Incidence of endocrine-related immune-related adverse events in Japanese subjects with various types of cancer

BackgroundImmune checkpoint inhibitors (ICIs), such as cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) inhibitors, and programmed cell death protein 1 ligand 1 (PD-L1) inhibitors, are often used to treat a variety of malignancies. ICIs are known to cause endocrine-related immune-related adverse events (irAEs), but the incidence varies among reports and/or agents. This study evaluated the incidence of endocrine-related irAEs in patients who were treated with ICIs in Japan.MethodThis single-center, retrospective, observational study examined the incidence and clinical characteristics of endocrine-related irAEs in 466 participants who were treated with ICIs at Kawasaki Medical School Hospital.ResultThe mean age of participants with and without endocrine-related irAEs was 69.1 ± 1.8 years and 68.1 ± 1.1 years, respectively, with no difference between them. The overall incidence of any endocrine-related irAEs among the participants was 25.5%. Hypothyroidism was prevalent in 24.3%, hypoadrenocorticism in 3.2%, hypopituitarism in 0.9%, and insulin-dependent diabetes mellitus in 1.1%. Participants receiving combination therapy with CTLA-4 and PD-1 inhibitors had a significantly higher incidence of endocrine-related irAEs than those receiving monotherapy.ConclusionEndocrine-related irAEs correlated significantly with survival and mean observation period. There was substantial difference in the incidence of endocrine-related irAEs among various types of ICIs and types of cancer. We should bear in mind that endocrine testing is necessary during the treatment with ICIs

含糖酸化鉄注射液の長期投与でFGF23関連低リン血症性骨軟化症を来たしたクローン病の１例

症例は50歳代，男性．クローン病で２年前に右半結腸切除術，小腸部分切除を施行．術後に他院にてアダリムマブを導入され，クローン病は臨床的寛解の状態であった．４か月前より下肢を中心とした疼痛が出現した．アダリムマブによる薬剤起因性ループスあるいは腸炎性関節炎を疑い，２か月前よりアダリムマブ投与を中止し，プレドニゾロンの内服を開始するも改善を認めなかった．血液検査にて，低リン血症と高アルカリフォスファターゼ血症を認め，精査治療目的で当院に紹介入院となった．骨塩定量検査にて骨密度の低下を，骨シンチグラフィーで疼痛を認める骨への多発取り込みを認め，骨軟化症と診断した．血清のfibroblast growth factor 23（FGF23）が175pg/ml と高値であり，入院前まで定期的に使用されていた含糖酸化鉄注射液による，FGF23関連低リン血症性骨軟化症と診断した．含糖酸化鉄注射液投与を中止し，リン製剤とビタミンD 製剤の投与を開始したところ，徐々に低リン血症と高アルカリフォスファターゼ血症の改善を認めた．その後の経過は良好で，FGF23値は徐々に低下を示し，下肢を中心とした疼痛は軽快し，退院した．長期的に含糖酸化鉄注射液を投与する場合は，FGF23関連低リン血症の早期発見のため，血中リン濃度を定期的に測定する必要がある．The case is a man in his 50s. He underwent operations of right half colon resection and small intestine segmental resection due to Crohn’s disease two years ago. After surgery, Adalimumab was introduced in other hospital, and he was a state of the clinical remission in Crohn’s disease. The sharp pain mainly on lower limbs develops from four months ago. We doubted drug origin-related lupus with Adalimumab or enteritis-related joint pain. Therefore, we stopped Adalimumab injection and started internal use of the prednisolone, however the symptoms did not improve and had continued for two months.Laboratory test showed hypophosphatemia and hyperphosphatasemia and then he was transported to our hospital. Bone mineral quantity showed bone salt decrease and bone scan showed increased uptakes in multiple bones. Fibroblast growth factor23 (FGF23) of the serum was high (175pg/ml), and we diagnosed him FGF23-mediated hypophosphatemic osteomalasia induced by prolonged administration of saccharated ferric acid.Saccharated ferric acid has regularly been used until hospitalization. After stopping the ferric acid injection, and taking phosphorus and vitamin D, hypophosphatemia and hyperphosphatasemia was gradually improved. FGF23 level gradually reduced, and the sharp pain mainly on lower limbs was relieved, and it became a discharge. Regular measurement of serum phosphorus concentration is necessary for early detection of the FGF23-related hypophosphatemia in patients with long term use of saccharated ferric acid

A Male Subject with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency Which Was Diagnosed at 31 Years Old due to Infertility

