized clinical trial, PLoS ONE, 10.1371/journal.pone.0214727, 14, 4, e0214727, 2019.04, © 2019 Naruse et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Based on non-clinical data, it is expected that azilsartan, an angiotensin II receptor blocker, will help improve insulin resistance in addition to its hypotensive action. The present study is aimed to explore the effect of azilsartan compared to telmisartan on insulin sensitivity in hypertensive patients in the clinical setting. Methods This multicenter, randomized, open-label, parallel-group exploratory study was conducted in Japan. We randomized adult patients (20 years old) with grade I or II essential hypertension and coexisting type 2 diabetes (1:1) to receive either oral azilsartan (20 mg/day;17 patients) or telmisartan (40 mg/day;16 patients) for 12 weeks. The primary endpoint was the change in the homeostasis model assessment ratio of insulin resistance (HOMA-R) from the baseline at the end of the treatment period. We also evaluated its safety and efficacy on other diabetes-related variables and blood pressure. Findings The mean changes in HOMA-R at the end of treatment were 0.22 (95% CI, −1.09–1.52) in the azilsartan group and −0.23 (95% CI, −0.72–0.27) in the telmisartan group. We found no clinically remarkable changes between the groups in diabetes-related variables such as fasting blood glucose, fasting insulin, HbA1c (NGSP), HOMA-β, or 1,5-anhydroglucitol. Reductions in clinic systolic and diastolic blood pressure were observed at week 4 and the reduced levels were maintained throughout the treatment period in both groups. No serious treatment-emergent adverse events (TEAEs) were observed. Only one drug-related TEAE (mild decrease in blood pressure) was reported in one patient in the azilsartan group. Conclusion Neither azilsartan nor telmisartan had any clinically remarkable effects on insulin resistance parameters when administered for 12 weeks to patients with grade I or II essential hypertension and coexisting type 2 diabetes mellitus. Azilsartan (20 mg/day) and telmisartan (40 mg/ day) exerted comparable antihypertensive effects..
43. Ryoko Takei, Tomoaki Inoue, Noriyuki Sonoda, Motoyuki Kohjima, Misato Okamoto, Ryuichi Sakamoto, Toyoshi Inoguchi, Yoshihiro Ogawa, Bilirubin reduces visceral obesity and insulin resistance by suppression of inflammatory cytokines, PLoS ONE, 10.1371/journal.pone.0223302, 14, 10, e0223302, 2019.10, © 2019 Takei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective Although previous studies have reported a negative relationship between serum bilirubin concentration and the development of diabetes mellitus (DM), the relationship between bilirubin and insulin resistance has not been thoroughly assessed. This study was designed to determine the relationships between bilirubin, body fat distribution, and adipose tissue inflammation in patients with type 2 DM and the effect of bilirubin in an obese animal model. Method Body fat distribution was measured using an abdominal dual bioelectrical impedance analyzer in patients with type 2 DM. We also measured glycemic control, lipid profile, serum bilirubin concentration and other clinical characteristics, and determined their relationships with body fat distribution. In the animal study, biliverdin (20 mg/kg daily) was orally administered to high-fat diet (HFD)-induced obese (DIO) mice for 2 weeks, after which intraperitoneal insulin tolerance testing was performed. Then, adipocyte area, adipocytokine expression, and macrophage polarization were evaluated in epididymal adipose tissues. Results In the clinical study, univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower HDL-C. In multivariate analyses, bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area. However, there was no association between bilirubin concentration and subcutaneous fat area. In the animal study, DIO mice treated with biliverdin had smaller adipocytes than untreated DIO mice and biliverdin improved HFD-induced insulin resistance. Biliverdin treatment reversed the higher gene expression of Cd11c, encoding an M1 macrophage marker, and Tnfa, encoding the proinflammatory cytokine tumor necrosis factor-α, in the adipose tissues of DIO mice. These data suggest biliverdin administration alleviates insulin resistance by ameliorating inflammation and the dysregulation of adipocytokine expression in adipose tissues of DIO mice. Conclusions Bilirubin may protect against insulin resistance by ameliorating visceral obesity and adipose tissue inflammation..
44. Taisuke Narazaki, Motoaki Shiratsuchi, Takamitsu Matsushima, Mariko Tsuda, Yasuhiro Tsukamoto, Hiroki Muta, Toru Masuda, Daisaku Kimura, Akiko Takamatsu, Hidetaka Yamamoto, Yoshinao Oda, Hiroaki Miyoshi, Koichi Ohshima, Yayoi Matsuda, Ryuichi Sakamoto, Yasuhiro Nakashima, Yoshihiro Ogawa, Clinico-pathological characteristics of primary adrenal lymphomas–potential efficacy of autologous stem cell transplantation, Leukemia and Lymphoma, 10.1080/10428194.2020.1725507, 2020.01.
45. , Hiroki Kobayashi, Yoshihiro Nakamura, Masanori Abe, Isao Kurihara, Hiroshi Itoh, Takamasa Ichijo, Yoshiyu Takeda, Takashi Yoneda, Takuyuki Katabami, Mika Tsuiki, Norio Wada, Yoshihiro Ogawa, Ryuichi Sakamoto, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Takanobu Yoshimoto, Tetsuya Yamada, Ryuji Okamoto, Yuichi Matsuda, Megumi Fujita, Minemori Watanabe, Kouichi Tamura, Akiyo Tanabe, Mitsuhide Naruse, Effect of cosyntropin during adrenal venous sampling on subtype of primary aldosteronism
Analysis of surgical outcome, European journal of endocrinology, 10.1530/EJE-19-0860, 182, 3, 265-273, 2020.01, Objectives: We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA). Design: Multicenter retrospective study by Japan PA study. Method: We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI <2 with ACTH-stimulated LI ≥4 (Bilateral (B) to U group, n = 15); and basal LI ≥2 with ACTH-stimulated LI <4 (U to B group, n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria. Results: Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI. Conclusions: Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group..
46. , Yuichi Fujii, Yoshiyu Takeda, Isao Kurihara, Hiroshi Itoh, Takuyuki Katabami, Takamasa Ichijo, Norio Wada, Yui Shibayama, Takanobu Yoshimoto, Yoshihiro Ogawa, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Katsutoshi Takahashi, Minemori Watanabe, Yuichi Matsuda, Hiroki Kobayashi, Hirotaka Shibata, Kohei Kamemura, Michio Otsuki, Koichi Yamamto, Atsushi Ogo, Toshihiko Yanase, Shintaro Okamura, Shozo Miyauchi, Megumi Fujita, Tomoko Suzuki, Hironobu Umakoshi, Tatsuki Ogasawara, Mika Tsuiki, Mitsuhide Naruse, Masanobu Yamada, Hiromi Rakugi, Takashi Kawamura, Osamu Ogawa, Akiyo Tanabe, Tomonobu Hasegawa, Masanori Abe, Ryuichi Sakamoto, Takuro Shinbo, Tatsuya Kai, Tomikazu Fukuoka, Masanori Murakami, Shigeatsu Hashimoto, Makito Tanabe, Mitsuhiro Kometani, Yuichirou Yoshikawa, Youichi Oono, Hisashi Fukuda, Takashi Yoneda, Historical changes and between-facility differences in adrenal venous sampling for primary aldosteronism in Japan, Journal of human hypertension, 10.1038/s41371-019-0229-4, 34, 1, 34-42, 2020.01, Primary aldosteronism (PA) is a common curable cause of hypertension. Adrenal venous sampling (AVS) is recommended for subtype diagnosis but is a difficult procedure. Recently, an increased prevalence of PA was reported, creating a greater demand for treatment of the condition in clinical facilities. The aim of the present study was to identify the historical changes over time and the differences between facilities in the success rate and subtype diagnosis of PA. The database of the PA registry developed by the Japan PA Study (JPAS) was used. A total of 2599 patients with PA who underwent AVS were evaluated. The overall success rate of AVS was 88%. The bilateral subtype was the dominant subtype, comprising 69% of cases. During the period 2004−2011 to 2011−2017, there were significant changes in the total number of AVS procedures (from 562 to 1732), ratio of ACTH administration with AVS (75 to 97%), success rate (79 to 90%), and proportion with bilateral subtype diagnosis (53 to 72%). There were also significant inter-facility differences in the number of AVS procedures (6 to 322), success rate (59 to 97%), and proportion with the bilateral subtype (44 to 86%). The principal enrolled department was Endocrinology (86%), and the ratio of unilateral PA was significantly higher in this department than in others (32% vs. 25%). In conclusion, the number of AVS procedures performed, the success rate, and the proportion with the bilateral subtype increased over time after normalizing the centre difference. Significant differences were observed between the centres..
