Proteomic profiles of peritoneal fluid-derived small extracellular vesicles correlate with patient outcome in ovarian cancer.

Cancer-derived small extracellular vesicles (sEVs) are capable of modifying the tumor microenvironment and promoting tumor progression. Ovarian cancer (OvCa) is a lethal malignancy that preferentially spreads through the abdominal cavity. Thus, the secretion of such vesicles into the peritoneal fluid could be a determinant factor in the dissemination and behavior of this disease. We designed a prospective observational study to assess the impact of peritoneal fluid-derived sEVs (PFD-sEVs) in OvCa clinical outcome. For this purpose, 2 patient cohorts were enrolled: patients with OvCa who underwent a diagnostic or cytoreductive surgery and nononcological patients, who underwent abdominal surgery for benign gynecological conditions and acted as the control group. Systematic extraction of PFD-sEVs from surgical samples enabled us to observe significant quantitative and qualitative differences associated with cancer diagnosis, disease stage, and platinum chemosensitivity. Proteomic profiling of PFD-sEVs led to the identification of molecular pathways and proteins of interest and to the biological validation of S100A4 and STX5. In addition, unsupervised analysis of PFD-sEV proteomic profiles in high-grade serous ovarian carcinomas (HGSOCs) revealed 2 clusters with different outcomes in terms of overall survival. In conclusion, comprehensive characterization of PFD-sEV content provided a prognostic value with potential implications in HGSOC clinical management.

TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy response.

BACKGROUND: Melanoma, the most lethal form of skin cancer, has undergone a transformative treatment shift with the advent of checkpoint blockade immunotherapy (CBI). Understanding the intricate network of immune cells infiltrating the tumor and orchestrating the control of melanoma cells and the response to CBI is currently of utmost importance. There is evidence underscoring the significance of tissue-resident memory (TRM) CD8 T cells and classic dendritic cell type 1 (cDC1) in cancer protection. Transcriptomic studies also support the existence of a TCF7+ (encoding TCF1) T cell as the most important for immunotherapy response, although uncertainty exists about whether there is a TCF1+TRM T cell due to evidence indicating TCF1 downregulation for tissue residency activation. METHODS: We used multiplexed immunofluorescence and spectral flow cytometry to evaluate TRM CD8 T cells and cDC1 in two melanoma patient cohorts: one immunotherapy-naive and the other receiving immunotherapy. The first cohort was divided between patients free of disease or with metastasis 2 years postdiagnosis while the second between CBI responders and non-responders. RESULTS: Our study identifies two CD8+TRM subsets, TCF1+ and TCF1-, correlating with melanoma protection. TCF1+TRM cells show heightened expression of IFN-γ and Ki67 while TCF1- TRM cells exhibit increased expression of cytotoxic molecules. In metastatic patients, TRM subsets undergo a shift in marker expression, with the TCF1- subset displaying increased expression of exhaustion markers. We observed a close spatial correlation between cDC1s and TRMs, with TCF1+TRM/cDC1 pairs enriched in the stroma and TCF1- TRM/cDC1 pairs in tumor areas. Notably, these TCF1- TRMs express cytotoxic molecules and are associated with apoptotic melanoma cells. Both TCF1+ and TCF1- TRM subsets, alongside cDC1, prove relevant to CBI response. CONCLUSIONS: Our study supports the importance of TRM CD8 T cells and cDC1 in melanoma protection while also highlighting the existence of functionally distinctive TCF1+ and TCF1- TRM subsets, both crucial for melanoma control and CBI response.

How much flow is enough: the use of fractional flow reserve in chronic limb-threatening ischemia in a series of patients with isolated occlusive tibial disease.

The role of the fractional flow reserve to guide lower extremity peripheral vascular intervention, specifically in chronic limb-threatening ischemia, has remained unclear. This series presents a novel use of the fractional flow reserve in four patients to guide lower extremity endovascular interventions in patients with chronic limb-threatening ischemia.

Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03.

