Intermittent Bi-Daily Sub-cutaneous Teriparatide Administration in Children With Hypoparathyroidism: A Single-Center Experience

Introduction: The use of teriparatide has been reported in children with hypoparathyroidism as an investigational physiologic replacement therapy.Methods: We aimed to retrospectively report our pediatric experience of bi-daily sub-cutaneous teriparatide. Results are presented as median (25th−75th quartile). As part of the routine follow-up of these patients with hypoparathyroidism, total calcium at H0 (i.e., just before injection) and H4 (i.e., 4 h after teriparatide injection) and other biomarker parameters were regularly assessed.Results: At a median age of 10.7 (8.1–12.6) years, an estimated glomerular filtration rate (eGFR) of 110 (95–118) mL/min/1.73 m2, calcium levels of 1.87 (1.81–1.96) mmol/L and an age-standardized phosphate of 3.8 (2.5–4.9) SDS, teriparatide therapy was introduced in 10 patients at the dose of 1.1 (0.7–1.5) μg/kg/day (20 μg twice daily), with further adjustment depending on calcium levels. Six patients already displayed nephrocalcinosis. Severe side effects were reported in one child: two episodes of symptomatic hypocalcemia and one of iatrogenic hypercalcemia; one teenager displayed dysgueusia. Calcium levels at H0 did not significantly increase whilst calcium at H4 and phosphate levels significantly increased and decreased, respectively. After 12 months, eGFR, calcium and age-standardized phosphate levels were 108 (90–122) mL/min/1.73 m2, 2.36 (2.23–2.48) mmol/L, 0.5 (−0.1 to 1.5), and 68 (63–74) nmol/L, respectively, with a significant decrease in phosphate levels (p = 0.01). Urinary calcium and calcium/creatinine ratio remained stable; no nephrolithiasis was observed but two moderate nephrocalcinosis appeared.Conclusion: Intermittent teriparatide therapy significantly improves calcium and phosphate control, without increasing calciuria. It appears to be safe and well-tolerated in children.

P1564 Changes in coronary flow velocity measuring during coronary bypass grafting can predict elevation of cardiac troponin

Background Stenosis of a coronary artery results in an increase in flow velocity in the pathologic segment. Effective grafting should decrease the stenotic native coronary velocity according to a hemodynamic law. The range of decreased velocity can hypothetically reflect the effectiveness of a graft. Grafting effect insufficiencies often cause elevations in periprocedural cardiac troponin (cTn) elevation. The aim of the study is to determine, if measuring coronary flow velocity changes during coronary artery bypass grafting (CABG) can predict further cTn elevation. Methods and results Consecutive 68 patients (48 men, 64 ± 9 years old), who were referred for CABG, were included into the study. A standard basic perioperative transesophageal echocardiography (TEE) examination was performed with additional scans of the left main, left anterior descending (LAD), and circumflex (LCx) arteries’ proximal segments. Measurements of coronary flow velocities was performed before and after grafting in the same sites of the arteries. The maximal value of cTnI within 48 hours after CABG was accounted for in the analysis. All patients had arterial hypertension, 15 patients (22%) had diabetes mellitus, 12 patients (18%) was current smokers. Forty-one patients (60%) had prior myocardial infarctions, 18 persons (26%) had previous coronary stenting. The ejection fraction before the operation was 56 ± 13%. Before grafting the mean velocity in the left main artery was 79 cm/s (25th-75th quartile, 42-111), in LAD 98 cm/s (25th-75th quartile, 71-125), and in LCx 116 cm/s (25th-75th quartile, 68-156). There was a strong significant correlation between changes in coronary flow velocities and the value of cTnI (R = 0.56, p < 0.0004). The patients with and without significant elevations in cTnI had differences in coronary velocity changes before and after grafting (p < 0.009). Patients with elevated cTnI in more than 5 times, had, on average, an increase in the velocities for native arteries of 21 ± 19 cm/s. Conclusion Coronary flow velocity assessment during CABG could predict an elevation of cardiac troponins after cardiac surgery. Abstract P1564 Figure.

