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Metastatic renal-cell carcinoma (RCC) is resistant to chemotherapy, and patients with this disease have a poor outlook. Immunotherapy by use of cytokines and vaccines against tumour antigens has shown encouraging results in a small group of patients. Advances in the understanding of the graft-versus-tumour effect in haematological malignant disorders have led to the use of stem-cell transplantation for treatment of solid-organ malignant diseases such as RCC. Techniques of bone-marrow ablation have been superseded by safer conditioning regimens, with occasional complete remission and partial remission in some patients. Graft-versus-host disease, engraftment failure, and disease progression remain important obstacles to the widespread use of new techniques for metastatic RCC. Here, we summarise important issues surrounding immunotherapy for RCC, the problems encountered with use of immunotherapy, and the present use of non-myeloablative techniques for treatment of this disease. [ABSTRACT FROM AUTHOR]

Metastatic prostate cancer (PCa) poses a significant therapeutic challenge with high mortality rates. Utilizing CRISPR-Cas9 in vivo, we target five potential tumor suppressor genes (Pten, Trp53, Rb1, Stk11, and RnaseL) in the mouse prostate, reaching humane endpoint after eight weeks without metastasis. By further depleting three epigenetic factors (Kmt2c, Kmt2d, and Zbtb16), lung metastases are present in all mice. While whole genome sequencing reveals few mutations in coding sequence, RNA sequencing shows significant dysregulation, especially in a conserved genomic region at chr5qE1 regulated by KMT2C. Depleting Odam and Cabs1 in this region prevents metastasis. Notably, the gene expression signatures, resulting from our study, predict progression-free and overall survival and distinguish primary and metastatic human prostate cancer. This study emphasizes positive genetic interactions between classical tumor suppressor genes and epigenetic modulators in metastatic PCa progression, offering insights into potential treatments., (© 2024. The Author(s).)

Cancer spread beyond the prostate, including extraprostatic extension (other than seminal vesicle or bladder invasion; EPE)/microscopic bladder neck invasion and seminal vesicle invasion (SVI) currently classified as pT3a and pT3b lesions, respectively, does not uniformly indicate poor oncologic outcomes. Accurate risk stratification of current pT3 disease is therefore required. We herein further determined the prognostic impact of these histopathologic lesions routinely assessed and reported by pathologists, particularly their combinations. We assessed consecutive 2892 patients undergoing radical prostatectomy for current pT2 (n = 1692), pT3a (n = 956), or pT3b (n = 244) disease at our institution between 2009 and 2018. Based on our preliminary findings, point(s) were given (1 point to focal EPE, microscopic bladder neck invasion, or unilateral SVI; 2 points to nonfocal/established EPE or bilateral SVI) and summed up in each case. Our cohort had 0 point (n = 1692, 58.5%; P0), 1 point (n = 243, 8.4%; P1), 2 points (n = 657, 22.7%; P2), 3 points (n = 192, 6.6%; P3), 4 points (n = 76, 2.6%; P4), and 5 points (n = 32, 1.1%; P5). Univariate analysis revealed associations of higher points with significantly worse biochemical progression-free survival, particularly when P4 and P5 were combined. In multivariable analysis (P0 as a reference), P1 (hazard ratio [HR], 1.57; P = .033), P2 (HR, 3.25; P < .001), P3 (HR, 4.01; P < .001), and P4 + P5 (HR, 5.99; P < .001) showed significance for the risk of postoperative progression. Meanwhile, Harrell C-indexes for the current pT staging, newly developed point system, and the Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score were 0.727 (95% CI, 0.706-0.748), 0.751 (95% CI, 0.729-0.773), and 0.774 (95% CI, 0.755-0.794), respectively, for predicting progression. We believe our data provide a logical rationale for a novel pathologic T-staging system based on the summed points, pT1a (0 point), pT1b (1 point), pT2 (2 points), pT3a (3 points), and pT3b (4 or 5 points), which more accurately stratifies the prognosis of prostate cancer., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) is an aggressive brain tumor with a median survival of 15 months and has limited treatment options. Immunotherapy with checkpoint inhibitors has shown minimal efficacy in combating GBM, and large clinical trials have failed. New immunotherapy approaches and a deeper understanding of immune surveillance of GBM are needed to advance treatment options for this devastating disease. In this study, we used two preclinical models of GBM: orthotopically delivering either GBM stem cells or employing CRISPR-mediated tumorigenesis by adeno-associated virus, to establish immunologically proficient and non-inflamed tumors, respectively. After tumor development, the innate immune system was activated through long-term STING activation by a pharmacological agonist, which reduced tumor progression and prolonged survival. Recruitment and activation of cytotoxic T-cells were detected in the tumors, and T-cell specificity towards the cancer cells was observed. Interestingly, prolonged STING activation altered the tumor vasculature, inducing hypoxia and activation of VEGFR, as measured by a kinome array and VEGF expression. Combination treatment with anti-PD1 did not provide a synergistic effect, indicating that STING activation alone is sufficient to activate immune surveillance and hinder tumor development through vascular disruption. These results guide future studies to refine innate immune activation as a treatment approach for GBM, in combination with anti-VEGF to impede tumor progression and induce an immunological response against the tumor., Competing Interests: Declaration of competing interest Fabienne Vernejoul and Eric Perouzel are employees of InvivoGen. InvivoGen has financial interests in STING agonists, including some used in this study, which have been supplied by InvivoGen. However, the research was conducted unrestricted, and it had no impact on the development of the project. The rest of the authors have no conflict of interest to report., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Emotion recognition is key to interpersonal communication and to human-machine interaction. Body expression may contribute to emotion recognition, but most past studies focused on a few motions, limiting accurate recognition. Moreover, emotions in most previous research were acted out, resulting in non-natural motion, which is unapplicable in reality. We present an approach for emotion recognition based on body motion in naturalistic settings, examining authentic emotions, natural movement, and a broad collection of motion parameters. A lab experiment using 24 participants manipulated participants' emotions using pretested movies into five conditions: happiness, relaxation, fear, sadness, and emotionally-neutral. Emotion was manipulated within subjects, with fillers in between and a counterbalanced order. A motion capture system measured posture and motion during standing and walking; a force plate measured center of pressure location. Traditional statistics revealed nonsignificant effects of emotions on most motion parameters; only 7 of 229 parameters demonstrate significant effects. Most significant effects are in parameters representing postural control during standing, which is consistent with past studies. Yet, the few significant effects suggest that it is impossible to recognize emotions based on a single motion parameter. We therefore developed machine learning models to classify emotions using a collection of parameters, and examined six models: k-nearest neighbors, decision tree, logistic regression, and the support vector machine with radial base function and linear and polynomial functions. The decision tree using 25 parameters provided the highest average accuracy (45.8%), more than twice the random guess for five conditions, which advances past studies demonstrating comparable accuracies, due to our naturalistic setting. This research suggests that machine learning models are valuable for emotion recognition in reality and lays the foundation for further progress in emotion recognition models, informing the development of recognition devices (e.g., depth camera), to be used in home-setting human-machine interactions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Riemer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Objective: Ongoing seizure in the Emergency Department is a medical emergency and its aggressive management is essential. Prompt antiepileptic therapy with early cessation of seizure would minimize the morbidity and risk of recurrence. To compare time to seizure control with fosphenytoin to phenytoin protocol in the ED., Materials and Methods: We conducted an observational study on patients with active seizure in the Emergency Department comparing phenytoin versus fosphenytoin protocol over one year., Results: During the study period, we recruited 121 patients in the phenytoin group and 124 patients in the fosphenytoin group. Generalized tonic-clonic seizure (73.5% in phenytoin vs. 68.5% in fosphenytoin arm) was the most common type of seizure in both the arms. The mean time taken for cessation of seizure in the fosphenytoin arm (17.48 ± 49.24) was less than half of that in the phenytoin arm (37.20 ± 58.17) (mean difference: 19.72, P = 0.004, 95% CI: -33.27 to -6.17). There was a significant decrease in recurrence rates of seizure with phenytoin compared to the fosphenytoin arm (17.7% vs. 31.4%: OR: 0.47, P = 0.013; 95% CI: 0.26-0.86). Favorable STESS (≤2) was higher with phenytoin compared to fosphenytoin (60.3% vs. 48.4%). The overall in-hospital mortality rate in both arms was negligible (0.8%)., Conclusion: The mean time for cessation of active seizure with fosphenytoin was less than half that of phenytoin. Despite its higher cost and minor adverse effects when compared to phenytoin, benefits seem to outweigh its limitation., Competing Interests: None

