Generation of a mouse model of thyroid storm and preliminary investigation of the therapeutic effects of ghrelin.

BACKGROUND: Thyroid storm (TS), a life-threatening condition that can damage multiple organs, has limited therapeutic options. Hypercytokinemia is a suggested background, but the pathological condition is unclear and there are no appropriate animal models. We aimed to develop a TS mouse model by administration of triiodothyronine and lipopolysaccharide, and then to examine the effects of ghrelin on this model. METHODS: We evaluated the use of serum IL-6 levels as a representative marker of hypercytokinemia in patients with TS. To establish the mouse model, preliminary experiments were conducted to determine the non-lethal doses of triiodothyronine and lipopolysaccharide when administered individually. As a TS model, C57BL/6 mice were administered with triiodothyronine 1.0 mg/kg (subcutaneously, once daily for seven consecutive days) and lipopolysaccharide 0.5 mg/kg (intraperitoneally, on day 7) to develop a lethal model with approximately 30% survival on day 8. We assessed the survival ratio, mouse sepsis scores and blood biomarkers (IL-6, metanephrine, alanine aminotransferase) and evaluated the effects of ghrelin 300 µg/kg on these parameters in TS model. RESULTS: Serum IL-6 was increased in patients with TS compared with those with Graves' disease as the diseased control (18.2 vs. 2.85 pg/mL, P < .05, n = 4 each). The dosage for the murine TS model was triiodothyronine 1.0 mg/kg and lipopolysaccharide 0.5 mg/kg. The TS model group had increased mouse sepsis score, serum IL-6, metanephrine and alanine aminotransferase. In this model, the ghrelin improved the survival rate to 66.7% (P < .01, vs. 0% [saline-treated group]) as well as the mouse sepsis score, and it decreased the serum IL-6 and metanephrine. CONCLUSION: We established an animal model of TS that exhibits pathophysiological states similar to human TS with induction of serum IL-6 and other biomarkers by administration of T3 and LPS. The results suggest the potential effectiveness of ghrelin for TS in humans.

Prospective Multicenter Registry-Based Study on Thyroid Storm: The Guidelines for the Management from Japan are Useful.

CONTEXT: The mortality rate in thyroid storm (TS) has been reported to be higher than 10%. OBJECTIVE: We aimed to evaluate the effectiveness of the 2016 guidelines for the management of TS proposed by the Japan Thyroid Association and Japan Endocrine Society. DESIGN: Prospective registry-based study through a secure web platform. SETTING: Prospective multicenter registry. PATIENTS AND MEASUREMENTS: Patients with new-onset TS were registered in the Research Electronic Data Capture (REDCap). On day 30 after admission, clinical information and prognosis of each patient were added to the platform. On day 180, the prognosis was described. RESULTS: This study included 110 patients with TS. The median of Acute Physiology and Chronic Health Evaluation (APACHE) II score was 13, higher than the score in the previous nationwide epidemiological study, 10 (p = 0.001). Nonetheless, the mortality rate at day 30 was 5.5%, approximately half compared with 10.7% in the previous nationwide survey. Lower body mass index, shock and lower left ventricular ejection fraction were positively associated with poor prognosis at day 30, while the lack of fever ≥ 38℃ was related to the outcome. The mortality rate in patients with an APACHE II score ≥12 for whom the guidelines were not followed was significantly higher than the rate in patients for whom the guidelines were followed (50% vs. 4.7%) (p = 0.01). CONCLUSIONS: Prognosis seemed better than in the previous nationwide survey, even though disease severity was higher. The mortality rate was lower when the guidelines were followed. Thus, the guidelines are useful for managing TS.

Thyroid function, glycemic control, and diabetic nephropathy in patients with type 2 diabetes over 24 months: prospective observational study.

