Pooled ctDNA analysis of MONALEESA phase III advanced breast cancer trials.

BACKGROUND: The phase III MONALEESA trials tested the efficacy and safety of the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib with different endocrine therapy partners as first- or second-line treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). Using the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in ABC to date, we identified potential biomarkers of response to ribociclib. PATIENTS AND METHODS: Baseline circulating tumour DNA from patients in the MONALEESA trials was assessed using next-generation sequencing. An analysis of correlation between gene alteration status and progression-free survival (PFS) was carried out to identify potential biomarkers of response to ribociclib. RESULTS: Multiple frequently altered genes were identified. Alterations in ERBB2, FAT3, FRS2, MDM2, SFRP1, and ZNF217 were associated with a greater PFS benefit with ribociclib versus placebo. Patients with high tumour mutational burden (TMB) and with ANO1, CDKN2A/2B/2C, and RB1 alterations exhibited decreased sensitivity to ribociclib versus placebo. CONCLUSIONS: Although exploratory, these results provide insight into alterations associated with the improved response to ribociclib treatment and may inform treatment sequencing in patients with actionable alterations following progression on CDK4/6 inhibitors. Validation of potential biomarkers identified here and development of prospective trials testing their clinical utility are warranted. GOV IDENTIFIERS: NCT01958021, NCT02422615, NCT02278120.

Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer.

BACKGROUND: Alpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of alpelisib's safety profile should inform adverse event (AE) management and enhance patient care. PATIENTS AND METHODS: AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management. RESULTS: Patients were randomly assigned to receive fulvestrant plus alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median alpelisib dose intensity of 248 mg/day. Median progression-free survival with alpelisib was 12.5 and 9.6 months for alpelisib dose intensities of ≥248 mg/day and <248 mg/day, respectively, compared with 5.8 months with placebo. CONCLUSIONS: Hyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher alpelisib dose intensities support the need for optimal AE management. CLINICALTRIALS. GOV ID: NCT02437318.

Pediatric endocrine surgery: a 20-year experience at the Mayo Clinic.

CONTEXT: Surgically managed endocrinopathies are rare in children. Most surgeons have limited experience in this field. Herein we report our operative experience with pediatric patients, performed over two decades by high-volume endocrine surgeons. SETTING: The study was conducted at the Mayo Clinic (a tertiary referral center). PATIENTS: Patients were <19 years old and underwent an endocrine operation (1993-2012). MAIN OUTCOME MEASURES: Demographics, surgical procedure, diagnoses, morbidity, and mortality were retrospectively reviewed. RESULTS: A total of 241 primary cases included 177 thyroid procedures, 13 neck dissections, 24 parathyroidectomies, 14 adrenalectomies, 7 paragangliomas, and 6 pancreatic procedures. Average age of patients was 14.2 years. There were 133 total thyroidectomies and 40 hemithyroidectomies. Fifty-three cases underwent a central or lateral neck dissection. Six-month follow-up was available for 98 total thyroidectomy patients. There were four cases of permanent hypoparathyroidism (4%) and no permanent recurrent laryngeal nerve (RLN) paralyses. Sequelae of neck dissections included temporary RLN neurapraxia and Horner's syndrome. Parathyroidectomy was performed on 24 patients: 20 with primary hyperparathyroidism (HPT), three with tertiary HPT, and one with familial hypocalciuric hypocalcemia. Three patients (16%) had recurrent HPT, all with multiglandular disease. One patient had temporary RLN neurapraxia. We performed seven bilateral and seven unilateral adrenalectomies; eight were laparoscopic. Indications included pheochromocytoma, Cushing's syndrome, adrenocortical carcinoma, congenital adrenal hyperplasia, and ganglioneuroma. One death was due to adrenocortical carcinoma. Five paraganglioma patients had succinate dehydrogenase subunit B mutations, and one recurred. Six patients with insulinoma underwent enucleation (n = 5) or distal pancreatectomy (n = 1). A single postoperative abscess was managed nonoperatively. CONCLUSION: Pediatric endocrine procedures are uncommon but can be safely performed with complication rates comparable to those of the adult population. It is imperative that these operations be performed by high-volume surgeons.

Effects of losartan on whole body, skeletal muscle and vascular insulin responses in obesity/insulin resistance without hypertension.

