Screening for Prostate Cancer: Intermediate Outcome Measures and Active Surveillance

Prostate cancer is the most frequently diagnosed cancer in men in the Western world. The increasing use of PSA as a screening test for this disease has contributed to a marked increase in the number of newly diagnosed prostate cancers in countries where screening is prevalent. Whether screening actually influences prostate cancer mortality is still unclear. Regardless of the conclusions of ongoing trials on this question, it is likely that opportunistic screening will continue to be used. A confirmed positive effect of screening on the disease specific mortality would give a population based screening program a stronger scientific basis. The disputable performance of the PSA test, the high prevalence of the disease in older men, together with a high incidence-to mortality ratio have confronted the medical community and especially the urological world with new dilemmas. Until new predictors become available which are capable of only detecting the significant prostate cancers, the high incidence, the serious side effects of prostate cancer treatments, costs, and especially the ethical aspects oblige us to consider the disadvantages of the currently used screening tools for prostate cancer. Overdiagnosis is one of the main problems. Ideally, detection of insignificant cancers could be avoided, but that is not presently possible, and therefore a likely by-product of a PSA screening program will be the frequent diagnosis of insignificant cancers. This thesis focuses on active surveillance as a way out of the screening dilemma described above. Active surveillance manages selected men with prostate cancer expectantly with curative intent. These carefully selected men are actively observed in order to have the possibility to offer them deferred curative treatment once the tumour seems to progress. This thesis explores what kind of cancers are diagnosed by screening, how to subsequently risk-stratify those and what the best strategy is for active surveillance of a subset of these cancers

Intraoperative cone beam computed tomography for detecting residual stones in percutaneous nephrolithotomy:a feasibility study

Cone beam computed tomography (CBCT) provides multiplanar cross-sectional imaging and three-dimensional reconstructions and can be used intraoperatively in a hybrid operating room. In this study, we investigated the feasibility of using a CBCT-scanner for detecting residual stones during percutaneous nephrolithotomy (PCNL). Intraoperative CBCT-scans were made during PCNL procedures from November 2018 until March 2019 in a university hospital. At the point where the urologist would have otherwise ended the procedure, a CBCT-scan was made to image any residual fragments that could not be detected by either nephroscopy or conventional C-arm fluoroscopy. Residual fragments that were visualized on the CBCT-scan were attempted to be extracted additionally. To evaluate the effect of this additional extraction, each CBCT-scan was compared with a regular follow-up CT-scan that was made 4 weeks postoperatively. A total of 19 procedures were analyzed in this study. The mean duration of performing the CBCT-scan, including preparation and interpretation, was 8 min. Additional stone extraction, if applicable, had a mean duration of 11 min. The mean effective dose per CBCT-scan was 7.25 mSv. Additional extraction of residual fragments as imaged on the CBCT-scan occurred in nine procedures (47%). Of the follow-up CT-scans, 63% showed a stone-free status as compared to 47% of the intraoperative CBCT-scans. We conclude that the use of CBCT for the detection of residual stones in PCNL is meaningful, safe, and feasible

Cone beam computed tomography for detecting residual stones in percutaneous nephrolithotomy, a randomized controlled trial (CAPTURE) protocol

Abstract Introduction Percutaneous nephrolithotomy (PCNL) is the standard surgical treatment method for large kidney stones. Its aim is to achieve a stone-free status, since any residual fragments (RFs) after PCNL are likely to cause additional morbidity or stone growth. Enhancing intraoperative detectability of RFs could lead to increased stone-free rates and decreased re-intervention rates. Cone beam computed tomography (CBCT) has recently been introduced in urology as a feasible method for intraoperatively imaging RFs. The aim of this trial is to determine the added value of CBCT in percutaneous nephrolithotomy, by measuring differences in stone-related morbidity for patients with procedures in which a CBCT is used versus patients with procedures without the use of CBCT. Methods The CAPTURE trial is an investigator-initiated single-center, randomized controlled trial (RCT) in adult patients who have an indication for percutaneous nephrolithotomy. A contemporary percutaneous nephrolithotomy is performed. Once the surgeon is convinced of a stone-free status by means of fluoroscopy and nephroscopy, randomization allocates patients to either the study group in whom an intraoperative CBCT scan is performed or to the control group in whom no intraoperative CBCT scan is performed. The main endpoint is the stone-free status as assessed four weeks postoperatively by low-dose non-contrast abdominal CT, as a standard follow-up procedure. Secondary endpoints include the number of PCNL procedures required and the number of stone-related events (SREs) registered. The total study population will consist of 320 patients that undergo PCNL and are eligible for randomization for an intraoperative CBCT scan. Discussion We deem a randomized controlled trial to be the most effective and reliable method to assess the efficacy of CBCT in PCNL. Though some bias may occur due to the impossibility of blinding the urologist at randomization, we estimate that the pragmatic nature of the study, standardized circumstances, and follow-up methods with pre-defined outcome measures will result in a high level of evidence. Trial registration Netherlands Trial Register (NTR) NL8168 , ABR NL70728.042.19. Registered on 15 October 2019. Prospectively registered