BACKGROUND: Granulosa cell ovarian tumor (GCT) is characterized by a pathognomonic mutation in the FOXL2 gene (402 C > G) that leads to an overactivation of steroidogenesis. CYP17 is a key enzyme in such process and can be inhibited by ketoconazole. METHODS: We designed a phase II clinical trial to assess the efficacy of ketoconazole in advanced GCT and conducted several in vitro studies to support the clinical findings. RESULTS: From October 1st 2012 to January 31st 2014, six evaluable patients were recruited in ten hospitals of the Spanish Group for Transversal Oncology and Research in Orphan and Infrequent Tumors" (GETTHI). FOXL2 (402C > G) mutation was confirmed in three; two cases were wild type and it could not be assessed in one. No objective response by RECIST was observed, but five cases achieved stable disease longer than 12 months. Median progression-free survival was 14.06 months (CI 95% 5.43-22.69) for the whole study population (3.38 and 13.47 months for wild-type cases and 14.06, 20.67 and 26.51 for those with confirmed FOXL2 mutation). Median overall survival was 22·99 months (CI 95% 8.99-36.99). In vitro assays confirmed the activity of ketoconazole in this tumor and suggested potential synergisms with other hormone therapies. CONCLUSION: Ketoconazole has shown activity in advanced GCT in clinical and in vitro studies. Based on these data, an orphan designation was granted by the European Medicines Agency for ketoconazole in GCT (EU/3/17/1857). GOV IDENTIFIER: NCT01584297.

Breast Cancer Tissue Explants: An Approach to Develop Personalized Therapy in Public Health Services.

Breast cancer is one of the main causes of death worldwide. Lately, there is great interest in developing methods that assess individual sensitivity and/or resistance of tumors to antineoplastics to provide personalized therapy for patients. In this study we used organotypic culture of human breast tumor slices to predict the experimental effect of antineoplastics on the viability of tumoral tissue. Samples of breast tumor were taken from 27 patients with clinically advanced breast cancer; slices were obtained and incubated separately for 48 h with paclitaxel, docetaxel, epirubicin, 5-fluorouracil, cyclophosphamide, and cell culture media (control). We determined an experimental tumor sensitivity/resistance (S/R) profile by evaluating tissue viability using the Alamar Blue® metabolic test, and by structural viability (histopathological analyses, necrosis, and inflammation). These parameters were related to immunohistochemical expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The predominant histological type found was infiltrating ductal carcinoma (85.2%), followed by lobular carcinoma (7.4%) and mixed carcinoma (7.4%). Experimental drug resistance was related to positive hormone receptor status in 83% of samples treated with cyclophosphamide (p = 0.027). Results suggest that the tumor S/R profile can help to predict personalized therapy or optimize chemotherapeutic treatments in breast cancer.

Primary Chemoradiotherapy Treatment (PCRT) for HER2+ and Triple Negative Breast Cancer Patients: A Feasible Combination.

Primary systemic treatment (PST) downsizes the tumor and improves pathological response. The aim of this study is to analyze the feasibility and tolerance of primary concurrent radio−chemotherapy (PCRT) in breast cancer patients. Patients with localized TN/HER2+ tumors were enrolled in this prospective study. Radiation was delivered concomitantly during the first 3 weeks of chemotherapy, and it was based on a 15 fractions scheme, 40.5 Gy/2.7 Gy per fraction to whole breast and nodal levels I-IV. Chemotherapy (CT) was based on Pertuzumab−Trastuzumab−Paclitaxel followed by anthracyclines in HER2+ and CBDCA-Paclitaxel followed by anthracyclines in TN breast cancers patients. A total of 58 patients were enrolled; 25 patients (43%) were TN and 33 patients HER2+ (57%). With a median follow-up of 24.2 months, 56 patients completed PCRT and surgery. A total of 35 patients (87.5%) achieved >90% loss of invasive carcinoma cells in the surgical specimen. The 70.8% and the 53.1% of patients with TN and HER-2+ subtype, respectively, achieved complete pathological response (pCR). This is the first study of concurrent neoadjuvant treatment in breast cancer in which three strategies were applied simultaneously: fractionation of RT (radiotherapy) in 15 sessions, adjustment of CT to tumor phenotype and local planning by PET. The pCR rates are encouraging.

Data-driven classification of the certainty of scholarly assertions.

The grammatical structures scholars use to express their assertions are intended to convey various degrees of certainty or speculation. Prior studies have suggested a variety of categorization systems for scholarly certainty; however, these have not been objectively tested for their validity, particularly with respect to representing the interpretation by the reader, rather than the intention of the author. In this study, we use a series of questionnaires to determine how researchers classify various scholarly assertions, using three distinct certainty classification systems. We find that there are three distinct categories of certainty along a spectrum from high to low. We show that these categories can be detected in an automated manner, using a machine learning model, with a cross-validation accuracy of 89.2% relative to an author-annotated corpus, and 82.2% accuracy against a publicly-annotated corpus. This finding provides an opportunity for contextual metadata related to certainty to be captured as a part of text-mining pipelines, which currently miss these subtle linguistic cues. We provide an exemplar machine-accessible representation-a Nanopublication-where certainty category is embedded as metadata in a formal, ontology-based manner within text-mined scholarly assertions.