AIMS: Renin-angiotensin system antagonists have been found to improve glucose metabolism in obese hypertensive and type 2 diabetic subjects. The mechanism of these effects is not well understood. We hypothesized that the angiotensin receptor antagonist losartan would improve insulin-mediated vasodilation, and thereby improve insulin-stimulated glucose uptake in skeletal muscle of insulin-resistant subjects. METHODS: We studied subjects with obesity and insulin resistance but without hypertension, hypercholesterolaemia or dysglycaemia [age 39.0 ± 9.6 yr (mean ± SD), body mass index (BMI) 33.2 ± 5.9 kg/m(2) , BP 115.8 ± 12.2/70.9 ± 7.2 mmHg, LDL 2.1 ± 0.5 mmol/l]. Subjects were randomized to 12 weeks' double-blind treatment with losartan 100 mg once daily (n = 9) or matching placebo (n = 8). Before and after treatment, under hyperinsulinaemic euglycaemic clamp conditions we measured whole-body insulin-stimulated glucose disposal, insulin-mediated vasodilation, and insulin-stimulated leg glucose uptake by the limb balance technique. RESULTS: Whole-body insulin-stimulated glucose disposal was not significantly increased by losartan. Insulin-mediated vasodilation was augmented following both treatments [increase in leg vascular conductance: pretreatment 0.7 ± 0.3 l/min/mmHg (losartan, mean ± SEM) and 0.9 ± 0.3 (placebo), posttreatment 1.0 ± 0.4 (losartan) and 1.3 ± 0.6 (placebo)] but not different between treatment groups (p = 0.53). Insulin's action to augment nitric oxide (NO) production and to augment endothelium-dependent vasodilation was also not improved. Leg glucose uptake was not significantly changed by treatments, and not different between groups (p = 0.11). CONCLUSIONS: These findings argue against the hypothesis that losartan might improve skeletal muscle glucose metabolism by improving insulin-mediated vasodilation in normotensive insulin-resistant obese subjects. The metabolic benefits of angiotensin receptor blockers may require the presence of hypertension in addition to obesity-associated insulin resistance.

A cross-sectional evaluation of seasonality as a determinant of endothelial function.

Endothelium-dependent vasodilation is impaired in obese versus lean humans. We set out to evaluate whether agonist-mediated endothelium-dependent vasodilation varies by season in a cross-sectional dataset of lean and obese humans, and whether this effect differed by obesity status. All vascular studies performed in our laboratory over a 12 year period from 1997 to 2009 were evaluated. Endothelium-dependent vasodilation was measured invasively using thermodilution in the leg as the response to intra-arterially infused methacholine chloride. Resting blood pressure was measured concurrently by cuff and intra-arterially. The association of endothelium-dependent vasodilation and blood pressure measurements with season was evaluated, comparing responses in lean and obese subjects. Endothelium-dependent vasodilation differed between lean and obese subjects, and varied across seasons (p=0.02), but without an interaction between season effect and obesity status. The proportion of obese versus lean subjects differed significantly across seasons in our dataset, and after adjusting for this factor the apparent seasonal variation in endothelium-dependent vasodilation was lost (p=0.12), and was not present in either lean or obese subjects separately. Systolic arterial blood pressure varied across seasons, and this effect remained significant after adjusting obesity status (p=0.019 and p=0.043 for blood pressures measured intra-arterially and by cuff respectively). In our cross-sectional dataset, seasonal variations in blood pressure were seen but we did not observe an association between season and endothelium-dependent vasodilation in lean or obese subjects.

Contributions of dysglycaemia, obesity, and insulin resistance to impaired endothelium-dependent vasodilation in humans.

BACKGROUND: Individual effects of hyperglycaemia and obesity to impair vascular health are recognized. However, the relative contributions of dysglycaemia versus other obesity-related traits to vascular dysfunction have not been systematically evaluated. METHODS: We undertook a cross-sectional evaluation of factors contributing to vascular function in 271 consecutive subjects, categorized as non-obese normal glucose tolerant (n = 115), non-obese dysglycaemic (n = 32), obese normal glucose tolerant (n = 57), obese dysglycaemic (n = 38), or type 2 diabetic (n = 29). Vascular function was measured invasively as leg blood flow responses to methacholine chloride, an endothelium-dependent vasodilator. Categorical and continuous analyses were carried out to assess the contributions of hyperglycaemia to vascular dysfunction. RESULTS: Even among normoglycaemic subjects, obese subjects had impaired vascular function compared to non-obese subjects (p = 0.004). Vascular function was also impaired in non-obese dysglycaemic subjects (p = 0.04 versus non-obese normoglycaemic subjects), to a level comparable to normoglycaemic obese subjects. Within obese subject groups, gradations of dysglycaemia including the presence of diabetes were not associated with further worsening of these vascular responses beyond the effect of obesity alone (p = not significant comparing all obese groups, p < 0.001 versus lean normoglycaemic subjects). After univariate and multivariable modelling analyses we found that effects of glycaemia were less powerful than effects of insulin resistance and obesity on vascular dysfunction. CONCLUSIONS: Dysglycaemia contributes to impaired vascular function in non-obese subjects, but obesity and insulin resistance are more important determinants of vascular function in obese and diabetic subjects.

