Sexual dysfunction in women with PCOS: a case control study.

STUDY QUESTION: What is the relationship of sex steroid levels with sexual function in women with and without polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Women with PCOS reported more sexual dysfunction and more sexual distress compared to those without PCOS, but only few and weak associations between androgen levels and sexual function were observed. WHAT IS KNOWN ALREADY: The literature shows that women with PCOS report lower levels of sexual function and sexual satisfactionand more sexual distress. Contributing factors seem to be obesity, alopecia, hirsutism, acne, infertility, anxiety, depression, and low self-esteem. In women with PCOS clinical and/or biochemical hyperandrogenism is common; its relationship with sexualfunction is, however, inconclusive. STUDY DESIGN, SIZE, DURATION: This observational prospective case control study with 135 women (68 PCOS, 67 control) was conductedfrom March 2017 until March 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Heterosexual women with and without PCOS, aged 18-40 years, in a steady relationshipand without any comorbidities, underwent an extensive medical and endocrine screening using liquid chromatography-tandem mass spectrometry and validated sexual function questionnaires. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS reported significantly lower sexual function (Female Sexual Function Index (FSFI) P < 0.001, partial η2 = 0.104), higher levels of sexual distress (Female Sexual Distress Scale-Revised P < 0.001, partial η2 = 0.090), and they more often complied with the definition of sexual dysfunction (41.2% vs 11.9%, P < 0.001, Phi V = 0.331) and clinical sexual distress (51.5% vs 19.4%, P < 0.001, Phi V = 0.335). Regression analysis adjusted for confounders showed only few and weak associations between androgen levels and sexual function, with each model explaining a maximum of 15% sexual function. Following significant Group × Hormone interactions, analyses for both groups separately showed no significant associations in the PCOS group. The control group showed only weak negative associations between testosterone and FSFI pain (ß = -6.022, P = 0.044, Adj R2 = 0.050), between FAI and FSFI orgasm (ß = -3.360, P = 0.023, Adj R2 = 0.049) and between androstenedione and clinical sexual distress (ß = -7.293, P = 0.036, exp(ß) = 0.001). LIMITATIONS, REASONS FOR CAUTION: The focus of the study on sexual functioning potentially creates selection bias. Possibly women with more severe sexual disturbances did or did not choose to participate. Differences between women with PCOS and controls in relationship duration and hormonal contraceptive use might have skewed the sexual function outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Sexual function is impaired in women with PCOS. However, endocrine perturbations seem to have minimal direct impact on sexual function. Addressing sexuality and offering psychosexual counseling is important in the clinical care for women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the departments of the participating centers: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Psychosomatic OBGYN and Sexology, Leiden University Medical Center, Leiden, the Netherlands; and Department of Sexology and Psychosomatic OBGYN, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands. J.S.E.L. received unrestricted research grants from the following companies (in alphabetical order): Ansh Labs, Ferring, Merck Serono and Roche Diagnostics. He also received consultancy fees from Ansh Labs, Ferring, Titus Healthcare and Roche Diagnostics. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: CCMO register, registration number: NL55484.078.16, 10 March 2016. https://www.toetsingonline.nl/to/ccmo_search.nsf/Searchform?OpenForm.

Sexual functioning, sexual esteem, genital self-image and psychological and relational functioning in women with Mayer-Rokitansky-Küster-Hauser syndrome: a case-control study.

