Prognostic factors for tumor recurrence in patients with clinical stage I seminoma undergoing surveillance—protocol for a systematic review

Background: Testicular cancer is primarily treated with the surgical removal of the affected testis. About 50 % of testicular cancer patients present with a stage I seminoma. If no chemo- or radiotherapy as adjuvant treatment is initiated after orchiectomy, 15–20 % of these patients will develop metastases. Although adjuvant treatment is effective in reducing the relapse risk, there is rising concern about overtreatment of these patients. Prognostic factors at primary diagnosis might have the potential to identify patients at higher risk of tumor relapse, allowing to guide individual therapy and to avoid overtreatment. Therefore, we aim to synthesize the available evidence on tumor or patient characteristics as possible prognostic factors for cancer recurrence in patients with clinical stage I seminoma. Methods/design: We will conduct a broad systematic review to analyze what prognostic factors predict cancer recurrence in patients with a first time diagnosis of clinical stage I seminoma, who received no adjuvant chemo- or radiotherapy after orchiectomy. The literature search will comprise MEDLINE, Web of Science, the Cochrane Central Register of Controlled Trials (CENTRAL), and the conference proceedings of the American Society of Clinical Oncology (ASCO), American Urologic Association (AUA), and European Urologic Association (EAU) Annual Meetings. Prospective and retrospective longitudinal studies reporting on prognostic factors for cancer recurrence will be considered. We will consider the wealth of any candidate clinical or pathological prognostic factor reported in the literature. Our outcome of interest will be tumor recurrence at a minimum of 2 years follow-up. Study screening, data extraction, and quality assessment will be done by two reviewers independently. Hazard ratios will be used to measure the relationship between the potential prognostic factor and tumor recurrence. Meta-analyses will be conducted with sufficiently homogeneous studies and separately with respect to study design, by using the random-effects generic inverse variance model. Discussion: Limitations and strengths will be discussed in our review, and the results will be put into context with other studies in this field. Our results will help to guide evidence-based decision-making on patients with clinical stage I seminoma, allowing a better adjustment of therapies with regard to the individual patient’s risk. Our findings will furthermore help to formulate recommendations for future research. Systematic review registration: PROSPERO CRD4201400943

Tamoxifen for the management of breast events induced by non-steroidal antiandrogens in patients with prostate cancer: a systematic review

BACKGROUND: Tamoxifen has emerged as a potential management option for gynecomastia and breast pain due to non-steroidal antiandrogens, and it is considered an alternative to surgery or radiotherapy. The objective of this systematic review was to assess the benefits and harms of tamoxifen, in comparison to other treatment options, for either the prophylaxis or treatment of breast events induced by non-steroidal antiandrogens in prostate cancer patients. METHODS: We searched CENTRAL, MEDLINE, EMBASE, reference lists, the abstracts of three major conferences and three trial registers to identify ongoing randomized controlled trials (RCTs). Two authors independently screened the articles identified, assessed the trial quality and extracted data. The protocol was prospectively registered (CRD42011001320; http://www.crd.york.ac.uk/PROSPERO). RESULTS: Four studies were identified. Tamoxifen significantly reduced the risk of suffering from gynecomastia (risk ratio 9RR0 0.10, 95% CI 0.05 to 0.22) or breast pain (RR 0.06, 95% CI 0.02 to 0.17) at six months compared to untreated controls. Tamoxifen also showed a significant benefit for the prevention of gynecomastia (RR 0.22, 95% CI 0.08 to 0.58) and breast pain (RR 0.25, 95% CI 0.10 to 0.64) when compared to anastrozole after a median of 12 months. One study showed a significant benefit of tamoxifen for the prevention of gynecomastia (RR 0.24, 95% CI 0.09 to 0.65) and breast pain (RR 0.20, 95% CI 0.06 to 0.65) when compared with radiotherapy at six months. Radiotherapy increased the risk of suffering from nipple erythema and skin irritation, but there were no significant differences for any other adverse events (all P > 0.05). CONCLUSIONS: The currently available evidence suggests good efficacy of tamoxifen for the prevention and treatment of breast events induced by non-steroidal antiandrogens. The impact of tamoxifen therapy on long-term adverse events, disease progression and survival remains unclear. Further large, well-designed RCTs, including long-term follow-ups, are warranted. Also, the optimal dose needs to be clarified

