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Inés Velázquez-Quesada,1,2 Angel J Ruiz-Moreno,1,3,4 Diana Casique-Aguirre,1 Charmina Aguirre-Alvarado,1 Fabiola Cortés-Mendoza,1,5 Marisol de la Fuente-Granada,6 Carlos García-Pérez,7 Sonia M Pérez-Tapia,2,8 Aliesha González-Arenas,6 Aldo Segura-Cabrera,9 Marco A Velasco-Velázquez1,10 1Department of Pharmacology, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico; 2Research and Development in Bioprocess Unit, National School of Biological Sciences, Instituto Politécnico Nacional, Mexico City, Mexico; 3Graduate Program in Biomedical Sciences, Universidad Nacional Autónoma de México, Mexico City, Mexico; 4Department of Drug Design, Graduate School of Science and Engineering, University of Groningen (RUG), Groningen, The Netherlands; 5Graduate Program in Biochemical Sciences, Universidad Nacional Autónoma de México, Mexico City, Mexico; 6Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, Universidad Nacional Autónoma de México, Mexico City, Mexico; 7Center for Genomic Biotechnology, Instituto Politécnico Nacional, Reynosa, Tamaulipas, Mexico; 8National Laboratory for Specialized Services of Investigation, Development and Innovation (I+D+i) for Pharma Chemicals and Biotechnological Products, LANSEIDI-FarBiotec-CONACyT, Mexico City, Mexico; 9European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK; 10Peripherical Unit for Research in Translational Biomedicine, School of Medicine, Universidad Nacional Autónoma de México, Mexico City, MexicoCorrespondence: Marco A Velasco-VelázquezSchool of Medicine, Universidad Nacional Autónoma de México, Circuito Interno s/n, Mexico City 04510, MexicoTel/Fax +52 55 5623 2282Email marcovelasco@unam.mxIntroduction: Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists.Materials and Methods: We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clinically tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation.Results: Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces conformational changes in CD49f that affect its interaction with β 1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transactivation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC.Conclusion: Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients.Keywords: CD49f, alpha6 integrin, breast cancer stem cells, pranlukast, drug repositioning, triple-negative breast cancer cells

Based on the discussion of current state of research of relevant topics of metastatic bladder cancer (mBC) among a group of experts of a Spanish Oncology Genitourinary (SOGUG) Working Group, a set of recommendations were proposed to overcome the challenges posed by the management of mBC in clinical practice. First-line options in unfit patients for cisplatin are chemotherapy with carboplatin and immunotherapy in PD-L1 positive patients. FDG-PET/CT may be a useful imaging technique in the initial staging or re-staging. In patients with oligometastatic disease, it is important to consider not only the number of metastatic lesions, but also the tumor biology and the clinical course. The combination of stereotactic body radiotherapy and immunotherapy with anti-PD-L1 monoclonal antibodies is under investigation and could improve the results of systemic treatment in patient with oligometastatic disease. Rescue treatment with curative intent could be considered in patients with oligometastatic disease after complete response on FDG-PET/CT. Metastatic disease should be evaluated using the same imaging modality over the course of the disease from diagnosis until rescue treatment. For improving the outcome of patients with mBC, the involvement of a dedicated multidisciplinary team, including urologists, pathologists, oncologists, radiologists and other specialists is of outmost importance in the daily care of these patients.

Stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS) are essential tools in radiation oncology. In Spain, the use of these techniques continues to grow as older linear accelerators (linacs) are replaced with modern equipment. However, little is known about inter-centre variability in prescription and dose heterogeneity limits. Consequently, the SBRT-Spanish Task Group (SBRT-SG) of the Spanish Society of Radiation Oncology (SEOR) has undertaken an initiative to assess prescription and homogeneity in SRS/SBRT treatment. In the present study, we surveyed radiation oncology (RO) departments to obtain a realistic overview of prescription methods used for SBRT and SRS treatment in Spain.A brief survey was developed and sent to 34 RO departments in Spain, mostly those who are members of the SEOR SBRT-SG. The survey contained seven questions about the specific prescription mode, dose distribution heterogeneity limits, prescription strategies according to SRS/SBRT type, and the use of IMRT-VMAT (Intensity Modulated Radiation Therapy-Volumetric Modulated Arc Therapy).Responses were received from 29 centres. Most centres (59%) used the prescription criteria DThis survey about SRS/SBRT prescription and dose heterogeneity has evidenced substantial inter-centre variability in prescription criteria, particularly for intended and accepted dose heterogeneity. These differences could potentially influence the mean planning target volume dose and its correlation with treatment outcomes. The findings presented here will be used by the SEOR SBRT-SG to develop recommendations for SRS/SBRT dose prescription and heterogeneity.