STUDY QUESTION: Do sexual functioning, sexual esteem, genital self-image and psychological and relational functioning in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome differ from a comparison group of women without the condition? SUMMARY ANSWER: In comparison to controls, women with MRKH with a non-surgically or surgically created neovagina did not differ in psychological and relational functioning but reported lower sexual esteem and more negative genital self-image, intercourse-related pain, clinically relevant sexual distress and sexual dysfunction, with sexual esteem levels strongly associated with sexual distress and sexual dysfunction. WHAT IS KNOWN ALREADY: Studies on sexual functioning measured with standardized questionnaires in women with MRKH syndrome compared with women without the condition have yielded contradictory results. Factors associated with sexual functioning in this patient population have rarely been investigated. STUDY DESIGN, SIZE, DURATION: Between November 2015 and May 2017, 54 women with MRKH syndrome with a neovagina and 79 age-matched healthy women without the condition were enrolled in this case-control study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants had to be at least 18-years old and had to live in a steady heterosexual relationship. Women with MRKH syndrome were asked to participate by their (former) gynecologists at three university hospitals and by MRKH peer support group. Controls were recruited via advertisement in local newspapers and social media. Standardized questionnaires were administered to assess sexual functioning, sexual esteem, genital self-image and psychological and relational functioning. MAIN RESULTS AND THE ROLE OF CHANCE: Women with MRKH syndrome with a surgically or non-surgically created neovagina reported significantly more pain during intercourse (P < 0.05, d = 0.5), but did not differ in overall sexual functioning from control women. More women with MRKH syndrome reported clinically relevant sexuality-related distress (P < 0.05, odds ratio (OR): 2.756, 95% CI 1.219-6.232) and suffered a sexual dysfunction (P < 0.05, OR: 2.654, 95% CI: 1.088-6.471) in comparison with controls. MRKH women scored significantly lower on the sexual esteem scale (SES) (P < 0.01, d = 0.5) and the female genital self-image scale (FGSIS) (P < 0.01, d = 0.6) than controls. No significant differences were found between the two groups regarding psychological distress, anxiety and depression, global self-esteem and relational dissatisfaction. Sexual esteem was significantly associated with the presence of clinically relevant sexual distress (ß = 0.455, P = 0.001) and suffering a sexual dysfunction (ß = 0.554, P = 0.001) and explained, respectively, 40% and 28% of the variance. LIMITATIONS, REASONS FOR CAUTION: Given the nature of the study focusing on sexual functioning, a potential selection bias cannot be excluded. It is possible that those women with the most severe sexual and/or psychological disturbances did or did not choose to participate in our study. WIDER IMPLICATIONS OF THE FINDINGS: The study results add new data to the very limited knowledge about psychosexual functioning of women with MRKH syndrome and are of importance for more adequate counseling and treatment of these women. STUDY FUNDING/COMPETING INTEREST(S): The research was financially supported by the Dutch Scientific Society of Sexology (Nederlandse wetenschappelijke Vereniging Voor Seksuologie). The funding was unrestricted, and there was no involvement in the conduct of the research. There are no conflicts of interest to declare.

First-order perturbation theory for changes in the surrounding of open optical resonators.

The single-mode approximation of resonant state expansion has proven to give accurate first-order approximations of resonance shifts and linewidth changes when modifying the material properties inside open optical resonators. Here, we extend this first-order perturbation theory to modifications of the material properties in the surrounding medium. As a side product of our derivations, we retrieve the already known analytical normalization condition for resonant states. We apply our theory to two example systems: a metallic nanosphere and a periodic array of metallic nanoslits.

Discussing reproductive health in spinal care, part II: fertility issues.

PURPOSE: Due to advancing insights, discussing fertility in spinal care is an emerging topic. Studies among neurosurgeons to evaluate clinical practice about discussing fertility are non-existent. The aim of this study is to review knowledge, attitude and practice patterns regarding discussing fertility in spinal care. METHODS: Dutch neurosurgeons and residents were sent a mail-based questionnaire addressing attitude, knowledge and practice patterns regarding discussing fertility. RESULTS: Response rate was 62 % (compared to mean of 28 % in similar surveys) with 89 questionnaires suitable for analysis. Mean age was 42 years with 83 % of respondents being male. A quarter of respondents stated neurosurgeons are responsible to discuss fertility, with 12 % indicating to actually do this. Fertility is discussed more often with patients with cauda equina syndrome (70 %) and with men (p = 0.006). Merely 8 % of respondents stated to have adequate knowledge on fertility preservation (FP); this percentage was higher for doctors with spinal surgery as specialty (p = 0.015). In case of cauda equina syndrome, doctors with more knowledge discussed fertility more often (p = 0.002). Fifty-three percent of neurosurgeons wished to enhance their knowledge, in order to feel more comfortable to discuss fertility with their patients. Five percent indicated to have ever referred a patient to a fertility specialist. CONCLUSION: With the exception of cauda equina syndrome, fertility is not routinely discussed in spinal care. Fertility is discussed more often with men. Recent guidelines state that discussing fertility is an essential part of good practice in spinal care. Education on fertility and FP needs to be integrated in the neurosurgical training program to create more awareness, and to enable clinicians to provide adequate information and care to the patient.

Discussing sexual health in spinal care.

