Van Renterghem Research Articles

Abstract 2587: Evaluating the potential of radiomics features to predict outcome to an antibody-drug conjugate therapy in non-small cell lung cancer patients

Abstract This study evaluated radiomics, a non-invasive biomarker, for assessment of tumor heterogeneity in non-small cell lung cancer (NSCLC) patients treated with an AXL-targeting antibody-drug conjugate (ADC), enapotamab vedotin (EnaV), through analyzing baseline and post-treatment radiomic features from CT images for predicting outcome. Clinical development of EnaV was discontinued in 2020 due to low response rates unimproved by dose optimization and/or predictive biomarkers. Study data included CT images, target expression and clinical data from 77 advanced NSCLC patients treated at 1.0 mg/kg (3Q4W), 1.8 mg/kg (Q3W), or 2.2 mg/kg EnaV (1Q3W) in the first in human phase I/II study assessing safety and preliminary efficacy of EnaV (NCT02988817). Radiologist-segmented tumors were examined using the cancer imaging phenomics tooklit CaPTk1, deriving 225 radiomic features from 77 baseline and 50 Cycle 2 post-treatment CT images. Batch effects were balanced using nested ComBat2, and radiomic feature dimensionality was reduced in two stages: clustering features with ≥80% similarity followed by principal component analysis (PCA). Radiomic PC1 was utilized in statistical models to assess overall and progression-free survival (OS, PFS), overall response rate (ORR), and disease control rate (DCR). Both baseline and delta radiomic PC1 were evaluated for correlation with biomarker and clinical activity, independently and with soluble or tumoral AXL expression. Baseline radiomic PC1 significantly predicted DCR: confirmed (p=0.03), and unconfirmed (p=0.03). Baseline tumor membrane AXL predicted ORR for this NSCLC subset: confirmed (p=0.03) or unconfirmed (p=0.02). Delta analysis showed delta PC1 predicted unconfirmed (p=0.03) and confirmed (p=0.03) DCR and remained predictive for DCR with soluble AXL (p=0.04). No association was found between baseline and delta radiomics with OS or PFS. Baseline and delta radiomic signatures showed potential in predicting NSCLC response. Preliminary findings suggest that radiomics combined with target expression predicted DCR, an early clinical activity indicator, although they did not predict OS or PFS. These outcomes pertain to a NSCLC subset and might not apply to other tumor types. Tumoral AXL expression did not linearly correlate with EnaV activity in a patient-derived soft tissue sarcoma model3, possibly due to AXL expression in both tumor cells and myeloid-derived suppressor cells, or the presence of tumor-intrinsic MMAE resistance4, implying the AXL expression and EnaV activity relationship is contingent on the tumor microenvironment5. Further validation in larger cohorts is planned. 1 Davatzikos C, et al. J Med. Imaging 2018 2 Horng H, et al. Sci. Reports 2022 3 Van Renterghem B, et al. Int J Mol Sci. 2022 4 Holtzhausen A, et al. Cancer Immunol Res 2019 5 Boshuizen J, et al. Cancer Res. 2021 Citation Format: Andrew W. Chen, Lauren K. Brady, Eric A. Cohen, Walter C. Mankowski, Leonid Roshkovan, Mohammed Qutaish, Sharyn Katz, Patricia G. Castro, Nora Pencheva, Maria Jure-Kunkel, Brandon W. Higgs, Despina Kontos. Evaluating the potential of radiomics features to predict outcome to an antibody-drug conjugate therapy in non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2587.

Abstract A50: IFNλ1 is a marker of DNA damage-triggered STING-signaling in lung cancer that induces immune activation through macrophage stimulation

Abstract Immunotherapy is a fundamental pillar in the treatment of lung cancer but remains inefficient in half of the treated patients. Recent clinical trials showed synergistic effects of combining chemotherapy and immunotherapy for lung cancer, suggesting that increased DNA damage imposed by chemotherapy modulates the tumor microenvironment to aid the efficacy of immunotherapy. But the immunological mechanisms related to this remains to be fully elucidated. The cGAS-STING pathway senses cytosolic DNA introduced by DNA-damaging agents such as chemotherapy. Activation of this pathway and induction of inflammatory cytokines may contribute to better immunotherapy efficacy. In particular, the release of type I IFN is a hallmark for STING pathway activation. However, we also know that IFNλ – a type III IFN – can be induced by STING-signaling. Despite the relevance of IFNλ in controlling inflammatory responses, its contribution in cancer remains unclear. Here, we investigated cGAS-STING expression and signaling in a panel of lung cancer cells. We identified IFNλ1 as an alternative hallmark for cGAS-STING DNA-sensing with higher expression after DNA-stimulation than IFNb in 6 out of 8 cell lines with one cell line having no IFNb expression at all. We then tested IFN induction after chemotherapeutic treatment in three different NSCLC cell lines and saw significant increase in both IFNb and IFNλ1 expression across four different chemotherapeutics, but with a higher fold change for IFNλ1. The induction of both IFNb and IFNλ1 was abolished when STING KO cell lines were treated with doxorubicin pointing to a STING-dependent response. To access the effect of IFNλ1 on macrophages, a prevalent cell type in the tumor microenvironment expressing IFNLR1, we performed RNA-sequencing on four primary human macrophage donors stimulated with IFNλ1. This stimulation led to a significant increase in well-known interferon-stimulated genes including the chemokines CXCL10 and CXCL11. We also explored whether IFNλ1 stimulation led to increased macrophage-dependent activation of autologous CD8+ T-cells. Interestingly, we found increased expression of both IFNg (p = 0.0215, n = 6) and Granzyme B (p = 0.0033, n = 6) measured by flow cytometry and ELISA (p > 0.0001, n = 6 for both). The addition of IFNλ1 during direct co-culture of macrophages and lung tumor organoids furthermore dampened the induction of the signal regulatory protein-a (SIRPa), a phagocytosis-inhibiting receptor, (p = 0.0041, n = 4) otherwise induced by the tumor organoids, but not matched healthy organoids. In support of this, there was an increased activation of CD8+ T-cells measured by IFNg production in an organoid-macrophage-CD8+ T-cell co-culture model. To summarize, we demonstrate that IFNλ1 may be a strong and broad marker of STING activation induced by chemotherapy in NSCLC and that IFNλ1 has the ability to prime a wider immune response by targeting macrophages. Hence, we propose that an IFNλ1 induced immune response has the potential to support and boost the response induced by existing immunotherapies. Citation Format: Kristine R Gammelgaard, Stine H Godsk, Albert G Olivier, Maria Riedel, Silke D Nielsen, Allard van Renterghem, Trine V Larsen, Anders Etzerodt, Emile Voest, Martin R Jakobsen. IFNλ1 is a marker of DNA damage-triggered STING-signaling in lung cancer that induces immune activation through macrophage stimulation [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A50.

