Gal-3 blocks the binding between PD-1 and pembrolizumab.

INTRODUCTION: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of metastatic malignant melanoma (MM) and improved long-term survival. Despite the impressive results, some patients still have progressive disease, and the search for biomarkers predicting response to ICI treatment is ongoing. In this search, galectin-3 (Gal-3) has been suggested as a molecule of interest, both as a marker of treatment response and as a treatment target to potentiate ICI therapy. We have previously demonstrated the binding between programmed cell death 1 (PD-1) and Gal-3, and here, we investigated the interaction between PD-1, pembrolizumab, and Gal-3 in metastatic MM patients. METHODS: The binding between PD-1, pembrolizumab and Gal-3 was investigated by surface plasmon resonance (SPR) and cryogenic electron microscopy (cryo-EM). The function was studied in in vitro cultures and soluble levels of both PD-1 and Gal-3 were measured in metastatic MM patients, treated with pembrolizumab. RESULTS: By SPR, we demonstrated that Gal-3 can block the binding between PD-1 and pembrolizumab, and further visualized a steric inhibition using cryo-EM. T cells cultured with Gal-3 had reduced pro-inflammatory cytokine production, which could not be rescued by pembrolizumab. In patients with metastatic MM, high levels of Gal-3 in plasma were found in patients with a longer progression-free survival in the study period, whereas high Gal-3 expression in the tumor was seen in patients with disease progression. Soluble PD-1 levels in plasma increased after treatment with pembrolizumab and correlated with disease progression. CONCLUSION: We demonstrate that the interaction between PD-1 and Gal-3 interferes with the binding of pembrolizumab, supporting that an immune suppression induced by Gal-3 in the tumor microenvironment cannot be rescued by pembrolizumab.

EviGUIDE - a tool for evidence-based decision making in image-guided adaptive brachytherapy for cervical cancer.

PURPOSE: To develop a novel decision-support system for radiation oncology that incorporates clinical, treatment and outcome data, as well as outcome models from a large clinical trial on magnetic resonance image-guided adaptive brachytherapy (MR-IGABT) for locally advanced cervical cancer (LACC). METHODS: A system, called EviGUIDE, was developed that combines dosimetric information from the treatment planning system, patient and treatment characteristics, and established tumor control probability (TCP), and normal tissue complication probability (NTCP) models, to predict clinical outcome of radiotherapy treatment of LACC. Six Cox Proportional Hazards models based on data from 1341 patients of the EMBRACE-I study have been integrated. One TCP model for local tumor control, and five NTCP models for OAR morbidities. RESULTS: EviGUIDE incorporates TCP-NTCP graphs to help users visualize the clinical impact of different treatment plans and provides feedback on achievable doses based on a large reference population. It enables holistic assessment of the interplay between multiple clinical endpoints and tumour and treatment variables. Retrospective analysis of 45 patients treated with MR-IGABT showed that there exists a sub-cohort of patients (20%) with increased risk factors, that could greatly benefit from the quantitative and visual feedback. CONCLUSION: A novel digital concept was developed that can enhance clinical decision- making and facilitate personalized treatment. It serves as a proof of concept for a new generation of decision support systems in radiation oncology, which incorporate outcome models and high-quality reference data, and aids the dissemination of evidence-based knowledge about optimal treatment and serve as a blueprint for other sites in radiation oncology.