BACKGROUND: The possible detrimental effects of spinal disease on sexual health are widely recognized; however, it is not known to what extent neurosurgeons discuss this topic with their patients. The aim of this study is to identify knowledge, attitude and practice patterns of neurosurgeons counseling their patients about sexual health. METHODS: All members of the Dutch Association of Neurosurgery (neurosurgeons and residents) were sent a questionnaire addressing their attitudes, knowledge and practice patterns regarding discussing sexual health. RESULTS: Response rate was 62% with 89 questionnaires suitable for analysis. The majority of participants (83%) were male; mean age, 42.4 years. The mean experience in neurosurgical practice was 9 years. Respondents assumed that in 34% of their patients, sexual health was affected due to spinal disease. The majority of respondents (64%) stated that responsibility for discussing sexual health lies (partly) with the neurosurgeon; however, 73% indicated to (almost) never do this. The main reasons for not discussing sexual health were patients' old age (42%), lack of knowledge (38%) and lack of patients' initiative to bring up the subject (36%). Twenty-six percent indicated lack of time as a reason. There was no evidence for gender or doctor's age discordance as important barriers. Fifty percent of participants wished to gain more knowledge on discussing sexual health with patients. CONCLUSION: This study shows that despite high prevalence of sexual dysfunction (SD) in spinal patients, counseling about sexual health is not often done in neurosurgical care. More training on sexual health counseling early in the residency program seems critical. By initiating the discussion, clinicians who deal with spinal patients have the potential to detect sexual dysfunction (SD) and to refer adequately when necessary, thereby improving overall quality of life of their patients.

Performance of different three-dimensional scaffolds for in vivo endochondral bone generation.

In the context of skeletal tissue development and repair, endochondral ossification has inspired a new approach to regenerate bone tissue in vivo using a cartilage intermediate as an osteoinductive template. The aim of this study was to investigate the behavior of mesenchymal stem cells (MSCs) in regard to in vitro cartilage formation and in vivo bone regeneration when combined with different three-dimensional (3D) scaffold materials, i.e., hydroxyapatite/tricalcium phosphate (HA/TCP) composite block, polyurethane (PU) foam, poly(lactic-co-glycolic acid)/poly(ε-caprolactone) electrospun fibers (PLGA/PCL) and collagen I gel. To this end, rat MSCs were seeded on these scaffolds and chondrogenically differentiated in vitro for 4 weeks followed by in vivo subcutaneous implantation for 8 weeks. Nonetheless, the quality and maturity of in vivo ectopic bone formation appeared to be scaffold/material-dependent. Eight weeks of implantation was not sufficient to ossify the entire PLGA/PCL constructs, albeit a comprehensive remodeling of the cartilage had occurred. For HA/TCP, PU and collagen I scaffolds, more mature bone formation with rich vascularity and marrow stroma development could be observed. These data suggest that chondrogenic priming of MSCs in the presence of different scaffold materials allows the establishment of reliable templates for generating functional endochondral bone tissue in vivo without using osteoinductive growth factors. The morphology and maturity of bone formation.

A review of the positive and negative effects of cardiovascular drugs on sexual function: a proposed table for use in clinical practice.

Several antihypertensive drugs, such as diuretics and ß-blockers, can negatively affect sexual function, leading to diminished quality of life and often to noncompliance with the therapy. Other drug classes, however, such as angiotensin II receptor blockers (ARBs) are able to improve patients' sexual function. Sufficient knowledge about the effects of these widely used antihypertensive drugs will make it possible for cardiologists and general practitioners to spare and even improve patients' sexual health by switching to different classes of cardiac medication. Nevertheless, previous data (part I) indicate that most cardiologists lack knowledge about the effects cardiovascular agents can have on sexual function and will thus not be able to provide the necessary holistic patient care with regard to prescribing these drugs. To be able to improve healthcare on this point, we aimed to provide a practical overview, for use by cardiologists as well as other healthcare professionals, dealing with sexual dysfunction in their clinical practices. Therefore, a systematic review of the literature was performed. The eight most widely used classes of antihypertensive drugs have been categorised in a clear table, marking whether they have a positive, negative or no effect on sexual function.

Pelvic lymph node motion during cone-beam computed tomography guided stereotactic radiotherapy.