47. , Maki Yokomoto-Umakoshi, Ryuichi Sakamoto, Hironobu Umakoshi, Yayoi Matsuda, Hiromi Nagata, Tazuru Fukumoto, Masatoshi Ogata, Yoshihiro Ogawa, Unilateral primary aldosteronism as an independent risk factor for vertebral fracture, Clinical Endocrinology, 10.1111/cen.14145, 92, 3, 206-213, 2020.03, Context: Primary aldosteronism (PA) is known to increase vertebral fracture (VF), although the detailed mechanism remains to be elucidated. We hypothesized that the PA subtype is associated with VF. Objective: To evaluate whether unilateral PA is associated with the prevalence of VF. Design: This was a retrospective cross-sectional study in a single referral centre. Patients: We identified 210 hypertensive patients whose clinical data were available for case-detection results. One hundred and fifty-two patients were diagnosed with PA using captopril challenge tests. Measurements: We measured the prevalence of VF, according to PA subtype. Results: One hundred thirteen patients with PA were subtype classified by adrenal vein sampling. Of these, 37 patients had unilateral PA, 76 patients had bilateral PA, 58 patients had non-PA; 39 patients with PA were not subtype-classified. Patients with PA had a higher prevalence of VF (29%, 44/152) than those with non-PA (12%, 7/58; P =.011). Moreover, unilateral PA had a higher prevalence of VF (46%, 17/37) than bilateral PA (20%, 15/76; P =.021). There was no significant difference in the prevalence of VF between bilateral PA and non-PA. Unilateral PA was an independent risk factor for VF after adjusting for age and sex (OR: 3.16, 95% confidence interval: 1.12-8.92; P =.017). Among patients with unilateral PA, serum cortisol concentrations after 1-mg dexamethasone suppression test were higher in those with VF (1.32 ± 0.67 g/dL) than those without (0.96 ± 0.33 g/dL; P =.048). Conclusions: Unilateral PA is an independent risk factor for VF..
48. Maki Yokomoto-Umakoshi, Ryuichi Sakamoto, Hironobu Umakoshi, Yayoi Matsuda, Hiromi Nagata, Tazuru Fukumoto, Masatoshi Ogata, Yoshihiro Ogawa, Unilateral primary aldosteronism as an independent risk factor for vertebral fracture, Clinical Endocrinology, 10.1111/cen.14145, 92, 3, 206-213, 2020.03, © 2019 John Wiley & Sons Ltd Context: Primary aldosteronism (PA) is known to increase vertebral fracture (VF), although the detailed mechanism remains to be elucidated. We hypothesized that the PA subtype is associated with VF. Objective: To evaluate whether unilateral PA is associated with the prevalence of VF. Design: This was a retrospective cross-sectional study in a single referral centre. Patients: We identified 210 hypertensive patients whose clinical data were available for case-detection results. One hundred and fifty-two patients were diagnosed with PA using captopril challenge tests. Measurements: We measured the prevalence of VF, according to PA subtype. Results: One hundred thirteen patients with PA were subtype classified by adrenal vein sampling. Of these, 37 patients had unilateral PA, 76 patients had bilateral PA, 58 patients had non-PA; 39 patients with PA were not subtype-classified. Patients with PA had a higher prevalence of VF (29%, 44/152) than those with non-PA (12%, 7/58; P =.011). Moreover, unilateral PA had a higher prevalence of VF (46%, 17/37) than bilateral PA (20%, 15/76; P =.021). There was no significant difference in the prevalence of VF between bilateral PA and non-PA. Unilateral PA was an independent risk factor for VF after adjusting for age and sex (OR: 3.16, 95% confidence interval: 1.12-8.92; P =.017). Among patients with unilateral PA, serum cortisol concentrations after 1-mg dexamethasone suppression test were higher in those with VF (1.32 ± 0.67 g/dL) than those without (0.96 ± 0.33 g/dL; P =.048). Conclusions: Unilateral PA is an independent risk factor for VF..
49. Hiroki Kobayashi, Yoshihiro Nakamura, Masanori Abe, Isao Kurihara, Hiroshi Itoh, Takamasa Ichijo, Yoshiyu Takeda, Takashi Yoneda, Takuyuki Katabami, Mika Tsuiki, Norio Wada, Yoshihiro Ogawa, Ryuichi Sakamoto, Junji Kawashima, Masakatsu Sone, Nobuya Inagaki, Takanobu Yoshimoto, Tetsuya Yamada, Ryuji Okamoto, Yuichi Matsuda, Megumi Fujita, Minemori Watanabe, Kouichi Tamura, Akiyo Tanabe, Mitsuhide Naruse, Effect of cosyntropin during adrenal venous sampling on subtype of primary aldosteronism: analysis of surgical outcome., European journal of endocrinology, 10.1530/EJE-19-0860, 182, 3, 265-273, 2020.03, Objectives: We investigated the clinical significance of ACTH stimulation during adrenal venous sampling (AVS) by surgical outcome of primary aldosteronism (PA). Design: Multicenter retrospective study by Japan PA study. Method: We allocated 314 patients with both basal and ACTH-stimulated AVS data who underwent adrenalectomy to three groups: basal lateralization index (LI) ≥2 with ACTH-stimulated LI ≥4 on the ipsilateral side (Unilateral (U) to U group, n = 245); basal LI <2 with ACTH-stimulated LI ≥4 (Bilateral (B) to U group, n = 15); and basal LI ≥2 with ACTH-stimulated LI <4 (U to B group, n = 54). We compared surgical outcomes among the groups using the Primary Aldosteronism Surgical Outcome (PASO) criteria. Results: Compared with U to U group, U to B group had poor clinical and biochemical outcomes and low rates of adrenal adenoma as pathological findings (P = 0.044, 0.006, and 0.048, respectively), although there were no significant differences between U to U and B to U groups. All patients in U to B group with clinical and biochemical benefits, however, had adrenal adenoma as pathological findings and could be well differentiated from those with poor surgical outcomes via basal LI (>8.3), but not ACTH-stimulated LI. These results were similar even when we defined each group based on a cut-off value of 4 for basal LI. Conclusions: Although PA patients in U to B group had worse surgical outcomes than did those in U to U group, basal LI could discriminate among patients with better surgical outcomes in U to B group..
