Nivolumab-induced hypophysitis followed by acute-onset type 1 diabetes with renal cell carcinoma: a case report.

BACKGROUND: Immune checkpoint inhibitors have recently become widely used for the management of advanced cancer patients. During the development of immune checkpoint inhibitors (ICPIs), it was quickly recognized that they are associated with autoimmune or autoinflammatory side effects. These toxicities are known as immune-related adverse events (irAEs): common endocrine irAEs include hypophysitis and thyroid dysfunction, and uncommon irAEs include type 1 diabetes mellitus (T1DM). CASE PRESENTATION: A 62-year-old Japanese man with metastatic renal cell carcinoma was treated with sunitinib followed by the 10th cycle of treatment with the ICPI nivolumab. He had already had thyroiditis and hypophysitis due to these anti-cancer drugs. On admission, he showed an extremely elevated plasma glucose level (601 mg/dl) and a low C-peptide level, and was diagnosed with acute T1DM. The patient was treated with intravenous fluid infusion and continuous insulin infusion. On the second day, he was switched to multiple daily injections of insulin therapy. Since these treatments, his blood glucose levels have been stable and he has been treated with an additional 10 ICPI treatments for renal cell carcinoma for over a year. CONCLUSIONS: Treatment with ICPIs is expected to increase in the future. There may be cases in which their use for cancer treatment is inevitable despite the side effects. As long as treatment with ICPI continues, multiple side effects can be expected in some cases. It is important to carefully observe the side effects that occur during ICPI treatment and to provide appropriate treatment for each side effect.

Bilateral Adrenocortical Adenomas along with Virilization and Cushing's Syndrome.

We herein present the case of a 27-year-old woman with clinical and biochemical features of virilism. Imaging studies revealed the presence of a bilateral adrenal tumor. Although the secretion of androgens was remarkable, the autonomous production of cortisol was also evident because of a loss of circadian rhythm and the absence of cortisol suppression by dexamethasone. The surgical excision of both adrenal tumors was performed, and the histological examination showed no malignancy. We also report the successful pregnancy and delivery of the patient who showed evolving adrenocortical insufficiency along with virilization and Cushing's syndrome and who continued to receive glucocorticoid replacement therapy during pregnancy.

Effect of TNF-α on the expression of ABCA1 in pancreatic ß-cells.

ATP-binding cassette transporter A1 (ABCA1), a 254-kD membrane protein, is a key regulator of lipid efflux from cells to apolipoproteins. ABCA1 in pancreatic ß-cells influences insulin secretion and cholesterol homeostasis. Tumor necrosis factor (TNF)-α is a pleiotropic cytokine that elicits a wide spectrum of physiological events, including cell proliferation, differentiation, and apoptosis, and is also known to decrease glucose-dependent insulin secretion in pancreatic islets. In the present study, we examined the role of TNF-α on ABCA1 expression in rat pancreatic islets and INS-1 cells. ABCA1 protein levels decreased in response to rising concentrations of TNF-α in pancreatic islets. Real-time polymerase chain reaction analysis showed a significant decrease in ABCA1 mRNA expression. In parallel with its effect on endogenous ABCA1 mRNA levels, TNF-α suppressed the activity of a reporter construct containing the ABCA1 promoter. This effect was abrogated by BIRB796, but not by SB203580 or PD98095. The constitutively active form of p38 mitogen-activated protein kinase (MAPK) γ suppressed ABCA1 promoter activity but not p38-MAPK (α, ß), while a dominant-negative mutant of p38-MAPK γ blocked the effect of TNF-α on ABCA1 promoter activity. BIRB796 inhibited the increased cholesterol ester content induced by TNF-α. However, BIRB796 had no effect on the decreased insulin content nor ABCA1 suppression caused by TNF-α in INS-1 cells. In summary, TNF-α suppressed the expression of endogenous ABCA1 in pancreatic islets and INS-1 cells. These findings raise the possibility that TNF-α may affect insulin secretion by controlling ABCA1 expression.

Combination therapy of ipilimumab and nivolumab induced thyroid storm in a patient with Hashimoto's disease and diabetes mellitus: a case report.

BACKGROUND: Recently, immune checkpoint inhibitors have widely been used for the management of advanced melanoma. However, high-grade immune-related adverse events can occur, particularly with combination immunotherapy. We report a case of a patient with melanoma who developed thyroid storm following treatment with ipilimumab and nivolumab. CASE PRESENTATION: An 85-year-old Japanese man with a history of malignant melanoma presented to our department with severe thyrotoxicosis and poor blood glucose control. He was already being treated for Hashimoto's disease and type 2 diabetes mellitus before the treatment for the melanoma. During admission, laboratory investigations revealed the following thyroid functions: thyroid-stimulating hormone below sensitivity, free triiodothyronine 31.7 pg/ml, and thyroglobulin 48,000 IU/ml. Thyroid-stimulating hormone receptor antibody was negative, and a 99mTc-labeled thyroid scan revealed a markedly decreased uptake. He was treated with beta-blocker, orally administered potassium iodine, a relatively low dose of prednisolone, and insulin injection therapy to control his blood glucose, resulting in an improvement in thyroid function and his symptoms. CONCLUSION: It might be important to be aware of the possibility of thyroid storm induced by immune checkpoint inhibitors.