BACKGROUND: The higher prevalence of thyroid dysfunction in type 1 diabetes patients has been well established, whereas it is a matter of debate whether that is also observed in type 2 diabetes patients. This study was conducted to reveal whether higher prevalence of thyroid dysfunction is observed in patients with type 2 diabetes. METHODS: We examined thyroid functions and thyroid autoantibodies in 200 patients with type 2 diabetes and 225 controls, with 24 months follow up for those with type 2 diabetes. RESULTS: Serum free triiodothyronine (fT3) levels and fT3/free thyroxine (fT4) ratio were significantly lower, while fT4 levels were significantly higher in patients with type 2 diabetes. The number of patients with thyroid dysfunction or patients positive for thyroid autoantibodies were not different between the two groups. The fT3/fT4 ratio was positively and negatively correlated with serum c-peptide and HbA1c levels, respectively, suggesting that the difference can be attributable to insulin resistance and diabetic control. In the follow-up observation, we found no significant correlation between basal thyrotropin (TSH), fT3, fT4 or fT3/fT4 ratio with the amounts of changes of HbA1c levels at 12 or 24 months after the basal measurements. There was a negative relationship between TSH levels and eGFR at baseline measurements, but TSH levels did not seem to predict future decline of eGFR levels. No relationship was observed between urine albumin/ g‧cre levels and thyroid function. CONCLUSION: Thyroid dysfunction and thyroid autoantibodies were not different in prevalence between patients with type 2 diabetes and controls, although in patients with type 2 diabetes, the fT3/fT4 ratio was decreased. Basal thyroid function did not predict future diabetes control or renal function within 24 months of follow-up.

Effect of SARS-CoV-2 BNT162b2 mRNA vaccine on thyroid autoimmunity: A twelve-month follow-up study.

Objectives: Graves' disease (GD) has been highlighted as a possible adverse effect of the respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine. However, it is unknown if the SARS-CoV-2 vaccine disrupts thyroid autoimmunity. We aimed to present long-term follow-up of thyroid autoimmunity after the SARS-CoV-2 BNT162b2 mRNA vaccine. Methods: Serum samples collected from seventy Japanese healthcare workers at baseline, 32 weeks after the second dose (pre-third dose), and 4 weeks after the third dose of the vaccine were analyzed. The time courses of anti-SARS-CoV-2 spike immunoglobulin G (IgG) antibody, thyroid-stimulating hormone receptor antibody (TRAb), and thyroid function were evaluated. Anti-thyroglobulin antibodies (TgAb) and anti-thyroid peroxidase antibodies (TPOAb) were additionally evaluated in thirty-three participants. Results: The median age was 50 (IQR, 38-54) years and 69% were female. The median anti-spike IgG antibody titer was 17627 (IQR, 10898-24175) U/mL 4 weeks after the third dose. The mean TRAb was significantly increased from 0.81 (SD, 0.05) IU/L at baseline to 0.97 (SD, 0.30) IU/L 4 weeks after the third dose without functional changes. An increase in TRAb was positively associated with female sex (ß = 0.32, P = 0.008) and low basal FT4 (ß = -0.29, P = 0.02) and FT3 (ß = -0.33, P = 0.004). TgAb was increased by the third dose. Increase in TgAb was associated with history of the thyroid diseases (ß = 0.55, P <0.001). Conclusions: SARS-CoV-2 BNT162b2 mRNA vaccine can disrupt thyroid autoimmunity. Clinicians should consider the possibility that the SARS-CoV-2 vaccine may disrupt thyroid autoimmunity.

Clinical Challenges in Diagnosis, Tumor Localization and Treatment of Tumor-Induced Osteomalacia: Outcome of a Retrospective Surveillance.

