To evaluate prostate intrafraction motion using MRI during the full course of online adaptive MR-Linac radiotherapy (RT) fractions, in preparation of MR-guided extremely hypofractionated RT.
Five low ...and intermediate risk prostate cancer patients were treated with 20 × 3.1 Gy fractions on a 1.5T MR-Linac. Each fraction, initial MRI (Pre) scans were obtained at the start of every treatment session. Pre-treatment planning MRI contours were propagated and adapted to this Pre scan after which plan re-optimization was started in the treatment planning system followed by dose delivery. 3D Cine-MR imaging was started simultaneously with beam-on and acquired over the full beam-on period. Prostate intrafraction motion in this cine-MR was determined with a previously validated soft-tissue contrast based tracking algorithm. In addition, absolute accuracy of the method was determined using a 4D phantom.
Prostate motion was completely automatically determined over the full on-couch period (approx. 45 min) with no identified mis-registrations. The translation 95% confidence intervals are within clinically applied margins of 5 mm, and plan adaption for intrafraction motion was required in only 4 out of 100 fractions.
This is the first study to investigate prostate intrafraction motions during entire MR-guided RT sessions on an MR-Linac. We have shown that high quality 3D cine-MR imaging and prostate tracking during RT is feasible with beam-on. The clinically applied margins of 5 mm have proven to be sufficient for these treatments and may potentially be further reduced using intrafraction plan adaptation guided by cine-MR imaging.
•First study of seminal vesicle intrafraction motion during MR-Linac RT sessions.•High quality 3D cine-MRI and seminal vesicle tracking is feasible during RT beam-on.•Seminal vesicles show larger ...intrafraction rotational spread than prostate.•5 mm isometric expansion provides seminal vesicle coverage probability of 99%.
To evaluate seminal vesicle (SV) intrafraction motion using cinematic magnetic resonance imaging (cine-MR) during the delivery of online adaptive MR-Linac radiotherapy fractions, in preparation of MR-guided extremely hypofractionated radiotherapy for intermediate to high-risk prostate cancer patients.
Fifty prostate cancer patients were treated with 5 × 7.25 Gy on a 1.5 Tesla MR-Linac. 3D Cine-MR imaging was started simultaneously and acquired over the full beam-on period. Intrafraction motion in this cine-MR was determined for each SV separately with a previously validated soft-tissue contrast-based tracking algorithm. Motion statistics and coverage probability for the SVs and prostate were determined based on the obtained results.
SV motion was automatically determined during the beam-on period (approx. 10 min) for 247 fractions. SV intrafraction motion shows larger spread than prostate intrafraction motion and increases over time. This difference is especially evident in the anterior and cranial translation directions. Significant difference in rotation about the left–right axis was found, with larger rotation for the SVs than the prostate. Intra-fraction coverage probability of 99% can be achieved when using 5 mm isometric expansion for the left and right SV and 3 mm for the prostate.
This is the first study to investigate SV intrafraction motion during MR-guided RT sessions on an MR-Linac. We have shown that high quality 3D cine-MR imaging and SV tracking during RT is feasible with beam-on. The tracking method as described may be used as input for a fast replanning algorithm, which allows for intrafraction plan adaptation.
To investigate the dosimetric impact of intrafraction translation and rotation motion of the prostate, as extracted from daily acquired post-treatment 3D cine-MR based on soft-tissue contrast, in ...extremely hypofractionated (SBRT) prostate patients. Accurate dose reconstruction is performed by using a prostate intrafraction motion trace which is obtained with a soft-tissue based rigid registration method on 3D cine-MR dynamics with a temporal resolution of 11 s. The recorded motion of each time-point was applied to the planning CT, resulting in the respective dynamic volume used for dose calculation. For each treatment fraction, the treatment delivery record was generated by proportionally splitting the plan into 11 s intervals based on the delivered monitor units. For each fraction the doses of all partial plan/dynamic volume combinations were calculated and were summed to lead to the motion-affected fraction dose. Finally, for each patient the five fraction doses were summed, yielding the total treatment dose. Both daily and total doses were compared to the original reference dose of the respective patient to assess the impact of the intrafraction motion. Depending on the underlying motion of the prostate, different types of motion-affected dose distributions were observed. The planning target volumes (PTVs) ensured CTV_30 (seminal vesicles) D99% coverage for all patients, CTV_35 (prostate corpus) coverage for 97% of the patients and GTV_50 (local boost) for 83% of the patients when compared against the strict planning target D99% value. The dosimetric impact due to prostate intrafraction motion in extremely hypofractionated treatments was determined. The presented study is an essential step towards establishing the actual delivered dose to the patient during radiotherapy fractions.