50. , Maki Yokomoto-Umakoshi, Hironobu Umakoshi, Tazuru Fukumoto, Yayoi Matsuda, Hiromi Nagata, Masatoshi Ogata, Hisaya Kawate, Takashi Miyazawa, Ryuichi Sakamoto, Yoshihiro Ogawa, Pheochromocytoma and paraganglioma
An emerging cause of secondary osteoporosis, Bone, 10.1016/j.bone.2020.115221, 133, 2020.04, Context: Pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGLs) are catecholamine-producing neuroendocrine tumors, which are known to be associated with low bone mineral density (BMD). However, it remains unknown whether PPGLs are associated with high prevalence of osteoporotic fracture and if so, whether their surgical resection improves BMD has been addressed. Objective: To evaluate the risk of vertebral fracture (VF) in PPGLs and the improvement of BMD after surgery. Design and settings: A retrospective cross-sectional study in a single referral center. Participants: This study included the following patients: 1) 49 patients with PPGLs and 61 patients with non-functional AT who were examined radiograph of the spine, 2) 23 patients with PPGLs who were examined BMD at follow-up. Intervention: 1) The prevalence of VF was evaluated between PPGLs and non-functional AT. 2) In PPGLs, BMD was evaluated at baseline and after surgery. Results: PPGLs had a higher prevalence of VF (43% [21/49]) than non-functional AT (16% [10/61]; p = 0.002). PPGLs were associated with VF after adjusting for age and sex (odds ratio, 4.47; 95% confidence interval, 1.76–11.3; p = 0.001). In PPGLs, BMD at the lumber spine was improved (before: 0.855 ± 0.198 g/cm2, after: 0.888 ± 0.169 g/cm2, mean of the difference: 0.032 g/cm2, p = 0.026), with 3.8% increase. Conclusion: This study demonstrates that PPGLs was associated with VF and that their surgical resection contributes to the improvement of BMD in the trabecular bone. These observations support the notion that PPGLs are an emerging cause of secondary osteoporosis..
51. Hironobu Umakoshi, Ryuichi Sakamoto, Yayoi Matsuda, Maki Yokomoto-Umakoshi, Hiromi Nagata, Tazuru Fukumoto, Masatoshi Ogata, Yoshihiro Ogawa, Role of Aldosterone and Potassium Levels in Sparing Confirmatory Tests in Primary Aldosteronism, The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgz148, 105, 4, 2020.04, CONTEXT: The current clinical guidelines suggest that confirmatory tests for primary aldosteronism (PA) may be excluded in some of patients who have elevated plasma aldosterone concentration (PAC) under plasma renin suppression. However, this has low-priority evidence and is under debate in use of serum potassium. OBJECTIVE: This study aimed to investigate an appropriate setting for sparing confirmatory tests in PA. DESIGN AND SETTING: A retrospective cross-sectional study in a single referral center. PARTICIPANTS: This study included 327 patients who had hypertension under plasma renin suppression and underwent the captopril challenge test (CCT) between January 2007 and April 2019. CCT results were used to diagnose PA. MAIN OUTCOME MEASURE: Diagnostic value of PAC and serum potassium in confirmation of PA. RESULTS: Of the studied patients, 252 of 327 (77%) were diagnosed with PA. All 61 patients with PAC > 30 ng/dL were diagnosed with PA. In patients with PAC between 20 and 30 ng/dL, 44 of 55 (80%) were diagnosed with PA, while all 26 with PAC between 20 to 30 ng/dL who had spontaneous hypokalemia were diagnosed with PA. The proportion of unilateral PA determined by adrenal vein sampling (AVS) was higher in patients who had PAC > 30 ng/dL or those with spontaneous hypokalemia who had PAC between 20 and 30 ng/dL than those who did not meet the criteria (76% vs. 17%, P < .001). CONCLUSION: Confirmatory tests in PA could be spared in patients who have typical features of PA and these patients had a high probability of unilateral PA on AVS..
52. Mari Kurokawa, Michiko Torio, Kazuhiro Ohkubo, Vlad Tocan, Noriko Ohyama, Naoko Toda, Kanako Ishii, Kei Nishiyama, Yuichi Mushimoto, Ryuichi Sakamoto, Maki Nakaza, Riho Horie, Tomoya Kubota, Masanori P. Takahashi, Yasunari Sakai, Masatoshi Nomura, Shouichi Ohga, The expanding phenotype of hypokalemic periodic paralysis in a Japanese family with p.Val876Glu mutation in CACNA1S, Molecular Genetics and Genomic Medicine, 10.1002/mgg3.1175, 8, 4, 2020.04, Background: Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disease characterized by the episodic weakness of skeletal muscles and hypokalemia. More than half patients with HypoPP carry mutations in CACNA1S, encoding alpha-1 subunit of calcium channel. Few reports have documented the non-neuromuscular phenotypes of HypoPP. Methods: The proband is a Japanese woman who developed HypoPP at 6 years of age. An excessive insulin secretion with the oral glucose tolerance test rationalized that she had experienced frequent attacks of paralysis on high-carbohydrate diets. Results: Voglibose and acetazolamide effectively controlled her paralytic episodes. Her 8-year-old son and 2-year-old daughter started showing the paralytic symptoms from 4 and 2 years of age, respectively. Laboratory tests revealed high concentrations of creatinine kinase in serum and elevated renin activities in plasma of these children. The targeted sequencing confirmed that these three patients had an identical heterozygous mutation (p.V876E) in CACNA1S. Conclusion: Our data indicate that the p.V876E mutation in CACNA1S contributes to the early onset of neuromuscular symptoms and unusual clinical phenotypes of HypoPP..
53. Maki Yokomoto-Umakoshi, Hironobu Umakoshi, Tazuru Fukumoto, Yayoi Matsuda, Hiromi Nagata, Masatoshi Ogata, Hisaya Kawate, Takashi Miyazawa, Ryuichi Sakamoto, Yoshihiro Ogawa, Pheochromocytoma and paraganglioma: An emerging cause of secondary osteoporosis., Bone, 10.1016/j.bone.2020.115221, 133, 115221-115221, 2020.04, CONTEXT: Pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGLs) are catecholamine-producing neuroendocrine tumors, which are known to be associated with low bone mineral density (BMD). However, it remains unknown whether PPGLs are associated with high prevalence of osteoporotic fracture and if so, whether their surgical resection improves BMD has been addressed. OBJECTIVE: To evaluate the risk of vertebral fracture (VF) in PPGLs and the improvement of BMD after surgery. DESIGN AND SETTINGS: A retrospective cross-sectional study in a single referral center. PARTICIPANTS: This study included the following patients: 1) 49 patients with PPGLs and 61 patients with non-functional AT who were examined radiograph of the spine, 2) 23 patients with PPGLs who were examined BMD at follow-up. INTERVENTION: 1) The prevalence of VF was evaluated between PPGLs and non-functional AT. 2) In PPGLs, BMD was evaluated at baseline and after surgery. RESULTS: PPGLs had a higher prevalence of VF (43% [21/49]) than non-functional AT (16% [10/61]; p = 0.002). PPGLs were associated with VF after adjusting for age and sex (odds ratio, 4.47; 95% confidence interval, 1.76-11.3; p = 0.001). In PPGLs, BMD at the lumber spine was improved (before: 0.855 ± 0.198 g/cm2, after: 0.888 ± 0.169 g/cm2, mean of the difference: 0.032 g/cm2, p = 0.026), with 3.8% increase. CONCLUSION: This study demonstrates that PPGLs was associated with VF and that their surgical resection contributes to the improvement of BMD in the trabecular bone. These observations support the notion that PPGLs are an emerging cause of secondary osteoporosis..
