Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.

BACKGROUND: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. RESULTS: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels. CONCLUSIONS: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).

Perampanel in the treatment of partial seizures: Time to onset and duration of most common adverse events from pooled Phase III and extension studies.

Perampanel (PER) is a novel noncompetitive AMPA-receptor antagonist approved in over 40 countries for treatment of partial seizures. The safety and tolerability of PER have been well-documented in three double-blind, randomized, placebo (PBO)-controlled Phase III studies and an open-label extension (OLE). This post hoc analysis evaluated the occurrence and characteristics of the most common treatment-emergent adverse events (TEAEs) associated with PER. Results from the Phase III studies were pooled; post hoc analyses on the double-blind phase and up to 1 year of the OLE were performed on the four most common TEAEs for which incidence was higher for PER than PBO. The four most common TEAEs were dizziness, somnolence, fatigue, and irritability. For most subjects in the Phase III double-blind studies, these TEAEs were observed during 6-week titration and were mild or moderate in severity. For severe AEs, no dose-response relationship was observed. Patients in the PBO group during Phase III (who therefore received their first PER treatment during OLE) experienced these TEAEs with incidence and timing similar to that of PER-treated patients in Phase III. The first onset of these TEAEs occurred during the early weeks of PER conversion in the OLE. After 6months and up to 1 year of PER treatment, low to no incidence of the first onset of the four TEAEs was observed. Post hoc analyses of data from pooled Phase III studies provide greater insight into occurrence/duration of TEAEs. Phase III double-blind and OLE data showed that dizziness, somnolence, fatigue, and irritability were the most common TEAEs reported by patients taking PER. Additionally, these results suggest consistency between studies in patient responses to onset of these TEAEs. Although concomitant antiepileptic drugs (AEDs) might be predicted to affect development of TEAEs in patients taking PER, an effect was not observed in this analysis. The low incidence of TEAEs in these studies provides additional support for long-term PER treatment.

Jointly Modeling Event Time and Skewed-Longitudinal Data with Missing Response and Mismeasured Covariate for AIDS Studies.

In longitudinal studies it is often of interest to investigate how a repeatedly measured marker in time is associated with a time to an event of interest. This type of research question has given rise to a rapidly developing field of biostatistics research that deals with the joint modeling of longitudinal and time-to-event data. Normality of model errors in longitudinal model is a routine assumption, but it may be unrealistically obscuring important features of subject variations. Covariates are usually introduced in the models to partially explain between- and within-subject variations, but some covariates such as CD4 cell count may be often measured with substantial errors. Moreover, the responses may encounter nonignorable missing. Statistical analysis may be complicated dramatically based on longitudinal-survival joint models where longitudinal data with skewness, missing values, and measurement errors are observed. In this article, we relax the distributional assumptions for the longitudinal models using skewed (parametric) distribution and unspecified (nonparametric) distribution placed by a Dirichlet process prior, and address the simultaneous influence of skewness, missingness, covariate measurement error, and time-to-event process by jointly modeling three components (response process with missing values, covariate process with measurement errors, and time-to-event process) linked through the random-effects that characterize the underlying individual-specific longitudinal processes in Bayesian analysis. The method is illustrated with an AIDS study by jointly modeling HIV/CD4 dynamics and time to viral rebound in comparison with potential models with various scenarios and different distributional specifications.

Blunted glucagon but not epinephrine responses to hypoglycemia occurs in youth with less than 1 yr duration of type 1 diabetes mellitus.