Background and purpose: Stereotactic body radiotherapy (SBRT) is increasingly applied for pelvic lymph node recurrence. Thus far, knowledge on pelvic lymph node motion during CBCT-guided SBRT is lacking and the applied margins vary between institutions. This study evaluated pelvic lymph node motion during CBCT-guided SBRT and assessed the currently applied PTV margins of 3 and 5 mm. Material and methods: In total, 45 pelvic lymph node metastases were included. One observer delineated 45 GTVs on planning CT, 224 GTVs on pre-fraction and 216 on post-fraction CBCT. The GTV centroid coordinates were derived from all images for inter- and intrafraction motion analysis. Additionally, we assessed the influence of treatment time and lesion location on lesion motion. The expected coverage of a 3-mm and 5-mm PTV margin was assessed using the inclusiveness index for GTVs on pre- and post-fraction CBCT. Results: Lymph node interfraction motion was limited to 5 mm in 96-97 % of fractions for all translational directions and intrafraction lesion motion was limited to 3 mm in 97-100 % of fractions. Para-rectal lesions (11 %) were associated with significantly larger inter- and intrafraction motion compared to other pelvic locations and treatment duration showed no correlation with lesion motion. The mean (sd) lesion inclusiveness index was 99 % (5 %) for the 5-mm PTV margin and 96 % (9 %) for the 3-mm margin. Conclusion: Pelvic lymph node motion during CBCT-guided stereotactic radiotherapy was within the widely applied PTV margin of 5 mm, providing an opportunity to reduce this margin for pelvic lymph node SBRT.

Dextran-tryamine hydrogel maintains position and integrity under simulated loading in a human cadaver knee model.

Objective: This dextran-tyramine hydrogel is a novel cartilage repair technique, filling focal cartilage defects to provide a cell-free scaffold for subsequent cartilage repair. We aim to asses this techniques' operative feasibility in the knee joint and its ability to maintain position and integrity under expected loading conditions. Method: Seven fresh-frozen human cadaver legs (age range 55-88) were used to create 30 cartilage defects on the medial and lateral femoral condyles dependent of cartilage quality, starting with 1.0 â€‹cm2; augmenting to 1.5 â€‹cm2 and eventually 2.0 â€‹cm2. The defects were operatively filled with the injectable hydrogel scaffold. The knees were subsequently placed on a continues passive motion machine for 30 â€‹min of non-load bearing movement, mimicking post-operative rehabilitation. High resolution digital photographs documented the hydrogel scaffold after placement and directly after movement. Three independent observers blinded for the moment compared the photographs on outline attachment, area coverage and hydrogel integrity. Results: The operative procedure was uncomplicated in all defects, application of the hydrogel was straightforward and comparable to common cartilage repair techniques. No macroscopic iatrogenic damage was observed. The hydrogel scaffold remained predominately unchanged after non-load bearing movement. Outline attachment, area coverage and hydrogel integrity were unaffected in 87%, 93% and 83% of defects respectively. Larger defects appear to be more affected than smaller defects, although not statistically significant (p â€‹> â€‹0.05). Conclusion: The results of this study show operative feasibility of this cell-free hydrogel scaffold for chondral defects of the knee joint. Sustained outline attachment, area coverage and hydrogel integrity were observed after non-load bearing knee movement.

What do cardiologists know about the effects of cardiovascular agents on sexual function? A survey among Dutch cardiologists. Part I.

INTRODUCTION: Several cardiovascular agents, such as diuretics and ß-blockers, can negatively affect sexual function, leading to noncompliance with therapy. Others such as angiotensin II receptor blockers (ARBs) can improve patients' sexual function. AIMS: We aimed to gain insight into cardiologists' knowledge about the effects of cardiovascular drugs on sexual function and whether they take this knowledge into account when prescribing drugs. METHODS: An anonymous questionnaire was mailed to 980 members of the Netherlands Society of Cardiologists (cardiologists and residents in training). RESULTS: Almost 54 % of Dutch cardiologists responded; 414 questionnaires were analysed. Forty-five percent of cardiologists were aware that diuretics can negatively affect sexual function, 93.1 % knew about the negative effects ß-blockers can have, but only 9.2 % were aware that ARBs can have positive effects on sexual health. Almost half of respondents (48.2 %) stated they change medication regularly in an attempt to improve sexual function. Experienced cardiologists said they do this significantly more often than less experienced ones. CONCLUSIONS: Cardiologists' knowledge about the effects of cardiovascular drugs on sexual health appears to be insufficient. Sexual dysfunction is not routinely taken into account when cardiologists prescribe drugs.

Dosimetric consequences of pancreatic tumor motion when predetermined treatment margins are employed during intensity-modulated radiation therapy.