Bladder cancer - the neglected tumor: a descriptive analysis of publications referenced in MEDLINE and data from the register clinicaltrials.gov

Background: Uro-oncological neoplasms have both a high incidence and mortality rate and are therefore a major public health problem. The aim of this study was to evaluate research activity in uro-oncology over the last decade. Methods: We searched MEDLINE and ClinicalTrials.gov systematically for studies on prostatic, urinary bladder, kidney, and testicular neoplasms. The increase in newly published reports per year was analyzed using linear regression. The results are presented with 95% confidence intervals, and a p value <0.05 was considered statistically significant. Results: The number of new publications per year increased significantly for prostatic, kidney and urinary bladder neoplasms (all <0.0001). We identified 1,885 randomized controlled trials (RCTs); also for RCTs, the number of newly published reports increased significantly for prostatic (p = 0.001) and kidney cancer (p = 0.005), but not for bladder (p = 0.09) or testicular (p = 0.44) neoplasms. We identified 3,114 registered uro-oncological studies in ClinicalTrials.gov. However, 85% of these studies are focusing on prostatic (45%) and kidney neoplasms (40%), whereas only 11% were registered for bladder cancers. Conclusions: While the number of publications on uro-oncologic research rises yearly for prostatic and kidney neoplasms, urothelial carcinomas of the bladder seem to be neglected despite their important clinical role. Clinical research on neoplasms of the urothelial bladder must be explicitly addressed and supported

Perisylvian white matter connectivity in the human right hemisphere

Background By using diffusion tensor magnetic resonance imaging (DTI) and subsequent tractography, a perisylvian language network in the human left hemisphere recently has been identified connecting Brocas's and Wernicke's areas directly (arcuate fasciculus) and indirectly by a pathway through the inferior parietal cortex. Results Applying DTI tractography in the present study, we found a similar three-way pathway in the right hemisphere of 12 healthy individuals: a direct connection between the superior temporal and lateral frontal cortex running in parallel with an indirect connection. The latter composed of a posterior segment connecting the superior temporal with the inferior parietal cortex and an anterior segment running from the inferior parietal to the lateral frontal cortex. Conclusion The present DTI findings suggest that the perisylvian inferior parietal, superior temporal, and lateral frontal corticies are tightly connected not only in the human left but also in the human right hemisphere

Rapamycin Regulates Autophagy and Cell Adhesion in Induced Pluripotent Stem Cells

Background Cellular reprogramming is a stressful process, which requires cells to engulf somatic features and produce and maintain stemness machineries. Autophagy is a process to degrade unwanted proteins and is required for the derivation of induced pluripotent stem cells (iPSCs). However, the role of autophagy during iPSC maintenance remains undefined. Methods Human iPSCs were investigated by microscopy, immunofluorescence, and immunoblotting to detect autophagy machinery. Cells were treated with rapamycin to activate autophagy and with bafilomycin to block autophagy during iPSC maintenance. High concentrations of rapamycin treatment unexpectedly resulted in spontaneous formation of round floating spheres of uniform size, which were analyzed for differentiation into three germ layers. Mass spectrometry was deployed to reveal altered protein expression and pathways associated with rapamycin treatment. Results We demonstrate that human iPSCs express high basal levels of autophagy, including key components of APMKα, ULK1/2, BECLIN-1, ATG13, ATG101, ATG12, ATG3, ATG5, and LC3B. Block of autophagy by bafilomycin induces iPSC death and rapamycin attenuates the bafilomycin effect. Rapamycin treatment upregulates autophagy in iPSCs in a dose/time-dependent manner. High concentration of rapamycin reduces NANOG expression and induces spontaneous formation of round and uniformly sized embryoid bodies (EBs) with accelerated differentiation into three germ layers. Mass spectrometry analysis identifies actin cytoskeleton and adherens junctions as the major targets of rapamycin in mediating iPSC detachment and differentiation. Conclusions High levels of basal autophagy activity are present during iPSC derivation and maintenance. Rapamycin alters expression of actin cytoskeleton and adherens junctions, induces uniform EB formation, and accelerates differentiation. IPSCs are sensitive to enzyme dissociation and require a lengthy differentiation time. The shape and size of EBs also play a role in the heterogeneity of end cell products. This research therefore highlights the potential of rapamycin in producing uniform EBs and in shortening iPSC differentiation duration

Trophoblast organoids as a model for maternal-fetal interactions during human placentation.

