A structured curriculum supporting biomedical trainees' transition into independent academic positions and early career success.

The United States government makes a substantial investment in biomedical training programs each year. However, for most trainees, these opportunities do not translate into career progression in academic research pathways. Only about one-fifth of postdoctoral fellows eventually secure a tenure-track faculty position, and even among these candidates, attrition is high. Although a number of factors govern career choices and career longevity, the transition from trainee to faculty is a challenging process and requires knowledge and skills that are not necessarily developed during a traditional university experience. Many postdoctoral fellows receive adequate training in research skills and scientific communication, but new faculty report not being sufficiently prepared for the job search process and for starting their labs. To address this critical training gap, the ITERT core (Interdisciplinary Translational Education and Research Training) and the Office of Postdoctoral Fellows at the University of Texas MD Anderson Cancer Center implemented a structured course for both postdoctoral fellows and senior PhD students to provide formalized training for successfully navigating academic positions in biomedical research. Here we report on the pilot Navigating Academic Careers course conducted in 2021-2022 for 30 PhD students and postdocs. The nine-module course was conducted over 13 weeks in 25.5 h instructional sessions. The key educational objectives included 1) navigating the job application and the interview/negotiation process, 2) hiring, leading, and mentoring lab personnel and program support staff, 3) project administration and financial stewardship, 4) managing time and work-life balance and 5) developing collaborations, branding, personalized niche, and networking. Survey-based analysis at the time of the course was used to capture the participants' assessment of the course content, organization, and delivery, with a follow-up survey conducted approximately 2 years post-course (2024) to evaluate longer-term impacts of the training. Initial in-course assessment revealed that 89.9% of respondents found the scope and instructional content appropriate, and 91.1% found the course relevant and applicable to their career needs. Longer-term post-course evaluation indicated that 80% of respondents applied the learnings of the course, that 80% reported feeling more confident in navigating an academic job search, and that 66.6% continued to report agreement with the course preparing them for their current role/ongoing job search, with 46.7% already securing jobs in academic research, including as independent faculty. The outcomes of this pilot course suggest that integrating this into the broader postdoctoral training curriculum can enhance both the transition and early-career success of talented scientists-in-training into working professionals in biomedical careers, as faculty and science-trained staff.

An ex-vivo and in-vitro dynamic simulator for surgical and transcatheter mitral valve interventions.

PURPOSE: Minimally invasive mitral valve surgery (MIMVS) and transcatheter edge-to-edge repair (TEER) are complex procedures used to treat mitral valve (MV) pathologies, but with limited training opportunities available. To enable training, a realistic hemodynamic environment is needed. In this work we aimed to develop and validate a simulator that enables investigation of MV pathologies and their repair by MIMVS and TEER in a hemodynamic setting. METHODS: Different MVs were installed in the simulator, and pressure, flow, and transesophageal echocardiographic measurements were obtained. To confirm the simulator's physiological range, we first installed a biological prosthetic, a mechanical prosthetic, and a competent excised porcine MV. Subsequently, we inserted two porcine MVs-one with induced chordae tendineae rupture and the other with a dilated annulus, along with a patient-specific silicone valve extracted from echocardiography with bi-leaflet prolapse. Finally, TEER and MIMVS procedures were conducted by experts to repair the MVs. RESULTS: Systolic pressures, cardiac outputs, and regurgitations volumes (RVol) with competent MVs were 119 ± 1 mmHg, 4.78 ± 0.16 l min-1, and 5 ± 3 ml respectively, and thus within the physiological range. In contrast, the pathological MVs displayed increased RVols. MIMVS and TEER resulted in a decrease in RVols and mitigated the severity of mitral regurgitation. CONCLUSION: Ex-vivo modelling of MV pathologies and repair procedures using the described simulator realistically replicated physiological in-vivo conditions. Furthermore, we showed the feasibility of performing MIMVS and TEER at the simulator, also at patient-specific level, thus providing new clinical perspectives in terms of training modalities and personalized planning.

Surgical training of minimally invasive mitral valve repair on a patient-specific simulator improves surgical skills.

