Off-label medication use in rare pediatric diseases in the United States.

Many pediatric patients with rare diseases use drugs off-label due to limited data in pediatric patients. Off-label treatment remains an important public health issue for neonates, infants, children, and adolescents, especially for pediatric patients with rare diseases. For patients with rare diseases, the majority of medications have no or limited information in labelling for pediatric use. Children present unique considerations in clinical trials due to ethical and clinical concerns, which have limited and even discouraged testing of drugs in the pediatric population. Numerous legislative measures have been enacted to address barriers in pediatric drug testing. This research reviewed off-label medication use in rare pediatric diseases, evaluated recent medication uses in pediatric clinical practice, discussed key regulations for rare pediatric diseases, and summarized recent drug approvals for rare pediatric diseases. This study demonstrates the ongoing medical need for newly approved medications to treat pediatric rare diseases and revealed the positive impact of regulations from the Orphan Drug Act of 1983 to the Research to Accelerate Cures and Equity (RACE) for Children Act on drug development and off-label medication practice in rare pediatric disease management. This article provides informative historical background and current considerations of off-label use of medications in neonates, infants, children, and adolescents with rare diseases.

Response of the inner ear to lipopolysaccharide introduced directly into scala media.

In an attempt to develop an animal model of immune mediated Meniere's disease, we have injected lipopolysaccharide (LPS) directly into scala media of guinea pigs and monitored functional and morphological changes over a period of 6 weeks. Depending on the concentration of LPS, changes ranged from moderate-to-severe hearing loss and endolymphatic hydrops with minimal cellular infiltrate or fibrosis, to dense cellular infiltration that filled the scalae. Interestingly, higher concentrations of LPS not only induced severe cellular infiltration, hydrops, and hearing loss, but also a substantial enlargement of the endolymphatic duct and sac. Moreover, LPS injections into perilymph failed to induce hydrops, yet still resulted in cellular infiltration and fibrosis in the cochlea. This suggests that chronic hydrops resulting from an immune challenge of the cochlea may not be due to blockage of the endolymphatic duct and sac, restricting fluid absorption. Furthermore, injecting antigen into endolymph may produce chronic immune-mediated hydrops, and provide a more promising animal model of Meniere's, although animals did not display signs of vestibular dysfunction, and the hearing loss was relatively severe.

Depicting surgical anatomy of the porta hepatis in living donor liver transplantation.

Visualizing the complex anatomy of vascular and biliary structures of the liver on a case-by-case basis has been challenging. A living donor liver transplant (LDLT) right hepatectomy case, with focus on the porta hepatis, was used to demonstrate an innovative method to visualize anatomy with the purpose of refining preoperative planning and teaching of complex surgical procedures. The production of an animation-enhanced video consisted of many stages including the integration of pre-surgical planning; case-specific footage and 3D models of the liver and associated vasculature, reconstructed from contrast-enhanced CTs. Reconstructions of the biliary system were modeled from intraoperative cholangiograms. The distribution of the donor portal veins, hepatic arteries and bile ducts was defined from the porta hepatis intrahepatically to the point of surgical division. Each step of the surgery was enhanced with 3D animation to provide sequential and seamless visualization from pre-surgical planning to outcome. Use of visualization techniques such as transparency and overlays allows viewers not only to see the operative field, but also the origin and course of segmental branches and their spatial relationships. This novel educational approach enables integrating case-based operative footage with advanced editing techniques for visualizing not only the surgical procedure, but also complex anatomy such as vascular and biliary structures. The surgical team has found this approach to be beneficial for preoperative planning and clinical teaching, especially for complex cases. Each animation-enhanced video case is posted to the open-access Toronto Video Atlas of Surgery (TVASurg), an education resource with a global clinical and patient user base. The novel educational system described in this paper enables integrating operative footage with 3D animation and cinematic editing techniques for seamless sequential organization from pre-surgical planning to outcome.

Coadministration of Canagliflozin and Phentermine for Weight Management in Overweight and Obese Individuals Without Diabetes: A Randomized Clinical Trial.

