Clinical application of MOSkin dosimeters to rectal wall in vivo dosimetry in gynecological HDR brachytherapy

PurposeThree MOSkins dosimeters were assembled over a rectal probe and used to perform in vivo dosimetry during HDR brachytherapy treatments of vaginal cancer. The purpose of this study was to verify the applicability of the developed tool to evaluate discrepancies between planned and measured doses to the rectal wall.Materials and methodsMOSkin dosimeters from the Centre for Medical Radiation Physics are particularly suitable for brachytherapy procedures for their ability to be easily incorporated into treatment instrumentation. In this study, 26 treatment sessions of HDR vaginal brachytherapy were monitored using three MOSkin mounted on a rectal probe. A total of 78 measurements were collected and compared to doses determined by the treatment planning system.ResultsMean dose discrepancy was determined as 2.2 ± 6.9%, with 44.6% of the measurements within ±5%, 89.2% within ±10% and 10.8% higher than ±10%. When dose discrepancies were grouped according to the time elapsed between imaging and treatment (i.e., group 1: ≤90 min; group 2: >90 min), mean discrepancies resulted in 4.7 ± 3.6% and 7.1 ± 5.0% for groups 1 and 2, respectively. Furthermore, the position of the dosimeter on the rectal catheter was found to affect uncertainty, where highest uncertainties were observed for the dosimeter furthest inside the rectum.ConclusionsThis study has verified MOSkin applicability to in-patient dose monitoring in gynecological brachytherapy procedures, demonstrating the dosimetric rectal probe setup as an accurate and convenient IVD instrument for rectal wall dose verification. Furthermore, the study demonstrates that the delivered dose discrepancy may be affected by the duration of treatment planning.     

“Edge-on” MOSkin detector for stereotactic beam measurement and verification

Dosimetry in small radiation field is challenging and complicated because of dose volume averaging and beam perturbations in a detector. We evaluated the suitability of the “Edge-on” MOSkin (MOSFET) detector in small radiation field measurement. We also tested the feasibility for dosimetric verification in stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT). “Edge-on” MOSkin detector was calibrated and the reproducibility and linearity were determined. Lateral dose profiles and output factors were measured using the “Edge-on” MOSkin detector, ionization chamber, SRS diode and EBT2 film. Dosimetric verification was carried out on two SRS and five SRT plans. In dose profile measurements, the “Edge-on” MOSkin measurements concurred with EBT2 film measurements. It showed full width at half maximum of the dose profile with average difference of 0.11 mm and penumbral width with difference of ±0.2 mm for all SRS cones as compared to EBT2 film measurement. For output factor measurements, a 1.1% difference was observed between the “Edge-on” MOSkin detector and EBT2 film for 4 mm SRS cone. The “Edge-on” MOSkin detector provided reproducible measurements for dose verification in real-time. The measured doses concurred with the calculated dose for SRS (within 1%) and SRT (within 3%). A set of output correction factors for the “Edge-on” MOSkin detector for small radiation fields were derived from EBT2 film measurement and presented. This study showed that the “Edge-on” MOSkin detector is a suitable tool for dose verification in small radiation field.     

Portal dose measurements by a 2D array

A 2D array (PTW, type 10024), equipped with 729 vented plane parallel ion-chambers, has been calibrated as a detector for the in vivo comparison between measured and predicted portal doses for head–neck tumors. The comparison of absolute portal doses measured to ones predicted by a commercial treatment planning system within the field of view of the CT scanner, can help the delivered dose verification during different treatment fractions, in particular when the patient's present weight loss.This paper reports the preliminary results of the comparison of the portal doses measured by a PTW 2D array during several radiotherapy fractions and the predicted portal doses for seven patients undergoing head–neck tumor radiotherapy. The gamma index analysis supplied an agreement of more than 95% of the dose-point P_γ > 95% within acceptance criteria, in terms of dose difference, ΔD_max, and distance-agreement, Δd_max, equal to 5% and 4 mm, respectively. After the third week, one patient showed a decrease of P_γ values due to the markedly reduced patient's thickness. Even if the spatial resolution of the 2D array was 1 cm, there were two advantages in the use of this 2D array as a portal dose device for IMRT quality control. The first one was the use of a stable and efficient absolute dosimeter for in vivo verification, although its construction and behavior for other gantry angles need to be tested, and the second one was the time efficiency in verifying the correct dose delivery in several fractions of the therapy.This study presents acceptance criteria for the comparison of TPS-predicted portal dose images with in vivo 2D ion-chamber measurements for IMRT. In particular, portal dose measurements offer clues for additional studies as to which indicators can signal the need for replanning during treatment.     