OBJECTIVES: Minimally invasive mitral valve repair (MVR) is considered one of the most challenging operations in cardiac surgery and requires much practice and experience. Simulation-based surgical training might be a method to support the learning process and help to flatten the steep learning curve of novices. The purpose of this study was to show the possible effects on learning of surgical training using a high-fidelity simulator with patient-specific mitral valve replicas. METHODS: Twenty-five participants were recruited to perform MVR on anatomically realistic valve models during different training sessions. After every session their performance was evaluated by a surgical expert regarding accuracy and duration for each step. A second blinded rater similarly assessed the performance after the study. Through repeated documentation of those parameters, their progress in learning was analysed, and gains in proficiency were evaluated. RESULTS: Participants showed significant performance enhancements in terms of both accuracy and time. Their surgical skills showed sizeable improvements after only 1 session. For example, the time to implant neo-chordae decreased by 24.64% (354 s-264 s, P < 0.001) and the time for annuloplasty by 4.01% (54 s-50 s, P = 0.165), whereas the number of irregular stitches for annuloplasty decreased from 52% to 24%.The significance of simulation-based surgical training as a tool for acquiring and training surgical skills was reviewed positively. CONCLUSIONS: The results of this study indicate that simulation-based surgical training is a valuable and effective method for learning reconstructive techniques of minimally invasive MVR and overall general dexterity.The novel learning and training options should be implemented in the surgical traineeship for systematic teaching of various surgical skills.

Octogenarian patients and laser-assisted lead extraction: Should we put a limit?

BACKGROUND: Transvenous laser lead extraction (TLE) for cardiac implantable electric devices (CIED) is a challenging procedure especially if performed in octogenarians. In this study we evaluated the safety and efficacy of transvenous laser lead extraction in elderly patients. METHODS: This is a retrospective study of octogenarian patients who underwent laser-assisted lead extraction (LLE) (GlideLight laser sheath, Philips, San Diego, USA). 270 Consecutive patients were included. Patients were divided into two groups. Octogenarian group and non-octogenarian group. The Data was gathered from patients treated between September 2013 and January 2020 and is retrospectively analyzed. RESULTS: Of 270 consecutive patients, 38 (14.0%) were 80 years old or more. The total number of the extracted leads was 556 among which 84(15.0%) from the Octogenarian group. From these leads were 155 single coil leads, 82 dual coil leads, 129 right ventricular pacing leads, 155 right atrial leads, and 35 left ventricular leads. In the Octogenarian group the number of removed leads was as follows: 13 single coil leads, 10 dual coil leads, 28 right ventricular pacing leads, 28 right atrial leads and 5 left ventricular leads. No mortality was recorded in the Octogenarian group. One patient in the YG suffered from a superior vena cava tear and one patient suffered from pulmonary embolism. CONCLUSION: In octogenarian laser assisted lead extraction patients is a safe and effective procedure. No increase in morbidity, mortality or perioperative complication could be recorded in this group. Age should not be a limiting factor to perform this procedure.

Comparative evaluation of three commercially available markerless depth sensors for close-range use in surgical simulation.

PURPOSE: Minimally invasive surgeries have restricted surgical ports, demanding a high skill level from the surgeon. Surgical simulation potentially reduces this steep learning curve and additionally provides quantitative feedback. Markerless depth sensors show great promise for quantification, but most such sensors are not designed for accurate reconstruction of complex anatomical forms in close-range. METHODS: This work compares three commercially available depth sensors, namely the Intel D405, D415, and the Stereolabs Zed-Mini in the range of 12-20 cm, for use in surgical simulation. Three environments are designed that closely mimic surgical simulation, comprising planar surfaces, rigid objects, and mitral valve models of silicone and realistic porcine tissue. The cameras are evaluated on Z-accuracy, temporal noise, fill rate, checker distance, point cloud comparisons, and visual inspection of surgical scenes, across several camera settings. RESULTS: The Intel cameras show sub-mm accuracy in most static environments. The D415 fails in reconstructing valve models, while the Zed-Mini provides lesser temporal noise and higher fill rate. The D405 could reconstruct anatomical structures like the mitral valve leaflet and a ring prosthesis, but performs poorly for reflective surfaces like surgical tools and thin structures like sutures. CONCLUSION: If a high temporal resolution is needed and lower spatial resolution is acceptable, the Zed-Mini is the best choice, whereas the Intel D405 is the most suited for close-range applications. The D405 shows potential for applications like deformable registration of surfaces, but is not yet suitable for applications like real-time tool tracking or surgical skill assessment.

Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy in Melanoma.

Patients with BRAF-mutant melanoma show substantial responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically "cold" after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines as strongly upregulated initially and steeply decreasing as the immune response faded. Therefore, we hypothesized that sustaining chemokine signaling could impair MRD maintenance through increased recruitment of effector T cells. We found that intratumoral administration of recombinant Cxcl9 (rCxcl9), either naked or loaded in microparticles, significantly impaired MRD relapse in BRAF-inhibited tumors, including several complete pathologic responses after microparticle-delivered rCxcl9 combined with BRAF and MEK inhibition. Our experiments constitute proof of concept that chemokine-based microparticle delivery systems are a potential strategy to forestall tumor relapse and thus improve the clinical success of first-line treatment methods.

Surgical Rehearsal for Mitral Valve Repair: Personalizing Surgical Simulation by 3D Printing.

PURPOSE: The goal of this study was to show possible effects of performing the actual procedure of mitral valve repair (MVR) on personalized silicone models 1 day before operation. DESCRIPTION: Based on preoperative 3-dimensional echocardiography recordings, flexible 3-dimensional replicas of the depicted pathologic mitral valves could be produced and used for a simulation of reconstructive techniques analogous to the upcoming MVR procedure. We integrated this step of personalized surgical planning into the clinical routine of 6 MVR cases with 3 different surgeons. This pilot study was assessed by evaluating questionnaires and by comparing isolated surgical steps with conventional MVRs. EVALUATION: This approach was considered a better preparation for MVRs with overall positive responses from the surgeons. Simulation helped reduce the time of initial inspection of the valve because of better understanding of the valve's pathomorphologic features. Annuloplasty benefited from preoperative sizing by reducing the number of sizing attempts. CONCLUSIONS: These initial findings suggest that simulation-based surgical planning can be implemented into patients' and physicians' clinical workflow as a major technologic advancement for future MVR preparation.

Tumor Microenvironment and Immune Escape in the Time Course of Glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a malignant prognosis. GBM is characterized by high cellular heterogeneity and its progression relies on the interaction with the central nervous system, which ensures the immune-escape and tumor promotion. This interplay induces metabolic, (epi)-genetic and molecular rewiring in both domains. In the present study, we aim to characterize the time-related changes in the GBM landscape, using a syngeneic mouse model of primary GBM. GL261 glioma cells were injected in the right striatum of immuno-competent C57Bl/6 mice and animals were sacrificed after 7, 14, and 21 days (7D, 14D, 21D). The tumor development was assessed through 3D tomographic imaging and brains were processed for immunohistochemistry, immunofluorescence, and western blotting. A human transcriptomic database was inquired to support the translational value of the experimental data. Our results showed the dynamic of the tumor progression, being established as a bulk at 14D and surrounded by a dense scar of reactive astrocytes. The GBM growth was paralleled by the impairment in the microglial/macrophagic recruitment and antigen-presenting functions, while the invasive phase was characterized by changes in the extracellular matrix, as shown by the analysis of tenascin C and metalloproteinase-9. The present study emphasizes the role of the molecular changes in the microenvironment during the GBM progression, fostering the development of novel multi-targeted, time-dependent therapies in an experimental model similar to the human disease.

Multi-modal molecular programs regulate melanoma cell state.

Melanoma cells display distinct intrinsic phenotypic states. Here, we seek to characterize the molecular regulation of these states using multi-omic analyses of whole exome, transcriptome, microRNA, long non-coding RNA and DNA methylation data together with reverse-phase protein array data on a panel of 68 highly annotated early passage melanoma cell lines. We demonstrate that clearly defined cancer cell intrinsic transcriptomic programs are maintained in melanoma cells ex vivo and remain highly conserved within melanoma tumors, are associated with distinct immune features within tumors, and differentially correlate with checkpoint inhibitor and adoptive T cell therapy efficacy. Through integrative analyses we demonstrate highly complex multi-omic regulation of melanoma cell intrinsic programs that provide key insights into the molecular maintenance of phenotypic states. These findings have implications for cancer biology and the identification of new therapeutic strategies. Further, these deeply characterized cell lines will serve as an invaluable resource for future research in the field.

