Crossover-effects in technical skills between laparoscopy and robot-assisted surgery.

INTRODUCTION: Robot-assisted surgery is often performed by experienced laparoscopic surgeons. However, this technique requires a different set of technical skills and surgeons are expected to alternate between these approaches. The aim of this study is to investigate the crossover effects when switching between laparoscopic and robot-assisted surgery. METHODS: An international multicentre crossover study was conducted. Trainees with distinctly different levels of experience were divided into three groups (novice, intermediate, expert). Each trainee performed six trials of a standardized suturing task using a laparoscopic box trainer and six trials using the da Vinci surgical robot. Both systems were equipped with the ForceSense system, measuring five force-based parameters for objective assessment of tissue handling skills. Statistical comparison was done between the sixth and seventh trial to identify transition effects. Unexpected changes in parameter outcomes after the seventh trial were further investigated. RESULTS: A total of 720 trials, performed by 60 participants, were analysed. The expert group increased their tissue handling forces with 46% (maximum impulse 11.5 N/s to 16.8 N/s, p = 0.05), when switching from robot-assisted surgery to laparoscopy. When switching from laparoscopy to robot-assisted surgery, intermediates and experts significantly decreased in motion efficiency (time (sec), resp. 68 vs. 100, p = 0.05, and 44 vs. 84, p = 0.05). Further investigation between the seventh and ninth trial showed that the intermediate group increased their force exertion with 78% (5.1 N vs. 9.1 N, p = 0.04), when switching to robot-assisted surgery. CONCLUSION: The crossover effects in technical skills between laparoscopic and robot-assisted surgery are highly depended on the prior experience with laparoscopic surgery. Where experts can alternate between approaches without impairment of technical skills, novices and intermediates should be aware of decay in efficiency of movement and tissue handling skills that could impact patient safety. Therefore, additional simulation training is advised to prevent from undesired events.

Video-based learning of coping strategies for common errors improves laparoscopy training-a randomized study.

AIMS: The aim of this study was to investigate whether shifting the focus to solution orientation and developing coping strategies for common errors could increase the efficiency of laparoscopic training and influence learning motivation. The concept of coping has been particularly defined by the psychologist Richard Lazarus [Lazarus and Folkman in Stress, appraisal, and coping, Springer publishing company, New York, 1984]. Based on this model, we examined the use of observational learning with a coping model for its effectiveness as a basic teaching model in laparoscopic training. METHODS: 55 laparoscopically naive medical students learned a standardized laparoscopic knot tying technique with video-based instructions. The control group was only offered a mastery video that showed the ideal technique and was free from mistakes. The intervention group was instructed on active error analysis and watched freely selectable videos of common errors including solution strategies (coping model) in addition to the mastery videos. RESULTS: There was no statistically significant difference between the intervention and control groups for number of knot tying attempts until proficiency was reached (18.8 ± 5.5 vs. 21.3 ± 6.5, p = 0.142). However, there was a significantly higher fraction of knots achieving technical proficiency in the intervention group after first use of the coping model (0.7 ± 0.1 vs. 0.6 ± 0.2, p = 0.026). Additionally, the proportion of blinded attempts that met the criteria for technical proficiency was significantly higher for the intervention group at 60.9% vs. 38.0% in control group (p = 0.021). The motivational subscore "interest" of the validated score on current motivation (QCM) was significantly higher for the intervention group (p = 0.032), as well as subjective learning benefit (p = 0.002) and error awareness (p < 0.001). CONCLUSION: Using video-based learning of coping strategies for common errors improves learning motivation and understanding of the technique with a significant difference in its qualitative implementation in laparoscopy training. The ability to think in a solution-oriented, independent way is necessary in surgery in order to recognize and adequately deal with technical difficulties and complications.

Force-based assessment of tissue handling skills in simulation training for robot-assisted surgery.