The placenta is the extraembryonic organ that supports the fetus during intrauterine life. Although placental dysfunction results in major disorders of pregnancy with immediate and lifelong consequences for the mother and child, our knowledge of the human placenta is limited owing to a lack of functional experimental models1. After implantation, the trophectoderm of the blastocyst rapidly proliferates and generates the trophoblast, the unique cell type of the placenta. In vivo, proliferative villous cytotrophoblast cells differentiate into two main sub-populations: syncytiotrophoblast, the multinucleated epithelium of the villi responsible for nutrient exchange and hormone production, and extravillous trophoblast cells, which anchor the placenta to the maternal decidua and transform the maternal spiral arteries2. Here we describe the generation of long-term, genetically stable organoid cultures of trophoblast that can differentiate into both syncytiotrophoblast and extravillous trophoblast. We used human leukocyte antigen (HLA) typing to confirm that the organoids were derived from the fetus, and verified their identities against four trophoblast-specific criteria3. The cultures organize into villous-like structures, and we detected the secretion of placental-specific peptides and hormones, including human chorionic gonadotropin (hCG), growth differentiation factor 15 (GDF15) and pregnancy-specific glycoprotein (PSG) by mass spectrometry. The organoids also differentiate into HLA-G+ extravillous trophoblast cells, which vigorously invade in three-dimensional cultures. Analysis of the methylome reveals that the organoids closely resemble normal first trimester placentas. This organoid model will be transformative for studying human placental development and for investigating trophoblast interactions with the local and systemic maternal environment.Centre for Trophoblast Reearch Royal Society Dorothy Hodgkin Fellowship Marie Curie Intra-European Fellowshi

Sox2 Is Essential for Formation of Trophectoderm in the Preimplantation Embryo

In preimplantation mammalian development the transcription factor Sox2 (SRY-related HMG-box gene 2) forms a complex with Oct4 and functions in maintenance of self-renewal of the pluripotent inner cell mass (ICM). Previously it was shown that Sox2-/- embryos die soon after implantation. However, maternal Sox2 transcripts may mask an earlier phenotype. We investigated whether Sox2 is involved in controlling cell fate decisions at an earlier stage.We addressed the question of an earlier role for Sox2 using RNAi, which removes both maternal and embryonic Sox2 mRNA present during the preimplantation period. By depleting both maternal and embryonic Sox2 mRNA at the 2-cell stage and monitoring embryo development in vitro we show that, in the absence of Sox2, embryos arrest at the morula stage and fail to form trophectoderm (TE) or cavitate. Following knock-down of Sox2 via three different short interfering RNA (siRNA) constructs in 2-cell stage mouse embryos, we have shown that the majority of embryos (76%) arrest at the morula stage or slightly earlier and only 18.7-21% form blastocysts compared to 76.2-83% in control groups. In Sox2 siRNA-treated embryos expression of pluripotency associated markers Oct4 and Nanog remained unaffected, whereas TE associated markers Tead4, Yap, Cdx2, Eomes, Fgfr2, as well as Fgf4, were downregulated in the absence of Sox2. Apoptosis was also increased in Sox2 knock-down embryos. Rescue experiments using cell-permeant Sox2 protein resulted in increased blastocyst formation from 18.7% to 62.6% and restoration of Sox2, Oct4, Cdx2 and Yap protein levels in the rescued Sox2-siRNA blastocysts.We conclude that the first essential function of Sox2 in the preimplantation mouse embryo is to facilitate establishment of the trophectoderm lineage. Our findings provide a novel insight into the first differentiation event within the preimplantation embryo, namely the segregation of the ICM and TE lineages