OBJECTIVE: To assess the efficacy and safety of coadministration of canagliflozin (CANA) and phentermine (PHEN) compared with placebo (PBO) and CANA or PHEN monotherapies in individuals who were overweight and obese without type 2 diabetes. RESEARCH DESIGN AND METHODS: This 26-week, phase 2a, randomized, double-blind, PBO-controlled, multicenter, parallel-group study enrolled individuals who were obese or overweight without type 2 diabetes (N = 335, aged 18-65 years, BMI ≥30 to <50 kg/m2 or BMI ≥27 to <50 kg/m2 with hypertension and/or dyslipidemia). Participants were randomized (1:1:1:1) to receive PBO, CANA 300 mg, PHEN 15 mg, or coadministration of CANA 300 mg and PHEN 15 mg (CANA/PHEN) orally once daily. The primary end point was percent change in body weight from baseline to week 26; key secondary end points were the proportion of participants achieving weight loss ≥5% and change from baseline in systolic blood pressure. RESULTS: CANA/PHEN provided statistically superior weight loss from baseline versus PBO at week 26 (least squares mean difference -6.9% [95% CI -8.6 to -5.2]; P < 0.001). CANA/PHEN also provided statistically superior achievement of weight loss ≥5% and reduction in systolic blood pressure compared with PBO. CANA/PHEN was generally well tolerated, with a safety and tolerability profile consistent with that of the individual components. CONCLUSIONS: CANA/PHEN produced meaningful reductions in body weight and was generally well tolerated in individuals who were overweight or obese without type 2 diabetes. Further studies are warranted to evaluate potential use of this combination for long-term weight management.

Visualising a rare and complex case of advanced hilar cholangiocarcinoma.

The Toronto Video Atlas of Liver, Pancreas, Biliary, and Transplant Surgery (TVASurg) is a free online library of three-dimensional (3D) animation-enhanced surgical videos, designed to instruct surgical fellows in hepato-pancreato-biliary (HPB) and transplant procedures. The video 'Klatskin tumours: Extended left hepatectomy with complex portal vein reconstruction and in situ cold perfusion of the liver', which is available to watch at http://TVASurg.ca , is a unique and valuable visual resource for surgeons in training to assist them in learning this rare procedure. This paper describes the methodologies used in producing this 3D animation-enhanced surgical video.

Creating an animation-enhanced video library of hepato-pancreato-biliary and transplantation surgical procedures.

The potential for integrating real-time surgical video and state-of-the art animation techniques has not been widely applied to surgical education. This paper describes the use of new technology for creating videos of liver, pancreas and transplant surgery, annotating them with 3D animations, resulting in a freely-accessible online resource: The Toronto Video Atlas of Liver, Pancreas and Transplant Surgery ( http://tvasurg.ca ). The atlas complements the teaching provided to trainees in the operating room, and the techniques described in this study can be readily adapted by other surgical training programmes.

The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus.

BACKGROUND: Sodium glucose co-transporter 2 (SGLT2) inhibitors lower blood glucose levels in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. This review provides a comprehensive summary of preclinical and clinical data on the effects of the SGLT2 inhibitor canagliflozin on mineral balance and bone. METHODS: Published articles and internal study reports through November 2015 were included. RESULTS: In clinical studies, canagliflozin was not associated with meaningful changes in serum or urine calcium, parathyroid hormone, or vitamin D. Canagliflozin was associated with increases in serum magnesium and phosphate without changes in their urinary excretion. Increases in serum collagen type-1 beta-carboxy-telopeptide (beta-CTX), a bone resorption marker, and osteocalcin, a bone formation marker, were observed with canagliflozin. Decreases in total hip bone mineral density (BMD) of up to 1.2% were seen with canagliflozin after 2 years; no changes in BMD were seen at other skeletal sites. Changes in total hip BMD and serum beta-CTX with canagliflozin correlated with decreases in body weight. In a clinical program-wide analysis, canagliflozin was associated with increased fracture risk that was driven by a higher incidence in the cardiovascular safety study (CANVAS), with no fracture imbalance seen in pooled data from other Phase 3 studies. The fracture imbalance occurred within 12 weeks after initiating treatment, most frequently in the distal portion of the upper and lower extremities. CONCLUSIONS: Across clinical studies, canagliflozin did not meaningfully affect calcium homeostasis or hormones regulating calcium homeostasis. Increases in bone turnover markers and decreases in BMD at the total hip, but not at other sites, that correlated with weight loss were seen with canagliflozin. Canagliflozin was associated with a higher fracture incidence within 12 weeks, primarily in distal extremities. Data from ongoing canagliflozin studies will provide additional information on fracture risk.

Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks.

OBJECTIVES: Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been associated with weight loss in a broad range of patients with type 2 diabetes mellitus (T2DM). This analysis further evaluated changes in body weight and composition with canagliflozin in two 104-week, Phase 3 studies. METHODS: In Study 1, patients aged 18-80 years (N = 1,450) received canagliflozin 100 or 300 mg or glimepiride as add-on to metformin for a 52-week core treatment period, followed by a 52-week extension period. In Study 2, patients aged 55-80 years (N = 714) received canagliflozin 100 or 300 mg or placebo added to stable background antihyperglycemic agents for a 26-week core treatment period, followed by a 78-week extension period. Percent change from baseline in body weight; proportion of patients with any weight loss, ≥5% weight loss, and ≥10% weight loss; change in body mass index (BMI) and waist circumference; change in body weight across weight-loss quartiles; and changes in body composition were evaluated in both studies. RESULTS: Canagliflozin 100 and 300 mg provided sustained weight loss versus either glimepiride or placebo over 104 weeks. More patients experienced any weight loss and ≥5% weight loss with canagliflozin versus comparator. Across the 3 highest weight-loss quartiles, canagliflozin provided greater weight loss versus glimepiride or placebo. BMI and waist circumference reductions were observed with canagliflozin 100 and 300 mg versus either glimepiride or placebo over 104 weeks; more patients had BMI or waist circumference reductions with canagliflozin versus comparator. Body composition analysis indicated that the majority of weight loss was due to loss of fat mass. Canagliflozin was generally well tolerated, with increased incidence of adverse events related to the SGLT2 inhibition mechanism. CONCLUSIONS: Canagliflozin 100 and 300 mg provided sustained reductions in body weight, BMI, and waist circumference in a greater proportion of patients with T2DM versus glimepiride or placebo over 104 weeks. TRIAL REGISTRATION: ClinicalTrials.gov NCT00968812, NCT01106651.

Evaluation of Bone Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes Treated With Canagliflozin.

CONTEXT: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM). OBJECTIVE: Our objective is to describe the effects of canagliflozin on bone mineral density (BMD) and bone biomarkers in patients with T2DM. DESIGN: This was a randomized study, consisting of a 26-week, double-blind, placebo-controlled period and a 78-week, double-blind, placebo-controlled extension. SETTING: This study was undertaken in 90 centers in 17 countries. PATIENTS: Patients were aged 55-80 years (N = 716) and whose T2DM was inadequately controlled on a stable antihyperglycemic regimen. INTERVENTIONS: Canagliflozin 100 or 300 mg or placebo were administered once daily. OUTCOME AND MEASURES: BMD was assessed using dual-energy x-ray absorptiometry at weeks 26, 52, and 104. Bone strength was assessed using quantitative computed tomography and finite element analysis at week 52. Serum collagen type 1 ß-carboxy-telopeptide, osteocalcin, and estradiol were assessed at weeks 26 and 52. RESULTS: Canagliflozin doses of 100 and 300 mg were associated with a decrease in total hip BMD over 104 weeks, (placebo-subtracted changes: -0.9% and -1.2%, respectively), but not at other sites measured (femoral neck, lumbar spine, or distal forearm). No meaningful changes in bone strength were observed. At week 52, canagliflozin was associated with an increase in collagen type 1 ß-carboxy-telopeptide that was significantly correlated with a reduction in body weight, an increase in osteocalcin, and, in women, a decrease in estradiol. CONCLUSIONS: In older patients with T2DM, canagliflozin showed small but significant reductions in total hip BMD and increases in bone formation and resorption biomarkers, due at least in part to weight loss.

Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus.

The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure (BP) and osmotic diuresis- and intravascular volume reduction-related adverse events (AEs) were evaluated using pooled data from four placebo-controlled, phase 3 studies in patients with type 2 diabetes mellitus (T2DM; N=2313). At baseline, 1332 (57.6%) patients were taking an antihypertensive medication. Canagliflozin 100 mg and 300 mg provided reductions (95% confidence interval [CI]) from baseline in systolic BP (SBP) compared with placebo (-4.3 mm Hg [-5.0 to -3.5], -5.0 mm Hg [-5.8 to -4.2], and -0.3 mm Hg [-1.2 to 0.5], respectively) and in diastolic BP (DBP; -2.5 mm Hg [-2.9 to -2.0], -2.4 mm Hg [-2.9 to -1.9], and -0.6 mm Hg [-1.1 to -0.02], respectively). Placebo-subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were -4.0 mm Hg (-5.1 to -2.8) and -4.7 mm Hg (-5.8 to -3.5) and reductions in DBP were -1.9 mm Hg (-2.6 to -1.2) and -1.9 mm Hg (-2.6 to -1.1), respectively. Compared with the overall population, patients with elevated baseline SBP (≥140 mm Hg) had numerically greater absolute SBP reductions (95% CI) with canagliflozin 100 mg and 300 mg and placebo (-12.8 mm Hg [-15.2 to -10.5], -14.2 mm Hg [-16.4 to -12.0], and -6.8 mm Hg [-9.1 to -4.5], respectively). Numerically greater DBP reductions were seen in patients with DBP ≥90 mm Hg at baseline (-5.9 mm Hg [-8.2 to -3.6], -9.0 mm Hg [-11.1 to -6.9], and -7.4 mm Hg [-9.6 to -5.1], respectively). In patients with elevated SBP at baseline, placebo-subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were -6.0 mm Hg (-9.1 to -2.9) and -7.4 mm Hg (-10.4 to -4.4), respectively. Placebo-subtracted changes in DBP were 1.5 mm Hg (-1.6 to 4.5) and -1.6 mm Hg (-4.5 to 1.2), respectively, in those with elevated DBP at baseline. Canagliflozin 100 mg and 300 mg were associated with increased incidence of osmotic diuresis-related AEs (e.g., pollakiuria [increased urine volume] and polyuria [increased urine frequency]) vs placebo (6.7%, 5.6%, and 0.8%). The incidence of intravascular volume reduction-related AEs (eg, orthostatic hypotension and postural dizziness) was low across groups (1.2%, 1.3%, and 1.1%). In summary, canagliflozin was associated with reduced BP in patients with T2DM across a range of baseline BPs, with increased incidence of AEs related to osmotic diuresis but not intravascular volume reduction.

Safety and tolerability of canagliflozin in patients with type 2 diabetes mellitus: pooled analysis of phase 3 study results.

BACKGROUND: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed for treating type 2 diabetes mellitus (T2DM). METHODS: The safety/tolerability profile of canagliflozin 100 and 300 mg over 26 weeks was assessed using an integrated analysis of data pooled from 4 placebo-controlled, phase 3 studies representing a broad range of patients with T2DM (N = 2313; mean age, 56.0 years; glycated hemoglobin [HbA1c], 8.0%; body mass index, 32.1 kg/m2; estimated glomerular filtration rate, 88.1 mL/min/1.73 m2) on various prespecified background diabetes mellitus treatments. Safety/tolerability evaluations included adverse event (AE) reporting, with additional data collection prespecified for selected AEs, and assessments of renal-related, lipid, and other safety laboratory parameters. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690. RESULTS: The overall incidence of AEs was similar with canagliflozin 100 and 300 mg and placebo; incidences of serious AEs and AEs leading to study discontinuation were low across groups. Canagliflozin was associated with higher incidences than placebo of genital mycotic infections and osmotic diuresis-related AEs; these were generally considered by the investigator to be mild to moderate in intensity and infrequently led to discontinuation. Canagliflozin was associated with transient reductions in estimated glomerular filtration rate that trended toward baseline over the assessment period; incidences of renal-related AEs were low across groups. Dose-related increases in the incidence of hypoglycemia episodes were seen with canagliflozin versus placebo in patients on background sulfonylurea; incidences of severe hypoglycemia were low across groups. Hypoglycemia incidence was low overall in patients not on background sulfonylurea, but slightly higher with canagliflozin versus placebo. Relative to placebo, favorable changes in high-density lipoprotein cholesterol and triglycerides were seen with canagliflozin; increases in low-density lipoprotein cholesterol were also seen. Canagliflozin was associated with small changes in other safety laboratory parameters that were not clinically meaningful. CONCLUSIONS: Canagliflozin as monotherapy and as combination therapy was generally well tolerated in patients with T2DM inadequately controlled on their current diabetes mellitus treatment.

Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies.

BACKGROUND: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in patients with T2DM <65 and ≥65 years of age. METHODS: Pooled data from 4 randomised, placebo-controlled, 26-week, Phase 3 studies (N = 2,313) evaluating canagliflozin 100 and 300 mg were analysed by age: <65 years (n = 1,868; mean age, 52.8 years) or ≥65 years (n = 445; mean age, 69.3 years). Efficacy evaluations included change from baseline in glycaemic parameters and systolic blood pressure (BP), and percent change from baseline in body weight. Assessment of safety/tolerability included adverse event (AE) reports, incidence of documented hypoglycaemia, and percent change from baseline in fasting plasma lipids. RESULTS: Canagliflozin 100 and 300 mg reduced HbA1c and fasting plasma glucose relative to placebo in patients <65 and ≥65 years of age. Both canagliflozin doses reduced body weight and systolic BP relative to placebo in patients <65 and ≥65 years of age. Incidence of overall AEs was similar across all treatment groups in patients <65 and ≥65 years of age. Incidences of serious AEs and AE-related discontinuations were similar across all treatment groups in patients <65 years of age and higher with canagliflozin 100 mg than other groups in patients ≥65 years of age. As in patients <65 years of age, incidences of genital mycotic infections and osmotic diuresis-related AEs were higher with canagliflozin relative to placebo in those ≥65 years of age. Incidences of urinary tract infections (UTIs), renal-related AEs, AEs related to volume depletion, and documented hypoglycaemia episodes were similar across all treatment groups in patients ≥65 years of age; no notable trends were observed with canagliflozin 100 and 300 mg relative to placebo in these AEs among patients <65 years of age. Changes in lipid parameters with canagliflozin were similar in both age subsets. CONCLUSIONS: Canagliflozin improved glycaemic control, body weight, and systolic BP, and was generally well tolerated in older patients with T2DM. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834; NCT01106677; NCT01106625; NCT01106690.

Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies.

OBJECTIVE: To characterize genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) using pooled data from Phase 3 studies. RESEARCH DESIGN AND METHODS: Genital mycotic infections with canagliflozin 100 and 300 mg were evaluated in Population 1 (N = 2313; mean exposure [weeks]: canagliflozin, 24.3; placebo, 23.8), including patients from four placebo-controlled studies, and Population 2 (N = 9439; mean exposure [weeks]: canagliflozin, 68.1; control, 64.4), including patients from eight placebo/active-controlled studies (including older patients and those with renal impairment or high cardiovascular disease risk). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690; NCT01032629; NCT01064414; NCT01106651; NCT00968812. MAIN OUTCOME MEASURES: Adverse events suggestive of genital mycotic infections were recorded, with additional information collected using supplemental electronic case report forms. RESULTS: In Population 1, genital mycotic infection incidence was higher with canagliflozin 100 and 300 mg than placebo (95% confidence intervals excluded zero) in females (10.4%, 11.4%, 3.2%) and males (4.2%, 3.7%, 0.6%). These were generally mild to moderate in intensity, none were serious, and few led to discontinuation. Most events with canagliflozin were treated with antifungal therapies, and median symptom duration following treatment initiation was similar across groups; few patients had >1 event (females, 2.3%; males, 0.9%). Findings with canagliflozin 100 and 300 mg versus control were similar in Population 2 (females: 14.7%, 13.9%, 3.1%; males: 7.3%, 9.3%, 1.6%); a low proportion of males underwent circumcision across groups. Most events with canagliflozin occurred within the first 4 months in females and first year in males; no consistent evidence of dose dependence was observed. Key limitations included lack of laboratory confirmation for most events and variable treatment methods. CONCLUSIONS: Genital mycotic infection incidences were higher with canagliflozin than control in patients with T2DM; events were generally mild to moderate in intensity and responded to standard treatments.

