Integrating clinical research in an operative screening and diagnostic breast imaging department: First experience, results and perspectives using microwave imaging.

Clinical research is crucial for evaluating new medical procedures and devices. It is important for healthcare units and hospitals to minimize the disruptions caused by conducting clinical studies; however, complex clinical pathways require dedicated recruitment and study designs.This work presents the effective introduction of novel microwave breast imaging (MBI), via MammoWave apparatus, into the clinical routine of an operative screening and diagnostic breast imaging department for conducting a multicentric clinical study. Microwave breast imaging, using MammoWave apparatus, was performed on volunteers coming from different clinical pathways. Clinical data, comprising demographics and conventional radiologic reports (used as reference standard), was collected; a satisfaction questionnaire was filled by every volunteer. Microwave images were analyzed by an automatic clinical decision support system, which quantified their corresponding features to discriminate between breasts with no relevant radiological findings (NF) and breasts with described findings (WF). Conventional breast imaging (DBT, US, MRI) and MBI were performed and adapted to assure best clinical practices and optimum pathways. 180 volunteers, both symptomatic and asymptomatic, were enrolled in the study. After microwave images' quality assessment, 48 NF (15 dense) and 169 WF (88 dense) breasts were used for the prospective study; 48 (18 dense) breasts suffered from a histology-confirmed carcinoma. An overall sensitivity of 85.8 % in breasts lesions' detection was achieved by the microwave imaging apparatus. An optimum recruitment strategy was implemented to assess MBI. Future trials may show the clinical usefulness of microwave imaging, which may play an important role in breast screening. [Abstract copyright: © 2023 The Authors.

Development and tests of a new prototype detector for the XAFS beamline at Elettra Synchrotron in Trieste

The XAFS beamline at Elettra Synchrotron in Trieste combines X-ray absorption spectroscopy and X-ray diffraction to provide chemically specific structural information of materials. It operates in the energy range 2.4-27 keV by using a silicon double reflection Bragg monochromator. The fluorescence measurement is performed in place of the absorption spectroscopy when the sample transparency is too low for transmission measurements or the element to study is too diluted in the sample. We report on the development and on the preliminary tests of a new prototype detector based on Silicon Drift Detectors technology and the SIRIO ultra low noise front-end ASIC. The new system will be able to reduce drastically the time needed to perform fluorescence measurements, while keeping a short dead time and maintaining an adequate energy resolution to perform spectroscopy. The custom-made silicon sensor and the electronics are designed specifically for the beamline requirements.Comment: Proceeding of the 6YRM 12th-14th Oct 2015 - L'Aquila (Italy). Accepted for publication on Journal of Physics: Conference Serie

Working towards a consensus on the oncological approach of breakthrough pain: A Delphi survey of Spanish experts

Purpose: There is a lack of standards for the diagnosis, assessment and management of breakthrough cancer pain (BTcP). La Fundación ECO (the Foundation for Excellence and Quality in Oncology) commissioned a study to establish a consensus and lay the foundations for the appropriate management of BTcP in oncology patients. Patients and methods: A modified Delphi survey comprising two rounds was used to gather and analyze data, which was conducted over the Internet. Each statement that reached a consensus with the respondents was defined as a median consensus score (MED) of =7, and agreement among panelists as an interquartile range (IQR) of =3. Results: In total, 69 medical oncologists responded, with a broad consensus that BTcP implied exacerbations of high-intensity pain, as opposed to moderate pain. Furthermore, they concurred that appropriate diagnostic equipment is needed, and that rapid-onset fentanyl formulations should be the preferred treatment for BTcP management. The panelists agreed that a lack of appropriate information and training to attend to patients, as well as limited patient visitation rights, were barriers to effective BTcP management. Regarding gaps in detected knowledge, the panelists were unsure of the measures necessary to assess the burden of the disease on the patient’s quality of life and associated medication costs. Alongside this, there was a lack of awareness of the technical specifics of the different formulations of rapid-onset fentanyl. Conclusion: These results represent the current status of BTcP management. They may inform recommendations and provide a framework for future research

Detection of Early-Stage Pancreatic Ductal Adenocarcinoma From Blood Samples : Results of a Multiplex Biomarker Signature Validation Study