PURPOSE: To quantify the dosimetric consequences of pancreatic tumor motion on the pancreatic intensity-modulated radiation therapy (IMRT) plans. METHODS: Dose map of IMRT plans for 5 patients with pancreatic cancer were measured using a 2D diode array placed on a computer-controlled platform to simulate 2D pancreatic tumor motion. Dosimetric analysis was then performed to obtain IMRT quality assurance (QA) passing rates. The convolution method, which used a motion kernel to simulate 2D pancreatic motion, was also applied to the treatment and phantom verification plans for a wide range of magnitudes of motion (0.8-2.0 cm). The resulting motion-convolved verification dose maps (VDMs) were compared with the dynamic measurements to evaluate IMRT QA passing rates as well as the dose-volume histogram, the V95% of the planning target volume (PTV) and V98% of the clinical target volume (CTV). RESULTS: While CTV coverage was maintained when the simulated pancreatic tumor drifted inside the PTV with magnitudes of 1.0 cm and 1.5 cm, the V95% of the PTV was reduced by 10% and 17%, respectively. We also found that the differences between the measurements and the static VDMs increased proportional to the amplitude of motion, while the agreement between the measurements and the motion-convolved VDMs was excellent for any magnitude of motion. CONCLUSIONS: When the 4D technique is not available, predetermined margins must be used carefully to avoid possible under-dose to the target. Additionally, the phantom results show that the kernel convolution method provides an accurate evaluation of the dosimetric impact due to tumor motion and it should be employed in the planning process.

Preoperative pain measurements in correlation to deep endometriosis classification with Enzian

Background: Deep Endometriosis (DE) classification studies with Enzian never compared solitary compartments (A, B, C, F), and combinations of anatomical locations (A&B, A&C, B&C, A&B&C), in correlation to pain. Therefore, the results of these studies are challenging to translate to the clinical situation. Objectives: We studied pain symptoms and their correlation with the solitary and combinations of anatomical locations of deep endometriosis lesion(s) classified by the Enzian score. Materials and Methods: A prospective multi-centre study was conducted with data from university and non-university hospitals. A total of 419 surgical DE cases were collected with the web-based application called EQUSUM (www.equsum.org). Main Outcome Measures: Preoperative reported numeric rating scale (NRS) were collected along with the Enzian classification. Baseline characteristics, pain scores, surgical procedure and extent of the disease were also collected. Results: In general, more extensive involvement of DE does not lead to an increase in the numerical rating scale for pain measures. However, dysuria and bladder involvement do show a clear correlation AUC 0.62 (SE 0.04, CI 0.54-0.71, p< 0.01). Regarding the predictive value of dyschezia, we found a weak, but significant correlation with ureteric involvement; AUC 0.60 (SE 0.04, CI 0.53-0.67, p< 0.01). Conclusions: Pain symptoms poorly correlate with anatomical locations of deep endometriosis in almost all pain scores, with the exception of bladder involvement and dysuria which did show a correlation. Also, dyschezia seems to have predictive value for DE ureteric involvement and therefore MRI or ultrasound imaging (ureter and kidney) could be recommended in the preoperative workup of these patients. What's new?: Dyschezia might have a predictive value in detecting ureteric involvement.

Toxicity data for preoperative concurrent chemoradiotherapy with oxaliplatin and continuous infusion 5-fluorouracil for locally advanced esophageal cancer.

The purpose of this retrospective analysis was to characterize the feasibility and tolerability of oxaliplatin/5-fluorouracil (5-FU) given concurrently with radiotherapy for patients with locally advanced esophageal cancer. Between July 2005 and March 2009, 15 patients with clinical stage T3/T4 and/or N1/M1a lower esophageal or gastroesophageal junction adenocarcinoma were treated with preoperative chemoradiotherapy using oxaliplatin every 2 weeks and continuous infusion 5-FU. The main treatment-related toxicities were oral mucositis and dysphagia. During the first 2 weeks of treatment, 20% of patients presented with grade 1-2 oral mucositis, and one patient developed grade 1 dysphagia. In weeks 3-4, 53% of the patients experienced grade 1-2 mucositis, and 40% experienced grade 1-2 dysphagia. One patient only experienced grade 3 mucositis in week 4. Three patients (20%) had grade 3-4 dysphagia in weeks 3-4 and were continued on intravenous fluids and pain medications. During the last 2 weeks of chemoradiotherapy, 53% of patients reported grade 1-2 oral mucositis, mostly grade 1 and 73% of patients experienced grade 1-2 dysphagia and 26% patients experienced grade 3-4 dysphagia. Other toxicities included fatigue, nausea, neuropathy, and diarrhea. Only one patient experienced > 10% weight loss. The whole group was treated with aggressive supportive care during radiotherapy. Five (33%) patients achieved a pathological complete response. No patients developed locoregional failure. Sixty percent of the patients developed distant metastases and the 2-year disease-free survival was 53%. The median survival was 3.2 years with the 2-year overall survival of 73%. Preoperative oxaliplatin/5-FU-based chemoradiotherapy for locally advanced esophageal cancer is feasible, but associated with substantial gastrointestinal toxicity. A careful attention to nutrition and hydration throughout the course of therapy is required.

