Title Promoter Affiliations Abstract "Innovative therapies for pelvic floor dysfunction" "Jan Deprest" "Urogenital, Abdominal and Plastic Surgery, Woman and Child" "Current clinical practice forces us to think and explore new treatment options for both urinary incontinence and pelvic organ prolapse. This project will focus on: 1. The implementation of novel treatment options for pelvic floor dysfunction: vaginal laser treatment for prolapse and urinary incontinence and the cesa-vasa surgical technique for both prolapse and urinary incontinence) 2. Optimization of laparoscopic sacrocolpopexy (current surgical treatment of choice for apical prolapse): workflow analysis and optimization, institutial audit, MRI-study of the meshes after implantation etc..." "Automated Analysis of Ultrasound Images for the Assessment of Pelvic Floor Dysfunction" "Jan D'hooge" "Cardiovascular Imaging and Dynamics, Urogenital, Abdominal and Plastic Surgery" "Pelvic organ prolapse affects half of the women over 50, with one in four having disturbing symptoms. Other pelvic floor dysfunctions are urinary incontinence and fecal incontinence, which is very debilitating. Transperineal 3D/4D ultrasound is increasingly used to gain insights into the biomechanical support of the pelvic floor. In clinical practice, standardized measurements are often made manually leaving a lot of room for interpretation while being labor intensive. As such, our team recently proposed a semi-automatic algorithm to make this process more practical. We are currently also documenting the direct relationship between vaginal delivery trauma and these dysfunctions, using ultrasound as well as magnetic resonance. Also, imaging is used to measure postoperative changes for repairs of these pelvic floor dysfunctions, both clinically and experimentally. The aim of this PhD position is to further automate ultrasound measurements using state-of-the-art machine learning, segmentation and image analysis techniques. Moreover, together with our industrial partner, the main goal is to translate and integrate these techniques into commercial software implemented on high end ultrasound scanners. Next to the technical developments to be made, the student is also expected to lead validation efforts in an already acquired large patient database as well as to improve the workflow and optimize the user experience with the software. Over time, also MR imaging may be included." "Novel treatment modalities For Pelvic Floor Dysfunction" "Ladislav Krofta, Jan Deprest" "Urogenital, Abdominal and Plastic Surgery" "We aimed to test selected novel treatment modalities for pelvic floor dysfunctions and genitourinary syndrome of menopause. Both conditions are common in female, they negatively affect their quality of life, and current treatment options are not optimal." "Effectiveness of proprioceptive pelvic floor training for anorectal dysfunction after rectal cancer." "Anna Marie Devreese" "Research Group for Neurorehabilitation (eNRGy), Abdominal Surgical Oncology, Research Group for Musculoskeletal Rehabilitation" "Mesorectal excision with or without (neo)adjuvant chemoradiotherapy is the new standard for mid and low rectal cancer surgery. However, these treatment modalities affect postoperative continence and defecation. Specific symptoms such as urgency, diarrhoea, increased stool frequency, fragmentation and fecal incontinence have been reported. They vary in severity and are unpredictable. Despite spontaneous recovery during the first postoperative year, some side effects are long-lasting, may be progressive and may therefore impair social functioning, emotional well-being and quality of life. This study aims to evaluate long-term anorectal dysfunction after rectal cancer treatment, its specific influence on patients' well-being and the effectiveness of pelvic floor muscle training to improve anorectal function and therefore, quality of life." "New avenues in the management of pelvic floor disorders: experimental secondary prevention and medium term outcomes of abdominal mesh surgery" "Jan Deprest" "Urogenital, Abdominal and Plastic Surgery" "Pelvic floor disorders (PFD) include pelvic organ prolapse (POP), urinary (UI) & fecal incontinence (FI), sexual dysfunction and pelvic pain. Twelve years after first vaginal delivery around 23% of women leak urine at least once a week, and around 24% of women have stage 2+ POP1 The prevalence of FI in women increases with age, from 6% in women < 40 years rising to 15% in older women. Up to 50% of the patients with FI also report UI.2 PFD greatly affects the health-related quality of life of these women: 6.2% of patients with UI suffer from