Human Allogeneic Bone Marrow and Adipose Tissue Derived Mesenchymal Stromal Cells Induce CD8+ Cytotoxic T Cell Reactivity

INTRODUCTION: For clinical applications, Mesenchymal Stromal Cells (MSC) can be isolated from bone marrow and adipose tissue of autologous or allogeneic origin. Allogeneic cell usage has advantages but may harbor the risk of sensitization against foreign HLA. Therefore, we evaluated whether bone marrow and adipose tissue-derived MSC are capable of inducing HLA-specific alloreactivity. METHODS: MSC were isolated from healthy human Bone Marrow (BM-MSC) and adipose tissue (ASC) donors. Peripheral Blood Mononuclear Cells (PBMC) were co-cultured with HLA-AB mismatched BM-MSC or ASC precultured with or without IFNy. After isolation via FACS sorting, the educated CD8+ T effector populations were exposed for 4 hours to Europium labeled MSC of the same HLA make up as in the co-cultures or with different HLA. Lysis of MSC was determined by spectrophotometric measurement of Europium release. RESULTS: CD8+ T cells educated with BM-MSC were capable of HLA specific lysis of BM-MSC. The maximum lysis was 24% in an effector:target (E:T) ratio of 40:1. Exposure to IFNγ increased HLA-I expression on BM-MSC and increased lysis to 48%. Co-culturing of PBMC with IFNγ-stimulated BM-MSC further increased lysis to 76%. Surprisingly, lysis induced by ASC was significantly lower. CD8+ T cells educated with ASC induced a maximum lysis of 13% and CD8+ T cells educated with IFNγ-stimulated ASC of only 31%. CONCLUSION: Allogeneic BM-MSC, and to a lesser extend ASC, are capable of inducing HLA specific reactivity. These results should be taken into consideration when using allogeneic MSC for clinical therapy

Overdiagnosis and overtreatment of early detected prostate cancer

Early detection of prostate cancer is associated with the diagnosis of a considerable proportion of cancers that are indolent, and that will hardly ever become symptomatic during lifetime. Such overdiagnosis should be avoided in all forms of screening because of potential adverse psychological and somatic side effects. The main threat of overdiagnosis is overtreatment of indolent disease. Men with prostate cancer that is likely to be indolent may be offered active surveillance. Evaluation of active surveillance studies and validation of new biological parameters for risk assessment are expected

Do hypoxia/normoxia culturing conditions change the neuroregulatory profile of Wharton Jelly mesenchymal stem cells secretome?

Introduction: The use of human umbilical cord Wharton Jelly-derived mesenchymal stem cells (hWJ-MSCs) has been considered a new potential source for future safe applications in regenerative medicine. Indeed, the application of hWJ-MSCs into different animal models of disease, including those from the central nervous system, has shown remarkable therapeutic benefits mostly associated with their secretome. Conventionally, hWJ-MSCs are cultured and characterized under normoxic conditions (21 % oxygen tension), although the oxygen levels within tissues are typically much lower (hypoxic) than these standard culture conditions. Therefore, oxygen tension represents an important environmental factor that may affect the performance of mesenchymal stem cells in vivo. However, the impact of hypoxic conditions on distinct mesenchymal stem cell characteristics, such as the secretome, still remains unclear. Methods: In the present study, we have examined the effects of normoxic (21 % O2) and hypoxic (5 % O2) conditions on the hWJ-MSC secretome. Subsequently, we address the impact of the distinct secretome in the neuronal cell survival and differentiation of human neural progenitor cells. Results: The present data indicate that the hWJ-MSC secretome collected from normoxic and hypoxic conditions displayed similar effects in supporting neuronal differentiation of human neural progenitor cells in vitro. However, proteomic analysis revealed that the use of hypoxic preconditioning led to the upregulation of several proteins within the hWJ-MSC secretome. Conclusions: Our results suggest that the optimization of parameters such as hypoxia may lead to the development of strategies that enhance the therapeutic effects of the secretome for future regenerative medicine studies and applications. © 2015 Teixeira et al.Portuguese Foundation for Science and Technology (FCT) (Ciência 2007 program and IF Development Grant (AJS); and pre-doctoral fellowships to FGT (SFRH/69637/ 2010) and SIA (SFRH/BD/81495/2011); Canada Research Chairs (LAB) and a SSE Postdoctoral Fellowship (KMP); The National Mass Spectrometry Network (RNEM) (REDE/1506/REM/2005); co-funded by Programa Operacional Regional do Norte (ON.2 – O Novo Norte), ao abrigo do Quadro de Referência Estratégico Nacional (QREN), através do Fundo Europeu de Desenvolvimento Regional (FEDER).info:eu-repo/semantics/publishedVersio