INTRODUCTION: Although robotic-assisted surgery is increasingly performed, objective assessment of technical skills is lacking. The aim of this study is to provide validity evidence for objective assessment of technical skills for robotic-assisted surgery. METHODS: An international multicenter study was conducted with participants from the academic hospitals Heidelberg University Hospital (Germany, Heidelberg) and the Amsterdam University Medical Centers (The Netherlands, Amsterdam). Trainees with distinctly different levels of robotic surgery experience were divided into three groups (novice, intermediate, expert) and enrolled in a training curriculum. Each trainee performed six trials of a standardized suturing task using the da Vinci Surgical System. Using the ForceSense system, five force-based parameters were analyzed, for objective assessment of tissue handling skills. Mann-Whitney U test and linear regression were used to analyze performance differences and the Wilcoxon signed-rank test to analyze skills progression. RESULTS: A total of 360 trials, performed by 60 participants, were analyzed. Significant differences between the novices, intermediates and experts were observed regarding the total completion time (41 s vs 29 s vs 22 s p = 0.003), mean non zero force (29 N vs 33 N vs 19 N p = 0.032), maximum impulse (40 Ns vs 31 Ns vs 20 Ns p = 0.001) and force volume (38 N3 vs 32 N3 vs 22 N3 p = 0.018). Furthermore, the experts showed better results in mean non-zero force (22 N vs 13 N p = 0.015), maximum impulse (24 Ns vs 17 Ns p = 0.043) and force volume (25 N3 vs 16 N3 p = 0.025) compared to the intermediates (p ≤ 0.05). Lastly, learning curve improvement was observed for the total task completion time, mean non-zero force, maximum impulse and force volume (p ≤ 0.05). CONCLUSION: Construct validity for force-based assessment of tissue handling skills in robot-assisted surgery is established. It is advised to incorporate objective assessment and feedback in robot-assisted surgery training programs to determine technical proficiency and, potentially, to prevent tissue trauma.

[Traumatology-an interdisciplinary task: exclusively for educational purposes?] / Traumatologie ­ eine interdisziplinäre Aufgabe: nur in der Lehre?

BACKGROUND: Traumatology of the head and neck region is not only a part of otorhinolaryngology, but also has a large overlap with neighboring disciplines of the head and neck region. In Freiburg, an interdisciplinary lecture on "ENT emergencies" was implemented in the 21/22 winter semester. The aim was to provide an even more realistic view on interdisciplinary patient care and to make evident the areas of intersection of four of the major head disciplines (otorhinolaryngology, neurosurgery, ophthalmology, and maxillofacial surgery). MATERIALS AND METHODS: A new, special lecture in otorhinolaryngology was implemented as part of the regular online lecture series accompanying the semester. With reference to the clinical care of ENT emergencies, possible overlaps with neighboring disciplines were identified and explained by the discipline representatives or discussed in front of and with the auditorium. At the end of the semester, all participating students (n = 173) were invited to evaluate the seminar using the survey tool "EvaSys" (EvaSys GmbH, Lüneburg, Germany). In total, 78 students participated in the evaluation process. RESULTS: The new lecture concept was very well accepted and immediately ranked top among the interdisciplinary lecture titles within the ENT lecture series. The clear communication of the term "interdisciplinarity" in the sense of a complementary clinical cooperation was also very successful and was appreciated accordingly by students during the evaluation process. CONCLUSION: Pragmatic presentation of ideal clinical patient care using an interdisciplinary approach is possible within the regular ENT lecture series. This realistic portrayal, beyond any technical and/or professional differences, is of great interest to students and is considered clinically relevant. Thus, interdisciplinary lectures provide a valuable tool to teach the fundamental values of clinical interdisciplinary management for the best possible patient care.

Telestration with augmented reality for visual presentation of intraoperative target structures in minimally invasive surgery: a randomized controlled study.

AIMS: In minimally invasive surgery (MIS), intraoperative guidance has been limited to verbal communication without direct visual guidance. Communication issues and mistaken instructions in training procedures can hinder correct identification of anatomical structures on the MIS screen. The iSurgeon system was developed to provide visual guidance in the operating room by telestration with augmented reality (AR). METHODS: Laparoscopic novices (n = 60) were randomized in two groups in a cross-over design: group 1 trained only with verbal guidance first and then with additional telestration with AR on the operative screen and vice versa for group 2. Training consisted of laparoscopic basic training and subsequently a specifically designed training course, including a porcine laparoscopic cholecystectomy (LC). Outcome included time needed for training, performance with Global Operative Assessment of Laparoscopic Skills (GOALS), and Objective Structured Assessment of Technical Skills (OSATS) score for LC, complications, and subjective workload (NASA-TLX questionnaire). RESULTS: Telestration with AR led to significantly faster total training time (1163 ± 275 vs. 1658 ± 375 s, p < 0.001) and reduced error rates. LC on a porcine liver was performed significantly better (GOALS 21 ± 5 vs. 18 ± 4, p < 0.007 and OSATS 67 ± 11 vs. 61 ± 8, p < 0.015) and with less complications (13.3% vs. 40%, p < 0.020) with AR. Subjective workload and stress were significantly reduced during training with AR (33.6 ± 12.0 vs. 30.6 ± 12.9, p < 0.022). CONCLUSION: Telestration with AR improves training success and safety in MIS. The next step will be the clinical application of telestration with AR and the development of a mobile version for remote guidance.