The GermAn Laser Lead Extraction RegistrY: GALLERY.

AIMS: The GermAn Laser Lead Extraction RegistrY: GALLERY is a retrospective, national multicentre registry, investigating the safety and efficacy of laser lead extraction procedures in Germany. METHODS AND RESULTS: Twenty-four German centres that are performing laser lead extraction have participated in the registry. All patients, treated with a laser lead extraction procedure between January 2013 and March 2017, were consecutively enrolled. Safety and efficacy of laser lead extraction were investigated. A total number of 2524 consecutive patients with 6117 leads were included into the registry. 5499 leads with a median lead dwell time of 96 (62-141) months were treated. The mean number of treated leads per patient was 2.18 ± 1.02. The clinical procedural success rate was 97.86% and the complete lead removal was observed in 94.85%. Additional extraction tools were used in 6.65% of cases. The rate of procedural failure was 2.14% with lead age ≥10 years being its only predictor. The overall complication rate was 4.32%, including 2.06% major and 2.26% minor complications. Procedure-related mortality was 0.55%. Female sex and the presence of abandoned leads were predictors for procedure-related complications. The all-cause in-hospital mortality was 3.56% with systemic infection being the strongest predictor, followed by age ≥75 years and chronic kidney disease. CONCLUSION: In the GALLERY, a high success- and low procedure-related complication rates have been demonstrated. In multivariate analysis, female sex and the presence of abandoned leads were predictors for procedure-related complications, while the presence of systemic infection, age ≥75 years, and chronic kidney disease were independent predictors for all-cause mortality.

Mutually Improved Endoscopic Image Synthesis and Landmark Detection in Unpaired Image-to-Image Translation.

The CycleGAN framework allows for unsupervised image-to-image translation of unpaired data. In a scenario of surgical training on a physical surgical simulator, this method can be used to transform endoscopic images of phantoms into images which more closely resemble the intra-operative appearance of the same surgical target structure. This can be viewed as a novel augmented reality approach, which we coined Hyperrealism in previous work. In this use case, it is of paramount importance to display objects like needles, sutures or instruments consistent in both domains while altering the style to a more tissue-like appearance. Segmentation of these objects would allow for a direct transfer, however, contouring of these, partly tiny and thin foreground objects is cumbersome and perhaps inaccurate. Instead, we propose to use landmark detection on the points when sutures pass into the tissue. This objective is directly incorporated into a CycleGAN framework by treating the performance of pre-trained detector models as an additional optimization goal. We show that a task defined on these sparse landmark labels improves consistency of synthesis by the generator network in both domains. Comparing a baseline CycleGAN architecture to our proposed extension (DetCycleGAN), mean precision (PPV) improved by +61.32, mean sensitivity (TPR) by +37.91, and mean F1 score by +0.4743. Furthermore, it could be shown that by dataset fusion, generated intra-operative images can be leveraged as additional training data for the detection network itself.

Point detection through multi-instance deep heatmap regression for sutures in endoscopy.

PURPOSE: Mitral valve repair is a complex minimally invasive surgery of the heart valve. In this context, suture detection from endoscopic images is a highly relevant task that provides quantitative information to analyse suturing patterns, assess prosthetic configurations and produce augmented reality visualisations. Facial or anatomical landmark detection tasks typically contain a fixed number of landmarks, and use regression or fixed heatmap-based approaches to localize the landmarks. However in endoscopy, there are a varying number of sutures in every image, and the sutures may occur at any location in the annulus, as they are not semantically unique. METHOD: In this work, we formulate the suture detection task as a multi-instance deep heatmap regression problem, to identify entry and exit points of sutures. We extend our previous work, and introduce the novel use of a 2D Gaussian layer followed by a differentiable 2D spatial Soft-Argmax layer to function as a local non-maximum suppression. RESULTS: We present extensive experiments with multiple heatmap distribution functions and two variants of the proposed model. In the intra-operative domain, Variant 1 showed a mean [Formula: see text] of [Formula: see text] over the baseline. Similarly, in the simulator domain, Variant 1 showed a mean [Formula: see text] of [Formula: see text] over the baseline. CONCLUSION: The proposed model shows an improvement over the baseline in the intra-operative and the simulator domains. The data is made publicly available within the scope of the MICCAI AdaptOR2021 Challenge https://adaptor2021.github.io/ , and the code at https://github.com/Cardio-AI/suture-detection-pytorch/ .