The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications of mitochondria transfer on tumor biology are poorly understood. Here we show that mitochondria transfer is a prevalent phenomenon in glioblastoma (GBM), the most frequent and malignant primary brain tumor. We identified horizontal mitochondria transfer from astrocytes as a mechanism that enhances tumorigenesis in GBM. This transfer is dependent on network-forming intercellular connections between GBM cells and astrocytes, which are facilitated by growth-associated protein 43 (GAP43), a protein involved in neuron axon regeneration and astrocyte reactivity. The acquisition of astrocyte mitochondria drives an increase in mitochondrial respiration and upregulation of metabolic pathways linked to proliferation and tumorigenicity. Functionally, uptake of astrocyte mitochondria promotes cell cycle progression to proliferative G2/M phases and enhances self-renewal and tumorigenicity of GBM. Collectively, our findings reveal a host-tumor interaction that drives proliferation and self-renewal of cancer cells, providing opportunities for therapeutic development., (© 2023. The Author(s).)

Background: Robot-assisted simple prostatectomy (RASP) has emerged as a safe surgical treatment for patients with benign prostatic hyperplasia with large glands (>80 mL). Several studies reported on perioperative outcomes of RASP by the standard multiport (MP) da Vinci ® robotic system approach. Studies conducted on RASP utilizing the novel single-port (SP) da Vinci SP robotic platform (Intuitive Surgical, Sunnyvale, CA) are scarce. We aimed to compare intraoperative and short-term postoperative outcomes between the da Vinci MP and SP robots for patients undergoing RASP in a referral center. Methods: In this retrospective study, we reviewed all patients who underwent RASP using MP or SP robot from September 2016 to March 2021. Intraoperative data, overall 30-day complications, complications by Clavien-Dindo classification, and 90-day readmission and reoperation rates were assessed and compared between the two groups using appropriate statistical methods. Results: Seventy-five patients who underwent RASP were identified. Of these, 47 were in the MP group and 28 were in the SP. Compared with SP, mean operative time in MP group was 216.6 vs 232.4 minutes ( p  = 0.39), estimated blood loss was 195.7 vs 227.1 mL ( p  = 0.43), and length of stay was 2 vs 2.5 days ( p  = 0.45). There was a trend toward higher overall complication rate in SP group vs MP (42.86% vs 21.28%, p  = 0.09). There were no significant differences in the readmission (17.02% vs 10.71%, p  = 0.52) and reoperation (2.1% vs 7.14%, p  = 0.34) rates between MP vs SP group. Conclusion: SP-RASP is safe and shows equivalent perioperative outcomes when compared with the MP robotic system. A marginal increase of complication rate was recorded in the SP group; however, this did not demonstrate statistical significance.

Background: Microtubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular, glioblastomas (GBMs), while they are uncommon in chemosensitive IDH-mutant and 1p/19q co-deleted oligodendrogliomas. The aim of this study was to identify potential signaling pathways involved in MT formation., Methods: Bioinformatics analysis of TCGA was performed to analyze differences between GBM and oligodendroglioma. Patient-derived GBM stem cell lines were used to investigate MT formation under transforming growth factor-beta (TGF-β) stimulation and inhibition in vitro and in vivo in an orthotopic xenograft model. RNA sequencing and proteomics were performed to detect commonalities and differences between GBM cell lines stimulated with TGF-β., Results: Analysis of TCGA data showed that the TGF-β pathway is highly activated in GBMs compared to oligodendroglial tumors. We demonstrated that TGF-β1 stimulation of GBM cell lines promotes enhanced MT formation and communication via calcium signaling. Inhibition of the TGF-β pathway significantly reduced MT formation and its associated invasion in vitro and in vivo. Downstream of TGF-β, we identified thrombospondin 1 (TSP1) as a potential mediator of MT formation in GBM through SMAD activation. TSP1 was upregulated upon TGF-β stimulation and enhanced MT formation, which was inhibited by TSP1 shRNAs in vitro and in vivo., Conclusion: TGF-β and its downstream mediator TSP1 are important mediators of the MT network in GBM and blocking this pathway could potentially help to break the complex MT-driven invasion/resistance network., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Introduction: Current training for robotic surgery crisis management, specifically emergency robotic undocking protocol (ERUP), remains limited to anecdotal experience. A curriculum to impart the skills and knowledge necessary to recognize and complete a successful ERUP was developed using an education approach then evaluated., Methods: Baseline knowledge and confidence regarding ERUP were established for 5 robotic teams before completing 2 full-immersion simulations separated by an online self-paced learning module. In each simulation, teams operated on a perfused hydrogel model and were tasked to dissect a retroperitoneal tumor abutting a major vessel. During vascular pedicle ligation, a major vascular bleed and nonrecoverable robotic fault were remotely induced, necessitating ERUP with open conversion. After the simulation, participants completed surgery task load index (cognitive load assessment) and realism surveys. Weighted checklists scored participants' actions during each simulation. Surgical metrics including estimated blood loss, time to control bleeding, and undocking time were recorded. Curriculum retention was assessed by repeating the exercise at 6 months., Results: Participants experienced high levels of cognitive demand and agreed that the simulation's realism and stress mimicked live surgery. Longitudinal analysis showed significant knowledge (+37.5 points, p = 0.004) and confidence (+15.3 points, p < 0.001) improvements from baseline to completion. Between simulations, checklist errors, undocking time, and estimated blood loss decreased (38⇾17, -40 seconds, and -500 mL, respectively), whereas action scores increased significantly (+27 points, p = 0.008). At 6 months, insignificant changes from curriculum completion were seen in knowledge (-4.8 points, p = 0.36) and confidence (+3.7 points, p = 0.1)., Conclusions: This simulation-based curriculum successfully improves operative team's confidence, knowledge, and skills required to manage robotic crisis events., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Society for Simulation in Healthcare.)