Tumor-induced osteomalacia (TIO) is an acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemic osteomalacia caused by phosphaturic mesenchymal tumors (PMTs) developed in the bone or soft tissue. Diagnostic delay should be addressed, and ideal techniques to localize PMTs and efficient treatment options should be explored to improve the outcomes of this rare disease. To clarify the detailed clinical course and outcomes of TIO patients, retrospective questionnaire surveys were conducted among physicians from the Japanese Society for Bone and Mineral Research (JSBMR) and the Japan Endocrine Society (JES). The primary survey collected the number of TIO patients between January 2007 and December 2018. The secondary survey aimed to obtain the detailed characteristics, laboratory data, and outcomes. Eighty-eight patients (52 males, mean: 52 years old) were included, and 24 patients were clinically diagnosed with TIO without localized PMTs. The median duration from the onset to detection of high FGF23 levels was 3.4 years, with 77 patients being initially misdiagnosed. Among the methods used to detect small, localized PMTs (≤10 mm), fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography and somatostatin receptor scintigraphy were less sensitive than somatostatin receptor positron emission tomography/computed tomography (SRPET/CT). Systemic venous sampling (SVS) of FGF23 was performed in 53 patients; among them, SVS was considered useful for detecting localized PMTs in 45 patients with diverse tumor sizes. Finally, 45 patients achieved biochemical remission by surgery, 39 patients continued pharmaceutical treatment, including burosumab (11 patients), and four patients died. These results encouraged us to further increase the awareness of TIO and to improve the accessibility of SRPET/CT and SVS. Further evidence about the efficacy of new pharmaceutical treatments is awaited. © 2022 American Society for Bone and Mineral Research (ASBMR).

Hypopituitarism and cranial nerve involvement mimicking Tolosa-Hunt syndrome as the initially presenting feature of diffuse large B-cell lymphoma: a case report.

BACKGROUND: Early diagnosis of lymphoma involving the central nervous system is sometimes difficult but emergent to avoid the delay of therapeutic initiation. Pituitary insufficiencies are usually associated with lymphoma in the pituitary gland. There have been no cases of lymphoma originating from extra pituitary gland with hypopituitarism that simultaneously presenting unilateral upper cranial nerve palsies and ophthalmalgia. These symptoms are mostly caused by neoplastic involvement of the skull base or benign diseases such as Tolosa-Hunt syndrome (THS). We report a case of lymphoma with unique clinical courses initially presenting hypopituitarism and symptoms mimicking THS with a mass in sphenoidal and cavernous sinuses accompanying sphenoidal bone erosion. CASE PRESENTATION: A 71-year-old woman visited our hospital with left ophthalmalgia, ptosis, and diplopia. Neurological findings revealed left oculomotor, trochlear and abducent nerve palsies. Endocrine tests indicated partial hypopituitarism. Initial CT and MRI revealed that a mass in sphenoidal and cavernous sinuses had invaded the sella with osteolysis of the sphenoid bone. At around four weeks, almost all the symptoms of cranial nerve palsies were relieved. Seven weeks later, she had a high fever and cervical lymph node (CLN) swellings. CLN biopsy revealed CD20-positive B-cells. She was diagnosed with diffuse large B-cell lymphoma (DLBCL). 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) revealed elevated uptake at the erosion lesion of the sphenoidal bone, but not the pituitary gland. After chemotherapy, all the symptoms related to systemic lymphoma were relieved, but partial hypopituitarism remained. The mass in sphenoidal and cavernous sinuses and elevated uptake by PET/CT were dissolved. CONCLUSION: This case of DLBCL had a unique clinical course; initial presentation of hypopituitarism and symptoms mimicking THS. There was also rare demonstration of mass lesions related to DLBCL in the sphenoidal and cavernous sinuses compressing the pituitary gland through an eroded area of the sphenoidal bone. It should be clinically cautioned that DLBCL can be associated with erosion of the sphenoidal bone and cause both hypopituitarism and THS-mimicking symptoms.

Computed tomography imaging using split-bolus contrast injection with volume scan of aortic root and heart for preoperative evaluation of transcatheter aortic valve implantation.