The use of laser lead extraction sheath in the presence of supra-cardiac occlusion of the central veins for cardiac implantable electronic device lead upgrade or revision.

BACKGROUND: The implantation of cardiac implantable electronic devices (CIED) has increased in the last decades with improvement in the quality of life of patients with cardiac rhythm disorders. The presence of bilateral subclavian, innominate or superior vena cava obstruction is a major limitation to device revision and/or upgrade. METHODS AND MATERIAL: This is retrospective study of patients who underwent laser-assisted lead extraction (LLE) (GlideLight laser sheath, Spectranetics Corporation, Colorado Springs, USA) with lead revision or upgrade using the laser sheath as a guide rail. Patients with known occlusion, severe stenosis or functional obstruction of the venous access vessels with indwelling leads were included in this study. RESULTS: 106 patients underwent percutaneous LLE with lead revision and/or upgrade. Preoperative known complete occlusion or severe stenosis of access veins was present in 23 patients (21.5%). More patients with implantable cardioverter-defibrillator (ICD) underwent LLE (64.1%) than patients with CRT-Ds (24.5%) and pacemaker patients (11.3%). In total 172 leads were extracted: 79 (45.9%) single-coil defibrillator leads, 35 (20.3%) dual-coil defibrillator leads, 31 (18.0%) right atrial leads, 24 (13.9%) right ventricular leads and three (1.7%) malfunctional coronary sinus left ventricular pacing leads. The mean age of leads was 99.2±65.6 months. The implantation of new leads after crossing the venous stenosis/obstruction was successful in 98 (92.4%) cases. Postoperative complications were pocket hematoma in two cases and wound infection in one case. No peri-operative and no immediate postoperative death was recorded. One intraoperative superior vena cava tear was treated by immediate thoracotomy and surgical repair. CONCLUSION: In a single-center study on LLE in the presence of supra-cardiac occlusion of the central veins for CIED lead upgrade and revision we could demonstrate a low procedural complication rate with no procedural deaths. Most of the leads could be completely extracted to revise or upgrade the system. Our study showed a low complication rate, with acceptable mortality rates.

Adverse Events Detection Through Global Trigger Tool Methodology: Results From a 5-Year Study in an Italian Hospital and Opportunities to Improve Interrater Reliability.

OBJECTIVE: Global Trigger Tool (GTT) has been proposed as a low-cost method to detect adverse events (AEs). The validity of the methodology has been questioned because of moderate interrater agreement. Continuous training has been suggested as a means to improve consistency over time. We present the main findings of the implementation of the Italian version of the GTT and evaluate efforts to improve the interrater reliability over time. METHODS: The Italian version of the GTT was developed and implemented at the San Bonifacio Hospital, a 270-bed secondary care acute hospital in Verona, Italy. Ten clinical records randomly selected every 2 weeks were reviewed from 2009 to 2014. Two-stage interrater reliability assessment between team members was conducted on 2 subsamples of 50 clinical records before and after the implementation of specific review rules and staff training. RESULTS: Among 1320 medical records reviewed, a total of 366 AEs were found with at least 1 AE on 20.2% of all discharges, 27.7 AEs/100 admissions, and 30.6 AEs/1000 patient-days. Adverse events with harm score E and F were respectively 58.2% (n = 213) and 38.8% (n = 142). First round interrater reliability was comparable with other international studies. The interrater agreement improved significantly after intervention (κ interrater I = 0.52, κ interrater II = 0.80, P < 0.001). CONCLUSIONS: Despite the improvements in the interrater consistency, overall results did not show any significant trend in AEs over time. Future studies may be directed to apply and adapt the GTT methodology to more specific settings to explore how to improve its sensitivity.

Mitral valve flattening and parameter mapping for patient-specific valve diagnosis.