54. Hironobu Umakoshi, Ryuichi Sakamoto, Yayoi Matsuda, Maki Yokomoto-Umakoshi, Hiromi Nagata, Tazuru Fukumoto, Masatoshi Ogata, Yoshihiro Ogawa, Role of aldosterone and potassium levels in sparing confirmatory tests in primary aldosteronism, Journal of Clinical Endocrinology and Metabolism, 10.1210/clinem/dgz148, 105, 4, 1284-1289, 2020.04, © Endocrine Society 2019. All rights reserved. Context: The current clinical guidelines suggest that confirmatory tests for primary aldosteronism (PA) may be excluded in some of patients who have elevated plasma aldosterone concentration (PAC) under plasma renin suppression. However, this has low-priority evidence and is under debate in use of serum potassium. Objective: This study aimed to investigate an appropriate setting for sparing confirmatory tests in PA. Design and Setting: A retrospective cross-sectional study in a single referral center. Participants: This study included 327 patients who had hypertension under plasma renin suppression and underwent the captopril challenge test (CCT) between January 2007 and April 2019. CCT results were used to diagnose PA. Main Outcome Measure: Diagnostic value of PAC and serum potassium in confirmation of PA. Results: Of the studied patients, 252 of 327 (77%) were diagnosed with PA. All 61 patients with PAC > 30 ng/dL were diagnosed with PA. In patients with PAC between 20 and 30 ng/dL, 44 of 55 (80%) were diagnosed with PA, while all 26 with PAC between 20 to 30 ng/dL who had spontaneous hypokalemia were diagnosed with PA. The proportion of unilateral PA determined by adrenal vein sampling (AVS) was higher in patients who had PAC > 30 ng/dL or those with spontaneous hypokalemia who had PAC between 20 and 30 ng/dL than those who did not meet the criteria (76% vs. 17%, P <.001). Conclusion: Confirmatory tests in PA could be spared in patients who have typical features of PA and these patients had a high probability of unilateral PA on AVS..
55. Mari Kurokawa, Michiko Torio, Kazuhiro Ohkubo, Vlad Tocan, Noriko Ohyama, Naoko Toda, Kanako Ishii, Kei Nishiyama, Yuichi Mushimoto, Ryuichi Sakamoto, Maki Nakaza, Riho Horie, Tomoya Kubota, Masanori P. Takahashi, Yasunari Sakai, Masatoshi Nomura, Shouichi Ohga, The expanding phenotype of hypokalemic periodic paralysis in a Japanese family with p.Val876Glu mutation in CACNA1S, Molecular Genetics and Genomic Medicine, 10.1002/mgg3.1175, 8, 4, e1175, 2020.04, © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Background: Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disease characterized by the episodic weakness of skeletal muscles and hypokalemia. More than half patients with HypoPP carry mutations in CACNA1S, encoding alpha-1 subunit of calcium channel. Few reports have documented the non-neuromuscular phenotypes of HypoPP. Methods: The proband is a Japanese woman who developed HypoPP at 6 years of age. An excessive insulin secretion with the oral glucose tolerance test rationalized that she had experienced frequent attacks of paralysis on high-carbohydrate diets. Results: Voglibose and acetazolamide effectively controlled her paralytic episodes. Her 8-year-old son and 2-year-old daughter started showing the paralytic symptoms from 4 and 2 years of age, respectively. Laboratory tests revealed high concentrations of creatinine kinase in serum and elevated renin activities in plasma of these children. The targeted sequencing confirmed that these three patients had an identical heterozygous mutation (p.V876E) in CACNA1S. Conclusion: Our data indicate that the p.V876E mutation in CACNA1S contributes to the early onset of neuromuscular symptoms and unusual clinical phenotypes of HypoPP..
56. Seiichi Yano, Kenji Ashida, Ryuichi Sakamoto, Chihiro Sakaguchi, Masatoshi Ogata, Kengo Maruyama, Shohei Sakamoto, Munehiko Ikeda, Kenji Ohe, Shoko Akasu, Shimpei Iwata, Nobuhiko Wada, Yayoi Matsuda, Yoichi Nakanishi, Masatoshi Nomura, Yoshihiro Ogawa, Human leucocyte antigen DR15, a possible predictive marker for immune checkpoint inhibitor–induced secondary adrenal insufficiency, European Journal of Cancer, 10.1016/j.ejca.2020.02.049, 130, 198-203, 2020.05, Background: Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious ‘pituitary irAE.’ However, its precise mechanism remains unclear, and no definitive predictive markers have been reported. Patients and methods: We enrolled and studied 11 patients with advanced cancer (aged 39–70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls. Results: Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non–small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013). Conclusions: HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis..
57. Seiichi Yano, Kenji Ashida, Ryuichi Sakamoto, Chihiro Sakaguchi, Masatoshi Ogata, Kengo Maruyama, Shohei Sakamoto, Munehiko Ikeda, Kenji Ohe, Shoko Akasu, Shimpei Iwata, Nobuhiko Wada, Yayoi Matsuda, Yoichi Nakanishi, Masatoshi Nomura, Yoshihiro Ogawa, Human leucocyte antigen DR15, a possible predictive marker for immune checkpoint inhibitor-induced secondary adrenal insufficiency., European journal of cancer (Oxford, England : 1990), 10.1016/j.ejca.2020.02.049, 130, 198-203, 2020.05, BACKGROUND: Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious 'pituitary irAE.' However, its precise mechanism remains unclear, and no definitive predictive markers have been reported. PATIENTS AND METHODS: We enrolled and studied 11 patients with advanced cancer (aged 39-70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls. RESULTS: Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non-small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013). CONCLUSIONS: HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis..
58. Taisuke Narazaki, Motoaki Shiratsuchi, Takamitsu Matsushima, Mariko Tsuda, Yasuhiro Tsukamoto, Hiroki Muta, Toru Masuda, Daisaku Kimura, Akiko Takamatsu, Hidetaka Yamamoto, Yoshinao Oda, Hiroaki Miyoshi, Koichi Ohshima, Yayoi Matsuda, Ryuichi Sakamoto, Yasuhiro Nakashima, Yoshihiro Ogawa, Clinico-pathological characteristics of primary adrenal lymphomas - potential efficacy of autologous stem cell transplantation., Leukemia & lymphoma, 10.1080/10428194.2020.1725507, 61, 6, 1516-1518, 2020.06.