The purpose of this study was to investigate using split-bolus contrast injection (SPBI) with volume scanning of the heart and aortic root with helical scanning of the access route, compared to single bolus contrast injection (SI) with variable helical pitch scanning (VHP) of the heart and aortic root and access route in a preoperative evaluation before transcatheter aortic valve implantation (TAVI). Thirty-five patients who underwent preoperative CT before TAVI using SPBI (contrast media: 24.5 mgI /kg/s, injected for 12 s for heart scan and then injected for 8 s for access route) were examined. Electrocardiogram (ECG) gated scans of the heart were performed by volume scan, after a period of time, non-gated helical scans of the aorto-iliac were performed (SPBI method). For comparison, 40 patients who had a single bolus injection (26.5 mg I/kg/s, injected for period of the scan time plus 3 s) and a VHP scan (SI method) before the SPBI method was performed were included in the study. The image qualities of the coronary arteries, aortic root, and access route (aorta-iliac), as well as radiation and iodine doses, were assessed. In visual assessment, image quality of coronary artery was significantly better with the SPBI method (grade; excellent: 57.1% in SPBI vs. 24.3% in SI, p = 0.03). There was no significant difference in image quality of the aortic root by visual assessment. The signal-to-noise (SNR) and contrast-to-noise ratio (CNR) of coronary and aortic root were not significantly different between the two methods. The access route showed significantly higher SNR (45.7 ± 11.5 vs. 34.3 ± 9.8, p < 0.001) and CNR (36.0 ± 9.7 vs. 28.0 ± 8.8, p < 0.001) for the SPBI method. The SPBI method compared to SI method reduced iodine dose by 10% and radiation dose by 45%. Preoperative CT imaging before TAVI using SPBI with volume scan is useful and can reduce iodine and radiation doses.

A comparison of automatic and manual compensation methods for the calculation of tube currents during off-centered patient positioning with a noise-based automatic exposure control system in computed tomography.

Automatic exposure control (AEC) is used to optimize the X-ray tube output during computed tomography (CT) scans. However, calculation of the tube current by AEC can be affected when a patient is not aligned with the rotational center of the X-ray tube. An automatic couch height-positioning compensation mechanism provides a corrective function when the patient is off-center. In this study, we aimed to (a) evaluate the performance characteristics of the positioning compensation mechanism and (b) confirm whether our proposed compensation method can be properly applied to a noise-based AEC system even if the CT device is not equipped with a positioning compensation mechanism. An elliptical phantom was scanned at various table heights on systems without/with the positioning compensation mechanism. Expressions describing the offset from the gantry's isocenter and adjusted standard deviation settings were derived and used in our proposed compensation method. A phantom was scanned at various table heights with our proposed compensation method, and volume CT dose index (CTDIvol) and image noise levels were obtained. An anthropomorphic chest phantom was also scanned using the proposed compensation method to verify its accuracy. When the positioning compensation mechanism was used, it yielded a constant CTDIvol and image noise levels at various table heights tested. A comparison between our proposed method and the positioning compensation mechanism for both the elliptical and chest phantoms yielded similar CTDIvol. Therefore, both automatic and manual positioning compensation methods are useful for avoiding AEC miscalculations in off-centered patient positioning cases.

Characterization of Small Dosimeters Used for Measurement of Eye Lens Dose for Medical Staff during Fluoroscopic Examination.

This study aimed to evaluate the property of small dosimeters used for measuring eye lens doses for medical staff during fluoroscopic examination. Dose linearity, energy dependence, and directional dependence of scattered X-rays were evaluated for small radiophotoluminescence glass dosimeters (RPLDs), those with a tin filter (Sn-RPLDs), and small optically stimulated luminescence dosimeters (OSLDs). These dosimeters were pasted on radioprotective glasses, and accumulated air kerma was obtained after irradiating the X-rays to a patient phantom. Strong correlations existed between fluoroscopic time and accumulated air kerma in all types of dosimeters. The energy dependence of Sn-RPLD and OSLD was smaller than that of RPLD. The relative dose value of the OSLD gradually decreased as the angle of the OSLD against the scattered X-rays was larger or lower than the right angle in the horizontal direction. The ranges of relative dose values of RPLD and Sn-RPLD were larger than that of OSLD in the vertical direction. The OSLDs showed lower doses than the RPLDs and Sn-RPLDs, especially on the right side of the radioprotective glasses. These results showed that RPLDs, Sn-RPLDs, and OSLDs had different dosimeter properties, and influence measured eye lens doses for the physician, especially on the opposite side of the patient.

Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report.

We report the first case of intraoperatively detected euglycemic diabetic ketoacidosis (DKA) associated with sodium-glucose cotransporter 2 inhibitors during thoracic surgery. A 59-year-old man had a 12-year history of type 2 diabetes mellitus treated with insulin and empagliflozin. The patient developed bacterial empyema and was initiated with antibiotics at a local hospital. Owing to the persistence of his symptoms, he was transferred to our hospital after the medication of empagliflozin the day before surgery. After overnight fasting, the patient underwent thoracoscopic debridement and intrathoracic lavage surgery. During this surgery, he was noted to have euglycemic ketosis and acidosis, and diagnosed as euglycemic DKA. Immediately after the consultation in our department, the patient underwent treatment for DKA. He awoke from anesthesia normally and showed no symptoms of DKA. DKA gradually resolved over the next 24 h. Early identification and management are critical for rapid recovery from perioperative euglycemic DKA associated with sodium-glucose cotransporter 2 inhibitors, especially during thoracic surgery.

Inadequate object positioning and improvement of automatic exposure control system calculations based on an empirical algorithm.

When using automatic exposure control (AEC) systems in computed tomography (CT), miscalculation of tube current occurs when a patient is not aligned with the rotational center of the X-ray tube. A positioning compensation mechanism provides a corrective function when the patient is off-center; however, not all CT systems are equipped with this mechanism. AEC systems can broadly be divided into noise- and empirical-based. The authors studied empirical-based AEC systems to derive a compensation process to achieve an equivalent effect to that offered by the mechanism and to verify the accuracy of this process. A relational equation was derived to keep the tube current constant with variations in table height and quality reference milliampere-seconds (QRmAs), and this was adopted as the proposed compensation method. The radiation dose and image quality were evaluated for phantom imaging with and without the proposed compensation method using AEC and varying table heights. The output radiation dose and image quality were also evaluated for anthropomorphic chest phantom imaging to verify the compensatory effect of the proposed method. With the proposed compensation method, changes in the table height resulted in only small changes in the output radiation dose and noise level. Conversely, when the proposed compensation method was not used, changes in the table height resulted in widely varying output radiation dose and noise level. Imaging the anthropomorphic chest phantom with the proposed compensation method also yielded a stable output radiation dose.

False-positive staining of thyroglobulin distinguished from mixed medullary and follicular thyroid carcinoma by duplex in situ hybridization.

Medullary thyroid carcinoma (MTC) may mimic mixed medullary and follicular thyroid carcinoma (MMFTC). MTC originates from para-follicular cells, while MMFTC is an uncommon tumor characterized by coexistence of follicular and para-follicular cell-derived tumor populations. A 35-year-old woman was diagnosed with MTC but showed a hot nodule in thyroid scintigraphy. The tumor included diffusely-spread follicular lesions within it, which were immunostained with thyroglobulin and calcitonin. Immunofluorescence showed the presence of several tumor cells that were double-stained with thyroglobulin and calcitonin. To clarify whether or not the tumor was MMFTC, we used duplex in situ hybridization (ISH). Thyroglobulin and calcitonin-related polypeptide alpha mRNA were not expressed together in a single cell, so we suspected false-positive staining of tumor cells with thyroglobulin. To make comparisons with other follicular lesions in MTC, we searched our hospital database. Five cases within a ten-year period had been pathologically diagnosed as MTC. All had follicular lesions in the tumor, but unlike the other case, they were peripherally localized. Dual differentiation into follicular or para-follicular tumor cells was not indicated by either immunofluorescence or duplex ISH. Compared with the case suspected to be MMFTC, there was only mild invasion of tumor cells into the follicular epithelium. The extent of follicular lesions and invasiveness of tumor cells may be associated with pseudo-staining of thyroglobulin in MTC. Duplex ISH can distinguish MTC that are stained with thyroglobulin from MMFTC.