Overall Severe Morbidity After Chemo-Radiation Therapy and Magnetic Resonance Imaging-Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To evaluate overall severe late morbidity (grade ≥3) in patients with locally advanced cervical cancer treated with chemo-radiation therapy and magnetic resonance image guided adaptive brachytherapy within the prospective EMBRACE-I study, and to compare the results with published literature after standard radiograph based brachytherapy (BT). METHODS AND MATERIALS: From 2008 to 2015 the EMBRACE-I study enrolled 1416 patients. Morbidity was assessed (Common Terminology Criteria for Adverse Events version 3.0) every 3 months the 1st year, every 6 months the second and third year, and yearly thereafter and 1251 patients had available follow-up on late morbidity. Morbidity events (grade 3-5) were summarized as the maximum grade during follow-up (crude incidence rates) and actuarial estimates at 3 and 5 years. To compare with the published literature on standard radiograph based BT, Common Terminology Criteria for Adverse Events scores from the EMBRACE-I study were retrospectively converted into a corresponding score in the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer system. RESULTS: In total, 534 severe events occurred in 270 patients; 429 events were grade 3 and 105 were grade 4 events. Actuarial estimates for grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal and fistula events at 5 years were 8.5% (95% confidence interval [CI], 6.9%-10.6%), 6.8% (95% CI, 5.4%-8.6%), 5.7% (95% CI, 4.3%-7.6%), and 3.2% (95% CI, 2.2%-4.5%), respectively. The 5-year actuarial estimate for organ-related events (GI, GU, vaginal, or fistula) was 18.4% (95% CI, 16.0%-21.2%). The 5-year actuarial estimate when aggregating all G≥3 endpoints (GI, GU, vaginal, fistulas, and non-GI/GU/vaginal) was 26.6% (95% CI, 23.8%-29.6%). Thirteen patients had a treatment-related death, 8 of which were associated with GI morbidity. CONCLUSIONS: This report assesses severe morbidity from the largest prospective study on chemo-radiation therapy and image guided adaptive brachytherapy for locally advanced cervical cancer to date. Severe late morbidity was limited per endpoint and organ category, but considerable when aggregated across organs and all endpoints. The late morbidity results in the EMBRACE-I study compare favorably with published literature on standard radiograph based BT for GI morbidity, vaginal morbidity, and fistulas.

Methane emissions from five Danish pig farms: Mitigation strategies and inventory estimated emissions.

This study investigated whole-farm methane emissions from five Danish pig farms with different manure management practices and compared measured emission rates to international and national greenhouse gas inventory emission models. Methane emissions were quantified by using the tracer gas dispersion method. Farms were measured between five and eight times throughout a whole year. One of the farms housed sows and weaners (P1) and the others focused on fattening pigs (P2-P5). The farms had different manure treatment practices including biogasification (P3), acidification (P4-P5) and no manure treatment (liquid slurry) (P1-P2). Quantified methane emissions ranged from 0.2 to 20 kg/h and the highest rates were seen at the farms with fattening pigs and with no manure treatment (P2), while the lowest emissions were detected at farms with manure acidification (P4 and P5). Average methane emission factors (EFs), normalised based on livestock units, were 14 ± 6, 18 ± 9, 8 ± 7, 2 ± 1 and 1 ± 1 g/LU/h, for P1, P2, P3, P4 and P5, respectively. Emissions from fattening pig farms with biogasification (P3) and acidification (P4-P5) facilities were 55% and 91-93% lower, respectively, than from farm with no manure treatment (P2). Inventory models underestimated farm-measured methane emissions on average by 51%, across all models and farms, with the Danish model performing the worst (underestimation of 64%). A revision of model parameters related to manure emissions, such as the estimation of volatile solids excreted and methane conversion factor parameters, could improve model output, although more data needs to be collected to strengthen the conclusions. As one of the first studies assessing whole-pig farm emissions, the results showed the potential of the applied measuring method to identify mitigation strategy efficiencies and highlighted the necessity to investigate inventory model accuracy.

Human Gastrointestinal Transit and Hormonal Response to Different Meal Types: A Randomized Crossover Study.

BACKGROUND: The wireless motility capsule (WMC) technique is a noninvasive and radiation-free method for measuring regional and whole gut transit in response to ingestion of a granola bar (SmartBar) or an eggbeater meal. The WMC has the potential to measure gastrointestinal transit in metabolic research as part of a standardized mixed meal tolerance test. OBJECTIVES: To evaluate gastrointestinal transit with the WMC and postprandial plasma/serum concentrations of metabolites and gastrointestinal hormones as well as subjective appetite following ingestion of a SmartBar compared with a standardized mixed meal. METHODS: Fourteen healthy participants [3 men, median (IQR) age 53.8 (45.8; 64.50) y, body weight 63.9 (59.9; 69.7) kg, BMI 23.1 (21.8; 23.9) kg/m2] completed a 2-d crossover study. Following ingestion of either a SmartBar (260 kcal, 7 energy percent (E%) fat, 74E% carbohydrate, and 19E% protein) or a standardized mixed meal (498 kcal, 34E% fat, 49E% carbohydrate, and 17E% protein), participants swallowed the WMC. Blood samples were drawn in the fasted state and postprandially for analyses of gastrointestinal hormones and metabolites. The primary outcome was difference in gastric emptying time between the 2 test days. Wilcoxon signed rank tests were used to test differences between test days. RESULTS: Median (IQR) gastric emptying time was 98.0 (70.0; 113.0) min longer (P = 0.001) and incremental area under the curve of triglyceride, glucose-dependent insulinotropic polypeptide, and peptide YY were 40 mmol/L × min, 45.7%, and 63.7% greater after the standardized mixed meal compared with the SmartBar (all P < 0.001). CONCLUSIONS: The WMC can be used in combination with a standardized mixed meal for evaluation of gastrointestinal transit in healthy men and women. Gastric emptying time was prolonged in response to the standardized mixed meal whereas transit times of the small bowel, colon, and whole gut did not differ between the test meals.