In vivo skin dose measurement using MOSkin detectors in tangential breast radiotherapy

The purpose of this study is to measure patient skin dose in tangential breast radiotherapy. Treatment planning dose calculation algorithm such as Pencil Beam Convolution (PBC) and in vivo dosimetry techniques such as radiochromic film can be used to accurately monitor radiation doses at tissue depths, but they are inaccurate for skin dose measurement. A MOSFET-based (MOSkin) detector was used to measure skin dose in this study. Tangential breast radiotherapies (“bolus” and “no bolus”) were simulated on an anthropomorphic phantom and the skin doses were measured. Skin doses were also measured in 13 patients undergoing each of the techniques. In the patient study, the EBT2 measurements and PBC calculation tended to over-estimate the skin dose compared with the MOSkin detector (p < 0.05) in the “no bolus radiotherapy”. No significant differences were observed in the “bolus radiotherapy” (p > 0.05). The results from patients were similar to that of the phantom study. This shows that the EBT2 measurement and PBC calculation, while able to predict accurate doses at tissue depths, are inaccurate in predicting doses at build-up regions. The clinical application of the MOSkin detectors showed that the average total skin doses received by patients were 1662 ± 129 cGy (medial) and 1893 ± 199 cGy (lateral) during “no bolus radiotherapy”. The average total skin doses were 4030 ± 72 cGy (medial) and 4004 ± 91 cGy (lateral) for “bolus radiotherapy”. In some cases, patient skin doses were shown to exceed the dose toxicity level for skin erythema. Hence, a suitable device for in vivo dosimetry is necessary to accurately determine skin dose.     

eXaSkin: A novel high-density bolus for 6MV X-rays radiotherapy

PurposeTo evaluate eXaSkin, a novel high-density bolus alternative to commercial tissue-equivalent Superflab, for 6MV photon-beam radiotherapy.Materials and methodsWe delivered a 10 × 10 cm² open field at 90° and head-and-neck clinical plan, generated with the volumetric modulated arc therapy (VMAT) technique, to an anthropomorphic phantom in three scenarios: with no bolus on the phantom’s surface, with Superflab, and with eXaSkin. In each scenario, we measured dose to a central planning target volume (PTV) in the nasopharynx region with an ionization chamber, and we measured dose to the skin, at three different positions within the vicinity of a neck lymph node PTV, with MOSkin™, a semiconductor dosimeter. Measurements were compared against calculations with the treatment planning system (TPS).ResultsFor the static field, MOSkin results underneath the eXaSkin were in agreement with calculations to within 1.22%; for VMAT, to within 5.68%. Underneath Superflab, those values were 3.36% and 11.66%. The inferior agreement can be explained by suboptimal adherence of Superflab to the phantom’s surface as well as difficulties in accurately reproducing its placement between imaging and treatment session. In all scenarios, dose measured at the central target agreed to within 1% with calculations.ConclusionseXaSkin was shown to have superior adaptation to the phantom’s surface, producing minimal air gaps between the skin surface and bolus, allowing for accurate positioning and reproducibility of set-up conditions. eXaSkin with its high density material provides sufficient build-up to achieve full skin dose with less material thickness than Superflab.     