Urinary tract infection in randomized phase III studies of canagliflozin, a sodium glucose co-transporter 2 inhibitor.

BACKGROUND: Canagliflozin, a sodium glucose co-transporter 2 inhibitor, lowers plasma glucose in individuals with hyperglycemia by inhibiting renal glucose reabsorption and increasing glucosuria. Urinary tract infections (UTIs) were characterized in patients with type 2 diabetes mellitus enrolled in Phase III studies of canagliflozin. METHODS: Analyses were performed in 2 pooled datasets: Population 1 (N = 2313; mean exposure [weeks]: canagliflozin, 24.3; placebo, 23.8) including patients from 4 placebo-controlled studies; Population 2 (N = 9439; mean exposure [weeks]: canagliflozin, 68.1; control, 64.4) including patients from 8 placebo- and active-controlled studies (including patients with renal impairment or high risk of cardiovascular disease, and older patients). Individual studies in special patient populations and 2 active-controlled studies were analyzed separately. Patients with a prior history of UTIs were not excluded from these studies. Urinary tract infection frequency and characteristics were systematically collected, with additional information for each event collected using supplemental electronic case report forms. RESULTS: In Populations 1 and 2, canagliflozin 100 and 300 mg were associated with small increases in the incidence of UTIs compared with control, with no dose-dependence. Urinary tract infections with canagliflozin were similar to those with control in severity, and upper UTIs were infrequent across groups. No increase in serious events or those leading to discontinuation were seen with canagliflozin versus control. Time to the first occurrence of symptomatic UTIs tended to be earlier with canagliflozin than placebo in Population 1, and similar with canagliflozin and control in Population 2; median duration of events was similar across groups in both populations. The proportion of patients with recurrent events was low across groups. CONCLUSION: Canagliflozin was associated with a small increase in incidence of UTIs in patients with type 2 diabetes mellitus, with no increase in serious or upper UTIs.

Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial.

INTRODUCTION: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). Our randomized, double-blind, placebo-controlled, phase 3 study (www.clinicaltrials.gov: NCT01106651) evaluated the efficacy and safety of canagliflozin therapy in older subjects (aged 55-80 years) with T2DM inadequately controlled on their current regimen of blood glucose-lowering agents (any approved oral or injectable treatment). METHODS: Subjects (N = 716) aged 55 to 80 years (mean, 63.6 years) with glycated hemoglobin (HbA1c) levels ≥ 7.0% to ≤ 10.0% were randomized. Seven hundred fourteen received canagliflozin 100 mg or 300 mg or placebo (1:1:1) daily. The prespecified primary endpoint was change from baseline in HbA1c level at week 26. Prespecified secondary endpoints included proportion of subjects achieving HbA1c levels < 7.0%, change from baseline in fasting plasma glucose (FPG) level and systolic blood pressure (BP), and percent change from baseline in body weight, triglyceride levels, and high-density lipoprotein cholesterol (HDL-C) level. Adverse events (AEs) were reported throughout the study. RESULTS: At week 26, treatment with canagliflozin 100 mg and 300 mg significantly reduced HbA1c levels compared with placebo (-0.60%, -0.73%, -0.03%, respectively; P < 0.001); more subjects achieved HbA1c levels < 7.0% with both canagliflozin doses compared with placebo (P < 0.001). Both canagliflozin doses significantly reduced body weight, FPG level, and systolic BP, and increased HDL-C level compared with placebo (P < 0.001); low-density lipoprotein cholesterol level was increased with both canagliflozin doses compared with placebo. The overall AE incidence was slightly higher with canagliflozin 300 mg than with canagliflozin 100 mg or placebo (78.0%, 72.2%, 73.4%, respectively). Serious AE and AE-related discontinuation rates were low across groups. Both canagliflozin doses were associated with higher rates than placebo of genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs (ie, pollakiuria, polyuria). Documented hypoglycemia rates were modestly higher with both canagliflozin doses compared with placebo. CONCLUSION: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in older subjects with T2DM who were on background therapy with a variety of blood glucose-lowering agents.