Severity and Persistency of Late Gastrointestinal Morbidity in Locally Advanced Cervical Cancer: Lessons Learned From EMBRACE-I and Implications for the Future.

PURPOSE: The purpose was to evaluate patient- and treatment-related risk factors for physician-assessed and patient-reported gastrointestinal (GI) symptoms after radio(chemo)therapy and image guided adaptive brachytherapy in locally advanced cervical cancer. METHODS AND MATERIALS: Of 1416 patients from the EMBRACE-I study, 1199 and 1002 were prospectively evaluated using physician-assessed (Common Terminology Criteria for Adverse Events [CTCAE]) and patient-reported (European Organization for Research and Treatment of Cancer [EORTC]) GI symptoms, respectively. CTCAE severe grade (grade [G] ≥3) events were pooled according to the location in the GI tract (anus/rectum, sigmoid, and colon/small bowel). CTCAE G ≥2 and EORTC "very much" and "quite a bit" plus "very much" scores (≥ "quite a bit") were analyzed for individual symptoms with Cox regression. Logistic regression was used for persistent G ≥1 and EORTC ≥ "quite a bit" symptoms, defined if present in at least half of follow-ups. RESULTS: The incidence of G ≥3 events was 2.8%, 1.8%, and 2.3% for G ≥3 anus/rectum, sigmoid, and colon/small bowel events, respectively. Among G ≥2 symptoms, diarrhea and flatulence were the most prevalent (8.5% and 9.9%, respectively). Among patient-related factors, baseline morbidity, increasing age, smoking status, and low body mass index were associated with GI symptoms to varying degrees. Among treatment-related factors, rectum D2cm3 and the International Commission on Radiation Units and Measurements recto-vaginal reference point (ICRU RV-RP) correlated with G ≥3 anus/rectum events and moderate/persistent diarrhea, proctitis, bleeding, abdominal cramps, and difficulty in bowel control. Bowel D2cm3 correlated with G ≥3 sigmoid and colon/small bowel events and moderate/persistent diarrhea and flatulence. For external beam radiation therapy (EBRT), prescription dose correlated with G ≥3 anus/rectum, diarrhea, and difficulty in bowel control. Patients with large lymph-node boost (V57Gy) were at higher risk for G ≥3 sigmoid events, moderate/persistent diarrhea, proctitis, and cramps. CONCLUSIONS: The analysis showed that both EBRT and image guided adaptive brachytherapy contribute to GI symptoms after locally advanced cervical cancer treatment. Rectum D2cm3, ICRU RV-RP , and bowel D2cm3 are risk factors for GI morbidity. The risk for various symptoms was lower with an EBRT prescription of 45 Gy than 50 Gy and increased with larger V57Gy.

Associations between Postprandial Gut Hormones and Markers of Bone Remodeling.

Gut-derived hormones have been suggested to play a role in bone homeostasis following food intake, although the associations are highly complex and not fully understood. In a randomized, two-day cross-over study on 14 healthy individuals, we performed postprandial time-course studies to examine the associations of the bone remodeling markers carboxyl-terminal collagen type I crosslinks (CTX) and procollagen type 1 N-terminal propeptide (P1NP) with the gut hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) using two different meal types-a standardized mixed meal (498 kcal) or a granola bar (260 kcal). Plasma concentrations of total GIP, total GLP-1, total PYY, CTX, and P1NP were measured up to 240 min after meal intake, and the incremental area under the curve (iAUC) for each marker was calculated. The iAUC of CTX and P1NP were used to assess associations with the iAUC of GIP, GLP-1, and PYY in linear mixed effect models adjusted for meal type. CTX was positively associated with GIP and GLP-1, and it was inversely associated with PYY (all p < 0.001). No associations of P1NP with GIP or GLP-1 and PYY were found. In conclusion, the postprandial responses of the gut hormones GIP, GLP-1, and PYY are associated with the bone resorption marker CTX, supporting a link between gut hormones and bone homeostasis following food intake.