A randomized, placebo-controlled laboratory study of the effects of D-cycloserine on sexual memory consolidation in women.

RATIONALE AND OBJECTIVE: The aim of this study was to investigate the possible facilitating effect of the partial NMDA receptor agonist D-cycloserine (DCS) on memory consolidation of conditioned sexual responses and to examine the capability of DCS to reduce context-specificity of learning. METHODS: In a randomized placebo-controlled double-blind trial, 50 healthy females were exposed to a differential conditioning procedure. Two pictures of a male abdomen were used as conditional stimuli (CSs), of which one (the CS+) was followed by the unconditional stimulus (US), a genital vibrotactile stimulus. After the conditioning session on day 1, participants received either 125 mg of DCS or a placebo. The effects of DCS on affect, sexual arousal and US expectancy in response to the CS+ and CS- were examined 24 h after the conditioning procedure. RESULTS: A main effect of DCS was found on affect at the first test trials (p = 0.04, ηp2 = 0.09), and a similar non-significant but trend level effect was found for sexual arousal (p = 0.06, ηp2 = 0.07), which appeared to persist over a longer time (p = 0.07, ηp2 = 0.08). Unexpectedly, ratings of positive affect and sexual arousal in response to both the CS+ and the CS- were higher in the DCS condition compared to the control condition, possibly indicating that DCS administration reduced stimulus specificity. Since the results did not show clear evidence for context learning, we were not able to test effects on context-specificity of learning. CONCLUSION: Although largely inconclusive, the results provide tentative support for a facilitating effect of DCS on affect and sexual arousal in response to stimuli that were presented in a sexual conditioning procedure, however, no conclusions can be drawn about effects of DCS on sexual reward learning, since the design and results do not lend themselves to unambiguous interpretation.

Validation of the proton range accuracy and optimization of CT calibration curves utilizing range probing.

Proton therapy is affected by range uncertainty, which is partly caused by an ambiguous conversion from x-ray attenuation to proton stopping power. CT calibration curves, or Hounsfield look-up tables (HLUTs), are institution-specific and may be a source of systematic errors in treatment planning. A range probing method to verify, optimize and validate HLUTs for proton treatment is proposed. An initial HLUT was determined according to the stoichiometric approach. For HLUT validation, three types of animal tissue phantoms were prepared: a pig's head, 'thorax' and femur. CT scans of the phantoms were taken and a structure, simulating a water slab, was added on the scan distal to the phantoms to mimic the detector used for integral depth-dose measurements. The CT scans were imported into the TPS to calculate individual pencil beams directed through the phantoms. The phantoms were positioned at the therapy system isocenter using x-ray imaging. Shoot-through pencil beams were delivered, and depth-dose profiles were measured using a multi-layer ionization chamber. Measured depth-dose curves were compared to the calculated curves and the range error per spot was determined. Based on the water equivalent path length (WEPL) of individual spot, a range error margin was defined. Ratios between measured error and theoretical margin were calculated per spot. The HLUT optimization was performed by identifying systematic shifts of the mean range error per phantom and minimizing the ratios between range errors and uncertainty margins. After optimization, the ratios of the actual range error and the uncertainty margin over the complete data set did not exceed 0.75 (1.5 SD), indicating that the actual errors are covered by the theoretical uncertainty recipe. The feasibility of using range probing to assess range errors was demonstrated. The theoretical uncertainty margins in the institution-specific setting potentially may be reduced by ~25%.

Platform for automatic patient quality assurance via Monte Carlo simulations in proton therapy.