Dosimetric effects of brass mesh bolus on skin dose and dose at depth for postmastectomy chest wall irradiation

PurposeTo investigate the feasibility of using the brass mesh bolus as an alternative to tissue- equivalent bolus for post mastectomy chest wall cancer by characterizing the dosimetric effects of the 2-mm fine brass bolus on both the skin dose, the dose at depth and spatial distribution.Materials and methodsSurface dose and percent depth dose data were acquired for a 6 MV photon beam in a solid water phantom using MOSkin™, Gafchromic EBT3 film and an Advanced Markus ionization chamber. Data were acquired for the case of: no bolus, Face-up bass bolus, Face-down brass bolus, double brass bolus, 0.5 cm and 1.0 cm of Superflab TE bolus. The exit doses were also measured via MOSkin™ dosimeter and Markus ionization chamber. Gafchromic EBT3 film strips were used to plot dose profile at surface and 10 cm depth for Face-up brass, Face-down brass, double brass, 0.5 cm and 1.0 cm of Superflab TE bolus.ResultsThe surface dose measured via MOSkin™ dosimeter increased from 19.2 ± 1.0% to 63.1 ± 2.1% under Face-up brass discs, 51.2 ± 1.2% under Face-up brass spaces, 61.5 ± 0.5% under Face-down brass discs, and 41.3 ± 2.1% under Face-down brass spaces. The percentage difference in the dose measured under brass discs between Face-up versus Face-down was less than 2% for entrance dose and 10% for exit dose, whereas the percentage difference under brass spaces was approximately 3% for entrance dose and about 5% for the exit dose. Gafchromic EBT3 film strip measurements show that the mesh bolus produced ripple beam profiles due to the mesh brass construction.ConclusionsBrass bolus does not significantly change dose at depth (less than 0.5%), and the surface dose is increased similar to TE bolus. Considering this, brass mesh may be used as a substitute for TE bolus to increase superficial dose for chest wall tangent plans.     

Apple polyphenol-rich drinks dose-dependently decrease early-phase postprandial glucose concentrations following a high-carbohydrate meal: a randomized controlled trial in healthy adults and in vitro studies

BackgroundPrevious research demonstrated that a high dose of phlorizin-rich apple extract (AE) can markedly inhibit early-phase postprandial glycemia, but efficacy of lower doses of the AE is unclear.ObjectiveTo determine whether lower AE doses reduce early-phase postprandial glycemia in healthy adults and investigate mechanisms.DesignIn a randomized, controlled, double-blinded, cross-over acute trial, drinks containing 1.8 g (HIGH), 1.35 g (MED), 0.9 g (LOW), or 0 g (CON) of a phlorizin-rich AE were consumed before 75 g starch/sucrose meal. Postprandial blood glucose, insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP) and polyphenol metabolites concentrations were measured 0–240 min, acetaminophen concentrations to assess gastric emptying rate, and 24 h urinary glucose excretion. Effects of AE on intestinal glucose transport were investigated in Caco-2/TC7 cells.ResultsAE significantly reduced plasma glucose iAUC 0–30 min at all doses: mean differences (95% CI) relative to CON were −15.6 (−23.3, −7.9), −11.3 (−19.6, −3.0) and −8.99 (−17.3, −0.7) mmol/L per minute for HIGH, MEDIUM and LOW respectively, delayed T_max (HIGH, MEDIUM and LOW 45 min vs. CON 30 min), but did not lower C_max. Similar dose-dependent treatment effects were observed for insulin, C-peptide, and GIP. Gastric emptying rates and urinary glucose excretion did not differ. Serum phloretin, quercetin and epicatechin metabolites were detected postprandially. A HIGH physiological AE dose equivalent decreased total glucose uptake by 48% in Caco-2/TC7 cells.ConclusionsPhlorizin-rich AE, even at a low dose, can slightly delay early-phase glycemia without affecting peak and total glycemic response.     

EPID-based in vivo dosimetry for stereotactic body radiotherapy of non-small cell lung tumors: Initial clinical experience