Abstract 3100: XenoSarc: patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization

Abstract STS constitutes a family of rare mesenchymal tumors with more than 70 subtypes described. The limited treatment options available for advanced STS patients underline the need for reliable preclinical models to test new therapeutic approaches. We established a panel of PDX models (XenoSarc) by subcutaneous implantation of fresh tumor specimens in athymic mice (nu/nu NRMI). Once tumor growth was observed, pieces of tumor were re-transplanted to next generations of animals. At each passage tumor fragments were collected for histopathological and molecular characterization. In an ongoing effort 493 STS samples from 414 consenting patients treated at the University Hospitals, Leuven (Belgium) have been transplanted. A total of 67 PDX models from 20 STS subtypes have been established, meaning they have stable morphological, immunohistochemical and genetic characteristics over at least 2 passages. The PDX platform includes more common STS subtypes such as myxofibrosarcoma (n=12 models), gastrointestinal stromal tumors (9), dedifferentiated liposarcoma (10), and leiomyosarcoma (8), as well as models from ultra-rare subtypes, e.g. pulmonary intimal sarcoma, extraskeletal osteosarcoma, mesenchymal chondrosarcoma, myxoinflammatory fibroblastic sarcoma and others. All relevant details about the donor patient and tumor characteristics, including sensitivity to the standard treatments, are known for every model. The models are well-characterized, with availability of molecular information on genomic profile (by low-coverage whole genome sequencing), and expression profile (by RNA sequencing). Xenografts are accompanied by ready to use tissue microarrays (TMA) from the models, which can be exploited for target identification and model selection for preclinical studies. Ex-mouse material can also be used to establish primary cell cultures and 3D organoids for in vitro screening purposes. The XenoSarc platform offers opportunities for studying the biology of various sarcoma subtypes including ultra-rare entities and was found to be a very reliable tool for early drug screening in STS in preparation of clinical testing of novel compounds. The platform is available for collaborative preclinical projects with academic and industrial partners. Citation Format: Agnieszka Wozniak, Luna De Sutter, Lore De Cock, Britt Van Renterghem, Che-Jui Lee, Yannick Wang, Ulla Vanleeuw, Kimberly Verbeeck, Daphne Hompes, Friedl Sinnaeve, Hazem Wafa, Baki Topal, Joris Jaekers, Dirk Van Raemdonck, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski. XenoSarc: patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3100.

Etudes de genre et population fictionnelle des Mille et une nuits : nouvelle approche

Abstract Feminist approaches and gender studies are among the most notable works devoted to the Thousand and One Nights. Šahrazād monopolizes the attention and is treated as a monolithic character, there are in fact several Šahrazāds, depending on the textual version considered. The one who learns history and has three children (ZER) is not the same as the one who learns medicine and has no children (G/Kayseri). On the other hand, Šahrazād would benefit from being reintegrated into her universe beside the other characters: in the Nights, a story can occur with male protagonists (The Second Shaykh) and be repeated with female protagonists (The Eldest Lady), or feature characters who biologically change their gender, through metamorphosis or, in their appearance, through disguise. Such behavioral variations can affect the entire population of the Nights, which new work proposes to approach in the manner of demographers, as has been practiced for illustrated albums (Brugeilles, Cromer, and Cromer) and as Françoise Lavocat’s research on the French novel shows. Now, with some adjustments (Katz; van Renterghem), it seems possible to transpose this type of approach to medieval Arabic literature and more particularly to the Thousand and One Nights.

PD55-03 A RANDOMIZED TRIAL REGARDING ANTIMICROBIAL PROPHYLAXIS (AMP) IN TRANSURETHRAL RESECTION OF BLADDER TUMOR (TURB) IN SUPPORT OF ANTIMICROBIAL STEWARDSHIP

You have accessJournal of UrologyBladder Cancer: Invasive IV (PD55)1 Sep 2021PD55-03 A RANDOMIZED TRIAL REGARDING ANTIMICROBIAL PROPHYLAXIS (AMP) IN TRANSURETHRAL RESECTION OF BLADDER TUMOR (TURB) IN SUPPORT OF ANTIMICROBIAL STEWARDSHIP Evert Baten, Frank van der Aa, Hans Goethuys, Koen Slabbaert, Ingrid Arijs, and Koen van Renterghem Evert BatenEvert Baten More articles by this author , Frank van der AaFrank van der Aa More articles by this author , Hans GoethuysHans Goethuys More articles by this author , Koen SlabbaertKoen Slabbaert More articles by this author , Ingrid ArijsIngrid Arijs More articles by this author , and Koen van RenterghemKoen van Renterghem More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002089.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To determine whether omitting antimicrobial prophylaxis (AMP) in TURB is safe in patients undergoing TURB without an indwelling pre-operative catheter/nephrostomy/DJ and a negative pre-operative urinary culture. METHODS: A multi-centered randomized controlled trial (RCT) from 17-09-2017 until 31-12-2019 in 5 hospitals. Patients with a pre-operative indwelling catheter/DJ-stent or nephrostomy and a positive pre-operative urinary culture (> 104 uropathogens/mL) were excluded. Post-operative fever was defined as body temperature ≥ 38.3°C. A non-inferiority design with a 6% noninferiority margin and null hypothesis (H0) that the infection risk is at least 6% higher in the experimental (E) than in the control (C) group; H0: C (AMP-group) − E (no AMP-group) ≥ Δ (6% noninferiority margin) was used. A multivariable, logistic regression was performed with co-variates; AMP, tumor size and (clot-) retention. The R Project® for statistical computing was used for statistical analysis and a p value of 0.05 was considered as statistically significant. RESULTS: 459 Patients were included and 202/459 (44.1%) received AMP vs 257/459 (55.9%) without AMP. Fever occurred in 6/202 (2.9%; 95% CI [1.2%-6.6%]) patients with AMP vs 8/257 (3.1%; 95% CI [1.5%-6.1%]) without AMP (p=0.44). Multivariable, logistic regression showed no significant harm in omitting AMP when controlled for (clot-)retention and tumor size (p=0.85) and an adjusted risk difference in developing post-TURB fever of 0.0016; 95% CI [-0.029; 0.032]. CONCLUSIONS: Our data demonstrate the safety of omitting AMP in patients undergoing TURB without an indwelling, pre-operative catheter/nephrostomy/DJ and a negative pre-operative urinary culture. Source of Funding: / © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e997-e998 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Evert Baten More articles by this author Frank van der Aa More articles by this author Hans Goethuys More articles by this author Koen Slabbaert More articles by this author Ingrid Arijs More articles by this author Koen van Renterghem More articles by this author Expand All Advertisement Loading ...

