A Case of Nonislet Cell Tumor Hypoglycemia Due to Metastatic Salivary Myoepithelial Carcinoma.

Background/Objective: Nonislet cell tumor hypoglycemia (NICTH) is an uncommon cause of hypoglycemia due to a relative surplus of insulin-like growth factor 2 (IGF-2) or its precursor molecule. The diagnosis is confirmed by an elevated ratio of IGF-2 to insulin-like growth factor 1 (IGF-1). Myoepithelial carcinoma (MECA) is a rare and aggressive salivary gland cancer that has not been previously associated with NICTH. Case Report: A 63-year-old female with a past medical history of metastatic salivary MECA, type 2 diabetes mellitus previously on metformin, hypertension, and hypothyroidism presented to her oncologist for chemotherapy and was found to have a serum glucose of 30 mg/dL (reference: 65-99). She was admitted for further diagnostic work-up which revealed an insulin level of <1 µU/mL (reference: 3-25), C-peptide <0.5 ng/mL (reference: 1.1-4.3), IGF-1 of 15 ng/mL (reference: 41-279), and IGF-2 of 147 ng/mL (reference: 180-580) with an IGF-2:IGF-1 molar ratio of 10, consistent with NICTH. The patient's hypoglycemia unfortunately was quite resistant to treatment, requiring a combination of corticosteroids, continuous dextrose infusion, and somatostatin injections. The patient died 3 weeks after presenting with hypoglycemia. Discussion: Salivary MRCAs commonly contain pleomorphic adenoma gene 1 oncogene rearrangements which are associated with increased IGF-2 production and may predispose patients to hypoglycemia. Conclusion: This case demonstrates that NICTH can be associated with metastatic salivary MECA. The hypoglycemia in this scenario is challenging to manage and is associated with poor prognosis.

Management of Symptomatic Refractory Hypoglycemia at the End of Life in a Nondiabetic Patient With Metastatic Urothelial Carcinoma.

Patients with advanced cancer can develop symptomatic hypoglycemia at the end of life which can be associated with significant distress. We report the case of a man with metastatic urothelial carcinoma who developed acute-onset, recurrent, and symptomatic hypoglycemia concerning for non-islet cell tumor hypoglycemia (NICTH). Hypoglycemic episodes were physically and emotionally distressing and refractory to glucose tablets and a low concentration of dextrose infusion. Based on symptom burden and goals of care, treatment was escalated to a concentrated dextrose infusion requiring a central venous line, oral corticosteroids, and subcutaneous somatotropin. He was transferred to the inpatient palliative service, and on this treatment regimen, did not have additional distressing hypoglycemia. For patients with metastatic cancer and symptomatic hypoglycemia, applying a palliative-based framework with discussion of prognosis, values, and goals will lead to goal-concordant care at the end of life that can include aggressive maintenance of euglycemia to relieve suffering.

Optimal Thyroid Hormone Replacement Dose in Immune Checkpoint Inhibitor-Associated Hypothyroidism Is Distinct from Hashimoto's Thyroiditis.

Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many advanced cancers but are recognized to cause treatment-limiting immune-related adverse events (IrAE). ICI-associated thyroiditis is the most common endocrine IrAE and usually resolves to permanent hypothyroidism. Optimal thyroid hormone replacement in these patients remains unclear. We report the levothyroxine (LT4) dose needed to achieve stable euthyroid state in patients with hypothyroidism from ICI-associated thyroiditis, with comparison to patients with Hashimoto's thyroiditis (HT) and athyreotic state. Methods: We conducted a retrospective study of adults with ICI-associated hypothyroidism treated with LT4 at an academic medical center. Patient data were collected from the electronic medical record. Cases had ICI exposure followed first by hyperthyroidism and then subsequent hypothyroidism. Controls were HT (positive thyroid autoantibodies, requiring LT4) and athyreotic (total thyroidectomy or radioiodine ablation, requiring LT4) patients. Patients with central hypothyroidism, thyroid cancer, pregnancy, gastrointestinal stromal tumors, and use of L-triiodothyronine were excluded. Our primary outcome compared LT4 dose needed to achieve euthyroid state (thyrotropin 0.3-4.7 mIU/L over >6 consecutive weeks) for ICI-associated hypothyroidism, HT, and athyreotic patients, considering the impact of age and possible interfering medications by linear regression modeling. Secondary analysis considered the impact of endocrine specialty care on the time to euthyroid state. Results: One hundred three patients with ICI-associated thyroiditis were identified. Sixty-six of the 103 patients achieved euthyroid state; 2 with intrinsic thyroid gland function recovery and 64 on LT4. The mean LT4 dose achieving stable euthyroid state was 1.45 ± standard deviation (SD) 0.47 mcg/[kg·day] in ICI-associated hypothyroidism, 1.25 ± SD 0.49 mcg/[kg·day] in HT, and 1.54 ± SD 0.38 mcg/[kg·day] in athyreotic patients, using actual body weight. The difference in dose between ICI-associated hypothyroidism and HT was statistically significant (p = 0.0093). Dosing differences were not explained by age or use of interfering medications. Conclusions: ICI-associated thyroiditis represents an increasingly recognized cause of hypothyroidism. Our study demonstrates that patients with ICI-associated hypothyroidism have different thyroid hormone dosing requirements than patients with HT. Based on our findings and prior reports, we recommend that in patients with ICI-associated thyroiditis LT4 therapy be started at an initial weight-based dose of 1.45 mcg/[kg·day] once serum free thyroxine levels fall below the reference range.

Distribution of N-Acetylgalactosamine-Positive Perineuronal Nets in the Macaque Brain: Anatomy and Implications.

Perineuronal nets (PNNs) are extracellular molecules that form around neurons near the end of critical periods during development. They surround neuronal cell bodies and proximal dendrites. PNNs inhibit the formation of new connections and may concentrate around rapidly firing inhibitory interneurons. Previous work characterized the important role of perineuronal nets in plasticity in the visual system, amygdala, and spinal cord of rats. In this study, we use immunohistochemistry to survey the distribution of perineuronal nets in representative areas of the primate brain. We also document changes in PNN prevalence in these areas in animals of different ages. We found that PNNs are most prevalent in the cerebellar nuclei, surrounding >90% of the neurons there. They are much less prevalent in cerebral cortex, surrounding less than 10% of neurons in every area that we examined. The incidence of perineuronal nets around parvalbumin-positive neurons (putative fast-spiking interneurons) varies considerably between different areas in the brain. Our survey indicates that the presence of PNNs may not have a simple relationship with neural plasticity and may serve multiple functions in the central nervous system.