Glioblastoma (GBM) is the most prevalent form of primary malignant brain tumor in adults and remains almost invariably lethal owing to its aggressive and invasive nature. There have only been marginal improvements in its bleak survival rate of 12-15 months over the last four decades. The lack of preclinical models that efficiently recapitulate tumor biology and the tumor microenvironment is also in part responsible for the slow phase of translational GBM research. Emerging three-dimensional (3D) organoids and cell culture systems offer new and innovative possibilities for GBM modelling. These 3D models find their application to engineer the disease, screen drugs, establishing live biobank, and explore personalized therapy. Furthermore, these models can also be genetically modified by using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology, which would allow one to study the specific role of key genes associated with gliomagenesis. Establishment of a coculture system with GBM cells to understand its invasive behavior is yet another major application of this model. Despite these merits, the organoid models also have certain limitations, including the absence of immune responses and vascular systems. In recent years, major progress has been made in the development and refinement of 3D models of GBM. In this review, we intend to highlight these recent advances and the potential future implications of this rapidly evolving field, which should facilitate a better understanding of GBM biology., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Chloroform, a halogenated hydrocarbon, causes central nervous depression, hepatotoxicity, nephrotoxicity, and rhabdomyolysis. Historically, chloroform had been used as a general anaesthetic and today is still used in chemical industries. Lack of proper personal protective equipment and adequate knowledge about its toxic effects can lead to serious harm., Case Report: A 33-year-old gentleman presented to the emergency department (ED) with altered mental status. Given his depressed mental status, the decision was made to intubate shortly after arrival for airway protection. Further history raised suspicion of occupational chloroform exposure. Brown-colored urine further strengthened suspicion of chloroform poisoning with resultant rhabdomyolysis. Forced alkaline diuresis and N-acetylcysteine were started in the ED. His mental status and respiratory efforts improved on hospital day two, and he was ultimately extubated. Creatine phosphokinase and myoglobin levels were initially high but gradually came down by hospital day six. On hospital day 10, the patient was deemed stable and safely discharged., Conclusion: A patient with chloroform inhalation who suffered resultant rhabdomyolysis and hepatotoxicity was successfully treated with early initiation of forced alkaline diuresis, N-acetylysteine, and hemodialysis.

Background: The Surviving Sepsis Campaign recommends the administration of antibiotics within 1 hour of triage time in sepsis patients. The purpose of this study was to determine the factors affecting the time to first dose antibiotics in sepsis patients presenting to the emergency department (ED)., Methods: We conducted a prospective observational study on factors affecting the time to first dose antibiotics in patients with sepsis presenting to the ED over a period of 7 months (July 2019 to January 2020). The purpose of this study was to determine the factors affecting the time to first dose antibiotics in sepsis patients., Results: During the study period, a total of 410 patients with a mean age of 51.6 years were presented to the ED with sepsis. Majority was triaged to priority 1 (84.8%). The median door to antibiotic time was 50 minutes (IQR, 40-90). Two-thirds (68%) of the patients (279) received antibiotics within 60 minutes. The blood culture positivity rate was 22.9%, and the contamination rate was 6%. The most common factors for the delay were atypical presentation (36.6%) and unknown focus of infection (36.6%). Triage to non-acute areas of the ED (priority 2) was associated with delayed antibiotic administration [odds ratio (OR), 7.3; 95% confidence interval (CI), 4.03-13.36; p -value <0.001]. Patients presented with cellulitis and necrotizing soft tissue infection (NSTI) had received antibiotics within an hour compared to other diagnoses (18.3 vs 8.4%; OR, 2.4; 95% CI, 1.2-4.9; p = 0.009)., Conclusion: Two-thirds of our patients received their first dose of antibiotics within an hour of presentation to the ED. Triage to lower priorities was an independent risk factor for delay in first-dose antibiotic administration, and patients presented with an obvious focus of infections like cellulitis and NSTI received their first dose of antibiotic much earlier when compared to other diagnoses., How to Cite This Article: Joseph JV, Madhiyazhagan M, Roshan R, Dhanapal SG, Arul S, Abhilash KPP. Factors Affecting the Time to First Dose Antibiotic in Sepsis in Acute Emergency. Indian J Crit Care Med 2021;25(10):1155-1160., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.)

Robot-assisted radical prostatectomy (RARP) is currently the standard minimally invasive procedure for the surgical management of localized prostate cancer. It has been shown that the minimally invasive robotic approach offers comparable oncologic and functional outcomes with potential advantages, including decreased blood loss, shorter hospital stay, and recovery period when compared with open surgery. Generally, the transperitoneal RARP approach is the most commonly performed among robotic surgeons, owing to its wider space and early adoption. However, similar oncologic outcomes have been reported with the extraperitoneal approach. Owing to its perceived technical difficulty, extraperitoneal RARP is less adopted nowadays. This approach, however, has its merits particularly in cases where intraperitoneal access can be problematic with extensive adhesions from previous surgeries. Also, extraperitoneal approach allows for minimal bowel manipulation, less steep Trendelenburg positioning, and less pneumoperitoneum, which reflect on early recovery of bowel function after RARP. Both transperitoneal and extraperitoneal approaches can be performed using either the conventional multiport robotic system or the more recent single-port (SP) robotic system. With respect to extraperitoneal RARP, there has been an increased adoption of the SP system, with purported advantages such as better cosmesis, less postoperative analgesic and opioid requirements, and shorter duration of hospital stay. Herein, we describe the technical steps relevant to extraperitoneal single-port robot-assisted radical prostatectomy, and elaborate on the clinical outcomes reported in the literature.

Background: Organ culture models have been used over the past few decades to study development and disease. The in vitro three-dimensional (3D) culture system of organoids is well known, however, these 3D systems are both costly and difficult to culture and maintain. As such, less expensive, faster and less complex methods to maintain 3D cell culture models would complement the use of organoids. Chick embryos have been used as a model to study human biology for centuries, with many fundamental discoveries as a result. These include cell type induction, cell competence, plasticity and contact inhibition, which indicates the relevance of using chick embryos when studying developmental biology and disease mechanisms., Results: Here, we present an updated protocol that enables time efficient, cost effective and long-term expansion of fetal organ spheroids (FOSs) from chick embryos. Utilizing this protocol, we generated FOSs in an anchorage-independent growth pattern from seven different organs, including brain, lung, heart, liver, stomach, intestine and epidermis. These three-dimensional (3D) structures recapitulate many cellular and structural aspects of their in vivo counterpart organs and serve as a useful developmental model. In addition, we show a functional application of FOSs to analyze cell-cell interaction and cell invasion patterns as observed in cancer., Conclusion: The establishment of a broad ranging and highly effective method to generate FOSs from different organs was successful in terms of the formation of healthy, proliferating 3D organ spheroids that exhibited organ-like characteristics. Potential applications of chick FOSs are their use in studies of cell-to-cell contact, cell fusion and tumor invasion under defined conditions. Future studies will reveal whether chick FOSs also can be applicable in scientific areas such as viral infections, drug screening, cancer diagnostics and/or tissue engineering.