Randomized controlled trial of robotic-assisted versus conventional laparoscopic fundoplication: 12 years follow-up.

AIMS: Numerous reports have addressed the feasibility and safety of robotic-assisted (RALF) and conventional laparoscopic fundoplication (CLF). Long-term follow-up after direct comparison of these two minimally invasive approaches is scarce. The aim of the present study was to assess long-term disease-specific symptoms and quality of life (QOL) in patients with gastroesophageal reflux disease (GERD) treated with RALF or CLF after 12 years in the randomized ROLAF trial. METHODS: In the ROLAF trial 40 patients with GERD were randomized to RALF (n = 20) or CLF (n = 20) between August 2004 and December 2005. At 12 years after surgery, all patients were invited to complete the standardized Gastrointestinal Symptom Rating Scale (GSRS) and the Quality of Life in Reflux and Dyspepsia questionnaire (QOLRAD). Failure of treatment was assessed according to Lundell score. RESULTS: The GSRS score was similar for RALF (n = 15) and CLF (n = 15) at 12 years´ follow-up (2.1 ± 0.7 vs. 2.2 ± 1.3, p = 0.740). There was no difference in QOLRAD score (RALF 6.4 ± 1.2; CLF 6.4 ± 1.5, p = 0.656) and the QOLRAD score sub items. Long-term failure of treatment according to the definition by Lundell was not different between RALF and CLF [46% (6/13) vs. 33% (4/12), p = 0.806]. CONCLUSION: In accordance with previous short-term outcome studies, the long-term results 12 years after surgery showed no difference between RALF and CLF regarding postoperative symptoms, QOL and failure of treatment. Relief of symptoms and patient satisfaction were high after both procedures on the long-term. REGISTRATION NUMBER: DRKS00014690 ( https://www.drks.de ).

Robotic-assisted cholecystectomy is superior to laparoscopic cholecystectomy in the initial training for surgical novices in an ex vivo porcine model: a randomized crossover study.

BACKGROUND: Robotic-assisted surgery (RAS) potentially reduces workload and shortens the surgical learning curve compared to conventional laparoscopy (CL). The present study aimed to compare robotic-assisted cholecystectomy (RAC) to laparoscopic cholecystectomy (LC) in the initial learning phase for novices. METHODS: In a randomized crossover study, medical students (n = 40) in their clinical years performed both LC and RAC on a cadaveric porcine model. After standardized instructions and basic skill training, group 1 started with RAC and then performed LC, while group 2 started with LC and then performed RAC. The primary endpoint was surgical performance measured with Objective Structured Assessment of Technical Skills (OSATS) score, secondary endpoints included operating time, complications (liver damage, gallbladder perforations, vessel damage), force applied to tissue, and subjective workload assessment. RESULTS: Surgical performance was better for RAC than for LC for total OSATS (RAC = 77.4 ± 7.9 vs. LC = 73.8 ± 9.4; p = 0.025, global OSATS (RAC = 27.2 ± 1.0 vs. LC = 26.5 ± 1.6; p = 0.012, and task specific OSATS score (RAC = 50.5 ± 7.5 vs. LC = 47.1 ± 8.5; p = 0.037). There were less complications with RAC than with LC (10 (25.6%) vs. 26 (65.0%), p = 0.006) but no difference in operating times (RAC = 77.0 ± 15.3 vs. LC = 75.5 ± 15.3 min; p = 0.517). Force applied to tissue was similar. Students found RAC less physical demanding and less frustrating than LC. CONCLUSIONS: Novices performed their first cholecystectomies with better performance and less complications with RAS than with CL, while operating time showed no differences. Students perceived less subjective workload for RAS than for CL. Unlike our expectations, the lack of haptic feedback on the robotic system did not lead to higher force application during RAC than LC and did not increase tissue damage. These results show potential advantages for RAS over CL for surgical novices while performing their first RAC and LC using an ex vivo cadaveric porcine model. REGISTRATION NUMBER: researchregistry6029.