depression, compared to 2.2% from those without3. Of women with symptomatic POP, 22% of cases have moderate to severe depressive symptoms, in comparison with 6% in controls. These symptoms  improve after surgery, suggesting a causal relationship.4 Moreover many women alter their daily routine due to social stigma and embarrassment. As the aging population continues to grow, it is expected that the prevalence of PFD will further increase emphasizing the need for more basic research and the development of new strategies for the treatment and prevention of PFD.Current treatment options include conservative management such as physiotherapy, pharmacotherapy, the use of pessaries or surgery. While surgery for stress urinary incontinence (SUI) is successful, recurrence rates are high for prolapse repair 1 and surgical management of FI has failed to show long term results. The use of permanent synthetic meshes in prolapse repair has reduced the incidence of recurrence; however mesh-related complications occur in 10 to 15% of patients.5Vaginal delivery causes pelvic floor muscle and connective tissue trauma, and mechanical and ischemic nerve injury.6 Therefore, it is logic to consider interventions that might prevent this trauma either around the time of delivery. Primary caesarean section has been proposed yet is unrealistic because of increased morbidity and mortality,7 cost, yet mainly because its protective effect is only partial. 8, 9 We therefore propose an alternative strategy using stem cells, to be administrated to high risk patients after delivery. We hypothesize that stem cells will boost the innate healing response to birth-induced injury and aid in repairing damaged pelvic striated muscle (the levator ani and external anal sphincter), the smooth muscle of the internal anal sphincter and/or pelvic neural cells. High risk patients can be identified by screening ultrasound for uni- or bilateral levator avulsion or major anal sphincter trauma. 10-12 Ideally, one would use autologous stem cells harvested and processed prior to delivery, because they will cause minimal side effects if they would engraft.13 Moreover, adult somatic stem cells have no tumorigenicity unlike embryonic stem cells.14 Several stem cell types come to mind. We earlier used adipose derived stem cells (ADSCs) to prevent erectile dysfunction induced in rats by crush injury of the cavernous nerve.15 Though ADSCs were homing to the pelvic ganglion, most effects were believed to be paracrine. We speculate that ADSCs are not ideal because of their low capacity for muscle tissue regeneration. Bone marrow derived mesenchymal stem cells (MSC) have already been extensively studied by Damaser et al in a rat model for simulated birth injury. Administration of MSC 1h after vaginal distension increased urinary leak point pressure as well as elastin and smooth muscle surrounding the urethra16. Administration of MSC 24h after anal sphincterotomy increased anal pressure.17 The effect of MSC on the vaginal smooth muscle layer or the levator ani muscle was not studied. Again homing was demonstrated, though no persistent cells could be shown 9 d after intramuscular or intravenous administration.16-18Herein we will use mesangioblasts (MABs), also called pericytes or vessel-associated stem cells. These cells have the capacity to differentiate in to smooth and skeletal muscle tissue.19 We will use autologous cells so that eventual effects following engraftment are minimal. Autologous cell use would clinically also be acceptable as they can be isolated from minimally invasive “tru-cut” muscle biopsies 20. There is already clinical experience with stem cells in the treatment of stress urinary incontinence, on ongoing trial is using myoblasts (NCT01382602). In a mouse model for muscle dystrophy, two weeks after intra-arterial injection, LacZ labeled MABs were found in all the hind limbs.21 They were seen in the center of regenerating skeletal muscle fibers, in vessels expressing α- smooth muscle actin or endothelial markers, showing their capability to differentiate in striated and smooth muscle.21Rat mesoangioblasts will be collected by punch needle biopsy, processed and injected intramuscular in the levator ani plate or anal sphincter or administrated systemically by intra-arterial route following simulated vaginal birth injury. Vaginal distension (VD) and pudendal nerve crush (PNC) in rats are two relevant trauma, associated to simulated childbirth, leading to a decrease in leak point pressure (LPP), denervation, hypoxia, and atrophy of the external urethral sphincter (EUS) on histology.22-25 For the study of FI, usually an anal incontinence model is preferred, consisting of sphincterotomy, though  pudendal nerve transection,26 intra-abdominal balloon inflation,27 but also vaginal distension have been used.281.         