PurposeEPID-based in vivo dosimetry (IVD) has been implemented for stereotactic body radiotherapy treatments of non-small cell lung cancer to check both isocenter dose and the treatment reproducibility comparing EPID portal images.Methods15 patients with lung tumors of small dimensions and treated with volumetric modulated arc therapy were enrolled for this initial experience. IVD tests supplied ratios R between in vivo reconstructed and planned isocenter doses. Moreover a γ-like analysis between daily EPID portal images and a reference one, in terms of percentage of points with γ-value smaller than 1, P_γ<1, and mean γ-values, γ_mean, using a local 3%–3 mm criteria, was adopted to check the treatment reproducibility. Tolerance levels of 5% for R ratio, P_γ<1 higher than 90% and γ_mean lower than 0.67 were adopted.ResultsA total of 160 EPID images, two images for each therapy session, were acquired during the treatment of the 15 patients. The overall mean of the R ratios was equal to 1.005 ± 0.014 (1 SD), with 96.9% of tests within ± 5%. The 2 D image γ-like analysis showed an overall γ_mean of 0.39 ± 0.12 with 96.1% of tests within the tolerance level, and an average P_γ<1 value equal to 96.4 ± 3.6% with 95.4% of tests with P_γ<1 > 90%. Paradigmatic discrepancies were observed in three patients: a set-up error and a patient morphological change were identified thanks to CBCT image analysis whereas the third discrepancy was not fully justified.ConclusionsThis procedure can provide improved patient safety as well as a first step to integrate IVD and CBCT dose recalculation.     

A practical methodology to improve the dosimetric accuracy of MR-based radiotherapy simulation for brain tumors

PurposeTo investigate the dosimetric accuracy of synthetic computed tomography (sCT) images generated by a clinically-ready voxel-based MRI simulation package, and to develop a simple and feasible method to improve the accuracy.Methods20 patients with brain tumor were selected to undergo CT and MRI simulation. sCT images were generated by a clinical MRI simulation package. The discrepancy between planning CT and sCT in CT number and body contour were evaluated. To resolve the discrepancies, an sCT specific CT-relative electron density (RED) calibration curve was used, and a layer of pseudo-skin was created on the sCT. The dosimetric impact of these discrepancies, and the improvement brought about by the modifications, were evaluated by a planning study. Volumetric modulated arc therapy (VMAT) treatment plans for each patient were created and optimized on the planning CT, which were then transferred to the original sCT and the modified-sCT for dose re-calculation. Dosimetric comparisons and gamma analysis between the calculated doses in different images were performed.ResultsThe average gamma passing rate with 1%/1 mm criteria was only 70.8% for the comparison of dose distribution between planning CT and original sCT. The mean dose difference between the planning CT and the original sCT were −1.2% for PTV D₉₅ and −1.7% for PTV D_max, while the mean dose difference was within 0.7 Gy for all relevant OARs. After applying the modifications on the sCT, the average gamma passing rate was increased to 92.2%. Mean dose difference in PTV D₉₅ and D_max were reduced to −0.1% and −0.3% respectively. The mean dose difference was within 0.2 Gy for all OAR structures and no statistically significant difference were found.ConclusionsThe modified-sCT demonstrated improved dosimetric agreement with the planning CT. These results indicated the overall dosimetric accuracy and practicality of this improved MR-based treatment planning method.     

Implementation and evaluation of a transit dosimetry system for treatment verification

PurposeTo evaluate a formalism for transit dosimetry using a phantom study and prospectively evaluate the protocol on a patient population undergoing 3D conformal radiotherapy.MethodsAmorphous silicon EPIDs were calibrated for dose and used to acquire images of delivered fields. The measured EPID dose map was back-projected using the planning CT images to calculate dose at pre-specified points within the patient using commercially available software, EPIgray (DOSIsoft, France). This software compared computed back-projected dose with treatment planning system dose. A series of tests were performed on solid water phantoms (linearity, field size effects, off-axis effects). 37 patients were enrolled in the prospective study.ResultsThe EPID dose response was stable and linear with dose. For all tested field sizes the agreement was good between EPID-derived and treatment planning system dose in the central axis, with performance stability up to a measured depth of 18 cm (agreement within −0.5% at 10 cm depth on the central axis and within −1.4% at 2 cm off-axis). 126 transit images were analysed of 37 3D-conformal patients. Patient results demonstrated the potential of EPIgray with 91% of all delivered fields achieved the initial set tolerance level of Δ_D of 0 ± 5-cGy or %Δ_D of 0 ± 5%.ConclusionsThe in vivo dose verification method was simple to implement, with very few commissioning measurements needed. The system required no extra dose to the patient, and importantly was able to detect patient position errors that impacted on dose delivery in two of cases.     