For radiation therapy, it is crucial to ensure that the delivered dose matches the planned dose. Errors in the dose calculations done in the treatment planning system (TPS), treatment delivery errors, other software bugs or data corruption during transfer might lead to significant differences between predicted and delivered doses. As such, patient specific quality assurance (QA) of dose distributions, through experimental validation of individual fields, is necessary. These measurement based approaches, however, are performed with 2D detectors, with limited resolution and in a water phantom. Moreover, they are work intensive and often impose a bottleneck to treatment efficiency. In this work, we investigated the potential to replace measurement-based approach with a simulation-based patient specific QA using a Monte Carlo (MC) code as independent dose calculation engine in combination with treatment log files. Our developed QA platform is composed of a web interface, servers and computation scripts, and is capable to autonomously launch simulations, identify and report dosimetric inconsistencies. To validate the beam model of independent MC engine, in-water simulations of mono-energetic layers and 30 SOBP-type dose distributions were performed. Average Gamma passing ratio 99 ± 0.5% for criteria 2%/2 mm was observed. To demonstrate feasibility of the proposed approach, 10 clinical cases such as head and neck, intracranial indications and craniospinal axis, were retrospectively evaluated via the QA platform. The results obtained via QA platform were compared to QA results obtained by measurement-based approach. This comparison demonstrated consistency between the methods, while the proposed approach significantly reduced in-room time required for QA procedures.

Assessment of range uncertainty in lung-like tissue using a porcine lung phantom and proton radiography.

Thoracic tumours are increasingly considered indications for pencil beam scanned proton therapy (PBS-PT) treatments. Conservative robustness settings have been suggested due to potential range straggling effects caused by the lung micro-structure. Using proton radiography (PR) and a 4D porcine lung phantom, we experimentally assess range errors to be considered in robust treatment planning for thoracic indications. A human-chest-size 4D phantom hosting inflatable porcine lungs and corresponding 4D computed tomography (4DCT) were used. Five PR frames were planned to intersect the phantom at various positions. Integral depth-dose curves (IDDs) per proton spot were measured using a multi-layer ionisation chamber (MLIC). Each PR frame consisted of 81 spots with an assigned energy of 210 MeV (full width at half maximum (FWHM) 8.2 mm). Each frame was delivered five times while simultaneously acquiring the breathing signal of the 4D phantom, using an ANZAI load cell. The synchronised ANZAI and delivery log file information was used to retrospectively sort spots into their corresponding breathing phase. Based on this information, IDDs were simulated by the treatment planning system (TPS) Monte Carlo dose engine on a dose grid of 1 mm. In addition to the time-resolved TPS calculations on the 4DCT phases, IDDs were calculated on the average CT. Measured IDDs were compared with simulated ones, calculating the range error for each individual spot. In total, 2025 proton spots were individually measured and analysed. The range error of a specific spot is reported relative to its water equivalent path length (WEPL). The mean relative range error was 1.2% (1.5 SD 2.3 %) for the comparison with the time-resolved TPS calculations, and 1.0% (1.5 SD 2.2 %) when comparing to TPS calculations on the average CT. The determined mean relative range errors justify the use of 3% range uncertainty for robust treatment planning in a clinical setting for thoracic indications.

Log file-based dose reconstruction and accumulation for 4D adaptive pencil beam scanned proton therapy in a clinical treatment planning system: Implementation and proof-of-concept.

BACKGROUND AND PURPOSE: Motion-induced uncertainties hamper the clinical implementation of pencil beam scanning proton therapy (PBS-PT). Prospective pretreatment evaluations only provide multiscenario predictions without giving a clear conclusion for the actual treatment. Therefore, in this proof-of-concept study we present a methodology for a fraction-wise retrospective four-dimensional (4D) dose reconstruction and accumulation aiming at the evaluation of treatment quality during and after treatment. MATERIAL AND METHODS: We implemented an easy-to-use, script-based 4D dose assessment of PBS-PT for patients with moving tumors in a commercially available treatment planning system. This 4D dose accumulation uses treatment delivery log files and breathing pattern records of each fraction as well as weekly repeated 4D-CT scans acquired during the treatment course. The approach was validated experimentally and was executed for an exemplary dataset of a lung cancer patient. RESULTS: The script-based 4D dose reconstruction and accumulation was implemented successfully, requiring minimal user input and a reasonable processing time (around 10 min for a fraction dose assessment). An experimental validation using a dynamic CIRS thorax phantom confirmed the precision of the 4D dose reconstruction methodology. In a proof-of-concept study, the accumulation of 33 reconstructed fraction doses showed a linear increase of D98 values. Projected treatment course D98 values revealed a CTV underdosage after fraction 25. This loss of target coverage was confirmed in a dose volume histogram comparison of the nominal, the projected (after 16 fractions) and the accumulated (after 33 fractions) dose distribution. CONCLUSIONS: The presented method allows for the assessment of the conformity between planned and delivered dose as the treatment course progresses. The implemented approach considers the influence of changing patient anatomy and variations in the breathing pattern. This facilitates treatment quality evaluation and supports decisions regarding plan adaptation. In a next step, this approach will be applied to a larger patient cohort to investigate its capability as 4D quality control and decision support tool for treatment adaptation.