CONTEXT: Glycemic control is limited by the barrier of hypoglycemia. Recurrent hypoglycemia impairs counterregulatory (CR) hormone responses to subsequent hypoglycemia. OBJECTIVE: To determine the glucagon and epinephrine responses to insulin-induced hypoglycemia in adolescents with recent-onset type 1 diabetes mellitus (T1DM). METHODS: We assessed the CR responses to hypoglycemia by performing a hyperinsulinemic (2.0 mU/kg/min), euglycemic (BG 90 mg/dL; 5.0 mmol/L)-hypoglycemic (BG 55 mg/dL; 3.0 mmol/L) clamp in 25 recent-onset (<1 yr duration) patients 9-18 yr old (mean ± SD: 13.4 ± 2.7) with T1DM and 16 non-diabetic controls 19-25 yr old (mean ± SD 23.3 ± 1.8). Twenty of the T1DM subjects were retested 1-yr (53 ± 3 wk) later. RESULTS: At the initial and 1-yr studies, peak glucagon (pGON) and incremental glucagon (ΔGON) during hypoglycemia were lower in the T1DM subjects [median pGON = 47 pg/mL (quartiles: 34, 72), ΔGON = 16 (4, 27) initially and pGON = 50 pg/mL (42, 70), ΔGON = 12 (9, 19) at 1-yr] than in controls [pGON = 93 pg/mL (60, 111); ΔGON = 38 pg/mL (19, 66), p = 0.01 and p = 0.004 for ΔGON at initial and 1-yr study, respectively]. In contrast, peak epinephrine (pEPI) and incremental epinephrine (ΔEPI) levels were similar in the T1DM (pEPI = 356 pg/mL (174, 797) and ΔEPI = 322 pg/mL (143, 781) initially and pEPI = 469 pg/mL (305, 595) and ΔEPI = 440 pg/mL (285, 574) at 1 yr) and in controls (pEPI = 383 pg/mL (329, 493) and ΔEPI = 336 pg/mL (298, 471) p = 0.97 and 0.21 for ΔEPI at initial and 1-yr study, respectively). CONCLUSIONS: Even within the first year of T1DM, glucagon responses to hypoglycemia are blunted but epinephrine responses are not, suggesting that the mechanisms involved in the loss of these hormonal responses, which are key components in pathophysiology of hypoglycemia-associated autonomic failure, are different.

Severe hypoglycemia and diabetic ketoacidosis among youth with type 1 diabetes in the T1D Exchange clinic registry.

OBJECTIVE: Severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) are common serious acute complications of type 1 diabetes (T1D). The aim of this study was to determine the frequency of SH and DKA and identify factors related to their occurrence in the T1D Exchange pediatric and young adult cohort. RESEARCH DESIGN AND METHODS: The analysis included 13 487 participants in the T1D Exchange clinic registry aged 2 to <26 yr with T1D ≥2 yr. Separate logistic regression models were used to evaluate the association of baseline demographic and clinical factors with the occurrence of SH or DKA in the prior 12 months. RESULTS: Non-White race, no private health insurance, and lower household income were associated with higher frequencies of both SH and DKA (p < 0.001). SH frequency was highest in children <6 yr old (p = 0.005), but across the age range, SH was not associated with hemoglobin A1c (HbA1c) levels after controlling for other factors (p = 0.72). DKA frequency was highest in adolescents (p < 0.001) and associated with higher HbA1c (p < 0.001). CONCLUSIONS: Our data show that poor glycemic control increases the risk of DKA but does not protect against SH in youth and young adults with type 1 diabetes. The high frequencies of SH and DKA observed in disadvantaged minorities with T1D highlight the need for targeted interventions and new treatment paradigms for patients in these high risk groups.

Feasibility of prolonged continuous glucose monitoring in toddlers with type 1 diabetes.