Olsen AL et al. Obstet Gynecol 1997; 89(4):501-6.2.         Landefeld CS et al. Ann Intern Med 2008; 148(6):449-58.3.         Melville JL et al. Obstet Gynecol 2005; 106(3):585-92.4.         Ghetti C, Lowder JL, Ellison R, et al. Int Urogynecol J 2010; 21(7):855-60.5.         Maher C et al. Cochrane Database Syst Rev 2013; 4:CD004014.6.         Bortolini MA, et al. Int Urogynecol J 2010; 21(8):1025-30.7.         Deneux-Tharaux C, et al. Obstet Gynecol 2006; 108(3 Pt 1):541-8.8.         Rortveit G et al. N Engl J Med 2003; 348(10):900-7.9.         MacArthur C et al. BJOG 2011; 118(8):1001-7.10.       Schwertner-Tiepelmann N et al. Ultrasound Obstet Gynecol 2012; 39(4):372-83.11.       Dietz HP. Aust N Z J Obstet Gynaecol 2013; 53(3):220-30.12.       Meriwether KV et al. Int Urogynecol J 2014; 25(3):329-36.13.       Prasongchean Wet al. N Biotechnol 2012; 29(6):641-50.14.       Ben-David U, Benvenisty N. Nat Rev Cancer 2011; 11(4):268-77.15.       Qiu X et al. Eur Urol 2012; 62(4):720-7.16.       Dissaranan C et al. Cell Transplant 2013.17.       Salcedo L et al. Stem Cell Res. 2013; 10(1):95-102. doi: 10.1016/j.scr.2012.10.002. Epub 2012 Oct 16.18.       Salcedo L et al. Stem Cells Transl Med 2014.19.       Roobrouck VD et al. Stem Cells 2011; 29(5):871-82.20.       Quattrocelli M et al. Methods Mol Biol 2012; 798:65-76.21.       Sampaolesi M, et al. Science 2003; 301(5632):487-92.22.       Lin AS et al. Urology 1998; 52(1):143-51.23.       Cannon TW et al. BJU Int 2002; 90(4):403-7.24.       Damaser MS et al. J Urol 2003; 170(3):1027-31.25.       Jiang HH et al. Handb Exp Pharmacol 2011(202):45-67.26.       Zutshi M et al. Dis Colon Rectum. 2009; 52(7):1321-9. doi: 10.1007/DCR.0b013e31819f746d.27.       Peirce C. et al. Obstet Gynecol. 2008; 112(4):943-4; author reply 944. doi: 10.1097/AOG.0b013e3181892ef2.28.       Wai CY et al. Obstet Gynecol. 2008; 111(2 Pt 1):332-40. doi: 10.1097/AOG.0b013e318162f6a7." "The effect of pelvic floor muscle training on bowel symptoms after low anterior resection for rectal cancer." "Inge Geraerts" "Research Group for Rehabilitation in Internal Disorders" "Since several years, low anterior resection, with total mesorectal excision and preservation of the autonomic nerves of the pelvis has become the gold standard for rectal cancer surgery. However, this surgery affects bowel function in 60-90% of patients. These symptoms are referred to as the ‘low anterior resection syndrome’ and are associated with a large negative impact on quality of life. Currently, patients only receive some anti-diarrheal medication, diet advice or the advice to wait for spontaneous improvement. Although pelvic floor muscle training is highly recommended in the treatment of bowel problems in non-cancer populations, there is still no consensus about its effectiveness in rectal cancer patients. In this research we aim (1) to evaluate if patients, who receive 12 weeks of intensive pelvic floor muscle training, have less LARS symptoms then patients who had no treatment; (2) to examine urinary and sexual symptoms, associated with rectal cancer treatment; (3) to assess propulsive colonic contractions and the effect of hindgut denervation on the presence of coordinated proximal to distal contractions; (4) to study the influence of LAR for rectal cancer on all physical activity levels." "Modern technologies in the assessment and treatment of pelvic organ prolapse - experimental and clinical studies" "Jan Deprest" "Woman and Child, Urogenital, Abdominal and Plastic Surgery" "In this project, we aim to use modern assessment techniques to study certain risk factors related to the development of pelvic floor prolapse in a clinical setting as well as in an experimental model. Pelvic floor prolapse is a bothersome condition when the vaginal wall or the uterus protrudes through the vaginal opening. It affects mainly women who were at least once pregnant and delivered vaginally. The project includes clinical part during which we tried to contribute to the discussion on risk factors related to the development of pelvic organ prolapse and other pelvic floor dysfunctions. More extensive, experimental part, aimed to further characterize a large ovine animal model for the development of pelvic organ prolapse and for vaginal surgery.The clinical study was conducted in Prague, Czech Republic, and included a large cohort of nulliparous women who delivered vaginally. One year after delivery one-third of women reported urinary incontinence, 13% had pelvic organ prolapse reaching the