PD18-01 ANTIMICROBIAL PROPHYLAXIS (AMP) IN TRANSURETHRAL RESECTION OF THE PROSTATE (TURP): RESULTS OF A RANDOMIZED TRIAL

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Surgical Therapy & New Technology III (PD18)1 Sep 2021PD18-01 ANTIMICROBIAL PROPHYLAXIS (AMP) IN TRANSURETHRAL RESECTION OF THE PROSTATE (TURP): RESULTS OF A RANDOMIZED TRIAL Evert Baten, Frank van der Aa, Hans Goethuys, Koen Slabbaert, Ingrid Arijs, and Koen van Renterghem Evert BatenEvert Baten More articles by this author , Frank van der AaFrank van der Aa More articles by this author , Hans GoethuysHans Goethuys More articles by this author , Koen SlabbaertKoen Slabbaert More articles by this author , Ingrid ArijsIngrid Arijs More articles by this author , and Koen van RenterghemKoen van Renterghem More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002007.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To determine whether omitting antimicrobial prophylaxis (AMP) in TURP is safe in patients undergoing TURP without pre-operative pyuria and a pre-operative catheter. METHODS: A multi-centered randomized controlled trial (RCT) from 17-09-2017 until 31-12-2019 in 5 hospitals. Patients with pyuria (> 100 white blood cells (WBC)/mL)) and a pre-operative, indwelling catheter were excluded. Post-operative fever was defined as a body temperature ≥ 38.3°C. A non-inferiority design with a 6% noninferiority margin and null hypothesis (H0) that the infection risk is at least 6% higher in the experimental (E) than in the control (C) group; H0: C (AMP-group) − E (no AMP-group) ≥ Δ (6% noninferiority margin). A multivariable, logistic regression was performed regarding post-TURP fever and AMP with co-variates: (clot-)retention and operating time. The R Project® for statistical computing was used and a p value of 0.05 was considered as statistically significant. RESULTS: 474 Patients were included for multivariable analysis and 211/474 (44.5%) received AMP vs 263/474 (55.5%) patients without AMP. Antibiotics were fluoroquinolones in 140/211 (66.4%), cephazolin in 58/211 (27.5%) and amikacin in 13/211 (6.2%) patients. Fever occurred in 9/211 (4.4%) patients with AMP vs 13/263 (4.9%) without AMP (p 0.8, risk difference (RD) 0.006 (95% CI [-0.003; 0.06], relative risk (RR) 1.16)). We were able to exclude a meaningful increase in harm associated with omitting AMP (p 0.4; adjusted RD 0.016 (95% CI [-0.02, 0.05])). CONCLUSIONS: Our data demonstrate the safety of omitting AMP in patients undergoing TURP without pre-operative pyuria and a pre-operative, indwelling catheter. Source of Funding: / © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e355-e355 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Evert Baten More articles by this author Frank van der Aa More articles by this author Hans Goethuys More articles by this author Koen Slabbaert More articles by this author Ingrid Arijs More articles by this author Koen van Renterghem More articles by this author Expand All Advertisement Loading ...

MP57-11 SATISFACTION RATES OF INFLATABLE PENILE PROSTHESIS IN MEN WHO HAVE SEX WITH MEN

You have accessJournal of UrologySexual Function/Dysfunction: Surgical Therapy (MP57)1 Sep 2021MP57-11 SATISFACTION RATES OF INFLATABLE PENILE PROSTHESIS IN MEN WHO HAVE SEX WITH MEN Charles Loeb, Justin La, Eric Chung, Martin Gross, Georgios Hatzichristodoulou, Sung Hun Park, Paul Perito, Alfredo Suarez Sarmiento, Koenraad van Renterghem, and Faysal Yafi Charles LoebCharles Loeb More articles by this author , Justin LaJustin La More articles by this author , Eric ChungEric Chung More articles by this author , Martin GrossMartin Gross More articles by this author , Georgios HatzichristodoulouGeorgios Hatzichristodoulou More articles by this author , Sung Hun ParkSung Hun Park More articles by this author , Paul PeritoPaul Perito More articles by this author , Alfredo Suarez SarmientoAlfredo Suarez Sarmiento More articles by this author , Koenraad van RenterghemKoenraad van Renterghem More articles by this author , and Faysal YafiFaysal Yafi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002087.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Men with erectile dysfunction have high patient satisfaction after placement of inflatable penile prostheses (IPP), but the impact on satisfaction and quality of life has never been studied in men who have sex with men (MSM) with erectile dysfunction.To assess the satisfaction rates and quality of life of MSM after placement of IPP for erectile dysfunction. METHODS: A multi-institutional, retrospective study enrolled adult men who self-identified as MSM and underwent inflatable penile prosthesis placement with either AMS 700TM LGX, AMS 700TM CX or Coloplast TitanTM models. Two questionnaires were administered at one timepoint post-operatively. The Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) is a 11-item validated questionnaire measured on a 0-100 scale. The Quality of Life and Sexuality with Penile Prosthesis (QoLSPP) is a 16-item questionnaire subcategorized into 4 domains: functional, relational, social, and personal. Fisher’s exact test and paired t-test were used to calculate significance with p-values <0.05 considered significant. RESULTS: Forty-nine MSM were assessed with a median age of 62 years (interquartile range [IQR], 53-69) with median follow-up of 14.2 months (IQR, 8.1-21.9). AMS 700TM LGX, AMS 700TM CX or Coloplast TitanTM IPPs were placed in 2, 2 and 45 men, respectively. For the entire cohort, the median EDITS score was 93 (IQR, 91-95) and the median QoLSPP scores each domain were functional 23/25 (IQR, 22-24), relational 17/20 (IQR, 15-18), social 15/15 (12-15), personal 18/20 (IQR, 17-19) with a total of 72/80 (IQR, 68-76). CONCLUSIONS: MSM report high satisfaction rates and quality of life after IPP placement for ED. This data may be useful when counseling prospective patients. Source of Funding: n/a © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e982-e982 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Charles Loeb More articles by this author Justin La More articles by this author Eric Chung More articles by this author Martin Gross More articles by this author Georgios Hatzichristodoulou More articles by this author Sung Hun Park More articles by this author Paul Perito More articles by this author Alfredo Suarez Sarmiento More articles by this author Koenraad van Renterghem More articles by this author Faysal Yafi More articles by this author Expand All Advertisement Loading ...