59. Youichi Ohno, Masakatsu Sone, Nobuya Inagaki, Akiyuki Kawashima, Yoshiyu Takeda, Takashi Yoneda, Isao Kurihara, Hiroshi Itoh, Mika Tsuiki, Takamasa Ichijo, Takuyuki Katabami, Norio Wada, Ryuichi Sakamoto, Yoshihiro Ogawa, Takanobu Yoshimoto, Tetsuya Yamada, Junji Kawashima, Yuichi Matsuda, Hiroki Kobayashi, Kohei Kamemura, Koichi Yamamoto, Michio Otsuki, Shintaro Okamura, Shoichiro Izawa, Ryuji Okamoto, Kouichi Tamura, Akiyo Tanabe, Mitsuhide Naruse, Nadir Aldosterone Levels After Confirmatory Tests Are Correlated With Left Ventricular Hypertrophy in Primary Aldosteronism., Hypertension (Dallas, Tex. : 1979), 10.1161/HYPERTENSIONAHA.119.14601, 75, 6, 1475-1482, 2020.06, Left ventricular hypertrophy (LVH) is often seen in patients with primary aldosteronism (PA), and the prevalence of LVH is reportedly higher among patients with PA than patients with essential hypertension. However, the correlation between aldosterone levels and LVH is undefined, and how aldosterone affects LVH in patients with PA remains unclear. We, therefore, retrospectively assessed a large PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) to reveal the factors associated with LVH in patients with PA without suspected autonomous cortisol secretion. In the 1186 patients with PA studied, the basal plasma aldosterone concentration, plasma renin activity, and the aldosterone-to-renin ratio did not significantly correlate with left ventricular LV mass index (LVMI) in single or multiple regression analyses. However, the plasma aldosterone concentration after the captopril challenge test or saline-infusion test, which are associated with autonomous aldosterone secretion, correlated significantly with LVMI, even after adjusting for patients' backgrounds, including age and blood pressure. In addition, hypokalemia and the unilateral subtype also correlated with LVMI. Longitudinal subanalysis of medically or surgically treated patients with PA showed significant reductions in LVMI in both the surgery (63.0±18.1 to 55.3±19.5 g/m2.7, P<0.001) and drug treatment (56.8±14.1 to 52.1±13.5 g/m2.7, P<0.001) groups. Our results suggest the autonomous aldosterone secretion level, not the basal aldosterone level itself, is relevant to LVH in patients with PA. In addition, the elevated LVMI seen in patients with PA is at least partially reversible with surgical or medical treatment..
60. Tazuru Fukumoto, Hironobu Umakoshi, Masatoshi Ogata, Maki Yokomoto-Umakoshi, Yayoi Matsuda, Misato Motoya, Hiromi Nagata, Yui Nakano, Norifusa Iwahashi, Hiroki Kaneko, Norio Wada, Takashi Miyazawa, Ryuichi Sakamoto, Yoshihiro Ogawa, Significance of Discordant Results Between Confirmatory Tests in Diagnosis of Primary Aldosteronism., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgaa812, 106, 2, e866-e874, 2021.01, CONTEXT: Current clinical guidelines recommend confirmation of a positive result in at least one confirmatory test in the diagnosis of primary aldosteronism (PA). Clinical implication of multiple confirmatory tests has not been established, especially when patients show discordant results. OBJECTIVE: The aim of the present study was to explore the role of 2 confirmatory tests in subtype diagnosis of PA. DESIGN AND SETTING: A retrospective cross-sectional study was conducted at two referral centers. PARTICIPANTS AND METHODS: We identified 360 hypertensive patients who underwent both a captopril challenge test (CCT) and a saline infusion test (SIT) and exhibited at least one positive result. Among them, we studied 193 patients with PA whose data were available for subtype diagnosis based on adrenal vein sampling (AVS). MAIN OUTCOME MEASURE: The prevalence of bilateral subtype on AVS according to the results of the confirmatory tests was measured. RESULTS: Of patients studied, 127 were positive for both CCT and SIT (double-positive), whereas 66 were positive for either CCT or SIT (single-positive) (n = 34 and n = 32, respectively). Altogether, 135 were diagnosed with bilateral subtype on AVS. The single-positive patients had milder clinical features of PA than the double-positive patients. The prevalence of bilateral subtype on AVS was significantly higher in the single-positive patients than in the double-positive patients. (63/66 [95.5%] vs 72/127 [56.7%], P < .01). Several clinical parameters were different between CCT single-positive and SIT single-positive patients. CONCLUSION: Patients with discordant results between CCT and SIT have a high probability of bilateral subtype of PA on AVS..
61. Maki Yokomoto-Umakoshi, Hironobu Umakoshi, Ryuichi Sakamoto, Tazuru Fukumoto, Masatoshi Ogata, Yui Nakano, Norifusa Iwahashi, Hiroki Kaneko, Noriko Mizoguchi, Akiko Hattori, Takashi Miyazawa, Yayoi Matsuda, Hisaya Kawate, Yoshihiro Ogawa, Role of deteriorated bone quality in the development of osteoporosis in pheochromocytoma and paraganglioma., Bone, 10.1016/j.bone.2020.115607, 142, 115607-115607, 2021.01, CONTEXT: Pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGLs), catecholamine-producing tumors, represent an emerging cause of secondary osteoporosis. However, despite decreased bone mineral density (BMD), vertebral fracture (VF) is not associated with BMD in PPGLs. OBJECTIVE: To evaluate whether deteriorated bone quality is involved in the development of osteoporosis in PPGLs. PARTICIPANTS: Trabecular bone score (TBS), used to assess trabecular bone quality, was examined in 56 patients with PPGLs and 52 with non-functional adrenal tumors (AT). Radiograph of the spine was carried out in 35 patients with PPGLs, and TBS was analyzed in 18 patients with PPGLs at follow-up. MAIN OUTCOME MEASURE: TBS and BMD at the lumbar spine in patients with PPGLs with and without VF. RESULTS: PPGLs had a lower TBS (n = 56, 1.338 [1.294-1.420]) than non-functional AT (n = 52, 1.394 [1.342-1.444]; p = 0.033). Among those with PPGLs, patients with VF (n = 14, 1.314 [1.289-1.346]) had a lower TBS than those without VF (n = 21, 1.383 [1.324-1.426]; p = 0.046), despite no significant difference in BMD at the lumbar spine between the two groups (p = 0.501). An optimal cut-off level of TBS for diagnosing VF in PPGLs was 1.323, and its area under the curve was 0.702. The severity of catecholamine excess and maximal size of tumor were associated with decreased TBS in PPGLs patients (p = 0.016 and p = 0.020, respectively). Surgical resection of PPGLs improved TBS at follow-up, with 2.5% increase (p = 0.007). CONCLUSIONS: This study provides evidence for the importance of deteriorated bone quality rather than decreased bone mass in the development of VF in PPGLs..
62. Masatoshi Ogata, Hironobu Umakoshi, Tazuru Fukumoto, Yayoi Matsuda, Maki Yokomoto-Umakoshi, Hiromi Nagata, Norio Wada, Takashi Miyazawa, Ryuichi Sakamoto, Yoshihiro Ogawa, Significance of aldosterone gradient within left adrenal vein in diagnosing unilateral subtype of primary aldosteronism., Clinical endocrinology, 10.1111/cen.14320, 94, 1, 24-33, 2021.01, CONTEXT: The success rate of cannulation of the right adrenal vein is limited. The aldosterone gradient within the same adrenal vein branch is specific for aldosterone-producing adenoma. OBJECTIVE: This study was performed to investigate whether the absolute aldosterone gradient within the left adrenal vein (left-AV absolute aldosterone gradient) indicates unilateral excess aldosterone. DESIGN AND SETTING: A retrospective cross-sectional study in a single referral centre. PATIENTS AND METHODS: In total, 123 consecutive patients with primary aldosteronism who had successful adrenal vein sampling (AVS) data were examined. The left-AV absolute aldosterone gradient was considered significant when a gradient of >4:1 in the aldosterone-to-cortisol ratio between the common trunk vein and central vein was found. MAIN OUTCOME MEASURE: The prevalence of the unilateral subtype in patients with a significant left-AV absolute aldosterone gradient. RESULTS: The prevalence of the unilateral subtype was higher in patients with than without a significant left-AV absolute aldosterone gradient (88.2% [15/17] vs 21.7% [23/106], P < .001). Of 60 patients with spontaneous hypokalemia, left unilateral disease on computed tomography, or both, a significant left-AV absolute aldosterone gradient was present only in patients with the unilateral subtype on AVS (42.9% [15/35]), but not in those with the bilateral subtype (0.0% [0/25]). These data were validated in an external cohort. CONCLUSION: The presence of a significant left-AV absolute aldosterone gradient can be used to diagnose the left unilateral subtype of primary aldosteronism on AVS in patients with spontaneous hypokalemia, left unilateral disease on computed tomography or both..
