Treatment patterns and intensification within 5 year of follow-up of the first-line anti-TNFα used for the treatment of IBD: Results from the VERNE study.

BACKGROUND: Anti-TNFα represent one of the main treatment approaches for the management of inflammatory bowel diseases (IBD). Therefore,the evaluation of their treatment patterns over time provides valuable insights about the clinical value of therapies and associated costs. AIMS: To assess the treatment patterns with the first anti-TNFα in IBD. METHODS: Retrospective, observational study. RESULTS: 310 IBD patients were analyzed along a 5-year follow-up period. 56.2% of Crohn's disease (CD) patients started with adalimumab (ADA), while 43.8% started with infliximab (IFX). 12.9% of ulcerative colitis (UC) patients initiated with ADA, while 87.1% initiated with IFX. Treatment intensification was required in 28.9% of CD and 37.1% of UC patients. Median time to treatment intensification was shorter in UC than in CD (5.3 vs. 14.3 months; p = 0.028). Treatment discontinuation due to reasons other than remission were observed in 40.7% of CD and 40.5% of UC patients, although, in UC patients there was a trend to lower discontinuation rates with IFX (36.6%) than with ADA (66.7%). Loss of response accounted for approximately one-third of discontinuations, in both CD and UC. CONCLUSIONS: Around one-third of IBD biologic-naive patients treated with an anti-TNFα required treatment intensification (earlier in UC) and around 40% discontinued the anti-TNFα due to inappropriate disease control.

Elastin-like recombinamer-based devices releasing Kv1.3 blockers for the prevention of intimal hyperplasia: An in vitro and in vivo study.

Coronary artery disease (CAD) is the most common cardiovascular disorder. Vascular surgery strategies for coronary revascularization (either percutaneous or open) show a high rate of failure because of restenosis of the vessel, due to phenotypic switch of vascular smooth muscle cells (VSMCs) leading to proliferation and migration. We have previously reported that the inhibition of Kv1.3 channel function with selective blockers represents an effective strategy for the prevention of restenosis in human vessels used for coronary angioplasty procedures. However, delivery systems for controlled release of these drugs have not been investigated. Here we tested the efficacy of several formulations of elastin like recombinamers (ELRs) hydrogels to deliver the Kv1.3 blocker PAP-1 in various restenosis models. The dose and time course of PAP-1 release from ELRs click hydrogels was able to inhibit human VSMC proliferation in vitro as well as remodeling of human vessels in organ culture and restenosis in in vivo models. We conclude that this combination of active compound and advanced delivery method could improve the outcomes of vascular surgery in patients. STATEMENT OF SIGNIFICANCE: Vascular surgery strategies for coronary revascularization show a high rate of failure, because of occlusion (restenosis) of the vessel, due to vascular smooth muscle cells proliferation and migration. We have previously reported that blockers of Kv1.3 channels represent an effective anti-restenosis therapy, but delivery systems for their controlled release have not being explored. Here we tested the efficacy of several formulations of elastin like recombinamers (ELRs) hydrogels to deliver the Kv1.3 blocker PAP-1 in various restenosis models, both in vivo and in vitro, and also in human vessels. We demonstrated that combination of active compound and advanced delivery method could improve the outcomes of vascular surgery in patients.

Stereotactic body radiation therapy for liver metastasis from colorectal cancer: size matters.

PURPOSE: We analysed our initial experience with SBRT in liver metastasis from colorectal cancer at our institution. MATERIALS AND METHODS: Between January/2014 and December/2017, 22 patients with 31 LMCCR were treated. Local control (LC) was assessed using the Kaplan-Meier and log-rank tests. We analysed potential prognostic factors for LC: sex, PTV size, number of LM and the radiation scheme. RESULTS: Median age: 69 years. Prior chemotherapy or local liver treatments: 81.8% and 63.6% of patients, respectively. SBRT consisted of 3 × 20 Gy (42.9%) and 3 × 15 Gy (31.4%). There were 88.5% responses (57.1% CR and 31.4% PR). Median follow-up was 30 months. LC per lesion at 12 and 24 months was 85.3% and 61.8%, respectively. Tumour volumes > 30 cc correlated with worsened 2-year-control rates (90% vs 34.5%) (p = 0.005). There was only a patient with CTC-grade 3 toxicity. CONCLUSIONS: Liver SBRT is a safe and effective treatment that achieves high local control rates. We found a significant correlation between larger LMCRC and worse local control.