Management of Disastrous Complications of Penile Implant Surgery

Penile Prosthesis Implantation (PPI) is the definitive treatment for Erectile Dysfunction not responsive to conservative management strategies. Furthermore, it is a staple of surgical treatment of severe Peyronie's Disease (PD) and phallic reconstruction. Expert implantologists occasionally face disastrous complications of penile implant surgery which can prove to be very challenging. In this article we present a selected number of case reports which exemplify this kind of situations and discuss management strategies while also commenting on plausible aetiologies. The first case describes a PPI performed in end-stage fibrotic corpora after multiple instances of implantation/explant. The second and third cases show two diametrically opposed approaches to the management of glans necrosis after PPI in post-radical cystectomy patients. The fourth case describes the history of a diabetic patient suffering from glandular, corporal and urethral necrosis after a complicated PPI procedure. The fifth case reports the surgical treatment of a case of recurring PD due to severe scarring and shrinking of a vascular Dacron patch applied in a previous operation. Complication diagnosis in all patient was mainly clinical, intra- and postoperative, with Penile Color Doppler Ultrasonography performed when needed in order to demonstrate penile blood flow. The patients underwent complex surgical procedures that addressed each specific complication. Complex penile implants with fibrosis-related complications, penile prosthesis explant with and without surgical debridement of necrotic areas, penile prosthesis explant with necrotic penile shaft and urethral amputation with perineostomy, and complex corporoplasty with scar tissue excision and patch application with PPI were performed in the five patients. Penile anatomy and erectile function with PPI was achieved in 4 out of 5 patients. 1 of 5 patient is scheduled to undergo a total phallic reconstruction procedure at the time of this writing. Management of disastrous complications of penile implant surgery can be very challenging even in expert hands. In-and-out knowledge of possible PPI and PD complications is required to achieve an acceptable outcome. Bettocchi C, Osmonov D, van Renterghem K, etal. Management of Disastrous Complications of Penile Implant Surgery. J Sex Med 2021;18:1145-1157.

Antimicrobial Prophylaxis in Transurethral Resection of the Prostate: Results of a Randomized Trial.

We sought to determine whether omitting antimicrobial prophylaxis is safe in patients undergoing transurethral resection of the prostate without preoperative pyuria and a preoperative catheter. We conducted a multicenter randomized controlled trial from September 17, 2017 until December 31, 2019 in 5 hospitals. Patients with pyuria (>100 white blood cells/ml) and a preoperative indwelling catheter were excluded. Postoperative fever was defined as a body temperature ≥38.3C. A noninferiority design was used with a 6% noninferiority margin and null hypothesis (H0) that the infection risk is at least 6% higher in the experimental (E) than in the control (C) group; H0: C (antimicrobial prophylaxis group) - E (no antimicrobial prophylaxis group) ≥ Δ (6% noninferiority margin). A multivariable, logistic regression was performed regarding posttransurethral resection of the prostate fever and antimicrobial prophylaxis with co-variates: (clot-)retention and operating time. The R Project® for statistical computing was used and a p value of 0.05 was considered as statistically significant. Of the patients 474 were included for multivariable analysis and 211/474 (44.5%) received antimicrobial prophylaxis vs 263/474 (55.5%) patients without antimicrobial prophylaxis. Antibiotics were fluoroquinolones in 140/211 (66.4%), cephazolin in 58/211 (27.5%) and amikacin in 13/211 (6.2%) patients. Fever occurred in 9/211 (4.4%) patients with antimicrobial prophylaxis vs 13/263 (4.9%) without antimicrobial prophylaxis (p=0.8, risk difference 0.006 [95% CI -0.003-0.06, relative risk 1.16]). We were able to exclude a meaningful increase in harm associated with omitting antimicrobial prophylaxis (p=0.4; adjusted risk difference 0.016 [95% CI -0.02-0.05]). Our data demonstrate the safety of omitting antimicrobial prophylaxis in patients undergoing transurethral resection of the prostate without preoperative pyuria and a preoperative indwelling catheter.

First impressions: Use of the Azoth Systems O'Dive subclavian bubble monitor on a liveaboard dive vessel.

The Azoth Systems O'Dive bubble monitor is marketed at recreational and professional divers as a tool to improve personal diving decompression safety. We report the use of this tool during a 12-day dive trip aboard a liveaboard vessel. Six divers were consistently monitored according to the user manual of the O'Dive system. Data were synchronised with the Azoth server whenever possible (depending on cell phone data signal). Information regarding ease of use, diver acceptance and influence on dive behaviour were recorded. In total, 157 dives were completely monitored over 11 diving days. Formal evaluations were only available after six days because of internet connection problems. Sixty-one dives resulted in the detection of bubbles, mostly in one diver, none of which produced any symptoms of decompression illness. The O'Dive system may contribute to increasing dive safety by making divers immediately aware of the potential consequences of certain types of diving behaviour. It was noted that bubble monitoring either reinforced divers in their safe diving habits or incited them to modify their dive planning. Whether this is a lasting effect is not known.

Abstract 1117: XenoSarc: Patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization

Abstract Background: STS constitutes a rare family of mesenchymal tumors with more than 70 subtypes classified by WHO (2013). The limited treatment options available for advanced STS underline the need for reliable preclinical models, especially from ultra-rare subtypes, to test novel therapeutic strategies. Methods: A panel of PDX models was established by subcutaneous implantation of fresh tumor specimens in immunodeficient, athymic nude NMRI mice. Once tumor growth was observed, pieces of tumor were re-transplanted to next generations of mice. At each passage tumor fragments were collected for histopathological and molecular characterization. A model was considered “established” after observing stable histological and molecular features for at least two passages. Furthermore, ex-mouse tumor tissue samples were stored, further characterized by immunocytology and flow cytometry and cultured to be used for in vitro drug testing. Results: Between September 2011 and November 2019, 375 STS samples from 325 consenting patients treated at the University Hospitals, Leuven, Belgium have been transplanted. A total of 56 PDX models were established, maintaining the histopathological and molecular features of the original tumor. Detailed clinical information about the donor patient and tumor characteristics (including sensitivity to standard and experimental agents), is known for every model. At present the XenoSarc platform includes ready to use models of dedifferentiated liposarcoma (11 models), gastrointestinal stromal tumor (8), myxofibrosarcoma (8), leiomyosarcoma (7), malignant peripheral nerve sheath tumor (3), synovial sarcoma (2), pulmonary artery intimal sarcoma (2), epithelioid hemangioendothelioma (1), mesenchymal chondrosarcoma (1), pleomorphic rhabdomyosarcoma (1), CIC-rearranged round cell sarcoma (1), myxoinflammatory fibroblastic sarcoma (1), rhabdomyosarcoma not otherwise specified (NOS) (1), telangiectatic extraskeletal osteosarcoma (1), extraskeletal osteosarcoma (1) and high-grade undifferentiated pleomorphic sarcoma (7). These models are well-characterized, including molecular information on copy number changes (by low-coverage whole genome sequencing), gene expression profile (by RNA-Seq) and targeted sequencing to detect mutations in genes involved in tumorigenesis. In addition, we have constructed tissue microarrays (TMA) from the xenografts which are used for target identification and model selection for preclinical studies. We are using the xenografts for in vivo testing of novel agents, including targeted and cytotoxic (pro-)drugs, and results already served as rationale for a number of prospective clinical trials. A total of 27 other xenografts are still in early stages of engraftment, not yet fulfilling our criteria of an “established” model. Conclusion: The XenoSarc platform offers a lot of opportunities for studying the biology of a variety of important sarcoma subtypes including ultra-rare entities, and has proven efficiency for early drug screening in STS in preparation of clinical testing of novel compounds. The platform is well maintained and continuously expanded, and available to collaborators from academia and industry. Citation Format: Agnieszka Wozniak, Britt Van Renterghem, Jasmien Cornillie, Yannick Wang, Che-Jui Lee, Jasmien Wellens, Ulla Vanleeuw, Madita Nysen, Daphne Hompes, Friedl Sinnaeve, Hazem Wafa, Baki Topal, Tom Verbelen, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski. XenoSarc: Patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1117.

A Modified Surgical Technique for Reservoir Placement During Inflatable Penile Prosthesis Implantation.

IntroductionAt the moment, there is an ongoing debate regarding the controversial issue of the ideal reservoir placement (RP) surgical technique during implantation of a 3-piece inflatable penile prosthesis, but a definitive winner has not yet emerged.AimIn this light, we herein describe our modified technique for RP into the space of Retzius through the external oblique muscle fascia and present its results.MethodsIn total, 253 inflatable penile prosthesis procedures (110 AMS 700 and 143 Coloplast Titan) via a single transverse penoscrotal incision were retrospectively reviewed. 2 Kocher-Langenbeck retractors were placed over the right side of the penoscrotal incision and were used to retract the incision superior to the pubic bone. Then, the external oblique muscle fascia was incised medially to the spermatic cord which was retracted laterally. Next, a “W”, Vicryl 1, stay suture was placed to the incision, and under direct visualization, external oblique muscle fibers were dissected and fascia transversalis was perforated using a Metzenbaum scissor. A Foerster lung grasping clamp was then used to dissect further into the extraperitoneal space and create the reservoir space. The reservoir was placed into the created space and fascia incision was closed using the prepositioned stay suture. The procedure was then completed in a standard fashion.OutcomesThe main outcome measures were intraoperative or postoperative complications of our modified RP technique.ResultsAll 253 patients were available for short-term follow-up (average 9.1 months, range 3–22 months). No intraoperative or postoperative complications were reported. Reservoir-related prolonged pain (1 month) was reported by 1 patient, resolving completely after treatment with non-steroidal analgesics.ConclusionWe are, surely, not proposing that our modified RP technique should supplant all other methods; rather, it should be considered another useful option for RP in the implanter’s armamentarium.Mykoniatis I, Osmonov D, van Renterghem K. A Modified Surgical Technique for Reservoir Placement During Inatable Penile Prosthesis Implantation. Sex Med 2020;8:378–382.

Radiation effects across classes of materials

physica status solidi (a)Volume 213, Issue 11 p. 2959-2959 PrefaceFree Access Radiation effects across classes of materials First published: 15 November 2016 https://doi.org/10.1002/pssa.201670677AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL The Advances in Materials & Processing Technologies Conference, AMPT 2015, took place at the Carlos III University in Leganés, Madrid (Spain), from December 14–17, 2015. This conference series started in 1993 and it is held every two years with multiple parallel sessions covering a broad range of topics related to advances in materials engineering. This year, and for the first time in this conference series, there was a symposium devoted to radiation effects of materials: Characterization and Modelling of radiation effects across classes of materials. The goal of this symposium was to shed light on the physical mechanisms driving the change of properties due to irradiation in different classes of materials, from those used in nuclear applications to those of interest to the semiconductor industry, highlighting commonalities and differences. The symposium was very successful, with 41 oral presentations from 11 different countries. We want to thank all the participants and specially the keynote presenters that introduced the different topics discussed in this symposium: Cristelle Pareige (CNRS/GPM), Enrique Martínez (LANL), Antonio Rivera (UPM), Matthias Krack (PSI), Catherine Sabathier (CEA/DEN/ DEC), Frederic Mazen (CEA/LETI), Marta Serrano (CIEMAT), Michael Fluss (LLNL), Fernando Agullo- Lopez (UAM) and Kai Nordlund (UH). The topics covered included both experimental results and modelling in the area of radiation effects in different materials. Reflecting the current interest in this field, most of the talks were devoted to nuclear materials, both structural materials, mainly tungsten and iron based alloys, and nuclear fuels. Other topics discussed were the effect of irradiation in semiconductor materials, particularly silicon and the effect of radiation in complex materials such as high-entropy alloys. One common feature in this symposium was the importance of modelling in the understanding and development of materials. In this Special Section of physica status solidi (a) a representation of some of the topics covered in this symposium is presented, starting with a Feature Article on radiation effects in oxides 1 and followed by contributions on modelling microstructure evolution with object kinetic Monte Carlo in iron-based alloys 2-5, understanding point defects in silicon carbide 6 and modeling aluminum alloys 7. Guest Editors Ignacio Martin-Bragado, Lorenzo Malerba, María José Caturla, and Marjorie Bertolus References 1 F. Agulló-López, A. Climent-Font, A. Muñoz-Martin, and A. Zucchiatti, Phys. Status Solidi A. 213 (11), 2960 (2016), this issue. 2 M. J. Aliaga, I. Dopico, I. Martin-Bragado, and M. J. Caturla, Phys. Status Solidi A. 213 (11), 2969 (2016), this issue. 3 L. Messina, M. Chiapetto, P. Olsson, C. S. Becquart, and L. Malerba, Phys. Status Solidi A. 213 (11), 2974 (2016), this issue. 4 M. Chiapetto, L. Malerba, A. Puype, and C. S. Becquart, Phys. Status Solidi A. 213 (11), 2981 (2016), this issue. 5 M. J. Konstantinović, W. Van Renterghem, M. Matijašević, B. Minov, M. Lambrecht, T. Toyama, M. Chiapetto, and L. Malerba, Phys. Status Solidi A. 213 (11), 2988 (2016), this issue. 6 G. Roma, Phys. Status Solidi A. 213 (11), 2995 (2016), this issue. 7 S. I. Choi, G.-G. Lee, J. Kwon, and J. H. Kim, Phys. Status Solidi A. 213 (11), 3000 (2016), this issue. Volume213, Issue11November 2016Pages 2959-2959 ReferencesRelatedInformation