Introduction: Congenital adrenal hyperplasia is caused by deficiencies in a number of enzymes involved in hormone biosynthesis in the adrenal glands or sexual glands. Adrenocorticotropic hormone (ACTH) secretion is enhanced by decreased cortisol production, leading to adrenal hyperplasia. The frequency of 21-hydroxylase deficiency (21-OHD) was the highest among congenital hyperplasias, and in 1989 it became one of the target diseases for newborn screening in Japan. Case presentation: A 31-year-old Japanese male visited our institution due to infertility. On admission, his height was 151.7 cm (average ± SD in the same age, sex and population: 172.1 ± 6.1 cm). It was noted that his height had not changed since he was ten years old, and that pubic hair was observed when he was 7 years old. He had azoospermia and his gonadotropin level was low. He had low levels of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) but high levels of free testosterone. He had a low cortisol level and high ACTH level. Abdominal computed tomography (CT) showed swelling of bilateral adrenal glands, although morphology was normal. Based on these findings, he was diagnosed with primary adrenal insufficiency and admitted to our institution. His height had not changed since he was ten years old. In addition, pubic hair was observed when he was 7 years old. His sexual desire was decreased, although he had no general malaise or fatigue. He did not have pigmentation of the skin, genital atrophy or defluxion of pubic hair, although his body hair was relatively thin. In endocrinology markers, ACTH level was high (172.2 pg/mL) (reference range: 7.2–63.3 pg/mL), although his cortisol level was 6.9 μg/dL (4.5–21.1 μg/dL). These data suggest that he suffered from primary adrenal insufficiency. LH and FSH levels were both low, but free testosterone and estradiol levels were high. These data excluded the possibility of central hypogonadism. Furthermore, the level of 17a-hydroxyprogesterone, a substrate of 21-hydroxylase, and the level of pregnanetriol, a metabolite of progesterone in urine, were both markedly high. Based on these findings, we ultimately diagnosed this patient with 21-hydroxylase deficiency. Conclusions: We experienced a case of congenital adrenal hyperplasia due to 21-hydroxylase deficiency which was diagnosed in a 31-year-old male with infertility. Therefore, the possibility of 21-hydroxylase deficiency should be borne in mind in subjects with infertility who were born before 1989 and who had not undergone newborn screening for this disease

Comprehensive Search for GPCR Compounds which Can Enhance MafA and/or PDX-1 Expression Levels Using a Small Molecule Compound Library

It has been shown that chronic hyperglycemia gradually decreases insulin biosynthesis and secretion which is accompanied by reduced expression of very important insulin gene transcription factors MafA and PDX-1. Such phenomena are well known as β-cell glucose toxicity. It has been shown that the downregulation of MafA and/or PDX-1 expression considerably explains the molecular mechanism for glucose toxicity. However, it remained unknown which molecules can enhance MafA and/or PDX-1 expression levels. In this study, we comprehensively searched for G protein-coupled receptor (GPCR) compounds which can enhance MafA and/or PDX-1 expression levels using a small molecule compound library in pancreatic β-cell line MIN6 cells and islets isolated from nondiabetic C57BL/6 J mice and obese type 2 diabetic C57BL/KsJ-db/db mice. We found that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells. We confirmed that fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in islets from nondiabetic mice as well. Furthermore, these reagents more clearly enhanced MafA, PDX-1, or insulin expression levels in islets from obese type 2 diabetic db/db mice in which MafA and PDX-1 expression levels are reduced due to glucose toxicity. In conclusion, fulvestrant and dexmedetomidine hydrochloride increased MafA, PDX-1, or insulin expression levels in MIN6 cells and islets from nondiabetic mice and obese type 2 diabetic db/db mice. To the best of our knowledge, this is the first report showing some molecule which can enhance MafA and/or PDX-1 expression levels. Therefore, although further extensive study is necessary, we think that the information in this study could be, at least in part, useful at some point such as in the development of new antidiabetes medicine based on the molecular mechanism of β-cell glucose toxicity in the future

Dulaglutide exerts beneficial anti atherosclerotic effects in ApoE knockout mice with diabetes: the earlier, the better

Abstract There has been no report about the mechanism for anti-atherosclerotic effects of dulaglutide (Dula) and/or about the difference of its effectiveness between in an early and a late phase of diabetes. To address such questions, streptozotocin (STZ) was intraperitoneally injected to ApoE knockout mice at 8 weeks of age. Either Dula or vehicle was administered to STZ-induced diabetic ApoE knockout mice from 10 to 18 weeks of age as an early intervention group and from 18 to 26 weeks as a late intervention group. Next, non-diabetic ApoE knockout mice without STZ injection were subcutaneously injected with either Dula or vehicle. In an early intervention group, atherosclerotic lesion in aortic arch and Mac-2 and CD68-positive areas in aortic root were significantly smaller in Dula group. In abdominal aorta, expression levels of some villain factors were lower in Dula group. In a late intervention group, there were no immunohistological differences in aortic root and expression levels of various factors between two groups. Furthermore, even in non-diabetic ApoE knockout mice, expression levels of inflammatory and macrophage markers were reduced by treatment with Dula. Taken together, Dula exerts more beneficial anti-atherosclerotic effects in an early phase of diabetes rather than in a late phase