Risk factors and dose-effects for bladder fistula, bleeding and cystitis after radiotherapy with imaged-guided adaptive brachytherapy for cervical cancer: An EMBRACE analysis.

PURPOSE: To identify patient- and treatment-related risk factors for fistula, bleeding, cystitis, pain and difficulty in voiding in locally advanced cervical cancer patients treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). MATERIAL AND METHODS: Morbidity within the EMBRACE-I study was prospectively reported for physician-assessed (CTCAE) fistula, bleeding and cystitis and patient-reported (EORTC) pain and difficulty in voiding. Analysis of risk factors was performed in patients without bladder infiltration. Risk factors were tested with Cox regression for grade (G) ≥ 3 cystitis, for G ≥ 2 fistula, bleeding and cystitis, and for EORTC "very much" and "quite a bit" or worse. RESULTS: Of 1416 patients enrolled, 1153 and 884 patients without bladder infiltration were evaluable for the analysis of CTCAE and EORTC items, respectively. Median follow-up was 48[3-120] months. Crude incidence rates for G ≥ 2 fistula, bleeding and cystitis were 0.7%, 2.7% and 8.8%, respectively, and 16% and 14% for "quite a bit" or worse pain and difficulty in voiding, respectively. Baseline urinary morbidity and overweight/obesity were significant risk factors for most endpoints. Bladder D2cm3 correlated with G ≥ 2 fistula, bleeding and cystitis, while ICRU bladder point dose correlated with EORTC pain "quite a bit" or worse. An increase from 75 Gy to 80 Gy in bladder D2cm3 resulted in an increase from 8% to 13% for 4-year actuarial estimate of G ≥ 2 cystitis. CONCLUSION: Clinical and treatment-related risk factors for bladder fistula, bleeding and cystitis were identified within a prospective and multi-institutional setting. A dose-effect was established with bladder D2cm3, reinforcing the importance of continued optimization during individualized IGABT planning.

Dose-Volume Effects and Risk Factors for Late Diarrhea in Cervix Cancer Patients After Radiochemotherapy With Image Guided Adaptive Brachytherapy in the EMBRACE I Study.

PURPOSE: To evaluate patient- and treatment-related risk factors associated with incidence and persistence of late diarrhea after radiochemotherapy and image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. MATERIALS AND METHODS: Of 1416 patients from the EMBRACE I study, 1199 were prospectively evaluated using physician-reported (Common Terminology Criteria for Adverse Events version 3 [CTCAEv3]) assessment for diarrhea; median follow-up 48 months. Patient-reported outcome (EORTC) was available in 900 patients. Incidence of CTCAE G≥2, G≥3, and EORTC "very much" diarrhea was analyzed with Cox proportional hazards regression. Binary logistic regression was used for analysis of persistent G≥1 and EORTC "quite a bit" - "very much" (≥"quite a bit") diarrhea, defined if present in at least half of all follow-ups. RESULTS: Crude incidences of G≥2 and G≥3 diarrhea were 8.3% and 1.5%, respectively, and 8% of patients reported "very much" diarrhea. Persistent G≥1 and ≥"quite a bit" diarrhea was present in 16% and 7%, respectively. Patient-related risk factors were baseline diarrhea, smoking, and diabetes with hazard ratios of 1.4 to 7.3. Treatment-related risk factors included prescribed dose, V43 Gy, V57 Gy (lymph node boost), and para-aortic irradiation for external beam radiation therapy (EBRT). G≥2 diarrhea at 3 years increased from 9.5% to 19.9% with prescribed dose 45 Gy versus 50 Gy, 8.7% to 14.0% with V43 Gy <2500 cm3 versus >3000 cm3 and 9.4% to 19.0% with V57 Gy <165 cm3 versus ≥165 cm3. Brachytherapy-related bowel and rectum D2cm3 were also associated with diarrhea. CONCLUSION: Dose and volume effects have been established for late diarrhea after radiochemotherapy and IGABT in both CTCAE and EORTC reporting. The risk of diarrhea was lower with a pelvic EBRT prescription of 45 Gy, and higher with larger lymph node boosts volumes (ie, ≥165 cm3). The importance of EBRT volumes as determinants of late toxicity underline the need for continuous quality assurance of target contouring, dose planning, and conformity. The findings of brachytherapy dosimetric factors related to the intestines may become more important with highly conformal EBRT.