Accurate respiration measurement using DC-coupled continuous-wave radar sensor for motion-adaptive cancer radiotherapy.

Accurate respiration measurement is crucial in motion-adaptive cancer radiotherapy. Conventional methods for respiration measurement are undesirable because they are either invasive to the patient or do not have sufficient accuracy. In addition, measurement of external respiration signal based on conventional approaches requires close patient contact to the physical device which often causes patient discomfort and undesirable motion during radiation dose delivery. In this paper, a dc-coupled continuous-wave radar sensor was presented to provide a noncontact and noninvasive approach for respiration measurement. The radar sensor was designed with dc-coupled adaptive tuning architectures that include RF coarse-tuning and baseband fine-tuning, which allows the radar sensor to precisely measure movement with stationary moment and always work with the maximum dynamic range. The accuracy of respiration measurement with the proposed radar sensor was experimentally evaluated using a physical phantom, human subject, and moving plate in a radiotherapy environment. It was shown that respiration measurement with radar sensor while the radiation beam is on is feasible and the measurement has a submillimeter accuracy when compared with a commercial respiration monitoring system which requires patient contact. The proposed radar sensor provides accurate, noninvasive, and noncontact respiration measurement and therefore has a great potential in motion-adaptive radiotherapy.

Ultrasound-based guidance of intensity-modulated radiation therapy.

In ultrasound-guided intensity-modulated radiation therapy (IMRT) of prostate cancer, ultrasound imaging ascertains the anatomical position of patients during x-ray therapy delivery. The ultrasound transducers are made of piezoelectric ceramics. The same crystal is used for both ultrasound production and reception. Three-dimensional (3D) ultrasound devices capture and correlate series of 2-dimensional (2D) B-mode images. The transducers are often arranged in a convex array for focusing. Lower frequency reaches greater depth, but results in low resolution. For clear image, some gel is usually applied between the probe and the skin contact surface. For prostate positioning, axial and sagittal scans are performed, and the volume contours from computed tomography (CT) planning are superimposed on the ultrasound images obtained before radiation delivery at the linear accelerator. The planning volumes are then overlaid on the ultrasound images and adjusted until they match. The computer automatically deduces the offset necessary to move the patient so that the treatment area is in the correct location. The couch is translated as needed. The currently available commercial equipment can attain a positional accuracy of 1-2 mm. Commercial manufacturer designs differ in the detection of probe coordinates relative to the isocenter. Some use a position-sensing robotic arm, while others have infrared light-emitting diodes or pattern-recognition software with charge-couple-device cameras. Commissioning includes testing of image quality and positional accuracy. Ultrasound is mainly used in prostate positioning. Data for 7825 daily fractions of 234 prostate patients indicated average 3D inter-fractional displacement of about 7.8 mm. There was no perceivable trend of shift over time. Scatter plots showed slight prevalence toward superior-posterior directions. Uncertainties of ultrasound guidance included tissue inhomogeneities, speckle noise, probe pressure, and inter-observer variation. Some published studies detected improvement in treatment based on gastrointestinal toxicity and the reduction of prostate movement.

Effects of field parameters on IMRT plan quality for gynecological cancer: a case study.