Proton pencil beam scanning for mediastinal lymphoma: the impact of interplay between target motion and beam scanning.

The purpose of this study was to assess the feasibility of proton pencil beam scanning (PBS) for the treatment of mediastinal lymphoma. A group of 7 patients of varying tumor size (100-800 cc) were planned using a PBS anterior field. We investigated 17 fractions of 1.8 Gy(RBE) to deliver 30.6 Gy(RBE) to the internal target volume (ITV). Spots with σ ranging from 4 mm to 8 mm were used for all patients, while larger spots (σ = 6-16 mm) were employed for patients with motion perpendicular to the beam (⩾5 mm), based on initial 4-dimensional computed tomography (4D CT) motion evaluation. We considered volumetric repainting such that the same field would be delivered twice in each fraction. The ratio of extreme inhalation amplitude and regular tidal inhalation amplitude (free-breathing variability) was quantified as an indicator of potential irregular breathing during the scanning. Four-dimensional dose was calculated on the 4D CT scans based on the respiratory trace and beam delivery sequence, implemented by partitioning the spots into separate plans on each 4D CT phase. Four starting phases (end of inhalation, end of exhalation, middle of inhalation and middle of exhalation) were sampled for each painting and 4 energy switching times (0.5 s, 1 s, 3 s and 5 s) were tested, which resulted in 896 dose distributions for the analyzed cohort. Plan robustness was measured for the target and critical structures in terms of the percent difference between 'delivered' dose (4D-evaluated) and planned dose (calculated on average CT). It was found that none of the patients exhibited highly variable or chaotic breathing patterns. For all patients, the ITV D98% was degraded by <2% (standard deviations âˆ¼ 0.1%) when averaged over the whole treatment course. For six out of seven patients, the average degradation of ITV D98% per fraction was within 5% . For one patient with motion perpendicular to the beam (⩾5 mm), the degradation of ITV D98% per fraction was up to 15%, which was mitigated to 2% by employing larger spots and repainting. Deviation of mean lung dose was at most 0.2 Gy(RBE) (less than 1% of prescribed dose, 30.6 Gy(RBE)), while the deviation of heart maximum dose and cord maximum dose could exceed 5% of the prescribed dose. No significant difference in either target coverage or normal tissue dose was observed for different energy switching times compared via two-sided Wilcoxon signed-rank tests (p < 0.05). This feasibility study demonstrates that, for mediastinal lymphoma, the impact of the interplay effect on the PBS plan robustness is minimal when volumetric repainting and/or larger spots are employed.

Bone tissue-engineered implants using human bone marrow stromal cells: effect of culture conditions and donor age.

At present, it is well known that populations of human bone marrow stromal cells (HBMSCs) can differentiate into osteoblasts and produce bone. However, the amount of cells with osteogenic potential that is ultimately obtained will still be dependent on both patient physiological status and culture system. In addition, to use a cell therapy approach in orthopedics, large cell numbers will be required and, as a result, knowledge of the factors affecting the growth kinetics of these cells is needed. In the present study we investigated the effect of dexamethasone stimulation on the in vivo osteogenic potential of HBMSCs. After a proliferation step, the cells were seeded and cultured on porous calcium phosphate scaffolds for 1 week, and then subcutaneously implanted in nude mice for 6 weeks, in order to evaluate their in vivo bone-forming ability. Furthermore, the effect of donor age on the proliferation rate of the cultures and their ability to induce in vivo bone formation was studied. In 67% of the assayed patients (8 of 12), the presence of dexamethasone in culture was not required to obtain in vivo bone tissue formation. However, in cultures without bone-forming ability or with a low degree of osteogenesis, dexamethasone increased the bone-forming capacity of the cells. During cellular proliferation, a significant age-related decrease was observed in the growth rate of cells from donors older than 50 years as compared with younger donors. With regard to the effect of donor age on in vivo bone formation, HBMSCs from several donors in all age groups proved to possess in vivo osteogenic potential, indicating that the use of cell therapy in the repair of bone defects can be applicable irrespective of patient age. However, the increase in donor age significantly decreased the frequency of cases in which bone formation was observed.