63. Maki Yokomoto-Umakoshi, Hironobu Umakoshi, Takashi Miyazawa, Masatoshi Ogata, Ryuichi Sakamoto, Yoshihiro Ogawa, Investigating the causal effect of fibroblast growth factor 23 on osteoporosis and cardiometabolic disorders: A Mendelian randomization study., Bone, 10.1016/j.bone.2020.115777, 143, 115777-115777, 2021.02, Pathological excess of fibroblast growth factor 23 (FGF23) causes mineral and bone disorders. However, the causality of FGF23 in the development of osteoporosis remains unknown. Whether FGF23 has systemic effects on cardiometabolic disorders beyond regulating mineral metabolism is also controversial. In this study, we investigated the causal effect of FGF23 on osteoporosis and cardiometabolic disorders using Mendelian randomization (MR) analysis. Summary statistics for single-nucleotide polymorphisms with traits of interest were obtained from the relevant genome-wide association studies. As a result, FGF23 was found to be inversely associated with femoral neck-BMD (odds ratio [OR] 0.682, 95% confidence interval [CI] 0.546-0.853, p = 8e-04) and heel estimated BMD (eBMD) (OR 0.898, 95%CI 0.820-0.985, p = 0.022) in the inverse-variance-weighted analysis, but not lumbar spine-BMD and fractures. The results were supported by the weighted-median analysis, and there was no evidence of pleiotropy in the MR-Egger analysis. FGF23 was associated with FN-BMD and eBMD after adjustment for estimated glomerular filtration rate, height, and body mass index in multivariable MR analysis. On the other hand, there was no association between FGF23 and cardiometabolic traits including cardio artery disease, brachial-ankle pulse wave velocity, intima-media thickness of carotid arteries, systolic and diastolic blood pressure, fasting glucose, high and low-density lipoprotein cholesterol, and triglycerides. Therefore, this MR study established that FGF23 was involved in bone loss and, in contrast, was not involved in cardiometabolic disorders. Our findings provide important insights into the role of FGF23 in the pathogenesis of osteoporosis and cardiometabolic disorders..
64. Hiromi Nagata, Jingya Lyu, Hitomi Imachi, Kensaku Fukunaga, Seisuke Sato, Toshihiro Kobayashi, Takanobu Saheki, Kayoko Seo, Japar B Salimah, Hisakazu Iwama, Ryuichi Sakamoto, Yoshihiro Ogawa, Koji Murao, AGEs inhibit scavenger receptor class B type I gene expression via Smad1 in HUVECs., Journal of molecular endocrinology, 10.1530/JME-20-0177, 66, 3, 223-231, 2021.03, Vascular complications are the main cause of morbidity and mortality in diabetic patients, and advanced glycation end products (AGEs) play a critical role in promoting diabetic vascular dysfunction. The human homolog of scavenger receptor class B type I (SR-BI), CD36, and LIMPII analog-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from HDL. In endothelial cells, HDL activates endothelial nitric oxide synthase (eNOS) via hSR-BI/CLA-1. In this study, we elucidated the effects of AGEs on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells (HUVECs). HSR-BI/CLA-1 expression was examined by real-time PCR, western blot analysis, and reporter gene assay in HUVECs incubated with AGEs. eNOS activity was assessed by detecting the phosphorylation (Ser 1179) of eNOS. Our results showed that AGEs decreased the endogenous expression of hSR-BI/CLA-1. AGEs also inhibited the activity of the hSR-BI/CLA-1 promoter and its mRNA expression via receptor RAGE. We identified the binding site for Smad1 on the hSR-BI/CLA-1 promoter: Smad1 bound to its promoter. AGE treatment stimulated the transcriptional activity of Smad1, and mutation of the Smad1 binding site inhibited the effect of AGEs on the hSR-BI/CLA-1 promoter. HDL-treatment enhanced the phosphorylation of eNOS at Ser 1179, but pretreatment with AGEs inhibited the phosphorylation of eNOS Ser 1179. These results suggested that AGEs downregulate the expression of the endothelial hSR-BI/CLA-1 via the Smad1 pathway, which may be a therapeutic target for diabetic endothelial dysfunction..
65. Hiroki Kaneko, Hironobu Umakoshi, Masatoshi Ogata, Norio Wada, Norifusa Iwahashi, Tazuru Fukumoto, Maki Yokomoto-Umakoshi, Yui Nakano, Yayoi Matsuda, Takashi Miyazawa, Ryuichi Sakamoto, Yoshihiro Ogawa, Machine learning based models for prediction of subtype diagnosis of primary aldosteronism using blood test., Scientific reports, 10.1038/s41598-021-88712-8, 11, 1, 9140-9140, 2021.05, Primary aldosteronism (PA) is associated with an increased risk of cardiometabolic diseases, especially in unilateral subtype. Despite its high prevalence, the case detection rate of PA is limited, partly because of no clinical models available in general practice to identify patients highly suspicious of unilateral subtype of PA, who should be referred to specialized centers. The aim of this retrospective cross-sectional study was to develop a predictive model for subtype diagnosis of PA based on machine learning methods using clinical data available in general practice. Overall, 91 patients with unilateral and 138 patients with bilateral PA were randomly assigned to the training and test cohorts. Four supervised machine learning classifiers; logistic regression, support vector machines, random forests (RF), and gradient boosting decision trees, were used to develop predictive models from 21 clinical variables. The accuracy and the area under the receiver operating characteristic curve (AUC) for predicting of subtype diagnosis of PA in the test cohort were compared among the optimized classifiers. Of the four classifiers, the accuracy and AUC were highest in RF, with 95.7% and 0.990, respectively. Serum potassium, plasma aldosterone, and serum sodium levels were highlighted as important variables in this model. For feature-selected RF with the three variables, the accuracy and AUC were 89.1% and 0.950, respectively. With an independent external PA cohort, we confirmed a similar accuracy for feature-selected RF (accuracy: 85.1%). Machine learning models developed using blood test can help predict subtype diagnosis of PA in general practice..