Traditional external beam radiotherapy of gynecological cancer consists of a 3D, four-field-box technique. The radiation treatment area is a large region of normal tissue, with greater inhomogeneity over the treatment volume, which could benefit more with intensity-modulated radiation therapy (IMRT). This is a case report of IMRT planning for a patient with endometrial cancer. The planning target volume (PTV) spanned the intrapelvic and periaortic lymph nodes to a 33-cm length. Planning and treatment were accomplished using double isocenters. The IMRT plan was compared with a 3D plan, and the effects of field parameters were studied. Delineated anatomical contours included the intrapelvic nodes (PTV), bone marrow, small bowel, bladder, rectum, sigmoid colon, periaortic nodes (PTV), spinal cord, left kidney, right kidney, large bowel, liver, and tissue (excluding the PTVs). Comparisons were made between IMRT and 3D plans, 23-MV and 6-MV energies, zero and rotated collimator angles, different numbers of segments, and opposite gantry angle configurations. The plans were evaluated based on dosevolume histograms (DVHs). Compared with the 3D plan, the IMRT plan had superior dose conformity and spared the bladder and sigmoid colon embedded in the intrapelvic nodes. The higher energy (23 MV) reduced the dose to most critical organs and delivered less integral dose. Zero collimator angles resulted in a better plan than "optimized" collimator angles, with lower dose to most of the normal structures. The number of segments did not have much effect on isodose distribution, but a reasonable number of segments was necessary to keep treatment time from being prohibitively long. Gantry angles, when evenly spaced, had no noticeable effect on the plan. The patient tolerated the treatment well, and the initial complete blood count was favorable. Our results indicated that large-volume tumor sites may also benefit from precise conformal delivery of IMRT.

Prostate motion and isocenter adjustment from ultrasound-based localization during delivery of radiation therapy.

PURPOSE: To study prostate motion from 4,154 ultrasound alignment fractions on 130 prostate patients treated with conformal radiotherapy or intensity-modulated radiation therapy at the University of Nebraska Medical Center. METHODS AND MATERIALS: Each prostate patient was immobilized in a vacuum cradle. Daily treatment was verified by ultrasound scan after laser setup with skin marks and before radiation delivery by the same physician responsible for anatomic delineation during planning. Directional statistics were employed to test the significance of shift directions. RESULTS: Polar histograms showed the prevalence of prostate motion in superior-posterior directions. The average direction was about 27 degrees from the superior axis. The average changes of prostate position in superior to inferior (SI), anterior-posterior (AP), and left to right (LR) directions and in radial distance were 0.25, -0.13, 0.03, and 0.92, cm respectively. Our data indicated that prostate motion was not patient specific, and its average magnitude remained virtually unchanged over time. Recommended planning target volume (PTV) margins for use without ultrasound localization were 0.90 cm in SI, 1.02 cm in AP, and 0.80 cm in LR directions. CONCLUSION: Ultrasound localization revealed a predominance of prostate shift from planning position in the superior-posterior direction, with an average closer to the superior axis. The motion data provides recommended margins for PTV.

A comparison of two image fusion techniques in ct-on-rails localization of radiation delivery.

A computed tomography (ct) scanner on Rails has been installed in a linear accelerator room at Morristown Memorial Hospital since 2000. The ct-on-Rails has been used for the localization of patient position during radiation delivery for prostate, lung and liver cancer patients. The image management system, the Siemens Syngo system, is the primary software employed in the registration of the planning ct and the treatment ct images. This study compares the two image fusion methods available in the system: Landmark Registration and Visual Alignment. Shifts in 6 ct scans with Rando phantom were deduced from Landmark Registration (automatic algorithm) and from Visual Alignment (manual registration), and compared with the shifts directly measured on the phantom. For Visual Alignment, the isocenter shifts deduced from the fused images generally agreed well with the directly measured shifts on the Rando phantom, with average absolute error of 0.9 mm in anterior-posterior (ap) direction, 1.0 mm in right-left (rl) direction, and 2.0 mm in superior-inferior (si) direction. The image fusion algorithm was confirmed to be accurate. Some scans with Landmark Registration gave erroneous ap shifts when the anterior radio-opaque marker (bb) registration was of in the ap direction. Visual Alignment was more robust than Landmark Registration in these clinical situations.