The blind men and the elephant: Systematic review of systematic reviews of cannabis use related health harms.

Cannabis is the third most used psychoactive substance worldwide. The legal status of cannabis is changing in many Western countries, while we have very limited knowledge of the public health impact of cannabis-related harms. There is a need for a summary of the evidence of harms and risks attributed to cannabis use, in order to inform the definition of cannabis risky use. We have conducted a systematic review of systematic reviews, aiming to define cannabis-related harms. We included systematic reviews published until July 2018 from six different databases and following the PRISMA guidelines. To assess study quality we applied the AMSTAR 2 tool. A total of 44 systematic reviews, including 1,053 different studies, were eligible for inclusion. Harm was categorized in three dimensions: mental health, somatic harm and physical injury (including mortality). Evidence shows a clear association between cannabis use and psychosis, affective disorders, anxiety, sleep disorders, cognitive failures, respiratory adverse events, cancer, cardiovascular outcomes, and gastrointestinal disorders. Moreover, cannabis use is a risk factor for motor vehicle collision, suicidal behavior and partner and child violence. Cannabis use is a risk factor for several medical conditions and negative social consequences. There is still little data on the dose-dependency of these effects; evidence that is essential in order to define, from a public health perspective, what can be considered risky use of cannabis. This definition should be based on quantitative and qualitative criteria that informs and permits the evaluation of current approaches to a regulated cannabis market.

A double safety lock tumor-specific device for suicide gene therapy in breast cancer.

The complexity and continuous evolution of cancer make the design of novel strategies of treatment a constant challenge in biomedicine. Moreover, most of cancer treatments are still not tumor-specific and provoke high systemic toxicity. Herein we have developed a novel selective nanodevice to eliminate tumor cells while leaving healthy ones intact. To achieve this objective, a polyplex carrier, comprising an elastin like-recombinamer covalently conjugated to an aptamer and complexed with therapeutic DNA, was tested. This carrier forms a double-lock multifunctional device due to specific binding to a tumor cell marker and the selective expression of therapeutic DNA inside human breast-cancer cells. Due to the stability provided by ELRs, the homogeneous population of polyplexes obtained showed selective toxicity against cancer cells in in vitro and in vivo assay. Inhibition of tumor progression was detected early being very significant at the end point, with a dose-dependent reduction in tumor mass. Histological studies revealed a specific reduction in tumor parenchyma and in specific tumor cell markers. These results represent an important step toward the rational development of an efficient, safe and more specialized gene-delivery device for tumor therapy.

[Re-irradiation with SBRT (Stereotactic Body Radiation Therapy) for locoregional unresectable relapse of head and neck cancer: a case report]. / Reirradiación con radioterapia estereotáxica corporal (SBRT) en recidiva irresecable de cáncer de cabeza y cuello: a propósito de un caso.

Patients with an unresectable recurrence of head and neck carcinoma (HNC) have a poor prognosis, with limited treatment options. Recent technical advances allow radiotherapy (RT) to be handled with great precision, making it possible to re-irradiate recurrent tumors by means of stereotactic body radiotherapy (SBRT) with high doses of RT while protecting healthy tissues near the tumor. Although this technique has been used to irradiate different primary tumors and their metastases, SBRT in HNC has had a much slower evolution than in the mentioned locations. This is due to the difficulties in re-irradiating the HNC, because of the expected toxicity as it is a relatively small area with dense vascularization and innervation, and where several senses are located. We present the first case of a HNC re-irradiated with SBRT in the Complejo Hospitalario de Navarra; the patient showed a complete response and continues to be disease-free sixteen months after the irradiation.