OBJECTIVE: To examine the feasibility of continuous glucose monitoring (CGM) use in very young children with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Twenty-three children less than 4 yr of age with T1D were provided with a FreeStyle Navigator(®) (n = 21) or a Paradigm(®) (n = 2) CGM device. At baseline, mean age was 3.0 ± 0.8 yr, mean hemoglobin A1c (HbA1c) was 8.0 ± 0.8%, 10 were using an insulin pump and 13 were on multiple daily injections. CGM use was evaluated over a 6-month period. RESULTS: Three children dropped out of the study before the end of 6 months. Among the 20 children who completed 6 months of follow-up, CGM use in month 6 was ≥6 d/wk in 9 (45%), 4 ≤ 6 d/wk in 2 (10%), and <4 d/wk in 9 (45%). Skin reactions were minimal. Although there was no detectable change in mean HbA1c between baseline and 6 months (7.9 and 8.0%, respectively), there was a high degree of parental satisfaction with CGM as measured on the CGM satisfaction scale questionnaire. A high percentage of glucose values were in the hyperglycemic range, and biochemical hypoglycemia was infrequent. CONCLUSION: More than 40% of very young children were able to safely use CGM on a near-daily basis after 6 months. CGM demonstrated frequent hyperglycemic excursions, with a large variability in glucose readings. Although improvement in glycemic control was not detected in the group as a whole, parental satisfaction with CGM was high.

Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial.

BACKGROUND: Closed-loop systems link continuous glucose measurements to insulin delivery. We aimed to establish whether closed-loop insulin delivery could control overnight blood glucose in young people. METHODS: We undertook three randomised crossover studies in 19 patients aged 5-18 years with type 1 diabetes of duration 6.4 years (SD 4.0). We compared standard continuous subcutaneous insulin infusion and closed-loop delivery (n=13; APCam01); closed-loop delivery after rapidly and slowly absorbed meals (n=7; APCam02); and closed-loop delivery and standard treatment after exercise (n=10; APCam03). Allocation was by computer-generated random code. Participants were masked to plasma and sensor glucose. In APCam01, investigators were masked to plasma glucose. During closed-loop nights, glucose measurements were fed every 15 min into a control algorithm calculating rate of insulin infusion, and a nurse adjusted the insulin pump. During control nights, patients' standard pump settings were applied. Primary outcomes were time for which plasma glucose concentration was 3.91-8.00 mmol/L or 3.90 mmol/L or lower. Analysis was per protocol. This trial is registered, number ISRCTN18155883. FINDINGS: 17 patients were studied for 33 closed-loop and 21 continuous infusion nights. Primary outcomes did not differ significantly between treatment groups in APCam01 (12 analysed; target range, median 52% [IQR 43-83] closed loop vs 39% [15-51] standard treatment, p=0.06;

Continuous glucose monitoring and intensive treatment of type 1 diabetes.

BACKGROUND: The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined. METHODS: In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks. RESULTS: The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference. CONCLUSIONS: Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.)

Health utilities for children and adults with type 1 diabetes.

OBJECTIVE: We studied health utilities in patients with type 1 diabetes to understand potential differences in health utilities as function of age, type of respondent (self report vs. proxy report), and method of assessment (direct vs. indirect). RESEARCH DESIGN AND METHODS: We elicited self-reported health utilities for adults (n=213) and children (n=238) with type 1 diabetes, and by parent proxy report (n=223) for overall quality of life [Health Utilities Index (HUI) Mark 3 and experienced time-trade-off (TTO) questions] and hypothetical complication states (TTO questions). RESULTS: Mean health utilities for overall quality of life (QOL) ranged from 0.81 to 0.91. Children had significantly higher overall QOL compared with adults (0.89 vs. 0.85, P<0.01) by HUI, but had no significant difference in QOL by TTO. There were no significant differences in QOL between child self report and parent proxy report. Utilities were higher for HUI versus TTO for parent proxy report (P<0.01) but not for adult or child self report. Utilities for hypothetical complication states were lower than for current QOL. Values were lower for stroke (0.34 to 0.53), end stage renal disease (0.47 to 0.55), and blindness (0.52 to 0.69) than for amputation (0.73 to 0.82) and angina (0.74 to 0.80). Complication utilities for parent proxy report were higher compared with adult self report for most hypothetical complication states. CONCLUSIONS: Individuals with type 1 diabetes with few complications report a relatively high QOL; however, future end stage complications are rated as having a significant impact on QOL. Differences in utilities by age, self report versus proxy report, and method raise important questions about whose utilities should be used in economic analyses.