Objective: To describe our technique of robot-assisted synchronous bilateral nephrectomy (RASBN) for autosomal dominant polycystic kidney disease (ADPKD)., Methods: Given prior abdominal surgery/transplant in most patients, we prefer an open cut-down access to place a 12 mm port 10 cm infraumbilically. Four (8 mm) robotic ports are then placed under vision in a fan distribution along the umbilical level. The operating table is placed in reverse Trendelenburg and tilted opposite to the targeted side. Provided there are no concerns for malignancy, some cysts encountered in large kidneys (>2.5 L) may require puncture, to facilitate access and mobilization. The resected kidney is placed in a large bag and tucked in the pelvis. A similar procedure is carried out on the contralateral side after redocking the robot and tilting the table in the opposite direction. The specimen bags are extracted by elongating the lower midline 12 mm port site., Results: Seven cases of RASBN performed for ADPKD were identified (December 2015 to December 2018). Median (interquartile range, IQR) values for patient demographics were: Age = 59 years (47-63), body mass index = 29 (26-32), and American Society of Anaesthesiology grade = 3. Three patients had prior deceased- and 4 had prior living- donor transplants. Indication for nephrectomy were: pain (5), hemorrhage into cysts (3), and renal masses (2). Perioperative outcomes were: operating room time = 388 minutes, estimated blood loss = 200 mL, hemoglobin change = 1.3 g/dL, transfusion = 0, length of hospital stay = 3 days, Grade I Clavien-Dindo complications = 2 cases. All patients were alive at a median follow-up of 3.8 years., Conclusion: RASBN is safe and effective in ADPKD even in the context of prior renal transplant patients with attendant comorbidities., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to report on the safety (complications) and efficacy (oncological and functional outcomes) of robot-assisted radical prostatectomy (RARP), performed at our institution, in patients aged over 70., Patients and Methods: Review of our prospectively collected database [Cancer Information Systems (CAISIS)] identified two hundred and fifteen (215) patients, aged > 70, who underwent RARP for localized prostate cancer between July 2003 and August 2017. A propensity score-matched analysis, with multiple covariates, was performed to stratify the patients into Age ≤ 70 and Age > 70 comparison groups., Results: Apart from Age (mean ± SD years: 73.5 ± 2.1 vs 59.5 ± 5.9, p < 0.0001) and nerve-sparing status, the two groups were evenly matched for all covariates (p values > 0.05). Median follow-up was 10.6 years. There were no 90-day mortalities in either group. Minor complications (Clavien ≤ 2) were more common in the Age > 70 group (p = 0.0002). Operating room time (p = 0.83), length of hospital stay (p = 0.06) and catheterization duration (p = 0.13) were similar. On final pathology, a higher pT stage (p < 0.0001) and pN1 (p = 0.003) were observed in the Age > 70 group. However, this did not translate adversely into higher rates of positive surgical margin (p = 0.41) or biochemical relapse (p = 0.72). Allowing for the follow-up duration (median 10.6 years), cancer-specific survival was marginally significant (p = 0.05) with an observed lower rate in the Age > 70 group. In terms of functional outcomes, post-operative erectile dysfunction and pad-free continence were significantly better in the younger cohort (p < 0.0001)., Conclusions: Robot-assisted radical prostatectomy should not be denied to those over 70 years solely on the basis of age. Older men need to be counseled about the likelihood of encountering higher-risk features on final pathology and that their functional outcomes may be worse compared to a younger person.

Introduction: The use of volume-rendered images is gaining popularity in the surgical planning for complex procedures. IRIS™ is an interactive software that delivers three-dimensional (3D) virtual anatomical models. We aimed to evaluate the preoperative clinical utility of IRIS for patients with ≤T2 localized renal tumors who underwent either partial nephrectomy (PN) or radical nephrectomy (RN). Patients and Methods: Six urologists (four faculty and two trainees) reviewed CT scans of 40 cases over 2 study phases, using conventional two-dimensional (2D) CT alone (Phase-I), followed by the CT + IRIS 3D model (Phase-II). After each review, surgeons reported their decision on performing a PN or an RN and rated (Likert scale) their confidence in completing the procedure as well as how the imaging modality influenced specific procedural decisions. Modifications to the choice of procedure and confidence in decisions between both phases were compared for the same surgeon. Concordance between surgeons was also evaluated. Results: A total of 462 reviews were included in the analysis (231 in each phase). In 64% (95% CI: 58-70%) of reviews, surgeons reported that IRIS achieved a better spatial orientation, understanding of the anatomy, and offered additional information compared with 2D CT alone. IRIS impacted the planned procedure in 20% of the reviews (3.5% changed decision from PN to RN and 16.5% changed from RN to PN). In the remaining 80% of reviews, surgeons' confidence increased from 78% (95% CI: 72-84%) with 2D CT, to 87% (95% CI: 82-92%) with IRIS ( p  = 0.02); this confidence change was more pronounced in cases with a high RENAL score ( p  = 0.009). In 99% of the reviews, surgeons rated that the IRIS accurately represented the anatomical details of all kidney components. Conclusion: Application of IRIS 3D models could influence the surgical decision-making process and improve surgeons' confidence, especially for robot-assisted management of complex renal tumors.

This study focused on STK11, PTEN, KRAS, and TP53, which are often found to be mutated in lung cancer. We compared Stk11 and Pten implication in lung cancer in combination with loss of Trp53 and gain of function of Kras in a CRISPR/Cas9 mouse model. Mice with loss of Stk11, Trp53, and KrasG12D mutation (SKT) reached human endpoint at around four months post-initiation. In comparison, mice with loss of Pten, Trp53, and KrasG12D mutation (PKT) survived six months or longer post-initiation. Pathological examination revealed an increase in proliferation in SKT deficient lung epithelia compared to PKT. This difference was independent of Pten loss, indicating that loss of Pten is dispensable for cell proliferation in lung adenocarcinoma. Furthermore, tumors with loss of Stk11, Trp53, and KrasG12D mutation had a significantly higher progression rate, monitored by PET/MRI scanning, compared to mice with loss of Pten, Trp53, and KrasG12D mutation, revealing that mutations in Stk11 are essential for adenocarcinoma progression. Overall, by using the CRISPR/Cas9 mouse model of lung adenocarcinoma, we showed that mutations in Stk11 are a key driver, whereas loss of Pten is dispensable for adenocarcinoma progression.

Purpose: To assess the efficacy of an accelerated proficiency-based training protocol in robotic simulation practice in delivering durable proficiency compared to conventional training methods., Methods: Novice medical students (n = 16) were randomized into either the accelerated skills acquisition protocol (ASAP) or conventional training protocol (CTP). Subjects were trained to proficiency on the da Vinci Skills Simulator (dVSS) by an expert trainer. Differences in the repetitions required to achieve proficiency in two simple and two complex virtual reality (VR) training tasks were assessed as the primary outcome measure. Transfer of the acquired skills to two other non-practiced tasks was assessed immediately and prospectively followed through to 3, 6 and 12 months in the two groups. Retention of the practiced tasks was assessed along the same timeframe., Results: Subjects in the ASAP group acquired proficiency significantly faster in three of the four training tasks: camera control (p = 0.0002), suture sponge (p < 0.0001), ring walk3 (p < 0.0001), and peg board (p = 0.6936). When assessing transfer of skills, there were no significant differences between the two groups: Ring rail 3 (p = 0.6807) and Tubes (p = 0.2240). When assessing retention of skills at 3, 6 and 12 months, for all 6 tasks, no significant differences were seen between the ASAP and CTP groups., Conclusion: ASAP is proven to be an efficient approach for delivering proficiency in robotic VR simulation training. The results are durable when compared to conventional simulation training methods. The findings may have significant implications in the design of robotic VR simulation curricula.

Walking is one of the most relevant tasks that a person performs in their daily routine. Despite its mechanical complexities, any change in the external conditions that applies some external perturbation, or in the human musculoskeletal system that limits an individual's movement, entails a motor response that can either be compensatory or adaptive in nature. Incidentally, with aging or due to the occurrence of a neuro-musculoskeletal disorder, a combination of such changes including reduced sensory perception, muscle weakness, spasticity, etc. has been reported, and this can significantly degrade the human walking performance. Various studies in gait rehabilitation literature have identified a need for the development of better rehabilitation paradigms and have implied that an efficient human robot interaction is critical. Understanding how humans respond to a particular gait alteration can be beneficial in designing an effective rehabilitation paradigm. In this context, the current work investigates human locomotor adaptation to resistive alteration to the hip and ankle strategies of walking. A cable-driven robotic system, which does not add mobility constraints, was used to implement resistive force interventions within the hip and ankle joints separately through two experiments with eight healthy adult participants in each. In both cases, the intervention was applied during the push-off phase of walking, i.e., from pre-swing to terminal swing. The results showed that subjects in both groups adopted a compensatory response to the applied intervention and demonstrated intralimb and interlimb adaptation. Overall, the participants demonstrated a deviant gait implying lower limb musculoskeletal adjustments as if to compensate for a hip or ankle abnormality., (Copyright © 2020 Iyer, Joseph and Vashista.)