Expression of unfolded protein response markers in the pheochromocytoma with Waardenburg syndrome: a case report.

BACKGROUND: It is clinically emergent to further understand the pathological mechanism to advance therapeutic strategy for endocrine tumors. A high amount of secretory protein with tumorigenic triggers are thought to induce unfolded protein response in endoplasmic reticulum in endocrine tumors, but its evidence is limited. CASE PRESENTATION: A 40-year-old woman had an approximately 10-year history of intermittent headaches. After the incidental detection of a mass in her right adrenal gland by CT scan, she was admitted to our hospital. She had been diagnosed as type 1 Waardenburg syndrome with the symptoms of dystopia canthorum, blue iris, and left sensorineural hearing loss. Urinary catecholamine levels were markedly elevated. 123I-MIBG scintigraphy showed uptake in the mass in her adrenal gland. After the adrenalectomy, her headaches disappeared and urinary catecholamine levels decreased to normal range within 2 weeks. Genome sequencing revealed germline mutation of c.A175T (p.Ile59Phe) in transcription factor PAX3 gene and somatic novel mutation of c.1893_1898del (p. Asp631_Leu633delinsGlu) in proto-oncogene RET in her pheochromocytoma. RNA expression levels of RET were increased 139 times in her pheochromocytoma compared with her normal adrenal gland. Those of unfolded protein response markers, Bip/GRP78, CHOP, ATF4, and ATF6, were also increased in the pheochromocytoma. CONCLUSION: We report a rare case of pheochromocytoma with type 1 Waardenburg syndrome. This is the first case to show the activation of unfolded protein response in the pheochromocytoma with the novel somatic mutation in RET gene. Our findings may support that unfolded protein response is activated in endocrine tumors, which potentially could be a candidate of therapeutic target.

The influence of thyroid autoimmunity on pregnancy outcome in infertile women: a prospective study.

Thyroid dysfunction and thyroid autoimmunity (TAI) have been reported to be linked to infertility, pregnancy loss and preterm birth. Infertile women undergoing assisted reproductive technology are recommended to maintain thyroid stimulating hormone (TSH) levels below 2.5 µIU/mL. It is unclear, however, whether levothyroxine (L-T4) treatment decreases the effects of TAI on fertility and pregnancy outcome in infertile women. We therefore aimed to clarify the influence of TAI on pregnancy undergoing L-T4 treatment for hypothyroidism. Prospectively recruited to this study were the 595 infertile women who visited the Utsunomiya Ladies Clinic between January 2013 and December 2015. Five patients with Graves' disease were excluded. Clinical profiles of 590 women were as follows: proportion of SCH = 19.6%, thyroid peroxidase antibody (TPOAb) positivity = 10.4%, and thyroglobulin antibody (TgAb) positivity = 15.1%. Fertility was not affected by any thyroid-associated factors. Regarding pregnancy outcomes, TPOAb titers were significantly higher in women who had miscarriage than in those progressed to delivery (46.4 ± 114.1 vs. 18.9 ± 54.6 IU/mL, p = 0.039), notably in those undergoing intrauterine insemination (p = 0.046) and in vitro fertilization (p = 0.023). Multivariate logistic regression analysis revealed that higher age (odds ratio 26.4, p < 0.001) and higher TPOAb titer (odds ratio 11.8, p = 0.043) were risk factors for miscarriage. Higher TPOAb titer should be considered as one of the risk factors for miscarriage in infertile women, even if they have been treated with L-T4 for hypothyroidism.

Autoimmune polyglandular syndrome type 2 and autoimmune hepatitis with thymoma-associated myasthenia gravis: case report.