Thyroid stimulating hormone stimulates the expression of glucose transporter 2 via its receptor in pancreatic ß cell line, INS-1 cells.

Thyroid stimulating hormone (TSH) stimulates the secretion of thyroid hormones by binding the TSH receptor (TSHR). TSHR is well-known to be expressed in thyroid tissue, excepting it, TSHR has also been expressed in many other tissues. In this study, we have examined the expression of TSHR in rat pancreatic islets and evaluated the role of TSH in regulating pancreas-specific gene expression. TSHR was confirmed to be expressed in rodent pancreatic islets and its cell line, INS-1 cells. TSH directly affected the glucose uptake in INS cells by up-regulating the expression of GLUT2, and furthermore this process was blocked by SB203580, the specific inhibitor of the p38 MAPK signaling pathway. Similarly, TSH stimulated GLUT2 promoter activity, while both a dominant-negative p38MAPK α isoform (p38MAPK α-DN) and the specific inhibitor for p38MAPK α abolished the stimulatory effect of TSH on GLUT2 promoter activity. Finally, INS-1 cells treated with TSH showed increased protein level of glucokinase and enhanced glucose-stimulated insulin secretion. Together, these results confirm that TSHR is expressed in INS-1 cells and rat pancreatic islets, and suggest that activation of the p38MAPK α might be required for TSH-induced GLUT2 gene transcription in pancreatic ß cells.

The combination of OLmesartan and a CAlcium channel blocker (azelnidipine) or candesartan and a calcium channel blocker (amlodipine) in type 2 diabetic hypertensive patients: the OLCA study.

Angiotensin II receptor blockers (ARB) are often co-administered with a calcium channel blocker (CCB) for treating hypertension. In this open-label randomised study, untreated diabetic hypertensive patients were randomised to receive either olmesartan 20 mg/day or candesartan 8 mg/day for 12 weeks. Patients with blood pressure exceeding 130/80 mm Hg received add-on 16 mg/day azelnidipine to ongoing olmesartan (OL group) or 5 mg/day amlodipine to ongoing candesartan (CA group) for 24 weeks. Home-measured and clinic-measured blood pressure decreased in both groups. Fasting blood glucose, haemoglobin A1c (HbA1c) and urinary albumin levels decreased significantly in the OL group but not in the CA group. In conclusion, this study revealed clinically relevant differences between two combinations of an ARB+CCB in diabetic hypertensive patients. Olmesartan and azelnidipine had a more persistent early morning antihypertensive effect and produced greater decreases in heart rate, fasting blood glucose and HbA1c (National Glycohemoglobin Standardization Program values) levels, and microalbuminuria than did candesartan and amlodipine.

Novel mutations in the gene encoding acid α-1,4-glucosidase in a patient with late-onset glycogen storage disease type II (Pompe disease) with impaired intelligence.

A 17-year-old Japanese man was referred to our hospital because of highly elevated serum levels of creatine kinase (CK) and transaminases. On admission, the proximal muscles of the lower extremities were found to be predominantly affected, and a score of 3/5 was obtained on Medical Research Council (MRC) scale. Muscular atrophy was evident and Gowers' sign was positive. His functional vital capacity (FVC) was markedly reduced. The results of the third edition of the Wechsler Adult Intelligence Scale (WAIS-III) indicated impairment of the patient's intelligence. Muscle biopsy showed scattered intracytoplasmic vacuoles with basophilic amorphous materials inside which were strongly stained by both periodic acid Schiff (PAS) and acid phosphatase. Biochemical analysis of the muscle tissue confirmed the diagnosis of GSDII because the glucosidase activity was 1.0 nmol/4 MU/mg/30 min (control range, 7.3 ± 2.2). Genetic analysis revealed a novel compound heterozygous missense mutation in GAA--c.1814 G >A (p.Gly605Asp) and c.1846 G >A (p.Asp616Asn) both in exon 13.

[Pilot study on clinical effects of rebamipide gargle against oral mucositis induced by fluoropyrimidines].

Rebamipide, a cytoprotective agent, has been suspected to attenuate oral mucositis through anti-inflammatory potentials and induction of endogenous prostaglandin synthesis. This prospective study was designed to assess the clinical efficacy of rebamipide gargle against oral mucositis, which is induced by fluoropyrimidines in patients with stomach and colorectal cancer. We first conducted a pilot study on gargle flavors, because the solution in this agent has a strong and bitter after taste. Nine kinds of flavors were prepared, and six characteristics were evaluated by ten volunteers: sourness, bitterness, sweetness, remain, after taste, and hard to drink. We determined the contents of rebamipide using HPLC, which showed stability in an acidic condition. Finally, we decided that 100% Pokka Lemon should be used as the flavor of the rebamipide solution. A clinical study was then started to compare the preventive effects rebamipide gargle and placebo have on stomatitis, quality of life (QOL), and the therapeutic effects of chemotherapy.