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and the incidence of HCC is increasing. Recently, cancer immunotherapy has emerged as an efficient treatment against some cancers. Here we have used a mouse model of mutagen-induced HCC to explore the therapeutic usefulness of targeting the DNA-activated STING pathway in HCC. STING-deficient mice exhibited unaltered initial development of HCC, but had higher number of large tumors at late stages of disease. In the liver of STING-deficient HCC mice, we observed reduced levels of phospho-STAT1, autophagy, and cleaved caspase3. These responses were activated in the liver by treatment with a cyclic dinucleotide (CDN) STING agonist. Importantly, CDN treatment of mice after HCC development efficiently reduced tumor size. Initiation of CDN treatment at an even later stage of disease to allow HCC detection by MR scanning revealed that the majority of tumors regressed in response to CDN, but new tumors were also detected, which were unresponsive to CDN treatment. Overall, the modulation of the STING pathway affects the development of HCC, and holds promise for a use as a treatment of this disease, most likely in combination with other immunomodulatory treatments such as PD1 inhibitors or with standard of care.

Objectives: To incorporate and validate clinically relevant performance metrics of simulation (CRPMS) into a hydrogel model for nerve-sparing robot-assisted radical prostatectomy (NS-RARP)., Materials and Methods: Anatomically accurate models of the human pelvis, bladder, prostate, urethra, neurovascular bundle (NVB) and relevant adjacent structures were created from patient MRI by injecting polyvinyl alcohol (PVA) hydrogels into three-dimensionally printed injection molds. The following steps of NS-RARP were simulated: bladder neck dissection; seminal vesicle mobilization; NVB dissection; and urethrovesical anastomosis (UVA). Five experts (caseload >500) and nine novices (caseload <50) completed the simulation. Force applied to the NVB during the dissection was quantified by a novel tension wire sensor system fabricated into the NVB. Post-simulation margin status (assessed by induction of chemiluminescent reaction with fluorescent dye mixed into the prostate PVA) and UVA weathertightness (via a standard 180-mL leak test) were also assessed. Objective scoring, using Global Evaluative Assessment of Robotic Skills (GEARS) and Robotic Anastomosis Competency Evaluation (RACE), was performed by two blinded surgeons. GEARS scores were correlated with forces applied to the NVB, and RACE scores were correlated with UVA leak rates., Results: The expert group achieved faster task-specific times for nerve-sparing (P = 0.007) and superior surgical margin results (P = 0.011). Nerve forces applied were significantly lower for the expert group with regard to maximum force (P = 0.011), average force (P = 0.011), peak frequency (P = 0.027) and total energy (P = 0.003). Higher force sensitivity (subcategory of GEARS score) and total GEARS score correlated with lower nerve forces (total energy in Joules) applied to NVB during the simulation with a correlation coefficient (r value) of -0.66 (P = 0.019) and -0.87 (P = 0.000), respectively. Both total and force sensitivity GEARS scores were significantly higher in the expert group compared to the novice group (P = 0.003). UVA leak rate highly correlated with total RACE score r value = -0.86 (P = 0.000). Mean RACE scores were also significantly different between novices and experts (P = 0.003)., Conclusion: We present a realistic, feedback-driven, full-immersion simulation platform for the development and evaluation of surgical skills pertinent to NS-RARP. The correlation of validated objective metrics (GEARS and RACE) with our CRPMS suggests their application as a novel method for real-time assessment and feedback during robotic surgery training. Further work is required to assess the ability to predict live surgical outcomes., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Background: Natural killer (NK) cells are potential effectors in anti-cancer immunotherapy; however only a subset potently kills cancer cells. Here, we examined whether pretreatment of glioblastoma (GBM) with the proteasome inhibitor, bortezomib (BTZ), might sensitize tumour cells to NK cell lysis by inducing stress antigens recognized by NK-activating receptors. Methods: Combination immunotherapy of NK cells with BTZ was studied in vitro against GBM cells and in a GBM-bearing mouse model. Tumour cells were derived from primary GBMs and NK cells from donors or patients. Flow cytometry was used for viability/cytotoxicity evaluation as well as in vitro and ex vivo phenotyping. We performed a Seahorse assay to assess oxygen consumption rates and mitochondrial function, Luminex ELISA to determine NK cell secretion, protein chemistry and LC-MS/MS to detect BTZ in brain tissue. MRI was used to monitor therapeutic efficacy in mice orthotopically implanted with GBM spheroids. Results: NK cells released IFNγ, perforin and granzyme A cytolytic granules upon recognition of stress-ligand expressing GBM cells, disrupted mitochondrial function and killed 24-46% of cells by apoptosis. Pretreatment with BTZ further increased stress-ligands, induced TRAIL-R2 expression and enhanced GBM lysis to 33-76% through augmented IFNγ release ( p < 0.05). Blocking NKG2D, TRAIL and TRAIL-R2 rescued GBM cells treated with BTZ from NK cells, p = 0.01. Adoptively transferred autologous NK-cells persisted in vivo ( p < 0.05), diminished tumour proliferation and prolonged survival alone (Log Rank 10.19 , p = 0.0014, 95%CI 0.252-0.523) or when combined with BTZ (Log Rank 5.25 , p = 0.0219, 95%CI 0.295-0.408), or either compared to vehicle controls (median 98 vs. 68 days and 80 vs. 68 days, respectively). BTZ crossed the blood-brain barrier, attenuated proteasomal activity in vivo ( p < 0.0001; p < 0.01 compared to vehicle control or NK cells only, respectively) and diminished tumour angiogenesis to promote survival compared to vehicle-treated controls (Log Rank 6.57 , p = 0.0104, 95%CI 0.284-0.424, median 83 vs. 68 days). However, NK ablation with anti-asialo-GM1 abrogated the therapeutic efficacy. Conclusions: NK cells alone or in combination with BTZ inhibit tumour growth, but the scheduling of BTZ in vivo requires further investigation to maximize its contribution to the efficacy of the combination regimen.