["Online from tomorrow on please": comparison of digital framework conditions of curricular teaching at national university ENT clinics in times of COVID-19 : Digital teaching at national university ENT clinics]. / "Ab morgen bitte online": Vergleich digitaler Rahmenbedingungen der curricularen Lehre an nationalen Universitäts-HNO-Kliniken in Zeiten von COVID-19 : Digitale Lehre an nationalen Universitäts-HNO-Kliniken.

BACKGROUND: The corona crisis not only affects professional activities but also teaching and learning at universities. Buzzwords, such as e­learning and digitalization suggest the possibility of innovative teaching approaches that are readily available to solve the problems of teaching in the current COVID-19 pandemic. The current conversion to digital teaching is not primarily driven by didactic rationale or institutional strategy but by external circumstances. OBJECTIVE: The aim of the study was to determine the teaching situation at national university ENT clinics and academic teaching hospitals at the start of the virtual corona summer semester in 2020. MATERIAL AND METHODS: A specifically self-designed questionnaire regarding the local situation and conditions as well as nationwide scenarios was sent to all 39 national university ENT clinics and 20 ENT departments at academic teaching hospitals. RESULTS: A total of 31 university hospitals and 10 academic teaching hospitals took part in the survey. There were obvious discrepancies between available resources and effectively available digital teaching and learning contents. Further criticism was expressed regarding the communication with the medical faculty, the digital infrastructure and particularly the frequent lack of collaboration with central support facilities, such as media, didactics and datacenters. CONCLUSION: There are positive examples of successful transformation of classroom teaching to an exclusively virtual summer semester 2020 within the university ENT clinics; however, critical ratings of assistant professors and medical directors regarding the current teaching situation predominated. A time-critical strategic advancement is urgently needed.

Observation of a neutron spin resonance in the bilayered superconductor CsCa2Fe4As4F2.

We report inelastic neutron scattering (INS) investigations on the bilayer Fe-based superconductor CsCa2Fe4As4F2 above and below its superconducting transition temperature T c ≈ 28.9 K to investigate the presence of a neutron spin resonance. This compound crystallises in a body-centred tetragonal lattice containing asymmetric double layers of Fe2As2 separated by insulating CaF2 layers and is known to be highly anisotropic. Our INS study clearly reveals the presence of a neutron spin resonance that exhibits higher intensity at lower momentum transfer (Q) at 5 K compared to 54 K, at an energy of 15 meV. The energy E R of the observed spin resonance is broadly consistent with the relationship E R = 4.9k B T c, but is slightly enhanced compared to the values observed in other Fe-based superconductors. We discuss the nature of the electron pairing symmetry by comparing the value of E R with that deduced from the total superconducting gap value integrated over the Fermi surface.

Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small-cell lung cancer.

BACKGROUND: The tumor immune microenvironment (TIME) of lung cancer brain metastasis is largely unexplored. We carried out immune profiling and sequencing analysis of paired resected primary tumors and brain metastases of non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS: TIME profiling of archival formalin-fixed and paraffin-embedded specimens of paired primary tumors and brain metastases from 39 patients with surgically resected NSCLCs was carried out using a 770 immune gene expression panel and by T-cell receptor beta repertoire (TCRß) sequencing. Immunohistochemistry was carried out for validation. Targeted sequencing was carried out to catalog hot spot mutations in cancer genes. RESULTS: Somatic hot spot mutations were mostly shared between both tumor sites (28/39 patients; 71%). We identified 161 differentially expressed genes, indicating inhibition of dendritic cell maturation, Th1, and leukocyte extravasation signaling pathways, in brain metastases compared with primary tumors (P < 0.01). The proinflammatory cell adhesion molecule vascular cell adhesion protein 1 was significantly suppressed in brain metastases compared with primary tumors. Brain metastases exhibited lower T cell and elevated macrophage infiltration compared with primary tumors (P < 0.001). T-cell clones were expanded in 64% of brain metastases compared with their corresponding primary tumors. Furthermore, while TCR repertoires were largely shared between paired brain metastases and primary tumors, T-cell densities were sparse in the metastases. CONCLUSION: We present findings that suggest that the TIME in brain metastases from NSCLC is immunosuppressed and comprises immune phenotypes (e.g. immunosuppressive tumor-associated macrophages) that may help guide immunotherapeutic strategies for NSCLC brain metastases.