The interrelationships of glycemic control measures: HbA1c, glycated albumin, fructosamine, 1,5-anhydroglucitrol, and continuous glucose monitoring.

OBJECTIVES: To describe the interrelationships of glycemic control measures: hemoglobin A1c (HbA1c), glycated albumin, fructosamine, 1,5-anhydroglucitrol (1,5-AG), and continuous glucose monitoring (CGM) in children and adolescents with type 1 diabetes. METHODS: In total, 26 subjects of age 4-17 had HbA1c measurement followed within 14 d by three laboratory measures of glycemia and the collection of CGM glucose data (N = 21). RESULTS: Glycated albumin and fructosamine levels had a higher correlation with each other than with HbA1c. The correlation of 1,5-AG with HbA1c was lower (absolute r value = 0.25). All four measures had a similar degree of correlation with CGM-measured mean glucose (absolute r value = 0.50-0.56) and with hyperglycemic area under the curve (AUC) at 180 mg/dL (0.50-0.60). CONCLUSION: Each of the four measures (i.e., HbA1c, glycated albumin, fructosamine, and 1,5-AG) had a similar correlation with mean glucose and hyperglycemic AUC-180. 1,5-AG did not correlate with hyperglycemic AUC-180 better than did HbA1c.

Eribulin Plus Pembrolizumab in Patients with Metastatic Triple-Negative Breast Cancer (ENHANCE 1): A Phase Ib/II Study.

PURPOSE: As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings. PATIENTS AND METHODS: In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1-2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination. RESULTS: The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8-38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2-31.1) for stratum 2 (n = 101). Patients with PD-L1-positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1-negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9-54.3) vs 16.1% (95% CI: 5.5-33.7); stratum 2, 24.4% (95% CI: 12.9-39.5) vs 18.2% (95% CI: 8.2-32.7)]. CONCLUSIONS: Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.

Prolonged use of continuous glucose monitors in children with type 1 diabetes on continuous subcutaneous insulin infusion or intensive multiple-daily injection therapy.

OBJECTIVE: For continuous glucose sensors to improve the treatment of children with type 1 diabetes (T1D), they must be accurate, comfortable to wear, and easy to use. We conducted a pilot study of the FreeStyle Navigator Continuous Glucose Monitoring System (Abbott Diabetes Care) to examine the feasibility of daily use of a continuous glucose monitor (CGM) in an extended ambulatory setting. METHODS: Following a 13-wk trial of daily Navigator use, 45 children with T1D [10.7 +/- 3.7 yr, range 4.6-17.6, 24 using insulin pumps; continuous subcutaneous insulin infusion (CSII) and 21 using glargine-based multiple daily injections (MDI)] used the Navigator for an additional 13 wk. RESULTS: Navigator use was initially slightly higher in the CSII users than in the MDI users but declined similarly in both groups by 22-26 wk. After 26 wk, 11 (46%) of 24 CSII users and 7 (33%) of 21 MDI users were using the CGM at least 5 d a week. No baseline demographic or clinical factors were predictive of the amount of sensor use at 26 wk. However, Navigator use during weeks 1-13 and scores on a CGM satisfaction survey at 13 wk were predictive of use in weeks 22-26. CONCLUSIONS: CGM was generally well-tolerated in children with T1D for more than 6 months, and early acceptance of CGM was predictive of extended use of the device. Although many subjects and parents found CGM valuable, the declining usage over time underscores the need to develop new technologies and strategies to increase acceptance, effectiveness, and long-term use of these devices in youth with T1D.

Educating families on real time continuous glucose monitoring: the DirecNet navigator pilot study experience.