Background: Suicide gene therapy for malignant gliomas has shown encouraging results in the latest clinical trials. However, prodrug application was most often restricted to short-term treatment (14 days), especially when replication-defective vectors were used. We previously showed that a substantial fraction of herpes simplex virus thymidine kinase (HSV-TK) transduced tumor cells survive ganciclovir (GCV) treatment in an orthotopic glioblastoma (GBM) xenograft model. Here we analyzed whether these TK+ tumor cells are still sensitive to prodrug treatment and whether prolonged prodrug treatment can enhance treatment efficacy., Methods: Glioma cells positive for TK and green fluorescent protein (GFP) were sorted from xenograft tumors recurring after suicide gene therapy, and their sensitivity to GCV was tested in vitro. GBM xenografts were treated with HSV-TK/GCV, HSV-TK/valganciclovir (valGCV), or HSV-TK/valGCV + erlotinib. Tumor growth was analyzed by MRI, and survival as well as morphological and molecular changes were assessed., Results: TK-GFP+ tumor cells from recurrent xenograft tumors retained sensitivity to GCV in vitro. Importantly, a prolonged period (3 mo) of prodrug administration with valganciclovir (valGCV) resulted in a significant survival advantage compared with short-term (3 wk) application of GCV. Recurrent tumors from the treatment groups were more invasive and less angiogenic compared with primary tumors and showed significant upregulation of epidermal growth factor receptor (EGFR) expression. However, double treatment with the EGFR inhibitor erlotinib did not increase therapeutic efficacy., Conclusion: Long-term treatment with valGCV should be considered as a replacement for short-term treatment with GCV in clinical trials of HSV-TK mediated suicide gene therapy., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Multiparametric magnetic resonance imaging (mpMRI) for prostate cancer detection without careful patient selection may lead to excessive resource utilization and costs., Objective: To develop and validate a clinical tool for predicting the presence of high-risk lesions on mpMRI., Design, Setting, and Participants: Four tertiary care centers were included in this retrospective and prospective study (BiRCH Study Collaborative). Statistical models were generated using 1269 biopsy-naive, prior negative biopsy, and active surveillance patients who underwent mpMRI. Using age, prostate-specific antigen, and prostate volume, a support vector machine model was developed for predicting the probability of harboring Prostate Imaging Reporting and Data System 4 or 5 lesions. The accuracy of future predictions was then prospectively assessed in 214 consecutive patients., Outcome Measurements and Statistical Analysis: Receiver operating characteristic, calibration, and decision curves were generated to assess model performance., Results and Limitations: For biopsy-naïve and prior negative biopsy patients (n=811), the area under the curve (AUC) was 0.730 on internal validation. Excellent calibration and high net clinical benefit were observed. On prospective external validation at two separate institutions (n=88 and n=126), the machine learning model discriminated with AUCs of 0.740 and 0.744, respectively. The final model was developed on the Microsoft Azure Machine Learning platform (birch.azurewebsites.net). This model requires a prostate volume measurement as input., Conclusions: In patients who are naïve to biopsy or those with a prior negative biopsy, BiRCH models can be used to select patients for mpMRI., Patient Summary: In this multicenter study, we developed and prospectively validated a calculator that can be used to predict prostate magnetic resonance imaging (MRI) results using patient age, prostate-specific antigen, and prostate volume as input. This tool can aid health care professionals and patients to make an informed decision regarding whether to get an MRI., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction and Objectives: Robot-assisted simple prostatectomy (RASP) performed with the extraperitoneal (EP) technique (RASP-EP) minimizes the risk of bowel injury, particularly when bowel adhesions may be expected to be prominent, by negating the need to be in the transperitoneal space. However, there is a perception of its technical difficulty owing to the limited space that can be expanded within the space of Retzius. We aimed to describe, in the accompanying video, the step-by-step approach for a technically proficient procedure. Methods: From January 2010 to July 2018, 33 consecutive patients who had undergone RASP-EP were identified from our institutional database. Procedures were performed as described stepwise in the accompanying video. In RASP-EP, a 3 cm paraumbilical incision is made, anterior rectus sheath incised, muscle pushed laterally, and the EP space is entered. The EP space is expanded in the retropubic area using a balloon dilator and a blunt ended trocar, enabling the placement of further three ports for robot docking. A transverse capsulotomy, 2 cm from the bladder neck, is performed a la Millin's. Prostate adenoma is resected circumferentially. Electrocautery hemostasis is performed. Posterior bladder neck and urethra are sutured onto the prostatic fossa with 2-0 Vicryl. A 22F three-way catheter is placed. Anterior capsulotomy is closed in two layers with 2-0 and 0-0 Vicryl sutures. A drain is left in the retropubic space. Patient is discharged within 1-2 days with the catheter in situ , which is then removed 10 days later. Results: Of the 33 patients, median values were age (68), American Society of Anesthesiology (3), Charlson Comorbidity Index (3), and body mass index (28.5 kg/m 2 ). Eight (24.2%) patients had prior abdominal surgeries. Twenty-five (75.8%) patients were catheter dependent. Adjunctive procedures were cystolithotomy (5), umbilical hernia repair (2), and ureteroscopy (1). Median values were operative time (178 minutes), estimated blood loss (200 mL), hemoglobin change (2.8 g/dL), and hematocrit change (9%); only one patient (3.0%) required 1 U transfusion. Median length of stay was 2 days. Clavien-Dindo complications were 0 (21), I (7), II (3), IIIa (1), IIIb (1), IV, and V (0). Median resected prostate weight was 122 g. Incidental prostate cancer was found in three patients (9%); one patient required adjuvant radiotherapy. No patients were catheter-dependent postoperatively; mean postvoid residual was 29 mL (range 0-250 mL). Median follow-up was 4 months. Conclusions: RASP-EP is a safe and efficacious technique that should form the repertoire of a urologist's armamentarium when dealing with large adenomas, particularly when entry into the peritoneal cavity is to be avoided. No competing financial interests exist. Runtime of video: 7 mins 5 secs., Competing Interests: No competing financial interests exist., (© Pratik M. Gurung et al. 2020; Published by Mary Ann Liebert, Inc.)

Objective: To evaluate the role of antibiotic prophylaxis with oral ciprofloxacin prior to urinary catheter removal after radical prostatectomy in preventing urinary tract infection (UTI)., Materials and Methods: Patients undergoing radical prostatectomy were prospectively enrolled and randomized to either the antibiotic prophylaxis group (2 doses of oral ciprofloxacin prior to urinary catheter removal) or the control group (no antibiotics given prior to urinary catheter removal). Neither patients nor study providers were blinded to the group. The primary objective was to assess for development of UTI. The secondary objective was to assess for development of Clostridium difficile (C diff) enterocolitis. Continuous variables were compared using a 2-sample t test. Categorical variables were compared using Pearson's chi-squared test or Fisher's exact test., Results: One hundred seventy-five patients were enrolled and randomized (90 control and 85 antibiotic prophylaxis). After randomization, 4 patients were excluded and 4 patients withdrew voluntarily. One hundred sixty-seven patients (84 control and 83 antibiotic prophylaxis) completed the study and were available for analysis. There were no significant differences in baseline characteristics, perioperative data, or complications. There was no significant difference in the rate of UTI between the control group and antibiotic prophylaxis group (5.95% vs. 6.02%, P = 1). There was also no significant difference in the rates of C diff infection between the control and the antibiotic prophylaxis groups (3.57% vs. 0%, P = 0.21)., Conclusions: In this prospective, randomized, controlled trial, the use of antibiotic prophylaxis with oral ciprofloxacin prior to urinary catheter removal after radical prostatectomy did not decrease the rate of UTI, and was not associated with an increased incidence of C diff enterocolitis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) is the most aggressive brain malignancy in adults, where survival is approximately 14.6 months. Novel therapies are urgently needed and immunotherapy has hailed a new dawn for treatment of solid tumors. Natural killer (NK) cells may be amenable therapeutic effectors against heterogeneous GBM, since they also do not require co-stimulation and antigen specificity. However, it is unclear how culture media routinely used in pre-clinical studies affect GBM cell responses to NK-mediated cytotoxicity. We hypothesized that the culture medium would affect GBM cell phenotype, proliferation, and responses to NK cytotoxicity. We investigated in paired analyses n  = 6 patient-derived primary GBM cells propagated in stem cell or serum-containing medium for morphology, proliferation, as well as susceptibility to NK cytolysis and related this to expression of surface and intracellular lineage markers, as well as ligands for NK cell activating and inhibitory receptors. We genotyped the GBM cells for human leukocyte antigen (HLA) as well as the killer immunoglobulin-like receptors (KIR) of the n  = 6 allogeneic NK cells used as effector cells. Culture in serum-containing medium induced a switch in GBM cell morphology from suspension neuropsheres to adherent epithelial-mesenchymal-like phenotypes, which was partially reversible. The differentiated cells diminished expression of nestin, CD133 (prominin-1), and A2B5 putative glioma stem-cell markers, attenuated growth, diminished expression of ligands for activating NK cell receptors, while upregulating class I HLA ligands for NK cell inhibitory receptors. When maintained in serum-containing medium, fewer GBM cells expressed intercellular cell adhesion molecule-1 (ICAM-1) and were less susceptible to lysis by NK cells expressing α L β 2 integrin receptor (LFA-1), mediated through combination of inhibitory KIR-HLA ligand mismatch and diminished activation receptor-ligand interactions compared to cells maintained in stem cell media. We conclude that development of preclinical immunotherapy strategies against GBM should not use cells propagated in serum-containing media to avoid misinterpretation of potential therapeutic responses.