PURPOSE: Intensive planning and analysis from echocardiography are a crucial step before reconstructive surgeries are applied to malfunctioning mitral valves. Volume visualizations of echocardiographic data are often used in clinical routine. However, they lack a clear visualization of the crucial factors for decision making. METHODS: We build upon patient-specific mitral valve surface models segmented from echocardiography that represent the valve's geometry, but suffer from self-occlusions due to complex 3D shape. We transfer these to 2D maps by unfolding their geometry, resulting in a novel 2D representation that maintains anatomical resemblance to the 3D geometry. It can be visualized together with color mappings and presented to physicians to diagnose the pathology in one gaze without the need for further scene interaction. Furthermore, it facilitates the computation of a Pathology Score, which can be used for diagnosis support. RESULTS: Quality and effectiveness of the proposed methods were evaluated through a user survey conducted with domain experts. We assessed pathology detection accuracy using 3D valve models in comparison with the novel visualizations. Classification accuracy increased by 5.3% across all tested valves and by 10.0% for prolapsed valves. Further, the participants' understanding of the relation between 3D and 2D views was evaluated. The Pathology Score is found to have potential to support discriminating pathologic valves from normal valves. CONCLUSIONS: In summary, our survey shows that pathology detection can be improved in comparison with simple 3D surface visualizations of the mitral valve. The correspondence between the 2D and 3D representations is comprehensible, and color-coded pathophysiological magnitudes further support the clinical assessment.

BTK inhibitors synergise with 5-FU to treat drug-resistant TP53-null colon cancers.

Colorectal cancer (CRC) is the fourth cause of death from cancer worldwide mainly due to the high incidence of drug-resistance. During a screen for new actionable targets in drug-resistant tumours we recently identified p65BTK - a novel oncogenic isoform of Bruton's tyrosine kinase. Studying three different cohorts of patients here we show that p65BTK expression correlates with histotype and cancer progression. Using drug-resistant TP53-null colon cancer cells as a model we demonstrated that p65BTK silencing or chemical inhibition overcame the 5-fluorouracil resistance of CRC cell lines and patient-derived organoids and significantly reduced the growth of xenografted tumours. Mechanistically, we show that blocking p65BTK in drug-resistant cells abolished a 5-FU-elicited TGFB1 protective response and triggered E2F-dependent apoptosis. Taken together, our data demonstrated that targeting p65BTK restores the apoptotic response to chemotherapy of drug-resistant CRCs and gives a proof-of-concept for suggesting the use of BTK inhibitors in combination with 5-FU as a novel therapeutic approach in CRC patients. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Reducing interruptions during medication preparation and administration.

PURPOSE: According to literature, interruptions during drug administration lead to a significant proportion of medication errors. Evidence on the effectiveness of interventions to reduce interruption is still limited. The purpose of this paper is to explore main reasons for interruptions during drug administration rounds in a geriatric ward of an Italian secondary hospital and test the effectiveness of a combined intervention. DESIGN/METHODOLOGY/APPROACH: This is a pre and post-intervention observational study based on direct observation. All nurse staff (24) participated to the study that lead to observe a total of 44 drug dispensing rounds with 945 drugs administered to 491 patients in T0 and 994 drugs to 506 patients in T1. FINDINGS: A significant reduction of raw number of interruptions (mean per round from 17.31 in T0 to 9.09 in T1, p<0.01), interruptions/patient rate (from 0.78 in T0 to 0.40 in T1, p<0.01) and interruptions/drugs rate (from 0.44 in T0 to 0.22 in T1, p<0.01) were observed. Needs for further improvements were elicited (e.g. a greater involvement of support staff). PRACTICAL IMPLICATIONS: Nurse staff should be adequately trained on the risks related to interruptions during drug administration since routine activity is at high risk of distractions due to its repetitive and skill-based nature. ORIGINALITY/VALUE: A strong involvement of both MB and leadership, together with the frontline staff, helped to raise staff motivation and guide a bottom-up approach, able to identify tailored interventions and serve concurrently as training instrument tool.

Epicardial pacemaker as a bridge for pacemaker-dependent patients undergoing explantation of infected cardiac implantable electronic devices.