EURO-MUSCULUS/USPRM Global Report on Musculoskeletal Ultrasound Publications.

The developments in technology have improved access to the use of musculoskeletal ultrasound (MSUS) in different clinical settings. Accordingly, MSUS has been applied to a wide range of musculoskeletal problems including inflammatory and degenerative diseases, sport injuries, and regional pain syndromes both for clinical practice and research. In this report, the authors aimed to globally examine the publications on MSUS among different specialties, countries, and topics. Sixteen reviewers under the umbrella of the European Musculoskeletal Ultrasonography Society Group and the Ultrasound Study Group of International Society of Physical and Rehabilitation Medicine have evaluated approximately 15,000 publications on MSUS. The authors believe that the results of this comparative analysis may provide a holistic snapshot with regard to the utility of MSUS, not only for clinicians/academicians but also for the industry. Accordingly, while aiming to further increase their awareness, this article would possibly guide future investments as well.

Author Correction: Evaluating FAIR maturity through a scalable, automated, community-governed framework.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Evaluating FAIR maturity through a scalable, automated, community-governed framework.

Transparent evaluations of FAIRness are increasingly required by a wide range of stakeholders, from scientists to publishers, funding agencies and policy makers. We propose a scalable, automatable framework to evaluate digital resources that encompasses measurable indicators, open source tools, and participation guidelines, which come together to accommodate domain relevant community-defined FAIR assessments. The components of the framework are: (1) Maturity Indicators - community-authored specifications that delimit a specific automatically-measurable FAIR behavior; (2) Compliance Tests - small Web apps that test digital resources against individual Maturity Indicators; and (3) the Evaluator, a Web application that registers, assembles, and applies community-relevant sets of Compliance Tests against a digital resource, and provides a detailed report about what a machine "sees" when it visits that resource. We discuss the technical and social considerations of FAIR assessments, and how this translates to our community-driven infrastructure. We then illustrate how the output of the Evaluator tool can serve as a roadmap to assist data stewards to incrementally and realistically improve the FAIRness of their resources.

Rehabilitation service models for people with physical and/or mental disability living in low- and middle-income countries: A systematic review.

OBJECTIVE: To compare models of rehabilitation services for people with mental and/or physical disability in order to determine optimal models for therapy and interventions in low- to middle-income countries. DATA SOURCES: CINAHL, EMBASE, MEDLINE, CENTRAL, PsycINFO, Business Source Premier, HINARI, CEBHA and PubMed. STUDY SELECTION: Systematic reviews, randomized control trials and observational studies comparing >2 models of rehabilitation care in any language. Date extraction: Standardized forms were used. Methodological quality was assessed using AMSTAR and quality of evidence was assessed using GRADE. DATA SYNTHESIS: Twenty-four systematic reviews which included 578 studies and 202,307 participants were selected. In addition, four primary studies were included to complement the gaps in the systematic reviews. The studies were all done at various countries. Moderate- to high-quality evidence supports the following models of rehabilitation services: psychological intervention in primary care settings for people with major depression, admission into an inpatient, multidisciplinary, specialized rehabilitation unit for those with recent onset of a severe disabling condition; outpatient rehabilitation with multidisciplinary care in the community, hospital or home is recommended for less severe conditions; However, a model of rehabilitation service that includes early discharge is not recommended for elderly patients with severe stroke, chronic obstructive pulmonary disease, hip fracture and total joints. CONCLUSION: Models of rehabilitation care in inpatient, multidisciplinary and specialized rehabilitation units are recommended for the treatment of severe conditions with recent onset, as they reduce mortality and the need for institutionalized care, especially among elderly patients, stroke patients, or those with chronic back pain. Results are expected to be generalizable for brain/spinal cord injury and complex fractures.

Profile of Ventana ALK (D5F3) companion diagnostic assay for non-small-cell lung carcinomas.

The development of several ALK inhibitors means that the importance of accurately identifying ALK-positive lung cancer has never been greater. Therefore, it is crucial that ALK testing assays become more standardized. The aim of this review is to comment on the recently FDA-approved VENTANA ALK (D5F3) Companion Diagnostic (CDx) Assay. This kit provides high sensitivity and specificity for the detection of ALK rearrangements and seamless integration into the laboratory workflow, with a fully automated analytical phase and fast interpretation. The use of controls increases the sensitivity and specificity and a dichotomous scoring approach enhances reproducibility.