INTRODUCTION: The IMMray PanCan-d test combines an 8-plex biomarker signature with CA19-9 in a proprietary algorithm to detect pancreatic ductal adenocarcinoma (PDAC) in serum samples. This study aimed to validate the clinical performance of the IMMray PanCan-d test and to better understand test performance in Lewis-null (le/le) individuals who cannot express CA19-9. METHODS: Serum samples from 586 individuals were analyzed with the IMMray PanCan-d biomarker signature and CA19-9 assay, including 167 PDAC samples, 203 individuals at high risk of familial/hereditary PDAC, and 216 healthy controls. Samples were collected at 11 sites in the United States and Europe. The study was performed by Immunovia, Inc (Marlborough, MA), and sample identity was blinded throughout the study. Test results were automatically generated using validated custom software with a locked algorithm and predefined decision value cutoffs for sample classification. RESULTS: The IMMray PanCan-d test distinguished PDAC stages I and II (n = 56) vs high-risk individuals with 98% specificity and 85% sensitivity and distinguished PDAC stages I-IV vs high-risk individuals with 98% specificity and 87% sensitivity. We identified samples with a CA19-9 value of 2.5 U/mL or less as probable Lewis-null (le/le) individuals. Excluding these 55 samples from the analysis increased the IMMray PanCan-d test sensitivity to 92% for PDAC stages I-IV (n = 157) vs controls (n = 379) while maintaining specificity at 99%; test sensitivity for PDAC stages I and II increased from 85% to 89%. DISCUSSION: These results demonstrate the IMMray PanCan-d blood test can detect PDAC with high specificity (99%) and sensitivity (92%).Peer reviewe

Oncological translational research in the Spanish national health system: the INTRO study

Under the auspices of the Foundation for Excellence and Quality in Oncology (ECO), the Translational Research in Oncology Medical Services Study (INTRO) was conducted with the aim of describing the current state of, and future expectations for translational cancer research in Spanish medical centres. The first step in the investigation was intended to analyse the current condition of the national Medical Oncology Services network by examining different aspects of the oncology research field. A descriptive and observational multicentre study was performed at a statewide level; information was collected by surveying a cross-section of all those responsible for Medical Oncology Services in Spain. The survey was completed by key informants, who were selected independently by each service, between September 2010 and April 2011. We were able to gather comprehensive data from a total of 27 Spanish hospitals. These data enabled us to describe the allocation of human and material resources devoted to clinical and translational research across the Medical Oncology Services and to describe the organisational and functional components of these services and units. These data included information pertaining to the activities developed, their funding sources, and their functional dependence on other internal or external bodies. Finally, we explored the degree of dissemination and use of some specific techniques used for the genetic diagnosis of cancer, which have recently been introduced in Medical Oncology within the Spanish healthcare system. A wide range of variability exists between different oncology services in Spanish hospitals. Time should be spent reflecting on the need and opportunities for improvement in the development of translational research within the field of oncology.Caballero, C.; Jantus-Lewintre, E.; Carrato, A.; García Foncillas, J.; Gascon, P.; Blasco, A.; Moreno Nogueira, JA.... (2014). Oncological translational research in the Spanish national health system: the INTRO study. Clinical and Translational Oncology. 16(8):686-695. doi:10.1007/s12094-013-1138-6S686695168Díaz-Rubio E. Translational research in clinical oncology: challenges and opportunities. Farm Hosp. 2010;34(Supl.1):1–7.Marincola FM. Translational medicine: a two-way road. J Transl Med. 2003;1(1):1.Ablin RJ, Marincola FM, Natali PG. The “excellence in translational medicine” and “bedside-to-bench” awards 2008–09. J Transl Med. 2010;13(8):95.García-Sáenz JA, Bueno C, SanPedro T, Díaz-Rubio E. La nueva oncología médica: aportación de la biología molecular al diagnóstico y tratamiento del cáncer. In: Díaz-Rubio E, editor. Tomo IV. Madrid: You and Us; 2006. p. 1–24.ORDEN SCO/709/2002, Boletín Oficial del Estado, 3 de abril de 2003, núm. 80, pp. 12742–12746. http://www.boe.es/boe/dias/2002/04/03/pdfs/A12742-12746.pdf . Accessed 30 sept 2013.Soto-Martínez JL, Baselga-Torres J, Carrato-Mena A. La investigación Translacional en Oncología Médica. En Primer Libro blanco de la Oncología Médica en España. Dosier 2006. Madrid: Editorial Dispublic SL; 2007. p. 177–99.Ministerio de Sanidad y Consumo. Agencia de Calidad del Sistema Nacional de Salud. Estrategia en Cáncer del Sistema Nacional de Salud. 2006. http://www.msc.es/organizacion/ sns/planCalidadSNS/docs/estratCancerSNS.pdf. Accessed 30 sept 2013.Lenfant C. Shattuck lecture–clinical research to clinical practice-lost in translation? N Engl J Med. 2003;349(9):868–74.Laurence J. Translating translational research. Transl Res. 2006;148(1):1–3.Lemieux-Charles L, McGuire WL. What do we know about health care team effectiveness? A review of the literature. Med Care Res Rev. 2006;63(3):263–300.Oandasan I, Baker RG, Barker K, Bosco C, D’Amour D, Jones L, et al. Teamwork in health care: promoting effective teamwork in healthcare in Canada; policy synthesis and recommendations. June 2006. http://www.chsrf.ca/Migrated/PDF/teamwork-synthesis-report_e.pdf . Accessed 30 Sep 2013.Mankoff SP, Brander C, Ferrone S, Marincola FM. Lost in Translation: obstacles to translational medicine. J Transl Med. 2004;2(1):14.Curran T. Lost in translation: the future of cancer research? Clin Cancer Res. 2005;11(13):4644.Valladares Y. Memoria y actas del primer congreso de investigación sobre el cáncer en España. Madrid; 1983.Vicente J. Apuntes para una historia de la Oncología en España. Los orígenes. Oncología. 2000;23(7):310–7.Legido-Quigley H, Otero L, la Parra D, Alvarez-Dardet C, Martin-Moreno JM, McKee M. Will austerity cuts dismantle the Spanish healthcare system? BMJ. 2013;13(346):f2363