BACKGROUND: Autoimmune polyglandular syndrome type 2 (APS-2) is a rare and complex clinical entity, and little is known about its etiology and progression. CASE PRESENTATION: A 52-year-old woman with autoimmune hepatitis (AIH) and bronchial asthma was diagnosed with APS-2; autoimmune Addison's disease (AD), and Hashimoto's thyroiditis (HT), and she underwent prednisolone (PSL) treatment. Five months later, she presented ptosis and was diagnosed with thymoma-associated myasthenia gravis (MG). Thymectomy and PSL treatment with immuno-suppressants appeared to ameliorate MG, AD, AIH, HT, and bronchial asthma. HLA typing analysis revealed that the patient had susceptible HLA alleles to MG, AIH, and HT in a Japanese population. CONCLUSIONS: This case suggests common endocrinological and autoimmune aspects of APS-2 and AIH with thymoma-associated MG, which are considered to be extremely rare complications.

Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.

Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (≤4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1ß, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.

Nicotinic acetylcholine receptor signaling regulates inositol-requiring enzyme 1α activation to protect ß-cells against terminal unfolded protein response under irremediable endoplasmic reticulum stress.

AIMS/INTRODUCTION: Under irremediable endoplasmic reticulum (ER) stress, hyperactivated inositol-requiring enzyme 1α (IRE1α) triggers the terminal unfolded protein response (T-UPR), causing crucial cell dysfunction and apoptosis. We hypothesized that nicotinic acetylcholine receptor (nAChR) signaling regulates IRE1α activation to protect ß-cells from the T-UPR under ER stress. MATERIALS AND METHODS: The effects of nicotine on IRE1α activation and key T-UPR markers, thioredoxin-interacting protein and insulin/proinsulin, were analyzed by real-time polymerase chain reaction and western blotting in rat INS-1 and human EndoC-ßH1 ß-cell lines. Doxycycline-inducible IRE1α overexpression or ER stress agents were used to induce IRE1α activation. An α7 subunit-specific nAChR agonist (PNU-282987) and small interfering ribonucleic acid for α7 subunit-specific nAChR were used to modulate nAChR signaling. RESULTS: Nicotine inhibits the increase in thioredoxin-interacting protein and the decrease in insulin 1/proinsulin expression levels induced by either forced IRE1α hyperactivation or ER stress agents. Nicotine attenuated X-box-binding protein-1 messenger ribonucleic acid site-specific splicing and IRE1α autophosphorylation induced by ER stress. Furthermore, PNU-282987 attenuated T-UPR induction by either forced IRE1α activation or ER stress agents. The effects of nicotine on attenuating thioredoxin-interacting protein and preserving insulin 1 expression levels were attenuated by pharmacological and genetic inhibition of α7 nAChR. Finally, nicotine suppressed apoptosis induced by either forced IRE1α activation or ER stress agents. CONCLUSIONS: Our findings suggest that nAChR signaling regulates IRE1α activation to protect ß-cells from the T-UPR and apoptosis under ER stress partly through α7 nAChR. Targeting nAChR signaling to inhibit the T-UPR cascade may therefore hold therapeutic promise by thwarting ß-cell death in diabetes.

Thyroid storm with delayed hyperbilirubinemia and severe heart failure: indication and contraindication of plasma exchange.

SUMMARY: Thyroid storm (TS) is a life-threatening condition that may suffer thyrotoxic patients. Therapeutic plasma exchange (TPE) is a rescue approach for TS with acute hepatic failure, but it should be initiated with careful considerations. We present a 55-year-old male patient with untreated Graves' disease who developed TS. Severe hyperthyroidism and refractory atrial fibrillation with congestive heart failure aggregated to multiple organ failure. The patient was recovered by intensive multimodal therapy, but we had difficulty in introducing TPE treatment considering the risk of exacerbation of congestive heart failure due to plasma volume overload. In addition, serum total bilirubin level was not elevated in the early phase to the level of indication for TPE. The clinical course of this patient instructed delayed elevation of bilirubin until the level of indication for TPE in some patients and also demonstrated the risk of exacerbation of congestive heart failure by TPE. LEARNING POINTS: Our patient with thyroid storm could be diagnosed and treated promptly using Japan Thyroid Association guidelines for thyroid storm. Delayed elevation of serum bilirubin levels could make the decision of introducing therapeutic plasma exchange difficult in cases of thyroid storm with acute hepatic failure. The risk of worsening congestive heart failure should be considered carefully when performing therapeutic plasma exchange.