SBRT-SG 05 is a collaborative (SBRT-SG, GICOR and SEOR) prospective multicenter phase II trial testing SBRT and androgen deprivation therapy (ADT) in oligorecurrent prostate cancer patients.

Background: In a palliative situation like metastatic spinal cord compression (MSCC), overall treatment time of radiotherapy should be as short as possible. This study compared 5 x 5 Gy in 1 week to 10 x 3 Gy in 2 weeks in a prospective cohort. Methods: Forty patients receiving 5 x 5 Gy in a phase II trial were matched 1:2 to 213 patients receiving 10 x 3 Gy in two previous prospective studies for tumor type, ambulatory status, time developing motor deficits, interval between tumor diagnosis and MSCC and visceral metastases. These factors were consistent in all three patients (triple) used for each 1:2 matching. Groups were compared for local progression-free survival (LPFS), motor function, ambulatory status, and overall survival (OS). Results: After matching, 32 triples remained for analyses (N = 96 in total). Six-month LPFS-rates were 94% after 5 x 5 Gy and 87% after 10 x 3 Gy (p = 0.36), 6-month OS-rates 43% and 35% (p = 0.74). Improvement of motor function was achieved in 59% and 34% of patients (p = 0.028); overall response rates (improvement or no further progression of motor deficits) were 94% and 89% (p = 0.71). Post-treatment ambulatory rates were 81% after 5 x 5 Gy and 85% after 10 x 3 Gy (p = 0.61). Of non-ambulatory patients, 50% (6/12) and 46% (11/24) regained the ability to walk (p = 1.00). Conclusions: 5 x 5 Gy in 1 week appeared similarly effective as 10 x 3 Gy in 2 weeks. These results may not be applicable to long-term survivors and should be confirmed in a randomized trial directly comparing 5 x 5 Gy and 10 x 3 Gy.

Today, patient management generally requires a multidisciplinary approach. However, due to the growing knowledge base and increasing complexity of Medicine, clinical practice has become even more specialised. Radiation oncology is not immune to this trend towards subspecialisation, which is particularly evident in ablative radiotherapy techniques that require high dose fractions, such as stereotactic radiosurgery (SRS), and stereotactic body radiotherapy (SBRT). The aim of the present report is to establish the position of the Spanish Society of Radiation Oncology (SEOR), in collaboration with the Spanish Society of Medical Physics (SEFM), with regard to the roles and responsibilities of healthcare professionals involved in performing SRS and SBRT. The need for this white paper is motivated due to the recent changes in Spanish Legislation (Royal Decree [RD] 601/2019, October 18, 2019) governing the use and optimization of radiotherapy and radiological protection for medical exposure to ionizing radiation (article 11, points 4 and 5) [1 ], which states: "In radiotherapy treatment units, the specialist in Radiation Oncology will be responsible for determining the correct treatment indication, selecting target volumes, determining the clinical radiation parameters for each volume, directing and supervising treatment, preparing the final clinical report, reporting treatment outcomes, and monitoring the patient's clinical course." Consequently, the SEOR and SEFM have jointly prepared the present document to establish the roles and responsibilities for the specialists-radiation oncologists (RO), medical physicists (MP), and related staff -involved in treatments with ionizing radiation. We believe that it is important to clearly establish the responsibilities of each professional group and to clearly establish the professional competencies at each stage of the radiotherapy process.

To investigate precision radiotherapy for metastatic spinal cord compression (MSCC) and compare it to conventional radiotherapy.