Determination of available phosphorus for phytoplankton populations in lakes and rivers of southeastern Norway

A biotest method with diluted phytoplankton populations was used to determine external concentrations of available phosphorus in water samples with high concentrations of inorganic seston from River Rømua. RP (total molybdate reactive P measured on unfiltered samples) was approximately the P fraction available for Synedra cf. acus, Asterionella formosa and Oscillatoria agardhii. In filtered samples RP_F was the available concentration of P.The ratio RP:RP_F may give valuable information on the ratio between total available P (including available P in seston) and available P in filtered water. Different filter types may give different RP: RP_F ratios. The ratio RP:RP_F was often high during spring and autumn in River Rømua and the lakes studied. During the period June–September RP:RP_F 1 in most of the lakes and periodically in River Rømua.     

An in-vivo dosimetry procedure for Elekta step and shoot IMRT

PurposeThe aim of this work was to extend an in-vivo dosimetry (IVD) method, previously developed by the authors for 3D-conformal radiotherapy, to step and shoot IMRT treatments for pelvic tumors delivered by Elekta linacs.Materials and methodsThe algorithm is based on correlation functions to convert EPID transit signals into in-vivo dose values at the isocenter point, D_iso. The EPID images were obtained by the so-called “IMRT Dosimetric Weighting” mode as a superposition of many segment fields. This way each integral dosimetric image could be acquired in about 10 s after the end of beam delivery and could be processed while delivering the successive IMRT beams. A specific algorithm for D_iso reconstruction especially featured for step and shoot IMRT was implemented using a fluence inhomogeneity index, FI, introduced to describe the degree of beam modulation with respect to open beams. A γ-analysis of 2D-EPID images obtained day to day, resulted rapid enough to verify the plan delivery reproducibility.ResultsFifty clinical IMRT beams, planned for patients undergoing radiotherapy of pelvic tumors, were used to irradiate a homogeneous phantom. For each beam the agreement between the reconstructed dose, D_iso, and the TPS computed dose, D_iso,TPS, was well within 5%, while the mean ratio R = D_iso/D_iso,TPS resulted for 250 tests equal to 1.006 ± 0.036. The same beams were checked in vivo, i.e. during patient treatment delivery, obtaining 500 tests whose average R ratio resulted equal to 1.011 ± 0.042. The γ-analysis of the EPID images with 5% 3 mm criteria supplied 85% of the tests with pass rates γ_mean ≤ 0.5 and P_γ<1 ≥ 90%.     

DEMAT: A multi-institutional dosimetry audit of rotational and static intensity-modulated radiotherapy

PurposeStatic beam intensity-modulated-radiation-therapy (IMRT) and/or Volumetric-Modulated-Arc-Therapy (VMAT) are now available in many regional radiotherapy departments. The aim of this multi-institutional audit was to design a new methodology based on radiochromic films to perform an independent quality control.MethodsA set of data were sent to all participating centres for two clinical localizations: prostate and Head and Neck (H&N) cancers. The agreement between calculations and measurements was verified in the Octavius phantom (PTW) by point measurements using ionization chambers and by 2D measurements using EBT3 radiochromic films. Due to uncertainties in the whole procedure, criteria were set to 5% and 3% in local dose and 3 mm in distance excluding doses lower than 10% of the maximum doses. No normalization point or area was used for the quantitative analysis.Results13 radiotherapy centres participated in this audit involving 28 plans (12 IMRT, 16 VMAT). For point measurements, mean errors were −0.18 ± 1.54% and 0.00 ± 1.58% for prostate and H&N cases respectively. For 2D measurements with 5%/3 mm criteria, gamma map analysis showed a pixel pass rate higher than 95% for prostate and H&N. Mean gamma index was lower than 0.4 for prostate and 0.5 for H&N. Both techniques yielded similar results.ConclusionThis study showed the feasibility of an independent quality control by peers for conventional IMRT and VMAT. Results from all participating centres were found to be in good agreement. This regional study demonstrated the feasibility of our new methodology based on radiochromic films without dose normalization on a specific point.     

