Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab.

CONTEXT: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterized by MMR deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade with pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC. CASE REPORT: A 58-year-old female with known Lynch syndrome presented with severe Cushing's syndrome and was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after 12 weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure. CONCLUSION: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supraphysiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage.

Predictors of responders to insulin therapy at 1 year among adults with type 2 diabetes.

BACKGROUND: The effectiveness of insulin therapy to lower blood glucose levels in patients with type 2 diabetes (T2D) may depend on a variety of factors. This study aims to determine baseline parameters including body mass index (BMI) threshold that might predict responders to insulin therapy. METHODS: This was a retrospective UK population-based study derived from 358 general practices electronic dataset. We included all patients with T2D, diagnosed at the age of >18 years old and who were initiated on insulin from January 2000 to December 2006. Insulin responders were defined as HbA1c <7.5% and/or HbA1c reduction by >1% at 12 months postinsulin initiation. RESULTS: Results are expressed in mean (s.d.). A total of 6032 patients were identified. Baseline age was 63 years (11.7). In all, 61% of patients (3696) responded to insulin. At 1-year postinsulin initiation, HbA1c was significantly reduced (9.8 vs. 8.4%, p < 0.001) and weight increased (85.7 vs. 87.9 kg, p < 0.001). Using logistic regression model, older age (p < 0.001), lower BMI (p = 0.046), higher HbA1c (p < 0.001), basal-bolus insulin therapy and premixed insulin compared to basal insulin alone at baseline were independent predictors of responders to insulin. Gender and social class were not significant predictors of insulin responders. A BMI of <35.3 was derived as a cut-point for response to insulin (p = 0.038). CONCLUSION: Overall, insulin therapy confers significant HbA1c reduction and weight increase in patients with T2D. The responsiveness to insulin therapy however appears to depend on baseline age, BMI, HbA1c and insulin regime. Clinicians should take these factors into consideration when making a decision to initiate insulin therapy in patients with T2D.

Influence of maternal pre-pregnancy body composition and diet during early-mid pregnancy on cardiovascular function and nephron number in juvenile sheep.

The prenatal diet can program an individual's cardiovascular system towards later higher resting blood pressure and kidney dysfunction, but the extent to which these programmed responses are directly determined by the timing of maternal nutritional manipulation is unknown. In the present study we examined whether maternal nutrient restriction targeted over the period of maximal placental growth, i.e. days 28-80 of gestation, resulted in altered blood pressure or kidney development in the juvenile offspring. This was undertaken in 6-month-old sheep born to mothers fed control (100-150 % of the recommended metabolisable energy (ME) intake for that stage of gestation) or nutrient-restricted (NR; 50 % ME; n 6) diets between days 28 and 80 of gestation. Controls were additionally grouped according to normal (>3, n 7) or low body condition score (LBCS; <2, n 6), thereby enabling us to examine the effect of maternal body composition on later cardiovascular function. From day 80 to term (approximately 147 d) all sheep were fed to 100 % ME. Offspring were weaned at 12 weeks and pasture-reared until 6 months of age when cardiovascular function was determined. Both LBCS and NR sheep tended to have lower resting systolic (control, 85 (se 2); LBCS, 77 (se 3); NR, 77 (se 3) mmHg) and diastolic blood pressure relative to controls. Total nephron count was markedly lower in both LBCS and NR relative to controls (LBCS, 59 (se 6); NR, 56 (se 12) %). Our data suggest that maternal body composition around conception is as important as the level of nutrient intake during early pregnancy in programming later cardiovascular health.