Oncologist’s knowledge and implementation of guidelines for breakthrough cancer pain in Spain: CONOCE study

[Purpose]: Breakthrough cancer pain (BTcP) has been shown to be a prevalent and poor prognostic factor for oncologic patients, which remain under diagnosed and undertreated. In 2012, the Spanish Society of Medical Oncology (SEOM) published a clinical practice guideline (CPG) for the treatment of cancer pain which specifically addressed the management of BTcP.[Methods]: Fundación ECO designed a qualitative study using an Internet-based survey to investigate the attitudes toward, compliance with, and use of SEOM Guideline.[Results]: A total of 83 oncologists with a mean experience of 13 years responded. Overall, 82% were aware of different guidelines to manage BTcP. Notably, attitudes toward guidelines were highly positive and there was nearly unanimous agreement that CPG provided the best scientific evidence available (99%), on the minimum information to be gathered for the medical history (100%), on the need for a specific treatment for BTcP (100%), and fentanyl as the first-choice drug (99%). Interestingly, there were discrepancies between what oncologists agreed with and what they do in clinical practice. In fact, 87.6% declare full compliance with SEOM guideline, although adherence to registration of BTcP data in medical records ranged from 30.1 to 91.6% (mean 64.5%); therapeutic management compliance was higher ranging from 75.9 to 91.6%. Main barriers identified were time pressure together with vague statements and limited dissemination of the guidelines.[Conclusion]: Despite oncologist’s clinical practice is increasingly guided by GPC, it suffers from limited compliance, at least in part due to suboptimal statements. Improved dissemination and education are needed to enhance guideline implementation.This study was funded by Kyowa Kirin Farmacéutica S. L.U. through Fundación ECO

Active study: undetected prevalence and clinical inertia in the treatment of breakthrough cancer pain (BTcP)

Aims To prove if there is clinical inertia in the identification and treatment of episodes of breakthrough cancer pain (BTcP), comparing actual results from clinical practice with clinical oncologists’ prior perception. Design Observational and descriptive study, using information collected by practising medical oncologists, at three moments: (a) questionnaire regarding their professional judgement of the handling of patients with BTcP in their practice, (b) cross-sectional clinical screening, to detect possible existing cases of BTcP in a representative sample of their patients, (c) retrospective self-audit of clinical case histories of patients diagnosed with BTcP to find out about how it has been handled. Participants and study period A random sample on a state level of 108 specialists in medical oncology. 540 patients who suffer some type of cancer pain on the designated study date for each specialist (July–December 2016). Results The global prevalence of BTcP in the study sample covered 91.3% of the patients who were suffering some type of cancer pain. Barely 2% of the doctors surveyed suspected figures around this mark. 40.9% of the cases had not been previously detected as BTcP by their doctors. Although 90% of the patients who had previously been diagnosed with BTcP received a specific analgesic treatment for the symptoms, 42% of those patients with known BTcP were not able to control their episodes of pain. Conclusions Clinical inertia is a serious problem in the handling of BTcP in medical oncology services, where it is the subject of a significantly low level of detection and treatment, despite the contrasting perception of specialists.pre-print339 K