Obesity, insulin resistance, and the metabolic syndrome: determinants of endothelial dysfunction in whites and blacks.

BACKGROUND: Insulin resistance is strongly associated with obesity and other components of the metabolic syndrome (MS). The relative importance of these components in the determination of endothelial function is unknown. Furthermore, there is conflicting evidence about whether ethnic differences exist in the relative importance of these components in regard to other cardiovascular outcomes. We evaluated the contributions of insulin resistance, obesity, and the other components of the MS to impaired endothelial function. METHODS AND RESULTS: The relationships of the MS components (as defined according the National Cholesterol Education Program) and insulin resistance (estimated using the homeostasis model) with endothelium-dependent vasodilation were examined in 42 white and 55 black subjects. Endothelium-dependent vasodilation was assessed as the increment in leg blood flow (measured by thermodilution) after exposure to methacholine chloride. Waist circumference, glucose, blood pressure, and insulin resistance distributions did not differ between ethnic groups; blacks in our sample had higher HDL cholesterol (1.31 versus 1.09 mmol/L; P<0.001) and lower triglyceride levels (1.01 versus 1.37 mmol/L; P=0.005) than white subjects. In the absence of the MS, black subjects exhibited reduced endothelium-dependent vasodilation compared with white subjects (P=0.005), and both groups demonstrated significantly worse endothelial function when the MS was present (maximal increase in leg blood flow: blacks: 107+/-9% MS absent, 53+/-16% MS present; whites: 163+/-16% MS absent, 54+/-18% MS absent; P=0.007, MS absent versus present; P=NS for interaction of ethnicity and MS). Multivariable regression analysis examining relationships of endothelial function with the 5 MS components (analyzed as continuous variables) revealed independent relationships only with waist circumference (P=0.01) and systolic blood pressure (P=0.02). Waist circumference was no longer independently associated after adding insulin resistance to the modeling (P=0.02 for log of homeostasis model index of insulin resistance, P=0.02 for systolic blood pressure). Ethnicity still exerted an independent effect on endothelial function after accounting for the above components (P=0.04 for an additional effect of ethnic status on endothelial function), with an ethnic difference in the effect of insulin resistance on endothelial function (P=0.046 for interaction of ethnicity and log of homeostasis model index of insulin resistance). CONCLUSIONS: These findings suggest that insulin resistance and systolic blood pressure are the principal determinants of endothelial dysfunction in the MS and that there are ethnic differences in the relative importance of these factors. These differences may imply different benefits from treatments targeting blood pressure or insulin resistance in different ethnic groups.

A peripheral nerve stimulator for nerve location controlled by the scrubbed anaesthetist.

This newly designed peripheral nerve stimulator allows the scrubbed anaesthetist performing a nerve block to adjust the electrical current output needed for localisation of the target nerve without the need for an assistant.

Pump activated by a foot switch pedal for controlled administration of local anaesthetic drugs.

We describe a newly designed syringe pump which is electrically controlled by a dual foot switch pedal. The device enables the scrubbed anaesthetist performing the regional block to aspirate, as well as to inject, the local anaesthetic without the need for any additional personnel.

A modified Guedel airway for continuous oxygenation and suctioning during fibreoptic bronchoscopy.

We describe a modification to the Guedel airway that improves suction and oxygenation during fibreoptic bronchoscopy. The entire roof of a Guedel airway was removed. Two 2.5-mm internal diameter tracheal tubes were inserted into the modified airway to allow continuous oxygen delivery and suction throughout fibreoptic bronchoscopy. It was tested as a single-use device in ten patients undergoing awake fibreoptic bronchoscopy under sedation and topical anasthesia. During the procedure there were no problems with either fogging of the lens or secretions in the pharynx. In addition, oxyhaemoglobin saturation, as monitored continuously by pulse oximetry, was >/= 97% in all patients.

Hypoglycemia in infants and children.

Hypoglycemia is more common in the pediatric patient than in adults. This article discusses the many diagnoses that can be associated with hypoglycemia in infancy and childhood. A guide to help practitioners evaluate such patients and suggested treatments for many of these disorders are provided. As genetic diagnosis continues to develop, it is anticipated that the list of specific disorders associated with hypoglycemia in infancy and childhood will increase.

Accuracy of pen injectors versus insulin syringes in children with type 1 diabetes.