Comparative analysis of human leucocyte antigen between idiopathic and anti-PD-1 antibody induced isolated adrenocorticotropic hormone deficiency: A pilot study.

BACKGROUND: Adult-onset idiopathic isolated adrenocorticotropic hormone deficiency (id-IAD) is a rare disease with unknown aetiology. Recently, numerous cases of anti-PD-1 antibody-induced IAD (PD1-IAD) have been reported, but the clinical course, predictive factors and relationship to id-IAD have not been clarified. Moreover, associations of id-IAD and PD1-IAD with human leucocyte antigen (HLA) require elucidation. METHODS: Clinical characteristics of 13 Japanese patients with id-IAD and eight Japanese patients with PD1-IAD were analysed, and HLA-typing test was performed for each patient. Allele and haplotype frequencies of the patients were compared to those of healthy Japanese controls. RESULTS: In the HLA allele and haplotype analyses of id-IAD, the frequencies of HLA-C*14:02, HLA-DPB1*05:01, HLA-DRB1*04:05-DQB1*04:01-DPB1*05:01 and HLA-DRB1*09:01-DQB1*03:03-DPB1*05:01 were significantly increased. On the other hand, HLA alleles account for PD1-IAD susceptibility as follows: HLA-DQB1*06:01, HLA-DPB1*09:01 and HLA-DRB5*01:02. Moreover, protective effect for HLA-C*03:03 was suggested in combined id-IAD and PD1-IAD patients. Comparison of the effects of HLA on id-IAD and PD1-IAD revealed some differences. Alleles or haplotypes frequencies increased in id-IAD group were as follows: HLA-DPB1*05:01, HLA-DRB1*09:01, HLA-DRB4*01:03:02, HLA-DQB1*03:03 and HLA-DRB1*09:01-DQB1*03:03. In clinical settings, hyponatremia, disturbance of consciousness and hypoglycaemia were less frequently seen in patients with PD1-IAD than in patients with id-IAD. CONCLUSIONS: Distinct clinical characteristics and predisposing HLA allele contributions were proposed between id-IAD and PD1-IAD. Further investigations with greater number of cases are warranted to clarify the detailed mechanisms of id-IAD and PD1-IAD.

Thyrotoxicosis and Adrenocortical Hormone Deficiency During Immune-checkpoint Inhibitor Treatment for Malignant Melanoma.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) are novel promising agents for the treatment of malignant tumors. However, critical endocrine immune-related adverse events (irAEs) by ICIs often occur. CASE REPORT: A 63-year-old woman with advanced malignant melanoma had received anti-PD-1 antibody (nivolumab, 2 mg/kg every 3 weeks) for 8 cycles (from day 0 to day 147). On day 168, nivolumab was switched to anti-CTLA-4 antibody (ipilimumab, 3mg/kg every 3 weeks). Twenty-eight days later, she was diagnosed with thyrotoxicosis due to painless thyroiditis (day 196). Thirty-five days later (day 231), thyrotoxicosis turned to hypothyroidism. In addition, twenty-five days later (day 256), she was diagnosed with adrenocortical insufficiency due to adrenocortical hormone (ACTH) deficiency. Hormone replacements with levothyroxine and hydrocortisone were administered. She showed eosinophilia, ESR/CRP/LDH elevation, liver dysfunction and hyponatremia before diagnosis of ACTH insufficiency. Eosinophilia, thrombocytopenia, ESR/CRP/LDH elevation, and liver dysfunction might be important for early detection of thyrotoxicosis in our case. CONCLUSION: The present report provides the first detailed presentation of combined thyrotoxicosis and isolated ACTH deficiency induced by ICIs. Since rapidly progressive fatal endocrine system failure may be provoked during ICI therapy, precise diagnosis and prompt treatment as well as close follow-up is critical. We propose routine monitoring of endocrine functions and related symptoms (worsened fatigue, hypoglycemia, hypotension or hyponatremia), as well as other laboratory tests during ICI therapy.