Robot-assisted radical prostatectomy (RARP) may be performed via an extraperitoneal (eRARP) or transperitoneal (tRARP) approach. There are no published studies comparing these two methods in patients with a history of prior inguinal hernia repair with mesh (IHRm), but the latter is often advocated in this setting. A retrospective review of patients who underwent RARP with prior IHRm who had a minimum follow-up of 3 months from July 1, 2003 to December 31, 2014 was undertaken. Of 2927 patients who underwent RARP for primary treatment of adenocarcinoma of the prostate, 286 patients had a clear history of IHRm. Of these, 116 patients underwent eRARP and 170 patients underwent tRARP. No differences were noted between the groups with respect to age, body mass index or American Society of Anesthesiology score. Patients in the tRARP group had higher D'Amico risk classification scores (p < 0.0001) and as such, underwent less nerve-sparing procedures (p < 0.0001) and had a higher rate of concomitant pelvic lymph node dissections (p < 0.0001). The tRARP group had a higher incidence of laparoscopic and bilateral IHRm. On univariate analysis, EBL was lower in the tRARP group (172.41 vs. 201.98, p = 0.05) but all other parameters were similar. After controlling for covariates using regression analysis with model selection, a trend was noted towards lower operating room time in the tRARP group (p = 0.0624) but no other differences were noted. The presence of prior IHRm does not seem to be a contraindication to eRARP. OR time may be lower with tRARP (trend) but all other quality indicators studied were similar.

Introduction: We investigated local resistance patterns to guide antibiotic use for the prevention of infections associated with transrectal prostate biopsy with ultrasound guidance., Methods: Per the AUA (American Urological Association) recommendations (2014 and 2016) for transrectal prostate biopsy with ultrasound guidance prophylaxis, local antibiogram resistance was reviewed. Rates of Escherichia coli fluoroquinolone resistance were between 20% and 28%. Thus, the antibiotics chosen were a single dose of oral ciprofloxacin and intramuscular ceftriaxone at least 30 minutes before transrectal prostate biopsy with ultrasound guidance. Data were reviewed retrospectively between July 2012 and December 2015. There was no standard prophylaxis before protocol implementation in August 2014. Univariable analyses were performed with appropriate testing followed by multivariable logistic regression., Results: Of 2,351 biopsies 799 were performed in patients in the protocol group. Before protocol implementation 26 different antibiotic regimens were used. The protocol group had significantly more cases of chronic kidney disease, a history of cancer, larger prostate volume and greater number of cores during transrectal prostate biopsy with ultrasound guidance. The overall hospital admission rate after transrectal prostate biopsy with ultrasound guidance was 1.35% for the nonprotocol group and 0.4% for the protocol group (p = 0.026). The incidence of organisms with antimicrobial resistance in blood and urine decreased from 20.7% (23 cases) in the nonprotocol group and 7.1% (4) in the protocol group (p=0.030). All positive blood cultures occurred in the nonprotocol group and all were ciprofloxacin resistant E. coli . On multivariable logistic regression those patients requiring hospitalization were 12.9 (95% CI 2.81-58.96) times more likely to have resistant organisms cultured (p=0.001)., Conclusions: The transrectal prostate biopsy with ultrasound guidance antibiotic prophylaxis protocol decreased unwanted variation among practitioners, which is ultimately associated withimproved quality. Antibiogram directed prophylaxis where there is high fluoroquinolone resistance maintains low infection and hospital admission rates after transrectal prostate biopsy with ultrasound guidance.

Introduction and Objective: With the peritoneum acting as a natural surface for lymphatic reabsorption, transperitoneal robot-assisted radical prostatectomy (tRARP) is thought to be associated with a lower incidence of symptomatic lymphoceles (SLs) compared with its extraperitoneal counterpart (eRARP) when bilateral pelvic lymph node dissection (BPLND) is performed. In this study, we aim to determine if there is a difference in SL formation and characteristics between the two approaches., Materials and Methods: We retrospectively reviewed the records of patients who underwent eRARP or tRARP and BPLND by a single surgeon at a tertiary care academic center from July 1, 2003, to May 31, 2016. Patients with a history of prior pelvic radiotherapy, concomitant inguinal hernia repair, RARP without BPLND, or nonadenocarcinoma of the prostate were excluded. The resulting eRARP and tRARP groups were propensity matched for age, body mass index (BMI), American Association of Anesthesiologists (ASA) score, D'Amico risk classification, and pathological lymph node (LN) count., Results: A total of 3183 RARPs were performed during this time period. After applying exclusion criteria and propensity score matching, 671 patients remained in each group. No statistically significant differences were noted between the groups with regard to age, BMI, ASA, pre-RARP prostate-specific antigen, D'Amico risk classification, biopsy and pathological Gleason sum score, pathological T stage, or margin status. The tRARP group had a higher clinical T stage (p = 0.0015), length of stay (LOS; p = 0.005), pathological N stage (4.92% vs 1.36%, p = 0.0002), and high total LN count (7.22 ± 5.54 vs 5.78 ± 4.18 LNs, p < 0.0001). The eRARP group had higher operating room times (197.4 ± 48.96 minutes vs 192.2 ± 44.12 minutes, p = 0.04) and estimated blood loss (218.4 ± 152.0 mL vs 179.9 ± 119.4 mL, p < 0.0001). No differences were noted in the frequency of SL formation [eRARP: 19/671 (2.83%) vs tRARP: 10/671 (1.49%), p = 0.09] or any clinical characteristics of the SL. Logistic regression analysis showed no effect of LN count (p = 0.071), pathological N stage (p = 0.111), or both combined (p = 0.085) on SL formation., Conclusions: In this cohort, the rate and clinical characteristics of SL were similar among patients treated with eRARP or tRARP and BPLND. The low event rate of SL in each group and trends favoring higher SL with LN yield and pN1 disease in the tRAPR group may deem the study underpowered to make definitive conclusions.