BACKGROUND AND AIM OF THE STUDY: Cardiac implantable electronic device (CIED) implantation is associated with an increase in CIED infection. For pacemaker-dependent patients, temporary pacemaker leads are implanted until infection remission, which allows new CIED implantation. We compared the outcome of pacemaker-dependent patients with infected CIED based on whether a combined single procedure of epicardial pacemaker implantation with system extraction or a temporary transjugular pacemaker implantation with interval system implantation was performed. METHODS: This retrospective study included pacemaker-dependent patients with CIED infection who were divided into two groups: the Tempo and Epi groups. The Tempo group received temporary transvenous pacemaker connected to an external pulse generator. After infection remission, a new permanent pacemaker was implanted, and the temporary pacemaker leads were removed. The Epi group received implantable epicardial right-ventricular pacemaker through infrasternal inferior pericardiotomy, and a permanent pulse generator was implanted through the same incision between the subcutaneous tissue and abdominal fascia. RESULTS: Sixty-six patients were included. Forty-two patients with epicardial pacemakers were discharged after 9.5 ± 8.8 days without infection of the newly implanted epicardial pacemaker. Patients with temporary transjugular pacemaker lead were discharged 23 ± 15 days after receiving permanent pacemakers. No serious complications were recorded in the Epi group. CONCLUSIONS: CIED infections in pacemaker-dependent patients can be treated through epicardial pacemaker implantation that allows early patient mobility and reduces hospital stay with no risk of epicardial pacemaker infection. Epicardial pacemakers can be used as a bridge until permanent intravenous CIED is implanted or as a replacement for permeant intravenous CIED.

Specific Expression of a New Bruton Tyrosine Kinase Isoform (p65BTK) in the Glioblastoma Gemistocytic Histotype.

Bruton's tyrosine-kinase (BTK) is a non-receptor tyrosine kinase recently associated with glioma tumorigenesis and a novel prognostic marker for poor survival in patients with glioma. The p65BTK is a novel BTK isoform involved in different pathways of drug resistance of solid tumors, thus we aimed to investigate the expression and the putative role of p65BTK in tumors of the central nervous system (CNS). We selected a large cohort of patients with glial tumors (n = 71) and analyzed the expression of p65BTK in different histotypes and correlation with clinical parameters. Sections were stained with glial fibrillary acidic protein (GFAP), p53, epidermal growth factor receptor (EGFR), S100, vimentin, and epithelial membrane antigen (EMA) antibodies. Glioma stem cell (GSC) lines, isolated from glioblastoma multiforme (GBM), were treated with different concentrations of ibrutinib, a specific inhibitor of BTK, in order to evaluate their metabolic activity, mitotic index and mortality. Moreover, an orthotopic xenotransplant of GSC from human GBM was used to evaluate the expression of p65BTK in the brain of immunodeficient mice. p65BTK was expressed in GSC and in gemistocytes in human gliomas at different histological grade. We found a significant correlation between BTK expression and low-grade (LG) tumors (p ≤ 0.05) and overall survival (OS) of patients with grade III gliomas (p ≤ 0.05), suggestive of worst prognosis. Interestingly, the expression of p65BTK remained restricted exclusively to gemistocytic cells in the xenograft mouse model. Ibrutinib administration significantly reduced metabolic activity and mitotic index and increased mortality in GSC, highlighting the specific role of p65BTK in cell proliferation and survival. In conclusion, our data demonstrated that p65BTK is expressed in glioma tumors, restricted to gemistocytic cells, has a key role in GSC and has a bad prognostic value, thus highlighting the importance of future research for targeted therapy of human gliomas.

BRAF Dimerization: An Underlying Resistance Mechanism in Low-Grade Pediatric Gliomas.

BRAF fusions and mutations are the most frequent genetic alterations in pediatric low-grade gliomas. The work from Wang and colleagues identifies an acquired secondary BRAF mutation that confers resistance to pharmacologic BRAF inhibition in a BRAFV600E glioma. The authors demonstrate that the mutation results in increased BRAF homodimerization, which in turn is targetable with second-generation BRAF inhibitors. Cancer Discov; 8(9); 1064-5. ©2018 AACR.See related article by Wang et al., p. 1130.