Knowledge-based automatic optimization of adaptive early-regression-guided VMAT for rectal cancer

PurposeTo implement a knowledge-based (KB) optimization strategy to our adaptive (ART) early-regression guided boosting technique in neo-adjuvant radio-chemotherapy for rectal cancer.Material and methodsThe protocol consists of a first phase delivering 27.6 Gy to tumor/lymph-nodes (2.3 Gy/fr-PTV₁), followed by the ART phase concomitantly delivering 18.6 Gy (3.1 Gy/fr) and 13.8 Gy (2.3 Gy/fr) to the residual tumor (PTV_ART) and to PTV₁ respectively. PTV_ART is obtained by expanding the residual GTV, as visible on MRI at fraction 9. Forty plans were used to generate a KB-model for the first phase using the RapidPlan tool. Instead of building a new model, a robust strategy scaling the KB-model to the ART phase was applied. Both internal and external validation were performed for both phases: all automatic plans (RP) were compared in terms of OARs/PTVs parameters against the original plans (RA).ResultsThe resulting automatic plans were generally better than or equivalent to clinical plans. Of note, V_30Gy and V_40Gy were significantly improved in RP plans for bladder and bowel; gEUD analysis showed improvement for KB-modality for all OARs, up to 3 Gy for the bowel.ConclusionsThe KB-model generated for the first phase was robust and it was also efficiently adapted to the ART phase. The performance of automatically generated plans were slightly better than the corresponding manual plans for both phases.     

Dosimetric comparison of RapidPlan and manually optimized plans in volumetric modulated arc therapy for prostate cancer

PurposeThis study evaluated whether RapidPlan based plans (RP plans) created by a single optimization, are usable in volumetric modulated arc therapy (VMAT) for patients with prostate cancer.MethodsWe used 51 previously administered VMAT plans to train a RP model. Thirty RP plans were created by a single optimization without planner intervention during optimization. Differences between RP plans and clinical manual optimization (CMO) plans created by an experienced planner for the same patients were analyzed (Wilcoxon tests) in terms of homogeneity index (HI), conformation number (CN), D_95%, and D_2% to planning target volume (PTV), mean dose, V_50Gy, V_70Gy, V_75Gy, and V_78Gy to rectum and bladder, monitor unit (MU), and multi-leaf collimator (MLC) sequence complexity.ResultsRP and CMO values for PTV D_95%, PTV D_2%, HI, and CN were significantly similar (p < 0.05 for all). RP mean dose, V_50Gy, and V_70Gy to rectum were superior or comparable to CMO values; RP V_75Gy and V_78Gy were higher than in CMO plans (p < 0.05). RP bladder dose-volume parameter values (except V_78Gy) were lower than in CMO plans (p < 0.05). MU values were RP: 730 ± 55 MU and CMO: 580 ± 37 MU (p < 0.05); and MLC sequence complexity scores were RP: 0.25 ± 0.02 and CMO: 0.35 ± 0.03 (p < 0.05).ConclusionsRP plans created by a single optimization were clinically acceptable in VMAT for patient with prostate cancer. Our simple model could reduce optimization time, independently of planner’s skill and knowledge.     

Comparison of planned and measured rectal dose in-vivo during high dose rate Cobalt-60 brachytherapy of cervical cancer

Cobalt-60 (Co-60) is a relatively new source for the application of high-dose rate (HDR) brachytherapy. Radiation dose to the rectum is often a limiting factor in achieving the full prescribed dose to the target during brachytherapy of cervical cancer. The aim of this study was to measure radiation doses to the rectum in-vivo during HDR Co-60 brachytherapy. A total of eleven HDR brachytherapy treatments of cervical cancer were recruited in this study. A series of diodes incorporated in a rectal probe was inserted into the patient's rectum during each brachytherapy procedure. Real-time measured rectal doses were compared to calculated doses by the treatment planning system (TPS). The differences between calculated and measured dose ranged from 8.5% to 41.2%. This corresponds to absolute dose differences ranging from 0.3 Gy to 1.5 Gy. A linear relationship was observed between calculated and measured doses with linear regression R² value of 0.88, indicating close association between the measured and calculated doses. In general, absorbed doses for the rectum as calculated by TPS were observed to be higher than the doses measured using the diode probe. In-vivo dosimetry is an important quality assurance method for HDR brachytherapy of cervical cancer. It provides information that can contribute to the reduction of errors and discrepancies in dose delivery. Our study has shown that in-vivo dosimetry is feasible and can be performed to estimate the dose to the rectum during HDR brachytherapy using Co-60.     