We have developed a method to determine intrafraction motion of the prostate through automatic fiducial marker (FM) tracking on 3D cine-magnetic resonance (MR) images with high spatial and temporal ...resolution. Twenty-nine patients undergoing prostate stereotactic body radiotherapy (SBRT), with four implanted cylindrical gold FMs, had cine-MR imaging sessions after each of five weekly fractions. Each cine-MR examination consisted of 55 sequentially obtained 3D datasets ('dynamics'), acquired over a 11 s period, covering a total of 10 min. FM locations in the first dynamic were manually identified by a clinician, FM centers in subsequent dynamics were automatically determined. Center of mass (COM) translations and rotations were determined by calculating the rigid transformations between the FM template of the first and subsequent dynamics. The algorithm was applied to 7315 dynamics over 133 scans of 29 patients and the obtained results were validated by comparing the COM locations recorded by the clinician at the halfway-dynamic (after 5 min) and end dynamic (after 10 min). The mean COM translations at 10 min were X: 0.0 0.8 mm, Y: 1.0 1.9 mm and Z: 0.9 2.0 mm. The mean rotation results at 10 min were X: 0.1 3.9°, Y: 0.0 1.3° and Z: 0.1 1.2°. The tracking success rate was 97.7% with a mean 3D COM error of 1.1 mm. We have developed a robust, fast and accurate FM tracking algorithm for cine-MR data, which allows for continuous monitoring of prostate motion during MR-guided radiotherapy (MRgRT). These results will be used to validate automatic prostate tracking based on soft-tissue contrast.
To develop a method to automatically determine intrafraction motion of the prostate based on soft tissue contrast on 3D cine-magnetic resonance (MR) images with high spatial and temporal resolution. ...Twenty-nine patients who underwent prostate stereotactic body radiotherapy (SBRT), with four implanted cylindrical gold fiducial markers (FMs), had cine-MR imaging sessions after each of five weekly fractions. Each cine-MR session consisted of 55 sequentially obtained 3D data sets ('dynamics') and was acquired over an 11 s period, covering a total of 10 min. The prostate was delineated on the first dynamic of every dataset and this delineation was used as the starting position for the soft tissue tracking (SST). Each subsequent dynamic was rigidly aligned to the first dynamic, based on the contrast of the prostate. The obtained translation and rotation describes the intrafraction motion of the prostate. The algorithm was applied to 6270 dynamics over 114 scans of 29 patients and the results were validated by comparing to previously obtained fiducial marker tracking data of the same dataset. Our proposed tracking method was also retro-perspectively applied to cine-MR images acquired during MR-guided radiotherapy of our first prostate patient treated on the MR-Linac. The difference in the 3D translation results between the soft tissue and marker tracking was below 1 mm for 98.2% of the time. The mean translation at 10 min were X: 0.0 0.8 mm, Y: 1.0 1.8 mm and Z: mm. The mean rotation results at 10 min were X: , Y: 0.1 0.6° and Z: 0.0 0.7°. A fast, robust and accurate SST algorithm was developed which obviates the need for FMs during MR-guided prostate radiotherapy. To our knowledge, this is the first data using full 3D cine-MR images for real-time soft tissue prostate tracking, which is validated against previously obtained marker tracking data.
Objective
Iodine deficiency during pregnancy results in thyroid dysfunction and has been associated with adverse obstetric and foetal effects, leading to worldwide salt iodization programmes.
As ...nowadays 69% of the world's population lives in iodine‐sufficient regions, we investigated the effects of variation in iodine status on maternal and foetal thyroid (dys)function in an iodine‐sufficient population.
Design, Participants and Measurements
Urinary iodine, serum TSH, free T4 (FT4) and TPO‐antibody levels were determined in early pregnancy (13·3 (1·9) week; mean (SD)) in 1098 women from the population‐based Generation R Study. Newborn cord serum TSH and FT4 levels were determined at birth.
Results
The median urinary iodine level was 222·5 μg/l, indicating an iodine‐sufficient population. 30·8% and 11·5% had urinary iodine levels <150 and >500 μg/l, respectively.
When comparing mothers with urinary iodine levels <150 vs ≥150 μg/l, and >500 vs ≤500 μg/l, there were no differences in the risk of maternal increased or decreased TSH, hypothyroxinaemia or hyperthyroidism. Mothers with urinary iodine levels >500 μg/l had a higher risk of a newborn with decreased cord TSH levels (5·6 ± 1·4 (mean ± SE) vs 2·1 ± 0·5%, P = 0·04), as well as a higher risk of a hyperthyroid newborn (3·1 ± 0·9 vs 0·6 ± 0·3%, P = 0·02). These mothers had newborns with higher cord FT4 levels (21·7 ± 0·3 vs 21·0 ± 0·1 pm, P = 0·04).
Maternal urinary iodine levels <150 μg/l were not associated with newborn thyroid dysfunction.
Conclusions
In an iodine‐sufficient population, higher maternal urinary iodine levels are associated with an increased risk of a hyperthyroid newborn.