66. Maki Yokomoto-Umakoshi, Hironobu Umakoshi, Norifusa Iwahashi, Yayoi Matsuda, Hiroki Kaneko, Masatoshi Ogata, Tazuru Fukumoto, Eriko Terada, Yui Nakano, Ryuichi Sakamoto, Yoshihiro Ogawa, Protective Role of DHEAS in Age-related Changes in Bone Mass and Fracture Risk., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgab459, 106, 11, E4580-E4592, 2021.06, PURPOSE: Dehydroepiandrosterone sulfate (DHEAS) from the adrenal cortex substantially decreases with age, which may accelerate osteoporosis. However, the association of DHEAS with bone mineral density (BMD) and fracture is inconclusive. We conducted a Mendelian randomization (MR) analysis to investigate the role of DHEAS in age-related changes in BMD and fracture risk. METHODS: Single nucleotide polymorphisms (SNPs) associated with serum DHEAS concentrations were used as instrumental variables (4 SNPs for main analysis; 4 SNPs for men and 5 SNPs for women in sex-related analysis). Summary statistics were obtained from relevant genome-wide association studies. RESULTS: A log-transformed unit (µmol/L) increase in serum DHEAS concentrations was associated with an SD increase in estimated BMD at the heel (estimate, 0.120; 95% CI, 0.081-0.158; P = 9 × 10-10), and decreased fracture (odds ratio, 0.989; 95% CI, 0.981-0.996; P = 0.005), consistent with dual-energy X-ray absorptiometry-derived BMD at the femoral neck and lumbar spine. Their associations remained even after adjusting for height, body mass index, testosterone, estradiol, sex hormone-binding globulin, and insulin-like growth factor 1. The association of DHEAS with fracture remained after adjusting for falls, grip strength, and physical activity but was attenuated after adjusting for BMD. The MR-Bayesian model averaging analysis showed BMD was the top mediating factor for association of DHEAS with fracture. The association between DHEAS and BMD was observed in men but not in women. CONCLUSION: DHEAS was associated with increased BMD and decreased fracture. DHEAS may play a protective role in decreasing fracture risk, mainly by increasing bone mass..
67. Maki Yokomoto-Umakoshi, Hironobu Umakoshi, Norifusa Iwahashi, Yayoi Matsuda, Hiroki Kaneko, Masatoshi Ogata, Tazuru Fukumoto, Eriko Terada, Yui Nakano, Ryuichi Sakamoto, Yoshihiro Ogawa, Protective Role of DHEAS in Age-related Changes in Bone Mass and Fracture Risk: A Mendelian Randomization Study., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgab459, 2021.06, PURPOSE: Dehydroepiandrosterone sulfate (DHEAS) from the adrenal cortex substantially decreases with age, which may accelerate osteoporosis. However, the association of DHEAS with bone mineral density (BMD) and fracture is inconclusive. We conducted a Mendelian randomization (MR) analysis to investigate the role of DHEAS in age-related changes in BMD and fracture risk. METHODS: Single nucleotide polymorphisms (SNPs) associated with serum DHEAS concentrations were used as instrumental variables (4 SNPs for main analysis; 4 SNPs for men and 5 SNPs for women in sex-related analysis). Summary statistics were obtained from relevant genome-wide association studies. RESULTS: A log-transformed unit (μmol/L) increase in serum DHEAS concentrations was associated with SD increase in estimated BMD at the heel (estimate, 0.120; 95% confidence interval [CI], 0.081-0.158; P = 9 × 10 -10), and decreased fracture (odds ratio [OR], 0.989; 95%CI, 0.981-0.996; P = 0.005), consistent with dual-energy X-ray absorptiometry-derived BMD at the femoral neck and lumbar spine. Their associations remained even after adjusting for height, body mass index, testosterone, estradiol, sex hormone-binding globulin, and IGF-1. The association of DHEAS with fracture remained after adjusting for falls, grip strength, and physical activity but was attenuated after adjusting for BMD. The MR-Baysian model averaging analysis showed BMD was the top mediating factor for association of DHEAS with fracture. The association between DHEAS and BMD was observed in men but not in women. CONCLUSION: DHEAS was associated with increased BMD and decreased fracture. DHEAS may play a protective role in decreasing fracture risk, mainly by increasing bone mass..
68. Rikako Sagara, Tomoaki Inoue, Noriyuki Sonoda, Chieko Yano, Misato Motoya, Hironobu Umakoshi, Ryuichi Sakamoto, Yoshihiro Ogawa, Association between cortisol and left ventricular diastolic dysfunction in patients with diabetes mellitus., Journal of diabetes investigation, 10.1111/jdi.13653, 13, 2, 344-350, 2021.08, AIMS/INTRODUCTION: Diabetes mellitus is a major risk factor for the development of cardiovascular diseases. Heart failure with preserved ejection fraction is characterized by left ventricular diastolic dysfunction (LVDD). It has been reported that excess cortisol found in patients with Cushing's syndrome was associated with the development of LVDD. However, the relationship between cortisol concentration and LVDD in patients with diabetes mellitus has not been addressed. MATERIALS AND METHODS: We enrolled 109 patients with diabetes mellitus and 104 patients without diabetes mellitus who had undergone echocardiographic examination at Kyushu University Hospital, Fukuoka, Japan, between November 2016 and March 2019. Left ventricular function was evaluated and the ratio of early diastolic velocity from transmitral inflow to early diastolic velocity (E/e') was used as an index of diastolic function. Plasma cortisol concentrations, glycemic control, lipid profiles, treatment with antidiabetic drugs and other clinical characteristics were evaluated, and their associations with E/e' were determined using univariate and multivariate analyses. RESULTS: Multivariate linear regression analysis showed that log E/e' was positively correlated with age (P = 0.017), log systolic blood pressure (P = 0.004) and cortisol (P = 0.037), and negatively correlated with estimated glomerular filtration rate (P = 0.016) and the use of sodium-glucose cotransporter 2 inhibitors (P = 0.042) in patients with diabetes mellitus. Multivariate analysis showed that cortisol was positively correlated with age (P = 0.016) and glycated hemoglobin (P = 0.011). There was no association between E/e' and cortisol in patients without diabetes mellitus. CONCLUSIONS: Increased cortisol levels might increase the risk of developing LVDD in diabetes mellitus patients..
69. Satoko Oda, Kenji Ashida, Makiko Uchiyama, Shohei Sakamoto, Nao Hasuzawa, Ayako Nagayama, Lixiang Wang, Hiromi Nagata, Ryuichi Sakamoto, Junji Kishimoto, Koji Todaka, Yoshihiro Ogawa, Yoichi Nakanishi, Masatoshi Nomura, An Open-label Phase I/IIa Clinical Trial of 11β-HSD1 Inhibitor for Cushing's Syndrome and Autonomous Cortisol Secretion., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgab450, 106, 10, e3865-e3880, 2021.09, CONTEXT: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors demonstrate antimetabolic and antisarcopenic effects in Cushing's syndrome (CS) and autonomous cortisol secretion (ACS) patients. OBJECTIVE: To confirm the efficacy and safety of S-707106 (11β-HSD1 inhibitor) administered to CS and ACS patients. DESIGN: A 24-week single-center, open-label, single-arm, dose-escalation, investigator-initiated clinical trial on a database. SETTING: Kyushu University Hospital, Kurume University Hospital, and related facilities. PATIENTS: Sixteen patients with inoperable or recurrent CS and ACS, with mildly impaired glucose tolerance. INTERVENTION: Oral administration of 200 mg S-707106 after dinner, daily, for 24 weeks. In patients with insufficient improvement in oral glucose tolerance test results at 12 weeks, an escalated dose of S-707106 (200 mg twice daily) was administered for the residual 12 weeks. MAIN OUTCOME MEASURES: The rate of participants responding to glucose tolerance impairment, defined as those showing a 25% reduction in the area under the curve (AUC) of plasma glucose during the 75-g oral glucose tolerance test at 24 weeks. RESULTS: S-707106 administration could not achieve the primary endpoint of this clinical trial (>20% of responsive participants). AUC glucose decreased by -7.1% [SD, 14.8 (90% CI -14.8 to -1.0), P = 0.033] and -2.7% [14.5 (-10.2 to 3.4), P = 0.18] at 12 and 24 weeks, respectively. S-707106 administration decreased AUC glucose significantly in participants with a high body mass index. Body fat percentage decreased by -2.5% [1.7 (-3.3 to -1.8), P < 0.001] and body muscle percentage increased by 2.4% [1.6 (1.7 to 3.1), P < 0.001]. CONCLUSIONS: S-707106 is an effective insulin sensitizer and antisarcopenic and antiobesity medication for these patients..