PURPOSE: The purpose of this article is to describe the process of educating families and children with type 1 diabetes on real time continuous glucose monitoring (RT-CGM) and to note the similarities and differences of training patients using continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI). METHODS: A total of 30 CSII participants and 27 MDI participants were educated using the Navigator RT-CGM in a clinical trial. Time spent with families for visits and calls was tracked and compared between patient groups. The Diabetes Research in Children Network (DirecNet) educators were surveyed to assess the most crucial, time intensive, and difficult educational concepts related to CGM. RESULTS: Of the 27 MDI families, an average of 9.6 hours was spent on protocol-prescribed visits and calls (not measured in CSII) and 2 hours on participant-initiated contacts over 3 months. MDI families required an average of 5.4 more phone contacts over 3 months than CSII families. According to the DirecNet educators, lag time and calibrations were the most crucial teaching concepts for successful RT-CGM use. The most time was spent on teaching technical aspects, troubleshooting, and insulin dosing. The most unanticipated difficulties were skin problems including irritation and the sensor not adhering well. CONCLUSION: Educators who teach RT-CGM should emphasize lag time and calibration techniques, technical device training, and sensor insertion. Follow-up focus should include insulin dosing adjustments and skin issues. The time and effort required to introduce RT-CGM provided an opportunity for the diabetes educators to reemphasize good diabetes care practices and promote self-awareness and autonomy to patients and families.

Low-fat vs. high-fat bedtime snacks in children and adolescents with type 1 diabetes.

OBJECTIVE: The purpose of this study was to determine whether, in a group of children with type 1 diabetes using insulin pump, a prebedtime snack with a relatively high fat content provides greater protection from nocturnal hypoglycemia than a snack containing the same amount of carbohydrate and protein but a lower fat content. RESEARCH DESIGN AND METHODS: Ten subjects, aged 6 to <18 yr, in a trial evaluating the Abbott Navigator glucose sensor, agreed to this ancillary study. On 12 or more separate nights, each subject was randomized by a Web site to a carbohydrate-low-fat (30 g CHO, 2.5 g protein, and 1.3 g fat; 138 kcal) snack or a carbohydrate-high-fat (30 g CHO, 2 g protein, and 20 g fat; 320 kcal) snack. Subjects used their usual evening snack algorithm to determine the size (in 15-g carbohydrate increments) and insulin dosage. RESULTS: Average glucose on 128 valid study nights before snack was similar in both groups. The proportion of nights with hypoglycemia (a sensor or meter glucose value or=200 mg/dL and at least 50 mg/dL above baseline, 35% high fat vs. 30% low fat). CONCLUSIONS: There were no statistical differences between the high- and low-fat snacks on the frequency of hyperglycemia or hypoglycemia. This study highlights the feasibility of web-based research in patients' home environment.

Use of the DirecNet Applied Treatment Algorithm (DATA) for diabetes management with a real-time continuous glucose monitor (the FreeStyle Navigator).

BACKGROUND: There are no published guidelines for use of real-time continuous glucose monitoring data by a patient; we therefore developed the DirecNet Applied Treatment Algorithm (DATA). The DATA provides algorithms for making diabetes management decisions using glucose values: (i) in real time which include the direction and rate of change of glucose levels, and (ii) retrospectively based on downloaded sensor data. OBJECTIVE: To evaluate the use and effectiveness of the DATA in children with diabetes using a real-time continuous glucose sensor (the FreeStyle Navigator). SUBJECTS: Thirty children and adolescents (mean +/- standard deviation age = 11.2 +/- 4.1 yr) receiving insulin pump therapy. METHODS: Subjects were instructed on use of the DATA and were asked to download their Navigator weekly to review glucose patterns. An Algorithm Satisfaction Questionnaire was completed at 3, 7, and 13 wk. RESULTS: At 13 wk, all of the subjects and all but one parent thought that the DATA gave good, clear directions for insulin dosing, and thought the guidelines improved their postprandial glucose levels. In responding to alarms, 86% of patients used the DATA at least 50% of the time at 3 wk, and 59% reported doing so at 13 wk. Similar results were seen in using the DATA to adjust premeal bolus doses of insulin. CONCLUSIONS: These results show the feasibility of implementing the DATA when real-time continuous glucose monitoring is initiated and support its use in future clinical trials of real-time continuous glucose monitoring.