Analytical challenges and solutions in doping control: a perspective from the Swedish Doping Control Laboratory.

BioanalysisVol. 8, No. 8 CommentaryAnalytical challenges and solutions in doping control: a perspective from the Swedish Doping Control LaboratoryMagnus EricssonMagnus Ericsson*Author for correspondence: E-mail Address: dopinglab@karolinska.se Doping Control Laboratory, Clinical Pharmacology, Karolinska University Hospital, Stockholm, SE 141 86, SwedenSearch for more papers by this authorPublished Online:23 Mar 2016https://doi.org/10.4155/bio-2016-0037AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: GC–MS/MSLC-HRMSOlympic GamesReferences1 World Anti-Doping Agency. The Prohibited List 2016. www.wada-ama.org.Google Scholar2 World Anti-Doping Agency. International Standard for Laboratories (ISL). www.wada-ama.org.Google Scholar3 Badoud F, Grataa E, Perrenoud L et al. Fast analysis of doping agents in urine by ultra-high-pressure liquid chromatography–quadrupole time-of-flight mass spectrometry I. Screening analysis. J. Chromatogr. A 1216, 4423–4433 (2009).Crossref, Medline, CAS, Google Scholar4 Girón A J, Deventer K, Roels K, Van Eenoo P. Development and validation of an open screening method for diuretics, stimulants and selected compounds in human urine by UHPLC–HRMS for doping control. Anal. Chim. Acta 721, 137–146 (2012).Crossref, Medline, Google Scholar5 World Anti-Doping Agency. The Technical document TD2016EAAS. www.wada-ama.org.Google Scholar6 Thörngren JO, Östervall F, Garle M. A high-throughput multicomponent screening method for diuretics, masking agents, central nervous system (CNS) stimulants and opiates in human urine by UPLC–MS/MS. J. Mass Spectrom. 43, 980–992 (2008).Crossref, Medline, Google Scholar7 World Anti-Doping Agency. The Technical document TD2015MRPL. www.wada-ama.org.Google Scholar8 Sottas PE, Saugy M, Saudan C. Endogenous steroid profiling in the athlete biological passport. Endocrinol. Metab. Clin. North Am. 39, 59 (2011).Crossref, Google Scholar9 Boscha J, Such-Sanmartína G, Seguraa J, Gutiérrez-Gallego B R. Tracking growth hormone abuse in sport: performance of marker proteins in a controlled setting. Anal. Chim. Acta 745, 118–123 (2012).Crossref, Medline, Google Scholar10 Van Renterghem P, Van Eenoo P, Sottas PE, Saugy M, Delbeke F. A pilot study on subject-based comprehensive steroid profiling: novel biomarkers to detect testosterone misuse in sports. Clin. Endocrinol. (Oxf.) 75(1), 134–140 (2011).Crossref, Medline, CAS, Google Scholar11 Schänzer W, Guddat S, Thomas A, Opfermann G, Geyer H, Thevis M. Expanding analytical possibilities concerning the detection of stanozolol misuse by means of high resolution/high accuracy mass spectrometric detection of stanozolol glucuronides in human sports drug testing. Drug Test. Anal. 5, 11–12 (2013).Crossref, Google Scholar12 Sobolevsky T, Rodchenkov G. Detection and mass spectrometric characterization of novel long-term dehydrochloromethyltestosterone metabolites in human urine. J. Steroid Biochem. Mol. Biol. 128(3–5), 121–127 (2012).Crossref, Medline, CAS, Google Scholar13 Buisson C, Marchand A, Bailloux I, Lahaussois A, Martin L, Molina A. Detection by LC–MS/MS of HIF stabilizer FG-4592 used as a new doping agent: Investigation on a positive case. J. Pharm. Biomed. Anal. 121, 181–187 (2016).Crossref, Medline, CAS, Google Scholar14 Leuenberger N, Barras L, Nicoli R et al. Hepcidin as a new biomarker for detecting autologous blood transfusion. Am. J. Hematol. doi: 10.1002/ajh.24313 (2016) (Epub ahead of print).Crossref, Medline, Google Scholar15 Malm C, Frangsmyr L, Holmberg S. Detection of autologous blood transfusion by proteomics: screening to find unique biomarkers. www.wada-ama.org/en/resources/science-medicine/detection-of-autologous-blood-transfusion-by-proteomicsscreening-to-find.Google ScholarFiguresReferencesRelatedDetailsCited ByCubosomic Supramolecular Solvents: Synthesis, Characterization, and Potential for High-Throughput Multiclass Testing of Banned Substances in Urine22 February 2022 | Analytical Chemistry, Vol. 94, No. 9Interest of HRMS systems in analytical toxicology: Focus on doping productsToxicologie Analytique et Clinique, Vol. 8A comprehensive study on the performance of different retention mechanisms in sport drug testing by liquid chromatography tandem mass spectrometryJournal of Chromatography B, Vol. 1178Supramolecular solvents in microextraction techniquesTwenty years of supramolecular solvents in sample preparation for chromatography: achievements and challenges ahead23 March 2020 | Analytical and Bioanalytical Chemistry, Vol. 412, No. 24Development and validation of a UHPLC-HRMS method for the simultaneous determination of the endogenous anabolic androgenic steroids in human serumJournal of Chromatography A, Vol. 1613Comprehensive analysis by liquid chromatography Q-Orbitrap mass spectrometry: Fast screening of peptides and organic molecules18 April 2018 | Journal of Mass Spectrometry, Vol. 53, No. 6 Vol. 8, No. 8 Follow us on social media for the latest updates Metrics Downloaded 162 times History Published online 23 March 2016 Published in print April 2016 Information© Future Science LtdKeywordsGC–MS/MSLC-HRMSOlympic GamesFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download

MP47-20 INCREASED RHO-KINASE 2 AND AN INCREASE OF SYNTHETIC SMOOTH MUSCLE-SPECIFIC MARKER EXPRESSION IS OBSERVED IN THE CORPUS CAVERNOSUM OF PATIENTS WITH SEVERE ERECTILE DYSFUNCTION.