OBJECTIVE: To compare the accuracy and precision of insulin syringes and pen devices used by children with type 1 diabetes and their parents. RESEARCH DESIGN AND METHODS: There were 48 subjects (32 patients, a parent of an additional 16 patients) instructed to measure out morning insulin doses three times from vials and/or cartridges containing saline mixed with small amounts of [14C]glucose (solution used as regular insulin) and [3H]glucose (solution used as NPH insulin) and to dispense the contents into a scintillation vial. Statistical analysis was used to determine the accuracy and precision of both methods of insulin delivery. RESULTS: The absolute error in measuring out doses of regular insulin < 5 U was greater with insulin syringes compared with pen injection devices (9.9 +/- 2.4 vs. 4.9 +/- 1.6%, respectively). Both were comparable for regular insulin doses > 5 U (3.2 +/- 0.6 vs. 2.2 +/- 0.4% for syringes and pens, respectively). The accuracy in drawing up NPH doses was similar for low and high insulin doses (mean percent error of 7.5 +/- 1.5 vs. 5.6 +/- 1.1%). CONCLUSIONS: Pen devices are more accurate than insulin syringes in measuring out insulin at low insulin doses. The accuracy of insulin syringes improves when higher doses of regular insulin are measured out and becomes comparable to pen devices.

Type 1 diabetes mellitus in early childhood: glycemic control and associated risk of hypoglycemic reactions.

OBJECTIVE: To assess the level of glycemic control and to determine whether more normal glycemic control, as measured by glycosylated hemoglobin, leads to frequent hypoglycemic episodes in young patients with type 1 diabetes mellitus. MATERIAL AND METHODS: We undertook a retrospective review of the medical records of 59 children with type 1 diabetes diagnosed at age 9 years or younger, who underwent follow-up at our institution for at least 2 years. For each follow-up, insulin requirements, levels of glycosylated hemoglobin, and frequency of hypoglycemic reactions were analyzed for three age-groups--0 to 2 years, 2 to 5 years, and 5 to 9 years old. RESULTS: The mean glycosylated hemoglobin for the first 2 years after diagnosis of type 1 diabetes was higher in children 0 to 2 years old in comparison with the other age-groups. This increased glycosylated hemoglobin occurred despite increased administration of insulin, expressed in units per kilogram daily, to these children (P < 0.05). Severe hypoglycemic reactions were more common in infants (55%) and children between 2 and 5 years old (45%) than in children from 5 to 9 years old (13%). In all age-groups, the mean glycosylated hemoglobin value closest to a hypoglycemic event and the mean glycosylated hemoglobin value for the 2-year study period were similar but were both less than 8% (the standard established by the Diabetes Control and Complications Trial). Most reactions had no clear cause in the youngest age-group, whereas a specific reason could usually be determined in children 2 to 5 years old. CONCLUSION: Tight glycemic control is achievable in young patients with type 1 diabetes mellitus. Such tight control, however, may lead to an increase in the frequency of severe hypoglycemic reactions in this patient population. Our data support the guideline that children younger than 5 years should have a higher goal for premeal plasma glucose levels.

Bisphosphonates for treatment of childhood hypercalcemia.

Most clinicians only have a limited experience in treating childhood hypercalcemia with bisphosphonates. We report our experience in the use of intravenous and oral bisphosphonates in a 5-year-old with hypercalcemia secondary to acute lymphocytic leukemia, a 16-year-old with immobilization hypercalcemia, and a 14-year-old with chronic hypercalcemia of unknown cause. Single infusions of 0.5 mg/kg and 1 mg/kg of intravenous pamidronate were administered over 4 hours. No adverse reactions were observed except for hypocalcemia. A dose between 10 and 20 mg of oral alendronate was successfully used to maintain normocalcemia in the patient with chronic hypercalcemia. In our experience, the administration of bisphosphonates has enabled us to achieve normocalcemia in all cases, and in all cases there were no significant side effects. Long-term potential side effects from their use in children during the active phase of growth remain unknown.

Breast milk: revisited.

Human milk has been shown to be the ideal source of nutrition for most growing infants. Its composition continues to be an active area of investigation. In several studies in preterm and term infants, long-chain polyunsaturated fatty acids were found to improve the maturation of visual evoked potentials. The clinical significance of this finding, however, remains unclear. Nucleotides present in breast milk or added to infant formula seem to enhance the humoral immune response to vaccination. Whether breastfeeding protects susceptible infants from the risk of the development of diabetes mellitus type 1 is still controversial. Breastfeeding by mothers infected with the human immunodeficiency virus is not recommended. Other viruses and pollutants have also been found in breast milk. The importance of these in the long-term health of children remains to be established.

Thyrotoxicosis in children.

Graves' disease is the predominant cause of hyperthyroidism in the pediatric age group. Other disorders must be recognized, however, because adequate management relies on a precise diagnosis. Careful monitoring of the thyroid status is required during this active phase of growth and development.