Self-Assembling ELR-Based Nanoparticles as Smart Drug-Delivery Systems Modulating Cellular Growth via Akt.

This work investigates the physicochemical properties and in vitro accuracy of a genetically engineered drug-delivery system based on elastin-like block recombinamers. The DNA recombinant techniques allowed us to create this smart complex polymer containing bioactive sequences for internalization, lysosome activation under acidic pH, and blockage of cellular growth by a small peptide inhibitor. The recombinant polymer reversibly self-assembled when the temperature was increased above 15 °C into nanoparticles with a diameter of 72 nm and negative surface charge. Furthermore, smart nanoparticles were shown to enter in the cells via clathrin-dependent endocytosis and properly blocked phosphorylation and consequent activation of Akt kinase. This system provoked apoptosis-mediated cell death in breast and colorectal cancer cells, which possess higher expression levels of Akt, whereas noncancerous cells, such as endothelial cells, fibroblasts, and mesenchymal stem cells, were not affected. Hence, we conclude that the conformational complexity of this smart elastin-like recombinamer leads to achieving successful drug delivery in targeted cells and could be a promising approach as nanocarriers with bioactive peptides to modulate multiple cellular processes involved in different diseases.

Does the Antitumor Necrosis Factor-α Therapy Decrease the Vertebral Fractures Occurrence in Inflammatory Bowel Disease?

BACKGROUND/OBJECTIVE: Osteoporosis and osteoporotic fracture risk are extraintestinal manifestations of the inflammatory bowel disease, whose etiopathogenic mechanisms have not been determined yet. Anti-tumor necrosis factor (TNF)-α are used in treatment of inflammatory bowel disease (IBD), but it is unknown if they play a role in osteoporotic fracture prevention. The objective of this study was to know if anti-TNF decreases fracture risk or modifies bone mineral density. To determine the possible risk factors associated with fractures, and assess the incidence of vertebral fractures in IBD patients. METHODS: Longitudinal prospective cohort study (7 yr of follow-up); which included 71 IBD patients, 23 received anti-TNF-α; the remaining 48 received conventional treatment, constituted the control group. Patients participated in a questionnaire which gathered risk factors associated with the development of osteoporosis and fractures. Radiographs of the dorsolumbar-spine were performed and also a bone density measurement. Their biochemical and bone remodeling parameters were determined. RESULTS: Although patients who did not receive anti-TNF-α, suffered more fractures but biologic therapy did not reduce the risk of new vertebral fractures. The increase of bone mass was significantly higher the group treated with anti-TNF-α. The increase in the lumbar spine was of 8% and in the femoral neck was of 6.7%. The only determinant factor for the incidence of vertebral fractures was a history of previous fractures (odds ratio of 12.8; confidence interval 95% 2.37-69.9; p = 0.003). The incidence of vertebral fractures in IBD patients was considerably high: 26.7/700 patient-yr. CONCLUSIONS: Anti-TNF-α, although increased bone mass in these patients, did not reduce the risk of new vertebral fractures. In this study, patients with IBD have a considerably high incidence of fractures. Only the existence of previous vertebral fractures was a predictive factor for consistent fractures.

Elastin-Like Recombinamers As Smart Drug Delivery Systems.