Merlin modulates process outgrowth and synaptogenesis in the cerebellum.

Neurofibromatosis type 2 (NF2) patients are prone to develop glial-derived tumors in the peripheral and central nervous system (CNS). The Nf2 gene product -Merlin is not only expressed in glia, but also in neurons of the CNS, where its function still remains elusive. Here, we show that cerebellar Purkinje cells (PCs) of isoform-specific Merlin-deficient mice were innervated by smaller vGluT2-positive clusters at presynaptic terminals than those of wild-type mice. This was paralleled by a reduction in frequency and amplitude of miniature excitatory postsynaptic currents (mEPSC). On the contrary, in conditional transgenic mice in which Merlin expression was specifically ablated in PCs (L7Cre;Nf2fl/fl), we found enlarged vGluT2-positive clusters in their presynaptic buttons together with increased amplitudes of miniature postsynaptic currents. The presynaptic terminals of these PCs innervating neurons of the deep cerebellar nuclei were also enlarged. When exploring mice with Merlin-deficient granule cells (GCs) (Math1Cre;Nf2fl/fl), we found cerebellar extracts to contain higher amounts of vGluT1 present in parallel fiber terminals. In parallel, mEPSC frequency was increased in Math1Cre;Nf2fl/fl mice. On the contrary, VGluT2 clusters in cerebellar glomeruli composed of NF2-deficient presynaptic Mossy fiber terminals and NF2-deficient postsynaptic GC were reduced in size as shown for isoform-specific knockout mice. These changes in Math1Cre;Nf2fl/fl-deficient mice were paralleled by an increased activation of Rac1-Cofilin signaling which is known to impact on cytoskeletal reorganization and synapse formation. Consistent with the observed synaptic alterations in these transgenic mice, we observed altered ultrasonic vocalization, which is known to rely on proper cerebellar function. No gross morphological changes or motor coordination deficits were observed in any of these transgenic mice. We therefore conclude that Merlin does not regulate overall cerebellar development, but impacts on pre- and post-synaptic terminal organization.

An update on the Golgi staining technique improving cerebellar cell type specificity.

The detailed morphological characterization of single cells was a major breakthrough in neuroscience during the turn of the twentieth century, enabling Ramon y Cajal to postulate the neuron doctrine. Even after 150 years, single cell analysis is an intriguing goal, newly motivated by the finding that autism might be caused by intricate and discreet changes in cerebellar morphology. Besides new single labelling technologies, the Golgi staining technique is still in use due to its whole cell labelling characteristics, its superior contrast performance over other methods and its apparent randomness of staining cells within a whole tissue block. However, the specificity and whole cell labelling of Golgi staining are also disputed controversially, and the method still has a poor reputation for being time consuming and needing high expenditures. We demonstrate here, how a classical Golgi technique can be adapted for staining different cerebellar cell types using a time-saving and efficient protocol, enabling the identification of the detailed morphological characteristics of single cells.

[Infantile hemangioma of the eyelid]. / Kindliches Hämangiom im Lidbereich.

Hemangiomas are one of the most common vascular tumors in infancy. In most cases no therapy is necessary and spontaneous regression is observed; however, if they arise in the periocular region, immediate action is required as rapid growth frequently leads to obstruction of the visual field with the risk of developing amblyopia and orbital suppression up to permanent disfigurement and stigmatization of those affected. Novel pharmaceutical treatment options led to a significant paradigm shift in the treatment of pediatric hemangiomas.

Glioblastoma stem cells exploit the αvß8 integrin-TGFß1 signaling axis to drive tumor initiation and progression.