Turner syndrome (TS) is the result of (partial) absence of one X-chromosome. Besides short stature, gonadal dysgenesis and other physical aspects, TS women have typical psychological features. Since ...psychological effects of androgen exposure in childhood probably are long-lasting, we explored long-term psychological functioning after oxandrolone (Ox) therapy during childhood in adults with TS in terms of neurocognition, quality of life and social–emotional functioning. During the initial study, girls were treated with growth hormone (GH) combined with placebo (Pl), Ox 0.03mg/kg/day, or Ox 0.06mg/kg/day from the age of eight, and estrogen from the age of twelve. Sixty-eight women participated in the current double-blinded follow-up study (mean age 24.0years, mean time since stopping GH/Ox 8.7years). We found no effects on neurocognition. Concerning quality of life women treated with Ox had higher anxiety levels (STAI 37.4±8.4 vs 31.8±5.0, p=0.002) and higher scores on the depression subscale of the SCL-90-R (25.7±10.7 vs 20.5±4.7, p=0.01). Regarding social–emotional functioning, emotion perception for fearful faces was lower in the Ox-treated patients, without effect on interpersonal behavior. Our exploratory study is the first to suggest that androgen treatment in adolescence possibly has long-term effects on adult quality of life and social–emotional functioning. However, differences are small and clinical implications of our results seem limited. Therefore we would not recommend against the use of Ox in light of psychological consequences.
•The weak androgen oxandrolone (Ox) enhances growth in Turner syndrome.•Ox does not affect neurocognition on long-term follow-up.•Ox reduces emotion perception for fear, without effects on interpersonal behavior.•On long-term follow-up Ox is associated with feelings of anxiety and depression.•No effect of childhood Ox use on overall adult quality of life was found.
Abstract
STUDY QUESTION
What is the optimal management of women with premature ovarian insufficiency (POI) based on the best available evidence in the literature?
SUMMARY ANSWER
The guideline ...development group (GDG) formulated 99 recommendations answering 31 key questions on the diagnosis and treatment of women with POI.
WHAT IS KNOWN ALREADY
NA.
STUDY DESIGN, SIZE, DURATION
This guideline was produced by a multidisciplinary group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to September 2014 and consensus within the guideline group on all recommendations. The GDG included a patient representative to ensure input from women with POI. After finalization of the draft, the European Society for Human Reproduction and Embryology (ESHRE) members and professional organizations were asked to review the guideline.
PARTICIPANTS/MATERIALS, SETTING, METHODS
NA.
MAIN RESULTS AND THE ROLE OF CHANCE
The guideline provides 17 recommendations on diagnosis and assessment of POI and 46 recommendations on the different sequelae of POI and their consequences for monitoring and treatment. Furthermore, 24 recommendations were formulated on hormone replacement therapy in women with POI, and two on alternative and complementary treatment. A chapter on puberty induction resulted in five recommendations.
LIMITATIONS, REASONS FOR CAUTION
The main limitation of the guideline is that, due to the lack of data, many of the recommendations are based on expert opinion or indirect evidence from studies on post-menopausal women or women with Turner Syndrome.
WIDER IMPLICATIONS OF THE FINDINGS
Despite the limitations, the guideline group is confident that this document will be able to guide health care professionals in providing the best practice for managing women with POI given current evidence. Furthermore, the guideline group has formulated research recommendations on the gaps in knowledge identified in the literature searches, in an attempt to stimulate research on the key issues in POI.
STUDY FUNDING/COMPETING INTEREST(S)
The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. Dr Davies reports non-financial support from Novo Nordisk, outside the submitted work; the other authors had nothing to disclose.
TRIAL REGISTRATION NUMBER
NA.
There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or ...the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3–4.6 cm. If Ox dosages<0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization(including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated,or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03–0.05 mg/kg/day starting from the age of 8–10 years onward scan be considered.
BACKGROUND The aim of this study was to evaluate the long-term gonadal sequelae after treatment for childhood Hodgkin’s lymphoma with combination chemotherapy, using up to date fertility parameters ...and andrological evaluation, including for the first time inhibin B. METHODS There were 56 male patients treated from 1974–1998 for childhood Hodgkin’s lymphoma with combination chemotherapy ABVD or EBVD (adriamycin/epirubicin, bleomycin, vinblastine, dacarbazine) with or without MOPP (mechlorethamine, vincristin, prednisone, procarbazine) with the intention to avoid radiotherapy. These men were studied 15.5 years (range 5.6–30.2 years) after cessation of therapy. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, testosterone, sex hormone-binding globulin (SHBG), sperm concentration and sperm DNA integrity were determined. RESULTS In men treated with MOPP, median FSH and LH were significantly increased (P < 0.001) and inhibin B (17.5 versus 143 ng/l; P < 0.001) and sperm concentration (1.05 versus 49.5 × 106/ml; P < 0.05) were significantly decreased compared with patients treated without MOPP. The number of MOPP courses was significantly correlated with FSH and inhibin B levels. Only inhibin B showed an independent correlation with sperm concentration (r = 0.86; P < 0.001). CONCLUSIONS The use of MOPP chemotherapy causes permanent gonadal damage in the far majority of male survivors of childhood Hodgkin’s lymphoma and inhibin B is the most valuable serum marker for gonadal function.
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