Nivel de conocimiento sobre exámenes diagnósticos para la detección precoz del cáncer colorrectal / Level of knowledge concerning the diagnostic tests for the early detection of colorectal cancer

RESUMEN Introducción: el cáncer colorrectal llegará a ser la neoplasia más frecuente en el siglo XXI, constituye un problema sanitario de gran magnitud, las pruebas de detección se realizan como parte del proceso de determinar la presencia de cáncer. Objetivo: determinar nivel de conocimiento sobre los exámenes diagnósticos para la detección precoz del cáncer colorrectal en el Policlínico Universitario Hermanos Cruz, en el periodo de 2016 a 2017. Métodos: se realizó un estudio observacional, descriptivo y transversal; se consideró como universo 652 pacientes de 50 años y más de la comunidad perteneciente al Policlínico Universitario Hermanos Cruz, se seleccionó una muestra intencionada de 118 pacientes. Se utilizaron métodos teóricos, empíricos a través de una encuesta diseñada para dar salida a los objetivos del estudio y estadísticos dados en frecuencia absoluta y relativa. Resultados: el 55 % de la muestra perteneció al grupo de edad de 50 a 54 años, con un 29 % del sexo femenino, prevaleció el nivel escolar de primaria terminada, el 61,9 % reconocieron la colonoscopia como examen para el diagnóstico de la enfermedad, el 61,7 % de las féminas mostraron disposición en realizarse los exámenes diagnósticos, el 62 % de sexo masculino no. Conclusiones: la realización de los exámenes diagnósticos para la detección precoz del cáncer colorrectal es una de las armas más poderosas para prevenir esta enfermedad, se hace necesario instruir la población en el conocimiento de estos exámenes para que sin temor alguno acuda a realizárselo, así mejorar los indicadores de morbimortalidad por esta enfermedad.

ABSTRACT Introduction: colorectal cancer will become the most frequent neoplasm in the 21st century, it is a major health problem, and screening tests are performed as part of the process of determining the presence of cancer. Objective: to determine the level of knowledge concerning the diagnostic tests for the early detection of colorectal cancer at Hermanos Cruz academic Polyclinic from 2016 to 2017. Methods: an observational, descriptive and cross-sectional study was conducted where 652 patients from 50 years old and older belonging to Hermanos Cruz academic Polyclinic were included as a target group; 118 patients comprised the intentional sample. Theoretical and empirical methods were used through a survey designed to achieve the objectives of the research; statistical data were expressed in absolute and relative frequencies. Results: 55 % of the sample belonged to the age group of 50 to 54 years, with 29 % of the female sex and 26 % of the male sex, prevailed the finished primary school level, 61.9 % recognize colonoscopy as an examination for the diagnosis of the disease, 61.7 % of women showed willingness to undergo diagnostic tests, 62 % of the male sex did not. Conclusions: carrying out diagnostic tests for the early detection of colorectal cancer is one of the most powerful weapons to prevent this disease, it is necessary to instruct the population in the knowledge of these tests so that without any fear of going to perform it, thus improving indicators of morbidity and mortality from this disease.

Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03

Background Granulosa cell ovarian tumor (GCT) is characterized by a pathognomonic mutation in the FOXL2 gene (402 C > G) that leads to an overactivation of steroidogenesis. CYP17 is a key enzyme in such process and can be inhibited by ketoconazole. Methods We designed a phase II clinical trial to assess the efficacy of ketoconazole in advanced GCT and conducted several in vitro studies to support the clinical findings. Results From October 1st 2012 to January 31st 2014, six evaluable patients were recruited in ten hospitals of the Spanish Group for Transversal Oncology and Research in Orphan and Infrequent Tumors” (GETTHI). FOXL2 (402C > G) mutation was confirmed in three; two cases were wild type and it could not be assessed in one. No objective response by RECIST was observed, but five cases achieved stable disease longer than 12 months. Median progression-free survival was 14.06 months (CI 95% 5.43–22.69) for the whole study population (3.38 and 13.47 months for wild-type cases and 14.06, 20.67 and 26.51 for those with confirmed FOXL2 mutation). Median overall survival was 22·99 months (CI 95% 8.99–36.99). In vitro assays confirmed the activity of ketoconazole in this tumor and suggested potential synergisms with other hormone therapies. Conclusion Ketoconazole has shown activity in advanced GCT in clinical and in vitro studies. Based on these data, an orphan designation was granted by the European Medicines Agency for ketoconazole in GCT (EU/3/17/1857) (AU)

Peritonitis causada por Pantoea agglomerans en diálisis peritoneal / Peritonitis caused by Pantoea agglomerans in peritoneal dialysis

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