The epithelial-to mesenchymal (EMT) process is increasingly recognized for playing a key role in the progression, dissemination, and therapy resistance of epithelial tumors. Accumulating evidence suggests that EMT inducers also lead to a gain in mesenchymal properties and promote malignancy of nonepithelial tumors. In this review, we present and discuss current findings, illustrating the importance of EMT inducers in tumors originating from nonepithelial/mesenchymal tissues, including brain tumors, hematopoietic malignancies, and sarcomas. Among these tumors, the involvement of mesenchymal transition has been most extensively investigated in glioblastoma, providing proof for cell autonomous and microenvironment-derived stimuli that provoke EMT-like processes that regulate stem cell, invasive, and immunogenic properties as well as therapy resistance. The involvement of prominent EMT transcription factor families, such as TWIST, SNAI, and ZEB, in promoting therapy resistance and tumor aggressiveness has also been reported in lymphomas, leukemias, and sarcomas. A reverse process, resembling mesenchymal-to-epithelial transition (MET), seems particularly relevant for sarcomas, where (partial) epithelial differentiation is linked to less aggressive tumors and a better patient prognosis. Overall, a hybrid model in which more stable epithelial and mesenchymal intermediates exist likely extends to the biology of tumors originating from sources other than the epithelium. Deeper investigation and understanding of the EMT/MET machinery in nonepithelial tumors will shed light on the pathogenesis of these tumors, potentially paving the way toward the identification of clinically relevant biomarkers for prognosis and future therapeutic targets., (© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Introduction: We sought to determine the value of obtaining preoperative urinary cytology when diagnostic workup of an upper tract mass is suspicious for upper tract urothelial carcinoma (UTUC), but biopsy fails to confirm the diagnosis., Methods: Using billing code data, 239 patients were identified as having undergone radical nephroureterectomy (RNU) by 16 urologists from September 29, 1998 to July 31, 2015. Of this group, 19 adult patients had a presumed preoperative diagnosis of UTUC in a native kidney, at least three months of followup, no history of concurrent radical cystectomy with RNU, and negative/non-diagnostic tissue biopsy. These patients were divided into three groups: Group A had no urinary cytology taken (n=6); Group B had upper and/or lower tract cytology performed with neither positive nor atypical (n=7); Group C had upper and/or lower tract cytology performed with at least one positive or atypical (n=6)., Results: Demographic information and diagnostic workup was similar between the groups, although Group A had more patients with a history of prior radical cystectomy for bladder cancer (p=0.02). One patient in Group B had benign tissue on final pathology. All patients in Groups A and C had malignancy on final pathology and overall, the three groups had similar rates of malignancy., Conclusions: When a composite of clinical findings suggest UTUC, performing urinary cytology may not be necessary. A negative result in this setting should not be used to rule out UTUC, as this is often discordant with final pathology. A positive cytology result may help solidify the diagnosis when other findings are less clear., Competing Interests: Competing interests: The authors report no competing personal or financial interests.

Introduction: During robot-assisted radical prostatectomy (RARP), the prostate may be approached extraperiteoneally (extraperitoneal robot-assisted radical prostatectomy [eRARP]) or transperitoneally (transperitoneal robot-assisted radical prostatectomy [tRARP]). The former avoids the abdominal cavity, which might be of benefit in patients who have had prior abdominal or pelvic surgery (PAPS). Our objective was to compare the outcomes of patients with PAPS undergoing either technique., Methods: A retrospective review of patients treated with RARP from July 1, 2003 to December 31, 2014 with a minimum follow-up of 3 months was undertaken. Of 2927 patients, 620 were identified as having undergone RARP (without concomitant unrelated procedures) and PAPS (excluding patients with prior inguinal hernia repair with mesh or unclear surgical histories) for prostate adenocarcinoma without prior pelvic radiotherapy. Of these, 340 patients underwent eRARP and 280 patients underwent tRARP., Results: Patients in the eRARP group were younger (61.04 years vs 62.32, p = 0.02), had a higher body mass index (29.65 vs 28.98, p = 0.09), lower American Society of Anesthesiologists scores (p = 0.03), and lower D'Amico risk classification disease (p < 0.0001). The two groups had similar rates of 1, 2, and >2 PAPS. On univariate analysis, the eRARP group had lower operative time (188.96 minutes vs 197.92 minutes, p = 0.003), extensive lysis of adhesions (0.9% vs 14.3%, p < 0.0001), length of hospital stay (LOS) (1.13 days ±0.45 vs 1.33 day ±1.08, p = 0.003), and higher estimated blood loss (210.74 mL vs 190.79 mL, p = 0.06). The eRARP group had a lower rate of gastrointestinal complications (0% vs 3.21%, p = 0.0007), a trend toward lower early post-operative complications (8.53% vs 12.86%, p = 0.08), and lower overall complications (9.41% vs 15%, p = 0.03). In regression analysis with model selection, only LOS was lower in the eRARP group (p = 0.02)., Conclusions: Both methods are safe in patients with prior abdominal surgeries. A lower incidence of gastrointestinal complications and a shorter length of stay were noted in the extraperitoneal cohort.

Background: Invasion and angiogenesis are major hallmarks of glioblastoma (GBM) growth. While invasive tumor cells grow adjacent to blood vessels in normal brain tissue, tumor cells within neovascularized regions exhibit hypoxic stress and promote angiogenesis. The distinct microenvironments likely differentially affect metabolic processes within the tumor cells., Methods: In the present study, we analyzed gene expression and metabolic changes in a human GBM xenograft model that displayed invasive and angiogenic phenotypes. In addition, we used glioma patient biopsies to confirm the results from the xenograft model., Results: We demonstrate that the angiogenic switch in our xenograft model is linked to a proneural-to-mesenchymal transition that is associated with upregulation of the transcription factors BHLHE40, CEBPB, and STAT3. Metabolic analyses revealed that angiogenic xenografts employed higher rates of glycolysis compared with invasive xenografts. Likewise, patient biopsies exhibited higher expression of the glycolytic enzyme lactate dehydrogenase A and glucose transporter 1 in hypoxic areas compared with the invasive edge and lower-grade tumors. Analysis of the mitochondrial respiratory chain showed reduction of complex I in angiogenic xenografts and hypoxic regions of GBM samples compared with invasive xenografts, nonhypoxic GBM regions, and lower-grade tumors. In vitro hypoxia experiments additionally revealed metabolic adaptation of invasive tumor cells, which increased lactate production under long-term hypoxia., Conclusions: The use of glycolysis versus mitochondrial respiration for energy production within human GBM tumors is highly dependent on the specific microenvironment. The metabolic adaptability of GBM cells highlights the difficulty of targeting one specific metabolic pathway for effective therapeutic intervention., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Amplification of the epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are among the most common genetic alterations in glioblastoma (GBM), the most frequent and most aggressive primary brain tumor., Methods: In the present work, we analyzed the clonal evolution of these major EGFR aberrations in a small cohort of GBM patients using a unique surgical multisampling technique. Furthermore, we overexpressed both receptors separately and together in 2 patient-derived GBM stem cell lines (GSCs) to analyze their functions in vivo in orthotopic xenograft models., Results: In human GBM biopsies, we identified EGFR amplification as an early event because EGFRvIII mutations emerge from intratumoral heterogeneity later in tumor development. To investigate the biological relevance of this distinct developmental pattern, we established experimental model systems. In these models, EGFR + tumor cells showed activation of classical downstream signaling pathways upon EGF stimulation and displayed enhanced invasive growth without evidence of angiogenesis in vivo. In contrast, EGFRvIII + tumors were driven by activation of the prototypical Src family kinase c-Src that promoted VEGF secretion leading to angiogenic tumor growth., Conclusions: The presented work shows that sequential EGFR amplification and EGFRvIII mutations might represent concerted evolutionary events that drive the aggressive nature of GBM by promoting invasion and angiogenesis via distinct signaling pathways. In particular, c-SRC may be an attractive therapeutic target for tumors harboring EGFRvIII as we identified this protein specifically mediating angiogenic tumor growth downstream of EGFRvIII., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)