BACKGROUND: Drug delivery systems that are able to control the release of bioactive molecules and designed to carry drugs to target sites are of particular interest for tissue therapy. Moreover, systems comprising materials that can respond to environmental stimuli and promote self-assembly and higher order supramolecular organization are especially useful in the biomedical field. Objetive: This review focuses on biomaterials suitable for this purpose and that include elastin-like recombinamers (ELRs), a class of proteinaceous polymers bioinspired by natural elastin, designed using recombinant technologies. The self-assembly and thermoresponsive behaviour of these systems, along with their biodegradability, biocompatibility and well-defined composition as a result of their tailormade design, make them particularly attractive for controlled drug delivery. RESULTS: ELR-based delivery systems that allow targeted delivery are reviewed, especially ELR-drug recombinant fusion constructs, ELR-drug systems chemically bioconjugated in their monomeric and soluble forms, and drug encapsulation by nanoparticle-forming ELRs. Subsequently, the review focuses on those drug carriers in which smart release is triggered by pH or temperature with a particular focus on cancer treatments. Systems for controlled drug release based on depots and hydrogels that act as both a support and reservoir in which drugs can be stored will be described, and their applications in drug delivery discussed. Finally, smart drug-delivery systems not based on ELRs, including those comprising proteins, synthetic polymers and non-polymeric systems, will also be briefly discussed. CONCLUSION: Several different constructions based on ELRs are potential candidates for controlled drug delivery to be applied in advanced biomedical treatments.

Multidisciplinary management of head and neck cancer: First expert consensus using Delphi methodology from the Spanish Society for Head and Neck Cancer (part 1).

Head and neck cancer is one of the most frequent malignances worldwide. Despite the site-specific multimodality therapy, up to half of the patients will develop recurrence. Treatment selection based on a multidisciplinary tumor board represents the cornerstone of head and neck cancer, as it is essential for achieving the best results, not only in terms of outcome, but also in terms of organ-function preservation and quality of life. Evidence-based international and national clinical practice guidelines for head and neck cancer not always provide answers in terms of decision-making that specialists must deal with in their daily practice. This is the first Expert Consensus on the Multidisciplinary Approach for Head and Neck Squamous Cell Carcinoma (HNSCC) elaborated by the Spanish Society for Head and Neck Cancer and based on a Delphi methodology. It offers several specific recommendations based on the available evidence and the expertise of our specialists to facilitate decision-making of all health-care specialists involved.

Fecal incontinence and radiation dose on anal sphincter in patients with locally advanced rectal cancer (LARC) treated with preoperative chemoradiotherapy: a retrospective, single-institutional study.

BACKGROUND: The objective of the study is to determine the correlations among the variables of dose and the sphincter function (SF) in patients with locally advanced rectal cancer treated with preoperative capecitabine/radiotherapy followed by low anterior resection (LAR) + TME. METHODS: We retrospectively reviewed 92 consecutive patients with LARC treated at our center with LAR from 2006 and more than 2 years free from disease. We re-contoured the anal sphincters (AS) of patients with the help of the radiologist. SF was assessed with the Wexner scale (0-20 points, being punctuation inversely proportional to annal sphincter functionality). All questionnaires were filled out between January 2010 and December 2012. Dosimetric parameters that have been studied include V 20, V 30, V 40, V 50, mean dose (D mean), minimum dose (D min), D 90 (dose received by 90% of the sphincter) and D 98. STATISTICAL ANALYSIS: The correlations among the variables of dose and SF were studied by the Spearman correlation coefficient. Differences in SF relating to maximum doses to the sphincter were assessed by the Mann-Whitney test. RESULTS: Mean Wexner score was 5.5 points higher in those patients with V 20 > 0 compared to those for which V 20 = 0 (p = 0.008). In a multivariate regression model, results suggest that the effect of V 20 on poor anal sphincter control is independent of the effect of distance, with an adjusted OR of 3.42. CONCLUSIONS: In order to improve the SF in rectal cancer treated with preoperative radiotherapy/capecitabine followed by conservative surgery, the maximum radiation dose to the AS should be limited, when possible, to <20 Gy.

Evolution After Anti-TNF Discontinuation in Patients With Inflammatory Bowel Disease: A Multicenter Long-Term Follow-Up Study.

OBJECTIVES: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed. METHODS: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included. RESULTS: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07-3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27-2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13-2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51-0.87) and age (HR=0.98; 95% CI=0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe. CONCLUSIONS: The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe.

Anti-Human Endoglin (hCD105) Immunotoxin-Containing Recombinant Single Chain Ribosome-Inactivating Protein Musarmin 1.