Importance of the ICRU bladder point dose on incidence and persistence of urinary frequency and incontinence in locally advanced cervical cancer: An EMBRACE analysis.

PURPOSE: To identify patient- and treatment-related risk factors and dose-effects for urinary frequency and incontinence in locally advanced cervical cancer (LACC) treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). MATERIAL AND METHODS: Physician-assessed (CTCAE) and patient-reported (EORTC) frequency and incontinence recorded in the EMBRACE-I study were analysed. Risk factors analysis was performed in patients without bladder infiltration and with baseline morbidity available. Cox regression was used for CTCAE grade (G) ≥ 3 and G ≥ 2 and for EORTC "very much" and "quite a bit" or worse. Logistic regression was used for late persistent morbidity defined when CTCAE G ≥ 1 or EORTC ≥ "quite a bit" were scored in at least half of follow-ups. RESULTS: Longitudinal data on 1153 and 884 patients were available for CTCAE and EORTC analysis, respectively. Median follow-up was 48[3-120] months. Crude incidence rates of G≥2 were 13% and 11% for frequency and incontinence, respectively. Baseline morbidity and overweight-obesity were risk factors for both symptoms. Elderly patients were at higher risk for incontinence. Patients receiving conformal-radiotherapy were at higher risk for frequency. ICRU bladder point (ICRU-BP) dose was a stronger predictor for incontinence than bladder D2cm3. The 5-year actuarial estimate of G ≥ 2 incontinence increased from 11% to 20% with ICRU-BP doses > 75 Gy compared to ≤ 65 Gy. Frequency showed weaker associations with dose. CONCLUSION: ICRU-BP dose, in addition to clinical parameters, is a risk factor for urinary incontinence and shows a dose-effect after radio(chemo)therapy and IGABT. ICRU-BP dose should be monitored during treatment planning alongside volumetric parameters. Frequency seems associated with larger irradiated volumes.

Persistence of Late Substantial Patient-Reported Symptoms (LAPERS) After Radiochemotherapy Including Image Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: A Report From the EMBRACE Study.

PURPOSE: This report describes the persistence of late substantial treatment-related patient-reported symptoms (LAPERS) in the multi-institutional EMBRACE study on magnetic resonance image guided adaptive brachytherapy in locally advanced cervical cancer (LACC). METHODS AND MATERIALS: Patient-reported symptoms (European Organization for Research and Treatment of Cancer [EORTC]-C30/CX24) and physician-assessed morbidity (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) were assessed at baseline and regular timepoints during follow-up. Patients with sufficient EORTC follow-up (baseline and ≥3 late follow-up visits) were analyzed. LAPERS events were defined as the presence of substantial EORTC symptoms (quite a bit/very much) for at least half of the assessments (persistence) and progression beyond baseline condition (treatment-related). For each EORTC symptom, the ratio between LAPERS rates and crude incidence rates of substantial symptoms was calculated to represent the proportion of symptomatic patients with persisting symptoms. For 9 symptoms with a corresponding EORTC/CTCAE assessment, the overlap of LAPERS and severe morbidity events (grades 3-5) was evaluated. RESULTS: Of 1047 patients with EORTC available, 741 had sufficient follow-up for the LAPERS analyses. The median follow-up was 59 months (interquartile range, 42-70 months). Across all symptoms, the proportion of patients with LAPERS events (LAPERS rates) was in median 4.6% (range, 0.0% vaginal bleeding to 20.4% tiredness). Urinary frequency, neuropathy, fatigue, insomnia, and menopausal symptoms revealed LAPERS rates of >10%. Vomiting, blood in stool, urinary pain/burning, and abnormal vaginal bleeding displayed LAPERS rates of <1%. A median of 19% of symptomatic patients (interquartile range, 8.0%-28.5%) showed persistent long-term symptoms (LAPERS events). In symptoms with a corresponding EORTC/CTCAE assessment, 12% of LAPERS events were accompanied by a severe CTCAE event. CONCLUSIONS: Within this large cohort of survivors of LACC, a subgroup of patients with persistent symptoms (LAPERS events) was identified. For symptoms with a corresponding EORTC/CTCAE assessment, the vast majority of LAPERS events occurred in patients without corresponding severe physician-assessed morbidity. These findings emphasize the importance of distinguishing between transient and persisting symptoms in the aftercare of LACC survivors.