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research II1 Apr 2014MP47-20 INCREASED RHO-KINASE 2 AND AN INCREASE OF SYNTHETIC SMOOTH MUSCLE-SPECIFIC MARKER EXPRESSION IS OBSERVED IN THE CORPUS CAVERNOSUM OF PATIENTS WITH SEVERE ERECTILE DYSFUNCTION. Maarten Albersen, Trinity Bivalacqua, Johanna Hannan, Loes Linsen, Emmanuel Weyne, Hanna Tinel, Peter Sandner, Pieter Uvin, and Koenraad Van Renterghem Maarten AlbersenMaarten Albersen More articles by this author , Trinity BivalacquaTrinity Bivalacqua More articles by this author , Johanna HannanJohanna Hannan More articles by this author , Loes LinsenLoes Linsen More articles by this author , Emmanuel WeyneEmmanuel Weyne More articles by this author , Hanna TinelHanna Tinel More articles by this author , Peter SandnerPeter Sandner More articles by this author , Pieter UvinPieter Uvin More articles by this author , and Koenraad Van RenterghemKoenraad Van Renterghem More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1473AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Various animal models of erectile dysfunction (ED) have consistently shown upregulation of the RhoA/Rho associated protein kinase (ROCK) pathway, specifically isoform ROCK2, in the corpus cavernosum (CC). In vascular diseases such as hypertension and atherosclerosis, a long-term increased ROCK activation and/or upregulation results in vascular wall fibrosis by inducing a phenotypical switch from contractile smooth muscle cells (SMCs) to synthetic SMCs, also termed myofibroblasts (MFs). This switch in phenotype reflects a continuum, in which various phenotypical states are reflected by the expression of a distinct set of markers. Alpha-SMC actin (aSMA) is expressed in both contractile SMCs as well as in MFs. SMC heavy chain kinase (MYH11)is almost exclusively expressed in contractile SMCs, and is not expressed in MFs. We aimed to see whether phenotypical changes are occurring in the human CC SMCs by examining expression of ROCK mRNA and evaluating the regulation of genes involved in the phenotypical switch of SMCs. Methods Specimen of human CC were harvested from consenting patients undergoing penile prosthesis implantation (n=14 patients) and potent control subjects (n=5 healthy controls, needle biopsy). Tissues of patients were compared to those of healthy controls for the expression of mRNA coding for ROCK1, ROCK2, MYH11 and aSMA by qPCR and normalized to the expression of beta-actin. ROCK and aSMA proteins were further localized using immunofluorescence. Statistical analysis was performed using Student’s t-test or Mann–Whitney test, depending on normality of data. Data are reported as mean±SEM. Results aSMA, was expressed more in CC from ED vs control men (relative expression 504243±15265 vs 385483±25456 P<0.05), while MYH11 was downregulated 6-fold in ED patients (26916±5131 vs 156658±14333 P<0.05). ROCK1 was unchanged (P>0.05), while ROCK2 (7570±3013 vs 2924±432 P<0.05) was significantly upregulated in ED patients. ROCK protein colocalized with aSMA, confirming the presence of this kinase in SMCs and MFs. Conclusions We provide evidence of a dysregulation between aSMA and MYH11 expression in human erectile tissue. A decrease of MYH11 expression is indicative of a loss of SMC contractile phenotype. As ROCK2 was upregulated, we postulate that chronic ROCK inhibition may be a future pharmacological target in humans for preventing ED by interfering with smooth muscle phenotype transition. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e526 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Maarten Albersen More articles by this author Trinity Bivalacqua More articles by this author Johanna Hannan More articles by this author Loes Linsen More articles by this author Emmanuel Weyne More articles by this author Hanna Tinel More articles by this author Peter Sandner More articles by this author Pieter Uvin More articles by this author Koenraad Van Renterghem More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

GABAA Receptor α and γ Subunits Shape Synaptic Currents via Different Mechanisms

Synaptic GABAA receptors (GABAARs) mediate most of the inhibitory neurotransmission in the brain. The majority of these receptors are comprised of α1, β2, and γ2 subunits. The amygdala, a structure involved in processing emotional stimuli, expresses α2 and γ1 subunits at high levels. The effect of these subunits on GABAAR-mediated synaptic transmission is not known. Understanding the influence of these subunits on GABAAR-mediated synaptic currents may help in identifying the roles and locations of amygdala synapses that contain these subunits. Here, we describe the biophysical and synaptic properties of pure populations of α1β2γ2, α2β2γ2, α1β2γ1 and α2β2γ1 GABAARs. Their synaptic properties were examined in engineered synapses, whereas their kinetic properties were studied using rapid agonist application, and single channel recordings. All macropatch currents activated rapidly (<1 ms) and deactivated as a function of the α-subunit, with α2-containing GABAARs consistently deactivating ∼10-fold more slowly. Single channel analysis revealed that the slower current decay of α2-containing GABAARs was due to longer burst durations at low GABA concentrations, corresponding to a ∼4-fold higher affinity for GABA. Synaptic currents revealed a different pattern of activation and deactivation to that of macropatch data. The inclusion of α2 and γ1 subunits slowed both the activation and deactivation rates, suggesting that receptors containing these subunits cluster more diffusely at synapses. Switching the intracellular domains of the γ2 and γ1 subunits substantiated this inference. Because this region determines post-synaptic localization, we hypothesize that GABAARs containing γ1 and γ2 use different mechanisms for synaptic clustering.