70. Yukina Takeichi, Takashi Miyazawa, Shohei Sakamoto, Yuki Hanada, Lixiang Wang, Kazuhito Gotoh, Keiichiro Uchida, Shunsuke Katsuhara, Ryuichi Sakamoto, Takaya Ishihara, Keiji Masuda, Naotada Ishihara, Masatoshi Nomura, Yoshihiro Ogawa, Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor., Diabetologia, 10.1007/s00125-021-05488-2, 64, 9, 2092-2107, 2021.09, AIMS/HYPOTHESIS: Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. METHODS: We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. RESULTS: MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. CONCLUSIONS/INTERPRETATION: We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH..
71. Hiroko Otsuka, Hisashi Yokomizo, Shintaro Nakamura, Yoshihiro Izumi, Masatomo Takahashi, Sachiko Obara, Motonao Nakao, Yosuke Ikeda, Naoichi Sato, Ryuichi Sakamoto, Yasutaka Miyachi, Takashi Miyazawa, Takeshi Bamba, Yoshihiro Ogawa, Differential effect of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice., The Biochemical journal, 10.1042/BCJ20210700, 479, 3, 425-444, 2022.02, There has been a concern that sodium-glucose cotransporter 2 (SGLT2) inhibitors could reduce skeletal muscle mass and function. Here, we examine the effect of canagliflozin (CANA), an SGLT2 inhibitor, on slow and fast muscles from nondiabetic C57BL/6J mice. In this study, mice were fed with or without CANA under ad libitum feeding, and then evaluated for metabolic valuables as well as slow and fast muscle mass and function. We also examined the effect of CANA on gene expressions and metabolites in slow and fast muscles. During SGLT2 inhibition, fast muscle function is increased, as accompanied by increased food intake, whereas slow muscle function is unaffected, although slow and fast muscle mass is maintained. When the amount of food in CANA-treated mice is adjusted to that in vehicle-treated mice, fast muscle mass and function are reduced, but slow muscle was unaffected during SGLT2 inhibition. In metabolome analysis, glycolytic metabolites and ATP are increased in fast muscle, whereas glycolytic metabolites are reduced but ATP is maintained in slow muscle during SGLT2 inhibition. Amino acids and free fatty acids are increased in slow muscle, but unchanged in fast muscle during SGLT2 inhibition. The metabolic effects on slow and fast muscles are exaggerated when food intake is restricted. This study demonstrates the differential effects of an SGLT2 inhibitor on slow and fast muscles independent of impaired glucose metabolism, thereby providing new insights into how they should be used in patients with diabetes, who are at a high risk of sarcopenia..
72. Shunsuke Katsuhara, Maki Yokomoto-Umakoshi, Hironobu Umakoshi, Yayoi Matsuda, Norifusa Iwahashi, Hiroki Kaneko, Masatoshi Ogata, Tazuru Fukumoto, Eriko Terada, Ryuichi Sakamoto, Yoshihiro Ogawa, Impact of Cortisol on Reduction in Muscle Strength and Mass: A Mendelian Randomization Study., The Journal of clinical endocrinology and metabolism, 10.1210/clinem/dgab862, 107, 4, e1477-e1487, 2022.03, CONTEXT: Prolonged exposure to pathological cortisol, as in Cushing's syndrome causes various age-related disorders, including sarcopenia. However, it is unclear whether mild cortisol excess, for example, accelerates sarcopenia due to aging or chronic stress. OBJECTIVE: We used Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass. METHODS: Three single-nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12 597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants. RESULTS: One SD increase in cortisol was associated with SD reduction in grip strength (estimate, -0.032; 95% CI -0.044 to -0.020; P = 3e-04), whole-body lean mass (estimate, -0.032; 95% CI, -0.046 to -0.017; P = 0.004), and appendicular lean mass (estimate, -0.031; 95% CI, -0.049 to -0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR Bayesian model averaging analysis. CONCLUSION: This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia..
73. Mitsuhide Naruse, Takuyuki Katabami, Hirotaka Shibata, Masakatsu Sone, Katsutoshi Takahashi, Akiyo Tanabe, Shoichiro Izawa, Takamasa Ichijo, Michio Otsuki, Masao Omura, Yoshihiro Ogawa, Yutaka Oki, Isao Kurihara, Hiroki Kobayashi, Ryuichi Sakamoto, Fumitoshi Satoh, Yoshiyu Takeda, Tomoaki Tanaka, Kouichi Tamura, Mika Tsuiki, Shigeatsu Hashimoto, Tomonobu Hasegawa, Takanobu Yoshimoto, Takashi Yoneda, Koichi Yamamoto, Hiromi Rakugi, Norio Wada, Aya Saiki, Youichi Ohno, Tatsuya Haze, Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021., Endocrine journal, 10.1507/endocrj.EJ21-0508, 2022.04, Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension..
74. Hiroki Kaneko, Hironobu Umakoshi, Masatoshi Ogata, Norio Wada, Takamasa Ichijo, Shohei Sakamoto, Tetsuhiro Watanabe, Yuki Ishihara, Tetsuya Tagami, Norifusa Iwahashi, Tazuru Fukumoto, Eriko Terada, Shunsuke Katsuhara, Maki Yokomoto-Umakoshi, Yayoi Matsuda, Ryuichi Sakamoto, Yoshihiro Ogawa, Machine learning-based models for predicting clinical outcomes after surgery in unilateral primary aldosteronism., Scientific reports, 10.1038/s41598-022-09706-8, 12, 1, 5781-5781, 2022.04, Unilateral subtype of primary aldosteronism (PA) is a common surgically curable form of endocrine hypertension. However, more than half of the patients with PA who undergo unilateral adrenalectomy suffer from persistent hypertension, which may discourage those with PA from undergoing adrenalectomy even when appropriate. The aim of this retrospective cross-sectional study was to develop machine learning-based models for predicting postoperative hypertensive remission using preoperative predictors that are readily available in routine clinical practice. A total of 107 patients with PA who achieved complete biochemical success after adrenalectomy were included and randomly assigned to the training and test datasets. Predictive models of complete clinical success were developed using supervised machine learning algorithms. Of 107 patients, 40 achieved complete clinical success after adrenalectomy in both datasets. Six clinical features associated with complete clinical success (duration of hypertension, defined daily dose (DDD) of antihypertensive medication, plasma aldosterone concentration (PAC), sex, body mass index (BMI), and age) were selected based on predictive performance in the machine learning-based model. The predictive accuracy and area under the curve (AUC) for the developed model in the test dataset were 77.3% and 0.884 (95% confidence interval: 0.737-1.000), respectively. In an independent external cohort, the performance of the predictive model was found to be comparable with an accuracy of 80.4% and AUC of 0.867 (95% confidence interval: 0.763-0.971). The duration of hypertension, DDD of antihypertensive medication, PAC, and BMI were non-linearly related to the prediction of complete clinical success. The developed predictive model may be useful in assessing the benefit of unilateral adrenalectomy and in selecting surgical treatment and antihypertensive medication for patients with PA in clinical practice..