To evaluate whether positron-emission tomography/computed tomography with 68 Ga-PSMA ( 68 Ga-PSMA PET/CT) influences the therapeutic management of patients with primary or recurrent prostate cancer (PCa).

Purpose Peer review has been proposed as a strategy to ensure patient safety and plan quality in radiation oncology. Despite its potential benefits, barriers commonly exist to its optimal implementation in daily clinical routine. Our purpose is to analyze peer-review process at our institution. Methods and materials Based on our group peer-review process, we quantified the rate of plan changes, time and resources needed for this process. Prospectively, data on cases presented at our institutional peer-review conference attended by physicians, resident physicians and physicists were collected. Items such as time to present per case, type of patient (adult or pediatric), treatment intent, dose, aimed technique, disease location and receipt of previous radiation were gathered. Cases were then analyzed to determine the rate of major change, minor change and plan rejection after presentation as well as the median time per session. Results Over a period of 4 weeks, 148 cases were reviewed. Median of attendants was six physicians, three in-training-physicians and one physicist. Median time per session was 38 (4-72) minutes. 59.5% of cases presented in 1-4 min, 32.4% in 5-9 min and 8.1% in >= 10 min. 79.1% of cases were accepted without changes, 11.5% with minor changes, 6% with major changes and 3.4% were rejected with indication of new presentation. Most frequent reason of change was contouring corrections (53.8%) followed by dose or fractionation (26.9%). Conclusion Everyday group consensus peer review is an efficient manner to recollect clinical and technical data of cases presented to ensure quality radiation care before initiation of treatment as well as ensuring department quality in a feedback team environment. This model is feasible within the normal operation of every radiation oncology Department.

Background/Aim: According to our randomized trial, 5x4Gy was comparable to 10x3Gy for metastatic spinal cord compression. Since it remained unclear whether findings applied to poor and intermediate prognoses patients, subgroup analyses were performed. Patients and Methods: In patients with poor prognoses, 58 received 5x4Gy, 53 received 10x3Gy. In intermediate-prognoses patients, numbers were 43 and 49. Results: In patients with poor prognoses, 1-month overall response (OR) was 85% after 5x4Gy and 10x3Gy (p=0.99), improvement 38% vs. 42%, ambulatory status 60% vs. 64% (p=0.83), 6-month local progression-free survival (LPFS) 75% vs. 69% (p=0.74) and 6-month overall survival (OS) 26% vs. 19% (p=0.43). In patients with intermediate prognoses, 1-month OR was 89% after 5x4Gy and 93% after 10x3Gy (p=0.85), improvement 39% vs. 45%, ambulatory status 84% vs. 82% (p=0.90), 6-month LPFS 79% vs. 92% (p=0.17) and 6-months OS 65% vs. 58% (p=0.65). Conclusion: 5x4Gy was not significantly inferior to 10x3Gy in both subgroups.

Background: This study provides separate comparisons of 1 x 8 Gy to 5 x 4 Gy for metastatic epidural spinal cord compression (MESCC) in patients with poor, intermediate and favorable survival prognoses. Methods: Patients receiving 1 x 8 Gy were matched to patients receiving 5 x 4 Gy for age, gender, performance status, tumor type, involved vertebrae, other bone metastases, visceral metastases, interval between tumor diagnosis and MESCC, ambulatory status and time developing motor deficits. From a study including patients with poor (N = 156) or intermediate (N = 86) survival prognoses, subgroup analyses were performed. Furthermore, 232 new patients with favorable prognoses matched the same way were included. Results: In poor prognoses patients, 6-month survival rates were 10% after 1 x 8 Gy and 6% after 5 x 4 Gy (p = 0.38); in-field reRT rates in few patients alive at 6 months were 15 and 2% (p = 0.16). In intermediate prognoses patients, 6-month survival rates were 49% after 1 x 8 Gy and 58% after 5 x 4 Gy (p = 0.30). ReRT rates at 6 months were 23 and 13% (p = 0.25). In favorable prognoses patients, 6-month survival rates were 89% after 1 x 8 Gy and 91% after 5 x 4 Gy. ReRT rates at 6 months were 14 and 3% (p = 0.007). In no subgroup, RT regimen had a significant impact on motor function. Conclusions: Since in patients with poor prognoses, outcomes after 1x8 Gy and 5x4 Gy were not significantly different, 1 x 8 Gy may be an option. In patients with intermediate prognoses, a trend was found in favor of 5 x 4 Gy. In patients with favorable prognoses, need for in-field reRT was greater after 1 x 8 Gy.