Soluble AXL is a novel blood marker for early detection of pancreatic ductal adenocarcinoma and differential diagnosis from chronic pancreatitis

Background: Early diagnosis is crucial for patients with pancreatic ductal adenocarcinoma (PDAC). The AXL receptor tyrosine kinase is proteolytically processed releasing a soluble form (sAXL) into the blood stream. Here we explore the use of sAXL as a biomarker for PDAC. Methods: AXL was analysed by immunohistochemistry in human pancreatic tissue samples. RNA expression analysis was performed using TCGA/GTEx databases. The plasma concentrations of sAXL, its ligand GAS6, and CA19-9 were studied in two independent cohorts, the HMar cohort (n = 59) and the HClinic cohort (n = 142), including healthy controls, chronic pancreatitis (CP) or PDAC patients, and in a familial PDAC cohort (n = 68). AXL expression and sAXL release were studied in PDAC cell lines and murine models. Findings: AXL is increased in PDAC and precursor lesions as compared to CP or controls. sAXL determined in plasma from two independent cohorts was significantly increased in the PDAC group as compared to healthy controls or CP patients. Patients with high levels of AXL have a lower overall survival. ROC analysis of the plasma levels of sAXL, GAS6, or CA19-9 in our cohorts revealed that sAXL outperformed CA19-9 for discriminating between CP and PDAC. Using both sAXL and CA19-9 increased the diagnostic value. These results were validated in murine models, showing increased sAXL specifically in animals developing PDAC but not those with precursor lesions or acinar tumours. Interpretation: sAXL appears as a biomarker for early detection of PDAC and PDAC–CP discrimination that could accelerate treatment and improve its dismal prognosis. Funding: This work was supported by grants PI20/00625 (PN), RTI2018-095672-B-I00 (AM and PGF), PI20/01696 (MG) and PI18/01034 (AC) from MICINN-FEDER and grant 2017/SGR/225 (PN) from Generalitat de Catalunya. © 2021 The Author(s

ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity

Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness

Telomerase Reverse Transcriptase Promoter Mutations in Bladder Cancer: High Frequency Across Stages, Detection in Urine, and Lack of Association with Outcome

Background: Hotspot mutations in the promoter of the gene coding for telomerase reverse transcriptase (TERT) have been described and proposed to activate gene expression. Objectives: To investigate TERT mutation frequency, spectrum, association with expression and clinical outcome, and potential for detection of recurrences in urine in patients with urothelial bladder cancer (UBC). Design, setting, and participants: A set of 111 UBCs of different stages was used to assess TERT promoter mutations by Sanger sequencing and TERT messenger RNA (mRNA) expression by reverse transcription-quantitative polymerase chain reaction. The two most frequent mutations were investigated, using a SNaPshot assay, in an independent set of 184 non-muscle-invasive and 173 muscle-invasive UBC (median follow-up: 53 mo and 21 mo, respectively). Voided urine from patients with suspicion of incident UBC (n = 174), or under surveillance after diagnosis of non-muscle-invasive UBC (n = 194), was tested using a SNaPshot assay. Outcome measurements and statistical analysis: Association of mutation status with age, sex, tobacco, stage, grade, fibroblast growth factor receptor 3 (FGFR3) mutation, progression-free survival, disease-specific survival, and overall survival. Results and limitations: In the two series, 78 of 111 (70%) and 283 of 357 (79%) tumors harbored TERT mutations, C228T being the most frequent substitution (83% for both series). TERT mutations were not associated with clinical or pathologic parameters, but were more frequent among FGFR3 mutant tumors (p = 0.0002). There was no association between TERT mutations and mRNA expression (p = 0.3). Mutations were not associated with clinical outcome. In urine, TERT mutations had 90% specificity in subjects with hematuria but no bladder tumor, and 73% in recurrence-free UBC patients. The sensitivity was 62% in incident and 42% in recurrent UBC. A limitation of the study is its retrospective nature. Conclusions: Somatic TERT promoter mutations are an early, highly prevalent genetic event in UBC and are not associated with TERT mRNA levels or disease outcomes. A SNaPshot assay in urine may help to detect UBC recurrences. (C) 2013 European Association of Urology. Published by Elsevier B. V. All rights reserved