Phase 2 Study of Dose-Dense Doxorubicin and Cyclophosphamide Followed by Eribulin Mesylate With or Without Prophylactic Growth Factor for Adjuvant Treatment of Early-Stage Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

BACKGROUND: Eribulin has significantly improved overall survival for patients with metastatic breast cancer who received ≥ 2 prior chemotherapy regimens for advanced disease. This trial assessed eribulin as adjuvant therapy for patients with early-stage breast cancer. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor 2-negative, stage I to III breast cancer received doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 provided intravenously on day 1 of each 14-day cycle for 4 cycles, with pegfilgrastim on day 2, followed by 4 cycles of eribulin mesylate 1.4 mg/m2 provided intravenously on days 1 and 8 every 21 days. There were 2 cohorts, as follows: cohort 1: no prophylactic growth factor with eribulin (allowed at physician's discretion only); cohort 2: prophylactic filgrastim with eribulin. The primary end point was feasibility, defined as the percentage of patients who completed the eribulin portion of the regimen without a dose omission, delay, or reduction due to an eribulin-related adverse event. Relative dose intensity of eribulin and toxicities are summarized by cohort. Exploratory end points included 3-year disease-free survival and overall survival. RESULTS: Eighty-one patients (cohort 1, n = 55; cohort 2, n = 26) entered the treatment phase; 88% completed treatment. Feasibility was 72.9 % (90% confidence interval, 60.4, 83.2) in cohort 1 and 60.0% (90% confidence interval, 41.7, 76.4) in cohort 2. The most frequent eribulin-related adverse events (all grades) were fatigue (75.9%), peripheral neuropathy (54.4%), nausea (39.2%), neutropenia (35.4% [31.5% of patients in cohort 1; 44.0% in cohort 2]), and arthralgia (26.6%). CONCLUSION: The primary end point of > 80% feasibility was not met. No unexpected adverse events were observed, and 62% of patients received full dosing with no dose delay or reduction. Further investigation of this regimen with alternative dosing schedules or use of growth factors could be considered.

Continuous glucose monitoring in children with type 1 diabetes.

OBJECTIVE: To examine the feasibility of daily use of a continuous glucose monitor, the FreeStyle Navigator Continuous Glucose Monitoring System ("Navigator"), in children with type 1 diabetes (T1D). STUDY DESIGN: After a masked Navigator was used for 4 to 7 days to establish a baseline level of glycemic control, 30 insulin pump users with T1D (average age 11.2 years) were asked to use the Navigator daily for 13 weeks. RESULTS: Subjects averaged 149 h/wk of Navigator use during the first 4 weeks, which decreased slightly to 134 h/wk during weeks 9 to 13 (P = .006). Mean hemoglobin A1c improved from 7.1% at baseline to 6.8% at 13 weeks (P = .02), and the percentage of glucose values between 71 and 180 mg/dL increased from 52% to 60% (P = .01). Subjects and parents reported high satisfaction with the Navigator on the Continuous Glucose Monitor Satisfaction Scale. Two subjects had severe skin reactions related to sensor mount adhesive. CONCLUSION: This study indicates that incorporating real-time continuous glucose monitoring into the daily treatment of children with T1D is feasible. The results provide a compelling rationale for conducting a randomized trial of daily use of a continuous glucose monitor in children with T1D.

The Medtronic Minimed Gold continuous glucose monitoring system: an effective means to discover hypo- and hyperglycemia in children under 7 years of age.