level of hymen or beyond and 3.3% reported some anorectal dysfunction mainly related to painful defecation. As a result of delivery, 18% of women sustained levator ani avulsion and 17% had levator hiatus ballooning. Both of which were tightly related to the current or future presence of pelvic organ prolapse and its recurrence after surgical correction. Demographic and obstetrical factors included age and body mass index increased the likely hood of urinary incontinence, age increases the risk for pelvic organ prolapse. Risk factors for levator ani avulsion included the forceps delivery, whereas epidural analgesia and perineal rupture grade I was decreasing.Experimentally we worked with the sheep as a large animal model. First, we characterized the pelvic floor of the virgin ewe and compared it to that of women. Second, we documented the effects of certain key life time events such as first delivery, menopause and under its replacement therapy. We identified many anatomical and structural similarities such as vaginal dimensions, the composition of the vaginal wall, attachments of levator ani muscle. Some anatomical structures present in women are not developed in sheep (i.e. the sacrospinous ligament, internal obturator muscle and obturator membrane) and their pelvic floor anatomy is adapted to their quadruped position and presence of the tail. We observed the effect of specific life span factors (first vaginal delivery, ovariectomy, hormonal replacement therapy) on active and passive biomechanical properties of the ovine vagina. Following the first vaginal delivery, ovine vagina became more spacious, its distal part was less stiff and smooth muscles generated lower contractile forces. Following artificially induced menopause vagina was narrower and its middle part becomes stiffer. Estradiol hormonal replacement returned the stiffness in within the range of the premenopausal animal. Histology showed only a limited amount of changes and had not sufficiently explained observed changes in biomechanics.The experimental work was dedicated to studying the effect of novel implants in the treatment of pelvic organ prolapse. In a comparative study, we used a bovine-derived acellular cross-linked collagen matrix (ACM) as an alternative to polypropylene flat meshes. Both types of implants were inserted in the ovine rectovaginal septum. After 6 months, ACMs showed more local graft-related complications and biomechanical properties comparable to polypropylene. Moreover, partial degradation of ACM had a negative impact on smooth muscle contractility. Due to theses observation, we concluded that ACM does not seem to have better biosafety profile than polypropylene.To proceed with last experimental study in sheep we firstly need to further explore the potential and feasibility of arm anchored implant. In a small study, we performed a trocar guided transvaginal insertion of an H-shaped implant self-tailored to fit ovine anatomy and dimensions. No serious complications were identified therefore we used the technique for bigger prospective study. Moreover, the surgical procedure was recorded for educational purposes.The subsequent study included previously described H-shaped mesh and flat mash, both fabricated from polymeric polyvinidylene fluoride loaded with iron particles that allow its visualization with magnetic resonance (MRI). In a longitudinal manner, we collected data documenting stable shape and position of implants. Initially, there was a drop in the effective surface area observed in both types of implants that remained stable until the end of the observational period. More detail analysis of thickness maps obtained from MRI data revealed two deformations patterns each of them specific for H-shape to flat mesh. Deformation of H-shaped implants was most probably related to distinct biomechanical properties of its central part and arms, whereas flat implants displayed heterogenic pattern most probably linked with pore aggregation caused with suturing. The polymer also showed a low rate of graft related complications, did not affect smooth muscle contractility yet increased the stiffness of augmented tissue.In general, this project has shown that pelvic organ prolapse is linked with maternal age and delivery-related injuries. Up to every eight women may have a symptomatic prolapse already 1 year after her first delivery. Moreover, those with muscle injury are in higher risk of POP development in the future and its recurrence after the primary surgical repair. To improve our knowledge on POP development and treatment we further explored the potential of a large ovine model for prolapse and vaginal surgery. We showed that