Structural Basis for Allosteric Coupling at the Membrane-Protein Interface in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC)

Ligand binding at the extracellular domain of pentameric ligand-gated ion channels initiates a relay of conformational changes that culminates at the gate within the transmembrane domain. The interface between the two domains is a key structural entity that governs gating. Molecular events in signal transduction at the interface are poorly defined because of its intrinsically dynamic nature combined with functional modulation by membrane lipid and water vestibules. Here we used electron paramagnetic resonance spectroscopy to delineate protein motions underlying Gloeobacter violaceus ligand-gated ion channel gating in a membrane environment and report the interface conformation in the closed and the desensitized states. Extensive intrasubunit interactions were observed in the closed state that are weakened upon desensitization and replaced by newer intersubunit contacts. Gating involves major rearrangements of the interfacial loops, accompanied by reorganization of the protein-lipid-water interface. These structural changes may serve as targets for modulation of gating by lipids, alcohols, and amphipathic drug molecules.

Costs in medicine - the lesser of two evils.

Many aspire to drive a modern car with high engine power and modern equipment with all the new fancy tools rather than the average, small and poorly outfitted one. However, can we all afford it? The answer seems obvious, doesn't it?! We deeply acknowledge the thoughtful editorial by Prof. Mark Soloway [1] written in response to the article published in a recent edition of CEJU [2] and agree with the statement that it is better to have a pathological report instead of having only preoperative diagnostics. The purpose of the study was to establish the subgroup of surgically managed patients due to BPH who might be spared the histologic evaluation of the specimen, yet have no compromise in the diagnosis of contingent cancer (PCa – prostate cancer). Although we feel such a group exists, we were unable to discover clinical features to support the hypothesis. It is reasonable to consider that the better the diagnostic modalities implemented in prostate cancer explorations, the lower the need for pathological evaluation of the specimens received after BPH surgery. After all, ablative techniques are becoming more widely applied year by year. According to our data, it is easier to select patients in whom pathological examination of the specimen taken during BPH surgery is mandatory than those in whom it would bring only benign histology. These are mainly young adults in whom omitting potentially curable cancer may be harmful, including those who underwent negative biopsy before prostate surgery but are still suspected to have cancer. Our data suggests that the risk of incidental cancer diagnosis is greater in those patients. A few years ago van Renterghem et al. showed that TURP performed in patients previously subjected to multiple prostate biopsies improves prostate cancer diagnosis [3]. Even extended biopsy protocols are not fully accurate in regard to the oncological characteristics of cancer. To elaborate active surveillance (AS) mentioned in the editorial, we may speculate upon those who undergo management yet still experience deterioration of their lower urinary tract symptoms and deny radical surgery. In the absence of data suggesting otherwise, we think pathological examination of specimen taken after BPH surgery should not be omitted in patients submitted to AS. If cancer progression is observed, radiation may be introduced. Nowadays, with the availability of sophisticated diagnostic tools, the need for searching for cancer in surgical specimens extracted from elderly males with no suggestive clinical symptoms needs at least some attention. The risk of diagnosis and death due to PCa in this cohort is extremely low. If it is too risky to abandon histological examination of tissue removed during benign prostate hyperplasia surgery should we eliminate minimally invasive or vaporization techniques from our practice altogether?

Propofol Binding to the Resting State of the Gloeobacter violaceus Ligand-gated Ion Channel (GLIC) Induces Structural Changes in the Inter- and Intrasubunit Transmembrane Domain (TMD) Cavities

General anesthetics exert many of their CNS actions by binding to and modulating membrane-embedded pentameric ligand-gated ion channels (pLGICs). The structural mechanisms underlying how anesthetics modulate pLGIC function remain largely unknown. GLIC, a prokaryotic pLGIC homologue, is inhibited by general anesthetics, suggesting anesthetics stabilize a closed channel state, but in anesthetic-bound GLIC crystal structures the channel appears open. Here, using functional GLIC channels expressed in oocytes, we examined whether propofol induces structural rearrangements in the GLIC transmembrane domain (TMD). Residues in the GLIC TMD that frame intrasubunit and intersubunit water-accessible cavities were individually mutated to cysteine. We measured and compared the rates of modification of the introduced cysteines by sulfhydryl-reactive reagents in the absence and presence of propofol. Propofol slowed the rate of modification of L240C (intersubunit) and increased the rate of modification of T254C (intrasubunit), indicating that propofol binding induces structural rearrangements in these cavities that alter the local environment near these residues. Propofol acceleration of T254C modification suggests that in the resting state propofol does not bind in the TMD intrasubunit cavity as observed in the crystal structure of GLIC with bound propofol (Nury, H., Van Renterghem, C., Weng, Y., Tran, A., Baaden, M., Dufresne, V., Changeux, J. P., Sonner, J. M., Delarue, M., and Corringer, P. J. (2011) Nature 469, 428-431). In silico docking using a GLIC closed channel homology model suggests propofol binds to intersubunit sites in the TMD in the resting state. Propofol-induced motions in the intersubunit cavity were distinct from motions associated with channel activation, indicating propofol stabilizes a novel closed state.

Novel Activation of Voltage-gated K+ Channels by Sevoflurane

Halogenated inhaled anesthetics modulate voltage-gated ion channels by unknown mechanisms. Biophysical analyses revealed novel activation of K(v) channels by the inhaled anesthetic sevoflurane. K(v) channel activation by sevoflurane results from the positive allosteric modulation of activation gating. The unique activation of K(v) channels by sevoflurane demonstrates novel anesthetic specificity and offers new insights into allosteric modulation of channel gating. Voltage-gated ion channels are modulated by halogenated inhaled general anesthetics, but the underlying molecular mechanisms are not understood. Alkanols and halogenated inhaled anesthetics such as halothane and isoflurane inhibit the archetypical voltage-gated Kv3 channel homolog K-Shaw2 by stabilizing the resting/closed states. By contrast, sevoflurane, a more heavily fluorinated ether commonly used in general anesthesia, specifically activates K-Shaw2 currents at relevant concentrations (0.05-1 mM) in a rapid and reversible manner. The concentration dependence of this modulation is consistent with the presence of high and low affinity interactions (K(D) = 0.06 and 4 mM, respectively). Sevoflurane (<1 mM) induces a negative shift in the conductance-voltage relation and increases the maximum conductance. Furthermore, suggesting possible roles in general anesthesia, mammalian Kv1.2 and Kv1.5 channels display similar changes. Quantitative description of the observations by an economical allosteric model indicates that sevoflurane binding favors activation gating and eliminates an unstable inactivated state outside the activation pathway. This study casts light on the mechanism of the novel sevoflurane-dependent activation of Kv channels, which helps explain how closely related inhaled anesthetics achieve specific actions and suggests strategies to develop novel Kv channel activators.