Characterization of mutational load in patients with advanced urothelial cancer.

460 Background: The efficacy of novel immunotherapeutic agents (e.g., PD-1/PD-L1 and CTLA4 inhibitors) in advanced cancer is linked to tumor mutational load. We assessed mutational load via comprehensive genomic profiling (CGP) performed in the course of clinical care for patients with advanced urothelial cancer (UC). Methods: DNA was extracted from 40 microns of FFPE sections from 760 consecutive patients with relapsed/metastatic UC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 646X for at least 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Mutational load was characterized as the number of such SUBs or INDELs per megabase (Mb) after filtering to remove known somatic and deleterious mutations, given that these are selected for with hybrid capture. Results: The median age of the patients was 66 years old with a 3:1 male:female ratio. Mean mutations per megabase were assessed as a range of 0 to 79, and the 25th, median, and 75th quartile thresholds were 3.2, 5.5, and 8.8. MSH6 alterations in 0.8% cases had a median of 15.2 mutations per megabase. However, the ten most frequently altered genes in this series- TERT (64%), TP53 (54%), CDKN2A (35%), CDKN2B (28%), KDM6A (24%), ARID1A (23%), MLL2 (22%), PIK3CA (21%), RB1 (21%) and FGFR3 (19%) - were not associated with differences in mutational load. Conclusions: A highly variable mutational load was seen in patients with advanced UC. A subpopulation of MSH6-altered UC had very high mutational loads relative to other UCs. Further correlation to clinical outcomes will be investigated to assess the correlation between mutational load and response to immunotherapy.

Abstract 20074: Hemodynamic Profile of Prolonged Normothermic, Mild Hypothermic, and Deep Hypothermic Emergency Cardiopulmonary Bypass Reperfusion in Rats

Background: The hemodynamic profile of rats randomized into prolonged normothermic (NT, 37±0.5°C), mild hypothermic (MH, 33±0.5°C) or deep hypothermic (DH, 27±0.5°C) reperfusion with emergency cardiopulmonary bypass (ECPB), following refractory ventricular fibrillation cardiac arrest (VF CA) was explored. Methods: Fifty adult male Sprague-Dawley rats were put on bypass for 15 min, following 10 min of VF CA. The ECPB setup included a circulating water bath which temperature controlled all animals at target. After 15 min, rats were defibrillated, weaned from bypass, and controlled at 33°C (MH, DH) or 37°C (NT) externally. All rats received a single dose of epinephrine (30 μg/kg), heparin and sodium bicarbonate with the crystalloid priming of the ECPB circuit. ECPB flow rate was kept at 100 mL/kg in all groups. Mean arterial pressure (MAP) was continuously monitored in the femoral artery and is presented as median with 25th/75th quartile mmHg. Results: See figure. There was no difference in MAP before or during CA. For the first 5 min of resuscitation, MAP at a given ECPB flow rate was highest in the DH group (DH 84(69;89), MH 51(49;61), NT 48(37;55) , p = <.001). This was reversed during the last 5 min on bypass (DH 35(30;42), MH 44(37;64), NT 42(33;67), p = .034). For 10 min off bypass, the DH group was relatively hypotensive (DH 46(40;62, MH 64(60;77), NT 61(54;77), p = .005), which was again reversed for the remaining post resuscitation period (DH 68(60;78), MH 59(54;66), NT 53(49;62), p = .008). Conclusions: While the temperature profiles of NT and MH reperfusion were similar, DH caused initially higher pressures followed by a period of hypotension as compared to NT and MH groups at identical epinephrine doses and ECPB flow rates. Off bypass, DH animals were again relatively hypotensive, coinciding with their rewarming to mild hypothermia. Further experiments are needed to determine the cause of this, like hypothermic vasoconstriction, or altered pharmacokinetics.