BACKGROUND: The glycemic patterns of children less than 7 years with type 1 diabetes have not been well studied using continuous glucose monitoring. Our goal was to assess the incidence of hypoglycemia as well as postprandial glycemic patterns in this age group utilizing continuous glucose monitoring. METHODS: Nineteen children used the Medtronic MiniMed (Northridge, CA) CGMS System Gold on three to seven occasions over approximately 6 months. RESULTS: Nineteen children (nine girls and 10 boys; mean age 4.8 +/- 1.4 years, range 1.6-6.8 years) used the CGMS 102 times, providing 434 days of data; 79% of days were optimal based on CGMS Solutions software version 3.0. Mild hypoglycemia (glucose or=2 mg/dL/min following 50% of breakfasts. Children with hemoglobin A1c levels >or=8% had higher postprandial glucose concentrations. There was no significant advantage of continuous subcutaneous insulin infusion therapy over multiple daily injection therapy in decreasing postprandial hyperglycemia. CONCLUSIONS: CGMS tracings from young children with diabetes demonstrate frequent mild nocturnal hypoglycemia and significant postprandial hyperglycemia, with a rapid rise in glucose following the meal. The most rapid rate of rise and the most severe postprandial hyperglycemia occurred after breakfast.

Prevention of hypoglycemia during exercise in children with type 1 diabetes by suspending basal insulin.

OBJECTIVE: Strategies for preventing hypoglycemia during exercise in children with type 1 diabetes have not been well studied. The Diabetes Research in Children Network (DirecNet) Study Group conducted a study to determine whether stopping basal insulin could reduce the frequency of hypoglycemia occurring during exercise. RESEARCH DESIGN AND METHODS: Using a randomized crossover design, 49 children 8-17 years of age with type 1 diabetes on insulin pump therapy were studied during structured exercise sessions on 2 days. On day 1, basal insulin was stopped during exercise, and on day 2 it was continued. Each exercise session, performed from approximately 4:00-5:00 p.m., consisted of four 15-min treadmill cycles at a target heart rate of 140 bpm (interspersed with three 5-min rest breaks over 75 min), followed by a 45-min observation period. Frequently sampled glucose concentrations (measured in the DirecNet Central Laboratory) were measured before, during, and after the exercise. RESULTS: Hypoglycemia (< or = 70 mg/dl) during exercise occurred less frequently when the basal insulin was discontinued than when it was continued (16 vs. 43%; P = 0.003). Hyperglycemia (increase from baseline of > or = 20% to > or = 200 mg/dl) 45 min after the completion of exercise was more frequent without basal insulin (27 vs. 4%; P = 0.002). There were no cases of abnormal blood ketone levels. CONCLUSIONS: Discontinuing basal insulin during exercise is an effective strategy for reducing hypoglycemia in children with type 1 diabetes, but the risk of hyperglycemia is increased.

The effects of aerobic exercise on glucose and counterregulatory hormone concentrations in children with type 1 diabetes.

OBJECTIVE: To examine the acute glucose-lowering effects of aerobic exercise in children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Fifty children and adolescents with type 1 diabetes (ages 10 to <18 years) were studied during exercise. The 75-min exercise session consisted of four 15-min periods of walking on a treadmill to a target heart rate of 140 bpm and three 5-min rest periods. Blood glucose and plasma glucagon, cortisol, growth hormone, and norepinephrine concentrations were measured before, during, and after exercise. RESULTS: In most subjects (83%), plasma glucose concentration dropped at least 25% from baseline, and 15 (30%) subjects became hypoglycemic (< or = 60 mg/dl) or were treated for low glucose either during or immediately following the exercise session. The incidence of hypoglycemia and/or treatment for low glucose varied significantly by baseline glucose, occurring in 86 vs. 13 vs. 6% of subjects with baseline values <120, 120-180, and >180 mg/dl, respectively (P < 0.001). Exercise-induced increases in growth hormone and norepinephrine concentrations were marginally higher in subjects whose glucose dropped < or = 70 mg/dl. Treatment of hypoglycemia with 15 g of oral glucose resulted in only about a 20-mg/dl rise in glucose concentrations. CONCLUSIONS: In youth with type 1 diabetes, prolonged moderate aerobic exercise results in a consistent reduction in plasma glucose and the frequent occurrence of hypoglycemia when preexercise glucose concentrations are <120 mg/dl. Moreover, treatment with 15 g of oral glucose is often insufficient to reliably treat hypoglycemia during exercise in these youngsters.