Purpose/Objective: A 5x4 Gy program is commonly used for metastatic epidural spinal cord compression (MESCC). It is unclear whether an overall treatment time (OTT) of 5 days (5 consecutive fractions) results in better outcomes than an OTT of 7 days (ie, no irradiation during the weekend). Methods and materials: A total of 111 patients who received 5x4 Gy over 5 consecutive days were retrospectively compared with 277 patients treated with 5x4 Gy over 7 days (no irradiation during the weekend) for effect on motor function, local control of MESCC, and overall survival (OS). Ten further characteristics were evaluated: age, gender, interval tumor diagnosis to MESCC, visceral metastases, other bone metastases, primary tumor type, time developing motor deficits, walking ability, vertebrae involved, and performance status. Results: On multivariate analysis regarding post-radiation therapy motor function, primary tumor type (P = .011) and time developing motor weakness (P < .001) were significant, whereas the OTT did not even achieve significance on univariate analysis (P = .99). On multivariate analysis of local control, visceral metastases (P = .006) were significant. Again, the OTT was not even significant on univariate analysis (P = .81). On multivariate analysis of OS, interval tumor diagnosis to MESCC (P = .015), visceral metastases (P = .001), tumor type (P = .003), walking ability (P < .001), and Eastern Cooperative Oncology Group performance score (P < .001) achieved significance. Even on univariate analysis, OTT did not have an effect on OS (P = .79). Conclusions: Longer OTT did not impair outcomes of irradiation with 5x4 Gy for MESCC; thus, no compensation (for example an additional radiation fraction) is necessary if the radiation treatment is not continued during the weekend. (C) 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Background: For metastatic spinal cord compression (MSCC), conventional radiotherapy with 10 x 3 Gy in 2 weeks results in better local progression-free survival (LPFS) than 5 x 4 Gy in 1 week. Since patients with MSCC are often significantly impaired, an overall treatment time of 1 week would be preferable if resulting in similar outcomes as longer programs. This may be achieved with 5 x 5 Gy in 1 week, since the biologically effective dose is similar to 10 x 3 Gy. It can be expected that 5 x 5 Gy (like 10 x 3) Gy results in better LPFS than 5 x 4 Gy in 1 week. Methods/Design: This phase 2 study investigates LPFS after high-precision RT with 5 x 5 Gy in 1 week. LPFS is defined as freedom from both progression of motor deficits during RT and new or progressive motor deficits dur to an in-field recurrence of MSCC following RT. Considering the tolerance dose of the spinal cord, 5 x 5 Gy can be safely administered with high-precision radiotherapy such as volumetric modulated arc therapy (MAT) or stereotactic body radiotherapy (SBRT). Maximum dose to the spinal cord should not exceed 101.5% of the prescribed dose to keep the risk of radiation myelopathy below 0.03%. Primary endpoint is LPFS at 6 months following radiotherapy; secondary endpoints include motor function/ability to walk, sensory function, sphincter dysfunction, LPFS directly and 1 and 3 months following radiotherapy, overall survival, pain relief, quality of life and toxicity. Follow-up visits will be performed directly and at 1, 3 and 6 months following radiotherapy. After completion of this phase 2 study, patients will be compared to a historical control group receiving conventional radiotherapy with 5 x 4 Gy in 1 week. Forty-four patients will be included assuming 5 x 5 Gy will provide the same benefit in LPFS when compared to 5 x 4 Gy as reported for 10 x 3 Gy. Discussion: If superiority regarding LPFS is shown for high-precision radiotherapy with 5 x 5 Gy when compared to conventional radiotherapy with 5 x 4 Gy, patients with MSCC would benefit from 5 x 5 Gy, since high LPFS rates could be achieved with 1 week of radiotherapy instead of 2 weeks (10 x 3 Gy).