Isolated torsion of a left normal fallopian tube during pregnancy.

We present here a case of isolated torsion of a left normal fallopian tube at 37 weeks' gestation. Although uncommon, especially on the left side, torsion of the fallopian tube should be included in the differential diagnosis of abdominal pain during pregnancy.

Positron emission tomography with 18F-fluorodeoxyglucose is a useful tool for the diagnosis of pheochromocytomas without distant metastasis, where malignancy is suspected on the basis of histopathologic analysis.

A 69-year-old woman, who had been undergoing treatment for hypertension, was admitted to the hospital for the evaluation of a tumor in the right adrenal gland and of episodic hypertension. She was diagnosed with pheochromocytoma on the basis of elevated urine catecholamine and metabolite concentrations and positron emission tomography (PET) results; however, the results of I-metaiodobenzylguanidine (I-MIBG) scintigraphy were negative. The patient underwent laparoscopic right adrenalectomy. Malignancy was suspected on the basis of histopathologic studies. After surgery, the elevated catecholamine and metabolite concentrations and the blood pressure returned to normal; furthermore, the symptoms, including severe headache, reduced. The authors report a case of pheochromocytoma that was suspected to be malignant on the basis of histopathologic analysis and was detected by F-fluorodeoxyglucose (FDG)-PET but not by MIBG. Thus, FDG-PET may be a prognostic marker for malignant pheochromocytomas with or without metastasis.

Acute leukemia of ambiguous lineage, biphenotype, without CD34, TdT or TCR-rearrangement.

Biphenotypic acute leukemia (BAL) is a rare entity that comprises 0.5-3% of all acute leukemias and probably arises from multipotent progenitor cells. The optimal approach for BAL therapy is unknown. Thus, it is important to elucidate the origin of the neoplastic cells for determination of the appropriate therapy. We report the case of a 41-year-old man with BAL having myeloid and T-lymphoid lineage phenotypes. Strangely, neither CD34 nor TdT expression nor rearrangement of TCR-alpha/beta, delta/gamma genes were shown. This pattern is rarely encountered and suggests that the blast cells were possibly considered immature with aspects of differentiation indicating myeloid lineage, rather than T-lymphoid lineage.

Co-existence of glucagonoma with recurrent insulinoma in a patient with multiple endocrine neoplasia-type 1 (MEN-1).

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroid glands, the anterior pituitary, and the endocrine pancreas. Our patient was a 58-year-old man who manifested typical features of MEN-1 including primary hyperparathyroidism, lung carcinoid, and lipomas and insulinoma. He was admitted to our hospital because of recurrent hypoglycemia and a growth of pancreatic tumors. The first operation for insulinoma was performed when he was 20 years old. We found a germline mutation of the MEN1 gene (E45G, exon 2) in this patient. According to these examinations and his clinical course, the patient was diagnosed as having a recurrence of insulinoma. He subsequently underwent surgery for the pancreatic tumors. The majority of these tumor cells were immunohistochemically positive for insulin and negative for glucagon. A few nodules showed immunohistochemical staining positivity for glucagon but they were negative for insulin. Although it is uncommon for patients with MEN1 to exhibit insulinoma and glucagonoma, this case suggests the need for careful analysis of pancreatic tumors in patients with MEN1.

Risk factors for postpartum hemorrhage after vaginal delivery of twins.

We examined vaginal deliveries of twins to identify factors most strongly associated with the increased risk of postpartum hemorrhage (estimated blood loss > or = 1,000 mL). We reviewed the obstetric records of all 171 twin vaginal deliveries at Japanese Red Cross Katsushika Maternity Hospital from January 2002 through August 2006. Of these deliveries, 41 (24%) were complicated by postopartum hemorrhage. Postpartum hemorrhage was significantly more likely in cases with gestational age > or = 39 weeks (odds ratio [OR], 3.47; 95% confidence interval [CI], 1.65-7.28), a combined birth weight of more than 5,500 g (OR, 2.53; 95% CI, 1.00-6.45), induction of labor (OR, 2.87; 95% CI, 1.38-5.98), oxytocin administration during labor (OR, 2.86; 95% CI, 1.27-6.48), or a duration of labor > or = 24 hours (OR, 2.55; 95% CI, 1.15-5.62). Postpartum hemorrhage is a frequent complication in twin pregnancies. Therefore, special attention should be given after birth to patients with induction of labor or intervened delivery especially at > or = 39 weeks gestation.