Glioblastoma (GBM) is a primary brain cancer that contains populations of stem-like cancer cells (GSCs) that home to specialized perivascular niches. GSC interactions with their niche influence self-renewal, differentiation and drug resistance, although the pathways underlying these events remain largely unknown. Here, we report that the integrin αvß8 and its latent transforming growth factor ß1 (TGFß1) protein ligand have central roles in promoting niche co-option and GBM initiation. αvß8 integrin is highly expressed in GSCs and is essential for self-renewal and lineage commitment in vitro. Fractionation of ß8high cells from freshly resected human GBM samples also reveals a requirement for this integrin in tumorigenesis in vivo. Whole-transcriptome sequencing reveals that αvß8 integrin regulates tumor development, in part, by driving TGFß1-induced DNA replication and mitotic checkpoint progression. Collectively, these data identify the αvß8 integrin-TGFß1 signaling axis as crucial for exploitation of the perivascular niche and identify potential therapeutic targets for inhibiting tumor growth and progression in patients with GBM.

TMEM43/LUMA is a key signaling component mediating EGFR-induced NF-κB activation and tumor progression.

Epidermal growth factor receptor (EGFR) family members play pivotal roles in cell proliferation, differentiation and survival. Overexpression and mutations of EGFRs, or aberrant EGFR signaling are commonly associated with the development of various cancers, where constitutive NF-κB activation is often found to promote the expression of various proteins involved in the proliferation, survival, migration and epithelial-to-mesenchymal transition of cancer cells. However, the mechanism of EGFR-induced NF-κB activation is not fully defined. Here, we used a Bimolecular Fluorescence Complementation-based functional genomics method to perform a high throughput screening and identified TMEM43/LUMA as a critical component in EGFR signaling network, mediating EGFR-induced NF-κB activation. Our data show that EGFR recruits TMEM43 following EGF stimulation. TMEM43 interacts with the scaffold protein CARMA3 and its associating complex to induce downstream NF-κB activation, and plays a critical role in controlling cell survival. TMEM43 deficiency significantly affects colony formation, survival of anoikis-induced cell death, migration and invasion of cancer cells in vitro, as well as tumor progression in vivo. Importantly, higher expression of TMEM43 closely correlates with brain tumor malignancy, and suppression of TMEM43 expression in brain tumor cells inhibited their growth both in vitro and in vivo. Altogether, our studies reveal a crucial link of EGF receptor to NF-κB activation and tumor progression.

Unravelling the low-temperature metastable state in perovskite solar cells by noise spectroscopy.

The hybrid perovskite methylammonium lead iodide CH3NH3PbI3 recently revealed its potential for the manufacturing of low-cost and efficient photovoltaic cells. However, many questions remain unanswered regarding the physics of the charge carrier conduction. In this respect, it is known that two structural phase transitions, occurring at temperatures near 160 and 310 K, could profoundly change the electronic properties of the photovoltaic material, but, up to now, a clear experimental evidence has not been reported. In order to shed light on this topic, the low-temperature phase transition of perovskite solar cells has been thoroughly investigated by using electric noise spectroscopy. Here it is shown that the dynamics of fluctuations detect the existence of a metastable state in a crossover region between the room-temperature tetragonal and the low-temperature orthorhombic phases of the perovskite compound. Besides the presence of a noise peak at this transition, a saturation of the fluctuation amplitudes is observed induced by the external DC current or, equivalently, by light exposure. This noise saturation effect is independent on temperature, and may represent an important aspect to consider for a detailed explanation of the mechanisms of operation in perovskite solar cells.

Pin1 promotes prostate cancer cell proliferation and migration through activation of Wnt/b-catenin signaling