Combined diffusion tensor imaging and functional MRI for visualizing the motor system in patients with cerebral tumors

Einleitung Raumforderungen der Zentralregion stellen für die neurochirurgische Behandlung eine besondere Herausforderung dar. Magnetresonanz- tomographische (MRT) Bildgebungsmodalitäten haben das Potential, als nicht-invasive Hirnkartierungsmethoden zur präoperative Planung und operativen Risikoverminderung beizutragen. Dabei bietet die funktionelle Magnetresonanztomographie (fMRT) wichtige Informationen über die kortikale Funktion, während die Diffusions-Tensor-Magnetresonanztomographie (DTI) die subkortikale Faserbahnarchitektur darstellt. Eine systematische Kombination dieser beiden kernspintomographischen Modalitäten für die neurochirurgische Operationsplanung bei Patienten mit Raumforderungen der Zentralregion steht aus. Methodik Durchführung und Visualisierung von strukturellen, funktionellen und diffusionsgewichteten MRT-Aufnahmen bei Probanden und neurochirurgischen Patienten mit kortikalen und subkortikalen Raumforderungen der Zentralregion. Akquirierung von fMRT-Daten mit motorischen Paradigmen zur Darstellung des primären, motorischen Kortex und von DTI-Daten zur Traktographie des motorischen Faserbahnsystems (Pyramidenbahn). Durchführung einer klassischen Traktographie mittels, vom Untersucher vordefinierter, Landmarken (regions of interest [ROI]). Etablierung einer fMRT-basierten Traktographie der Pyramidenbahn. Ergebnisse Erfolgreiche und bei allen Probanden (n=13) reproduzierbare Visualisierung des Motorkortex und der Pyramidenbahn durch eine fMRI-basierte DTI-Traktographie ohne die Notwendigkeit für Untersucher-definierter Landmarken (ROI). Diese neue Methode ermöglicht es im Gegensatz zur ROI-basierte DTI-Traktographie, funktionell zusammengehörige Faserbahnen innerhalb der Pyramidenbahn selektiv zu visualisieren. Hierdurch kann die somatotope Architektur der kortikalen Repräsentationsareale entlang der Faserbahnen bis zur Ebene der Capsula interna visualisiert werden. Die Methodik wird erfolgreich in das klinisches Umfeld neurochirurgischer Patienten implementiert (n=22) und liefert plausible Informationen in Bezug auf den pyramidalen Faserbahnverlauf in Relation zur Tumorlokalisation (n=18). Bei ödematös verändertem Gehirngewebe kommt es zum Abbruch des visualisierbaren Faserbahnverlaufes (n=4). Schlussfolgerung FMRT- und DTI-Daten können für eine fMRT-basierte DTI-Traktographie der Pyramidenbahn kombiniert werden, um die individuelle, somatotope Faserbahnarchitektur zu visualisieren. Diese Methode kann auch bei neurochirurgischen Patienten mit Raumforderungen der Zentralregion eingesetzt werden und ist hier nur durch ein peri-tumorales Ödem limitiert. Dieses Verfahren stellt eine Erweiterung der neurochirurgischen Operationsplanung in der funktionserhaltenden Neurochirurgie von kortikalen und subkortikalen Raumforderungen der Zentralregion dar.Cortico-subcortical information regarding the vicinity of cerebral tumors is essential for function preserving surgery. The combination of functional MRI (fMRI) and diffusion tensor imaging (DTI) promises to provide the information necessary to visualize the intracranial architecture of neurofunctional systems including their cortical representations and connecting fiber bundles. This study intended to implement a method to visualize functional connectivity of the motor system in the human brain by fMRI-based DTI-fiber tracking. Therefore healthy right-handed male subjects (n=13) and brain tumor patients (n=22) received a combined DTI and fMRI measurement. In all subjects, the data provided useful information concerning the intracranial architecture of the motor system. Only fiber tracking in brain tumor edema showed poor results (n=4). The presented method was able to differentiate subgroups of fiber bundles and to visualize the somatotopic architecture of the pyramidal tract. This technical feature will be particularly important for image-guided neurosurgery as well as for visualization of the individual architecture of the human brain