Dosimetric Impact of Intrafraction Motion in Online-Adaptive Intensity Modulated Proton Therapy for Cervical Cancer.

PURPOSE: A method was recently developed for online-adaptive intensity modulated proton therapy (IMPT) in patients with cervical cancer. The advantage of this approach, relying on the use of tight margins, is challenged by the intrafraction target motion. The purpose of this study was to evaluate the dosimetric effect of intrafraction motion on the target owing to changes in bladder filling in patients with cervical cancer treated with online-adaptive IMPT. METHODS AND MATERIALS: In 10 patients selected to have large uterus motion induced by bladder filling, the intrafraction anatomic changes were simulated for several prefraction durations for online (automated) contouring and planning. For each scenario, the coverage of the primary target was evaluated with margins of 2.5 and 5 mm. RESULTS: Using a 5- mm planning target volume margin, median accumulated D98% was greater than 42.75 GyRBE1.1 (95% of the prescribed dose) in the case of a prefraction duration of 5 and 10 minutes. For a prefraction duration of 15 minutes, this parameter deteriorated to 42.6 GyRBE1.1. When margins were reduced to 2.5 mm, only a 5-minute duration resulted in median target D98% above 42.75 GyRBE1.1. In addition, smaller bladders were found to be associated with larger dose degradations compared with larger bladders. CONCLUSIONS: This study indicates that intrafraction anatomic changes can have a substantial dosimetric effect on target coverage in an online-adaptive IMPT scenario for patients subject to large uterus motion. A margin of 5 mm was sufficient to compensate for the intrafraction motion due to bladder filling for up to 10 minutes of prefraction time. However, compensation for the uncertainties that were disregarded in this study, by using margins or robust optimization, is also required. Furthermore, a large bladder volume restrains intrafraction target motion and is recommended for treating patients in this scenario. Assuming that online-adaptive IMPT remains beneficial as long as narrow margins are used (5 mm or below), this study demonstrates its feasibility with regard to intrafraction motion.

Initiatives for education, training, and dissemination of morbidity assessment and reporting in a multiinstitutional international context: Insights from the EMBRACE studies on cervical cancer.

In 2008, the GEC ESTRO Gyn network launched the first multiinstitutional, observational, and prospective international study on MRI-guided brachytherapy in locally advanced cervical cancer patients (EMBRACE-I). EMBRACE-I was followed by EMBRACE-II from 2016 and ongoing. Among the aims of the EMBRACE studies are to benchmark morbidity outcomes and develop dose-volume effects and predictive models for morbidity. The EMBRACE studies collect both physician (CTCAE v.3) and patient (EORTC QLQ-C30/CX24) reported outcomes, including baseline information, in a regular follow-up schedule. The EMBRACE studies feature high numbers of patients (EMBRACE-I N = 1416, EMBRACE-II N = 1500 expected) enrolled from many institutions worldwide (EMBRACE-I n = 23, EMBRACE-II n = 45). This large-scale multiinstitutional approach offers a unique opportunity to investigate and develop new strategies for improving the quality of assessment and reporting of morbidity. This report presents an overview of the challenges and pitfalls regarding the assessment and reporting of morbidity encountered during more than a decade of development and research activities within the EMBRACE consortium. This includes the recognition and evaluation of inconsistencies in the morbidity assessment, and consequently, the provision of assistance and training in the scoring procedure to reduce systematic assessment bias. In parallel, a variety of methodological approaches were tested to comprehensively summarize morbidity outcomes, and a novel approach was developed to refine dose-effect models and risk factor analyses. The purpose of this report is to present an overview of these findings, describe the learning process, and the strategies that have consequently been implemented regarding educational activities, training, and dissemination.

Education and training for image-guided adaptive brachytherapy for cervix cancer-The (GEC)-ESTRO/EMBRACE perspective.

Image-guided adaptive brachytherapy (IGABT) has been shown to improve local/regional control and survival for cervix cancer patients while reducing morbidity. However, the technique is complex involving several conceptual, methodological, and technical innovations compared to conventional brachytherapy. The delivery of high-quality IGABT which will translate into improved outcomes is therefore critically dependent on effective education and training of all health professionals involved in the brachytherapy treatment process. This paper reviews the (GEC)-ESTRO/EMBRACE initiatives for education and training to promote the dissemination and implementation of IGABT for cervix cancer worldwide. The new skills required in different health professionals for successful implementation of IGABT are described. The achievements and challenges of current educational strategies for disseminating IGABT are discussed. Innovations to improve the effectiveness of current and future educational strategies are explored.