Efficacy and Safety of Linagliptin in Black/African American Patients with Type 2 Diabetes: A 6-Month,Randomized, Double-Blind,Placebo-Controlled Study

ObjectiveAlthough black/African American individuals are disproportionately affected by type 2 diabetes, there is scant clinical trial information available on antidiabetes therapies in this group. We compared linagliptin with placebo in black/African American adults who were treatment-naïve or receiving one oral antidiabetes drug.MethodsOf 226 patients randomized to 24 weeks’ linagliptin 5 mg/day or placebo, 208 had baseline and at least one on-treatment glycated hemoglobin (HbA_1c) measurement. Mean baseline HbA_1c was 8.6% in the linagliptin group (n = 98) and 8.68% in the placebo group (n = 110). The primary outcome was change in HbA_1c from baseline to week 24.ResultsBy week 24, mean HbA_1c changes were − 0.84% with linagliptin and − 0.25% with placebo (treatment difference, − 0.58%; P < .001), and more patients in the linagliptin group achieved HbA_1c < 7.0% (26.8% vs. 8.3%; P = .001) or an HbA_1c reduction ≥ 0.5% (54.1% vs. 30.0%; P < .001). Mean weight loss was − 1.1 kg in both groups. During the treatment period, 8 of 98 linagliptingroup patients and 17 of 110 placebo-group patients required rescue therapy (odds ratio, 0.5; P = .14). For postprandial glucose, values were available for few patients (11 placebo, 10 linagliptin), and thus the between-group difference was associated with wide confidence intervals (CIs) (difference, − 1.97 mg/dL; 95% CI, − 53.80 to 49.86; P = .94). In the overall study population, a similar proportion of patients in both groups had adverse events (58.5% vs. 61.7%); most events were mild or moderate and considered unrelated to study drug. Investigator-defined hypoglycemia was rare (3 linagliptin-group patients and 1 placebogroup patient), with no severe events (requiring external assistance).ConclusionThis study confirms that linagliptin is efficacious and well tolerated in black/African American patients with type 2 diabetes. (Endocr Pract. 2014;20: 412-420)     

Changes in prostate cancer incidence,mortality and survival in relation to prostate specific antigen testing in New South Wales,Australia

BackgroundTo examine changes in prostate cancer incidence and mortality rates, and 5-year relative survival, in relation to changes in the rate of prostate specific antigen (PSA) screening tests and the use of radical prostatectomy (RP) in the Australian population.MethodsProstate cancer stage-specific incidence rates, 5-year relative survival and mortality rates were estimated using New South Wales Cancer Registry data. PSA screening test rates and RP/Incidence ratios were estimated from Medicare Benefits Schedule claims data. We used multiple imputation to impute stage for cases with “unknown” stage at diagnosis. Annual percentage changes (APC) in rates were estimated using Joinpoint regression.ResultsTrends in the age-standardized incidence rates for localized disease largely mirrored the trends in PSA screening test rates, with a substantial ‘spike’ in the rates occurring in 1994, followed by a second ‘spike’ in 2008, and then a significant decrease from 2008 to 2015 (APC −6.7, 95% CI −8.2, −5.1). Increasing trends in incidence rates were observed for regional stage from the early 2000s, while decreasing or stable trends were observed for distant stage since 1993. The overall RP/Incidence ratio increased from 1998 to 2003 (APC 9.6, 95% CI 3.8, 15.6), then remained relatively stable to 2015. The overall 5-year relative survival for prostate cancer increased from 58.4% (95% CI: 55.0–61.7%) in 1981–1985 to 91.3% (95% CI: 90.5–92.1%) in 2011–2015. Prostate cancer mortality rates decreased from 1990 onwards (1990–2006: APC −1.7, 95% CI −2.1, −1.2; 2006–2017: APC −3.8, 95% CI −4.4, −3.1).ConclusionsOverall, there was a decrease in the incidence rate of localized prostate cancer after 2008, an increase in survival over time and a decrease in the mortality rate since the 1990s. This seems to indicate that the more conservative use of PSA screening tests in clinical practice since 2008 has not had a negative impact on population-wide prostate cancer outcomes.     