many anatomical and morphological features and vaginal wall changes induced by specific life span factors (first delivery, artificial menopause, hormonal replacement) are to a certain extent similar to observations in women. We further used this model for testing novel implants and visualization techniques. We believe that the ovine model should be used in future research of pelvic organ prolapse pathophysiology and novel treatment techniques." "Vaginal birth injury to the pelvic floor: early diagnosis and treatment" "Jan Deprest" "Woman and Child" "The applicant will work on several subprojects around this matter: 1. A prospective study in nullipara will be done to determine the magnitude of pelvic floor disorders in our local population and what is it's natural history. 2. She will determine the place of vaginal and perineal ultrasound in the diagnosis of structural damage to the posterior compartment early after delivery. Together with another student with expertise in image analysis, automated diagnostic algorithms will be developed.  3. In a later interventional study in women at high risk of, or with posterior compartment problems, the effect of a targeted pelvic floor rehabilitation program will be evaluated. 4. In an experimental study the effects of simulated vaginal delivery on the posterior compartment will be determined, and the effect of systemically administered mesoangioblasts will be investigated." "Urinary incontinence and erectile dysfunction after radical prostatectomy: longitudinal evolution and the effect of intensive treatment for erectile dysfunction minimum one year after surgery." "Marijke Van Kampen" "Research Group for Neurorehabilitation (eNRGy), Research Group for Rehabilitation in Internal Disorders, Woman and Child" "Based on the results of previous doctoral research, several aspects need further investigation. Traditionally, the role of surgery in clinical stage T3 prostate cancers was under debate. However, currently guidelines indicate a place for surgery in high risk patients and consequently functional outcomes (urinary incontinence, voiding symptoms and quality of life) after surgery have to be compared between low and intermediate versus high risk (clinical stage ≥cT3a or PSA > 20ng/ml or Gleason score 8-10) patients (longitudinal study). Secondly, recovery of sexual function after radical prostatectomy (RP) can take up to 40 months after surgery. No study monitored the different treatment strategies for erectile dysfunction (ED), patients followed and discontinued in their first postoperative year. The sexual (dys)function and the undertaken penile rehabilitation strategies in the first year after RP have to be mapped (longitudinal study). Thirdly, only limited research was reported concerning ED after RP, suggesting improved erectile function after pelvic floor muscle training (PFMT). A randomized controlled trial should reveal the effect of intensive PFMT for ED minimum one year after RP (randomized controlled trial)." "A cell based preventive strategy for birth induced pelvic floor disorders." "Jan Deprest" "Urogenital, Abdominal and Plastic Surgery, Patient Safety and Quality, Stem Cell and Developmental Biology" "Pelvic floor disorders (PFD) affect nearly one third of pre-menopausal and nearly half of postmenopausal women. PFD include pelvic organ prolapse, urinary and fecal incontinence and may be perceived as severe as stroke or dementia. The most important risk factor is vaginal birth. It causes direct trauma to the pelvic floor nerves and its supportive connective tissues and muscles. In most women, damage remains initially hidden, but surfaces later in life. The current treatment is surgery, with reasonable success for urinary incontinence, high recurrence rates for prolapse and deceiving results for anal incontinence. Prevention by prelabor cesarean section sounds tempting but is unrealistic. We propose prevention by action immediately after delivery by stimulation of the spontaneous repair mechanisms using stem cells, earlier harvested from the patient. We propose a stem cell called mesangioblast (MAB) because it can regenerate muscle and may also contribute to nerve recovery. MABs may work through local temporary release of factors promoting healing, but when they are from the same individual they may engraft and help repair injured structures and their function. Using MAB is realistic: they can be derived from simple needle muscle biopsies, expanded in the lab and reinjected into the host. This is already done in trials for muscle dystrophy patients. The current project will produce evidence of this concept by testing in a rat model for vaginal birth trauma."