Background: Recent evidence suggests that the peptidylprolyl isomerase Pin1 is an oncoprotein that acts as a novel therapeutic target in a variety of tumors. In this study, we investigated the clinical significance of Pin1 and its function in prostate cancer (PCa) tumor progression. Methods: Immunohistochemical and quantitative RT-PCR analyses were performed to detect the expression of Pin1 in 86 PCa tissue samples. The functional role of Pin1 was evaluated by small interfering RNA-mediated depletion in PCa cells followed by analyses of cell proliferation and migration. Furthermore, the association between expression of Pin1 and levels of b-catenin and cyclin D1 was also evaluated. Results: Our results showed that the high expression of Pin1 staining was 66 of 86 (76.74 %) PCa samples, and in 25 of 86 (29.07 %) BPH tissues, the difference was statistically significant (P 0.001). Pin1 was significantly elevated in all PCa cell lines when compared to the normal RWPE-1 cells. We observed that proliferation and migration of LNCaP cells were inhibited by Pin1 knockdown. The levels of b-catenin and cyclin D1 in clinical PCa specimens were positively associated with Pin1 expression. Conclusions: Our results suggest that Pin1 plays an important role in tumorigenesis of PCa, suggesting that targeting Pin1 pathway could represent a potential modality for treating PCa. Pin1 have not yet been identified in PCa. Therefore, the aim of this study is to determine the expression of Pin1 in clinical Pca tissues and cell lines, and analyzes the biological characteristics of Pin1 to explore the mechanism of PCa in vitro (AU)

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PD-1 expression conditions T cell avidity within an antigen-specific repertoire.

Despite its negative regulatory role on tumor-specific T cells, Programmed cell death 1 (PD-1) is also a marker of activated tumor-infiltrating T cells. In cancer, PD-1 blockade partially reverses T cell dysfunction allowing the amplification of tumor reactive T cells. Here, we investigated the role of PD-1 signaling on effector/memory human T cells specific for shared melanoma antigens, derived from blood. We documented for the first time the existence of melanoma-specific T cell clones unable to express PD-1. This stable feature was due to the persistent methylation of the PDCD1 promoter. These PD-1neg clones were of lower avidity than their PD-1pos counterparts, suggesting that high-affinity-specific T cell clones unable to express PD-1 are not or rarely present in peripheral blood, as they are probably eliminated by negative selection, due to their high reactivity. We also documented the existence of such PD-1neg T cell clones in melanoma tumor-infiltrating lymphocytes (TIL), which also exhibited a lower functional avidity than PD-1pos TIL clones. This clearly shows that PD-1 expression identifies antigen-specific T cell clonotypes of high functional avidity. Finally, we demonstrated that PD-1 blockade during the in vitro selection process of Melan-A-specific T cells favored the amplification of higher avidity T cell clonotypes. This preferential amplification of high-avidity memory T cells upon PD-1 blockade resonates with the expansion of reactive T cells, including neo-antigen-specific T cells observed in anti-PD-1-treated patients. This feature should also be a useful biomarker of clinical efficiency, while providing new insights for adoptive transfer treatments.

Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German SAL-MPN-registry.

BACKGROUND: Patients with Ph-negative myeloproliferative neoplasms (MPN), such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are at increased risk for thrombosis/thromboembolism and major bleeding. Due to the morbidity and mortality of these events, antiplatelet and/or anticoagulant agents are commonly employed as primary and/or secondary prophylaxis. On the other hand, disease-related bleeding complications (i.e., from esophageal varices) are common in patients with MPN. This analysis was performed to define the frequency of such events, identify risk factors, and assess antiplatelet/anticoagulant therapy in a cohort of patients with MPN. METHODS: The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008). For statistical analysis, descriptive methods and tests for significant differences as well as contingency tables were used to identify the odds of potential risk factors for vascular events. RESULTS: MPN subgroups significantly differed in sex distribution, age at diagnosis, blood counts, LDH levels, JAK2V617F positivity, and spleen size (length). While most thromboembolic events occurred around the time of MPN diagnosis, one third of these events occurred after that date. Splanchnic vein thrombosis was most frequent in post-PV-MF and MPN-U patients. The chance of developing a thromboembolic event was significantly elevated if patients suffered from post-PV-MF (OR 3.43; 95% CI = 1.39-8.48) and splenomegaly (OR 1.76; 95% CI = 1.15-2.71). Significant odds for major bleeding were previous thromboembolic events (OR = 2.71; 95% CI = 1.36-5.40), splenomegaly (OR = 2.22; 95% CI 1.01-4.89), and the administration of heparin (OR = 5.64; 95% CI = 1.84-17.34). Major bleeding episodes were significantly less frequent in ET patients compared to other MPN subgroups. CONCLUSIONS: Together, this report on an unselected "real-world" cohort of German MPN patients reveals important data on the prevalence, diagnosis, and treatment of thromboembolic and major bleeding complications of MPN.