IntroductionRadiotherapy alone still is the most commonly delivered treatment modality for metastatic spinal cord compression (MSCC). MSCC is an emergency situation, which requires treatment as soon as possible. When radiotherapy is performed with the most commonly used approach 10x3Gy (30Gy in 10 fractions) over 2weeks, the question has been asked whether an overall treatment time (OTT) of 14-15days including two weekends without irradiation leads to worse outcomes than OTT of 12days (beginning of radiotherapy on a Monday resulting in only one weekend break)? MethodsA total of 412 patients with MSCC were included in this retrospective study. Ninety-two patients receiving 10x3Gy over 12days were compared to 320 patients with an OTT of 14-15days. Ten additional factors were investigated. ResultsOn multivariate analysis, functional outcome was associated with tumour type (P

This study was designed to evaluate the effects of long-term treatment with alpha-naphthyl-isothiocyanate (ANIT) on liver histology and at the mitochondrial bioenergetic level. Since, ANIT has been used as a cholestatic agent and it has been pointed out that an impairment of mitochondrial function is a cause of hepatocyte dysfunction leading to cholestatic liver injury, serum markers of liver injury were measured and liver sections were analyzed in ANIT-treated rats (i.p. 80 mg/kg/week x 16 weeks). Mitochondrial parameters such as transmembrane potential, respiration, calcium capacity, alterations in permeability transition susceptibility and ATPase activity were monitored. Histologically, the most important features were the marked ductular proliferation, proliferation of mast cells and the presence of iron deposits in ANIT-treated liver. Mitochondria isolated from ANIT-treated rats showed no alterations in state 4 respiration, respiratory control ratio and ADP/O ratio, while state 3 respiration was significantly decreased. No changes were observed on transmembrane potential, but the repolarization rate was decreased in treated rats. Consistently with these data, there was a significant decrease in the ATPase activity of treated mitochondria. Associated with these parameters, mitochondria from treated animals exhibited increased susceptibility to mitochondrial permeability transition pore opening (lower calcium capacity). Since, human cholestatic liver disease progress slowly overtime, these data provide further insight into the role of mitochondrial dysfunction in the process.

Camptodactyly is a permanent flexion deformity at the interphalangeal joints, usually at the proximal, interphalangeal joints. It is by far most commonly encountered in the little finger, but it can occur in any of the others, and may be associated with a deformity in the little finger or not. It is usually bilateral. It can also appear in the toes, the second toe being the most frequently affected. This deformity can appear in two different situations: it can occur in isolation, or can be a part of a malformative syndrome. It can also be sporadic or be transmitted as an autosomal dominant trait [1, 5, 7, 8]. We report a case of familial camptodactyly not associated with any other disorders: the differential diagnoses included scleroderma and Dupuytren's contracture.

We present molecular dynamics (MD) simulations results for dense fluids of ultrasoft, fully penetrable particles. These are a binary mixture and a polydisperse system of particles interacting via the generalized exponential model, which is known to yield cluster crystal phases for the corresponding monodisperse systems. Because of the dispersity in the particle size, the systems investigated in this work do not crystallize and form disordered cluster phases. The clustering transition appears as a smooth crossover to a regime in which particles are mostly located in clusters, isolated particles being infrequent. The analysis of the internal cluster structure reveals microsegregation of the big and small particles, with a strong homo-coordination in the binary mixture. Upon further lowering the temperature below the clustering transition, the motion of the clusters' centers-of-mass slows down dramatically, giving way to a cluster glass transition. In the cluster glass, the diffusivities remain finite and display an activated temperature dependence, indicating that relaxation in the cluster glass occurs via particle hopping in a nearly arrested matrix of clusters. Finally we discuss the influence of the microscopic dynamics on the transport properties by comparing the MD results with Monte Carlo simulations. © 2012 American Institute of Physics., We acknowledge financial support from the projects MAT2007-63681 (Spain) and IT-436-07 (GV, Spain).