Evidence-Based Dose Planning Aims and Dose Prescription in Image-Guided Brachytherapy Combined With Radiochemotherapy in Locally Advanced Cervical Cancer.

The last 2 decades have witnessed the development and broad adoption of image-guided adaptive brachytherapy (IGABT) combined with radiochemotherapy in patients with locally advanced cervical cancer. A variety of brachytherapy techniques and dose/fractionation schedules have been applied, and until recently, there was no strong evidence available for preferring one approach to another. However, large volumes of data have now provided high level clinical evidence for dose-effect relations for both disease and morbidity endpoints. It is therefore now possible to apply evidence based dose planning aims and dose prescription protocols in IGABT for locally advanced cervical cancer. This review gives an overview of targets/organs-at-risk and disease/morbidity endpoints which are relevant in the context of treatment planning and dose prescription in IGABT. The dosimetric and clinical evidence is summarized to support the implementation of dose prescription protocols which include hard and soft constraints for targets and organs at risk.

Implementing an online radiotherapy quality assurance programme with supporting continuous medical education - report from the EMBRACE-II evaluation of cervix cancer IMRT contouring.

BACKGROUND AND PURPOSE: EMBRACE-II is an international prospective study of IMRT and MRI-guided adaptive brachytherapy (IGABT) in locally advanced cervix cancer. An online radiotherapy quality assurance (RTQA) programme with minimal data transfer and supporting continuing medical education (CME) was implemented for IMRT contouring. MATERIALS AND METHODS: Participant contours for six volumes-of-interest (VOIs) on one benchmark case were scored (2 = excellent, 1 = fair, 0 = revision required) against a consensus reference contour. For contours receiving a 0 or 1 score, additional qualitative comments were provided. The Jaccard conformity index (JCI) was retrospectively calculated. User interaction with CME content (pre-accreditation questionnaire, contouring atlas, practice cases, quizzes, internal target volume (ITV-T) guide) was analysed. RESULTS: 78 clinicians submitted contours for evaluation. 41% passed at the first attempt, 44% after one revision and 6% after two or more revisions. 9% did not re-submit after failing. The lowest mean scores were for the elective nodal CTV (CTV-E) (1.01/2) and ITV-T (1.06/2). 60 different errors across the six VOIs were identified; five potentially had high impact on loco-regional control. A JCI cut-off of 0.7 would have identified 87% contours that failed expert assessment, but also excluded 54% of passing contours. 39 clinicians responded to the pre-accreditation questionnaire - 36% anticipated difficulties with the ITV-T and 13% with the CTV-E. 35% clinicians contoured on the practice cases, 17% answered a quiz, 96% used the atlas and 38% the ITV-T guide. CONCLUSION: Expert evaluation with qualitative feedback improved contouring compliance. The JCI is not a reliable alternative to expert assessment. Moderate uptake of optional CME content limited evaluation.

VEGF-B ablation in pancreatic ß-cells upregulates insulin expression without affecting glucose homeostasis or islet lipid uptake.

Type 2 diabetes mellitus (T2DM) affects millions of people and is linked with obesity and lipid accumulation in peripheral tissues. Increased lipid handling and lipotoxicity in insulin producing ß-cells may contribute to ß-cell dysfunction in T2DM. The vascular endothelial growth factor (VEGF)-B regulates uptake and transcytosis of long-chain fatty acids over the endothelium to tissues such as heart and skeletal muscle. Systemic inhibition of VEGF-B signaling prevents tissue lipid accumulation, improves insulin sensitivity and glucose tolerance, as well as reduces pancreatic islet triglyceride content, under T2DM conditions. To date, the role of local VEGF-B signaling in pancreatic islet physiology and in the regulation of fatty acid trans-endothelial transport in pancreatic islet is unknown. To address these questions, we have generated a mouse strain where VEGF-B is selectively depleted in ß-cells, and assessed glucose homeostasis, ß-cell function and islet lipid content under both normal and high-fat diet feeding conditions. We found that Vegfb was ubiquitously expressed throughout the pancreas, and that ß-cell Vegfb deletion resulted in increased insulin gene expression. However, glucose homeostasis and islet lipid uptake remained unaffected by ß-cell VEGF-B deficiency.