A Comparison of Twice-Daily Biphasic Insulin Aspart 70/30 and Once-Daily Insulin Glargine in Persons With Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin and Oral Therapy: A Randomized,Open-Label Study

ObjectiveTo compare efficacy and safety of biphasic insulin aspart 70/30 (BIAsp 30) with insulin (glargine) in type 2 diabetic patients who were not maintaining glycemic control on basal insulin and oral antidiabetic drugs.MethodsIn a 24-week, open-label, parallel-group trial, type 2 diabetic patients who were not maintaining glycemic control on basal insulin (glargine or neutral protamine Hagedorn) + oral antidiabetic drugs were randomly assigned to twice-daily BIAsp 30 + metformin or oncedaily glargine + metformin + secretagogues (secretagogues were discontinued in the BIAsp 30 arm).ResultsOne hundred thirty-seven patients were randomly assigned to the BIAsp 30 group and 143 patients were randomly assigned to the glargine group. Of 280 patients randomized, 229 (81.8%) completed the study. End-of-trial hemoglobin A_1c reductions were − 1.3% (BIAsp 30) vs − 1.2% (glargine) (treatment difference: 95% confidence interval, − 0.06 [− 0.32 to 0.20]; P = .657). Of patients taking BIAsp 30, 27.3% reached a hemoglobin A_1c level < 7.0% compared with 22.0% of patients taking glargine (treatment difference: P = .388). Glucose increment averaged over 3 meals was lower in the BIAsp 30 arm (treatment difference: − 17.8 mg/dL, P = .001). Fasting plasma glucose reductions from baseline were − 13.8 mg/ dL (BIAsp 30) vs − 42.5 mg/dL (glargine) (P = .0002). Final minor hypoglycemia rate, insulin dose, and weight change were higher in the BIAsp 30 arm (6.5 vs 3.4 events/patient per year, P <.05; 1.19 vs 0.63 U/kg; and 3.1 vs 1.4 kg, P = .0004, respectively).ConclusionsDespite not receiving secretagogues, patients taking BIAsp 30 + metformin achieved similar hemoglobin A_1c levels and lower postprandial plasma glucose compared with those receiving glargine + metformin + secretagogues. The large improvement in the glargine group suggests the patients were not true basal failures at randomization. While switching to BIAsp 30 improves glycemic control in this patient population, remaining on basal insulin and optimizing the dose may be equally effective in the short term. (Endocr Pract. 2011;17:41-50)     

FTO Gene Polymorphism Is Associated with Type 2 Diabetes through Its Effect on Increasing the Maximum BMI in Japanese Men

AimSeveral studies have demonstrated that polymorphisms within the fat-mass and obesity-associated gene (FTO) are associated with type 2 diabetes (T2D). However, whether the effects of the FTO locus on T2D susceptibility are independent of fat-mass increases remains controversial. To investigate this issue, we examined the association of FTO variants with T2D and various aspects of BMI history during adult life in a Japanese population.MethodsWe genotyped SNPs within FTO (rs1121980 and rs1558902) in 760 Japanese patients with T2D who had reached a lifetime maximum BMI (BMI_max) before or at the time of diagnosis and 693 control individuals with information regarding their BMI_max.ResultsThe BMI_max showed the strongest association with T2D risk among the BMIs evaluated in this study. In the sex-combined analysis, FTO SNPs were not associated with any of the BMI variables or with T2D, but in sex-stratified analyses, both SNPs were significantly associated with the BMI_max and rs1558902 was associated with T2D in men. The association of the SNPs with T2D remained significant after adjustments for the current BMI and age, whereas the T2D association of the SNP was no longer significant after adjustments for BMI_max and age.ConclusionsThese results suggest that the effects of FTO polymorphisms on T2D susceptibility in Japanese men are mediated through their effect on increasing the BMI_max before or at the time of diagnosis.