Endoglin (CD105) is an accessory component of the TGF-ß receptor complex, which is expressed in a number of tissues and over-expressed in the endothelial cells of tumor neovasculature. Targeting endoglin with immunotoxins containing type 2 ribosome-inactivating proteins has proved an effective tool to reduce blood supply to B16 mice tumor xenografts. We prepared anti-endoglin immunotoxin (IT)-containing recombinant musarmin 1 (single chain ribosome-inactivating proteins) linked to the mouse anti-human CD105 44G4 mouse monoclonal antibody via N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP). The immunotoxin specifically killed L929 fibroblast mouse cells transfected with the short form of human endoglin with IC50 values in the range of 5 × 10(-10) to 10(-9) M.

Biocompatible ELR-Based Polyplexes Coated with MUC1 Specific Aptamers and Targeted for Breast Cancer Gene Therapy.

The search for new and biocompatible materials with high potential for improvement is a challenge in gene delivery applications. A cell type specific vector made of elastin-like recombinamer (ELR) and aptamers has been specifically designed for the intracellular delivery of therapeutic material for breast cancer therapy. A lysine-enriched ELR was constructed and complexed with plasmid DNA to give positively charged and stable polyplexes. Physical characterization of these polyplexes showed a particle size of around 140 nm and a zeta potential of approximately +40 mV. The incorporation of MUC1-specific aptamers into the polyplexes resulted in a slight decrease in zeta potential but increased cell transfection specificity for MCF-7 breast cancer cells with respect to a MUC1-negative tumor line. After showing the transfection ability of this aptamer-ELR vector which is facilitated mainly by macropinocytosis uptake, we demonstrated its application for suicide gene therapy using a plasmid containing the gene of the toxin PAP-S. The strategy developed in this work about using ELR as polymeric vector and aptamers as supplier of specificity to deliver therapeutic material into MUC1-positive breast cancer cells shows promising potential and continues paving the way for ELRs in the biomedical field.

Small Bowel Obstruction due to Intestinal Xanthomatosis.

Vast majority of bowel obstruction is due to postoperative adhesions, malignancy, intestinal inflammatory disease, and hernias; however, knowledge of other uncommon causes is critical to establish a prompt treatment and decrease mortality. Xanthomatosis is produced by accumulation of cholesterol-rich foamy macrophages. Intestinal xanthomatosis is an uncommon nonneoplastic lesion that may cause small bowel obstruction and several cases have been reported in the English literature as obstruction in the jejunum. We report a case of small intestinal xanthomatosis occurring in a 51-year-old female who presented with one day of copious vomiting and intermittent abdominal pain. Radiologic images revealed jejunal loop thickening and inflammatory changes suggestive of foreign body obstruction, diagnostic laparoscopy found two strictures at the jejunum, and a pathologic examination confirmed a segmental small bowel xanthomatosis. This case illustrates that obstruction even without predisposing factors such as hyperlipidemia or lymphoproliferative disorders.

Impact of initial FDG PET/CT in the management plan of patients with locally advanced head and neck cancer.

OBJECTIVE: To determine the impact of initial FDG PET/CT staging on clinical stage and the management plan in patients with locally advanced head and neck cancer (LAHNC). MATERIALS AND METHODS: We retrospectively reviewed the records of 72 consecutive patients (2007-2010) staged with PET/CT and conventional CT with tumours of hypopharynx/larynx (26 patients, 36 %), oral cavity (17 patients, 24 %), oropharynx (16 patients, 22 %), nasopharynx (12 patients, 17 %), and others (2 %). The impact of PET/CT on management plans was considered high when PET/CT changed the planned treatment modality or treatment intent, and intramodality changes were considered as minor changes with low impact. RESULTS: FDG PET/CT changed the stage in 27 patients and had high impact on the management plan in 12 % of patients (detection of distant metastases in 6 patients and stage II in 2 patients). Intramodality changes were more frequent: FDG PET/CT altered the TNM stage in 18/72 (25 %) of patients, upstaging N stage in 90 % of patients with low impact. CONCLUSIONS: Initial FDG PET/CT staging not only improves stage but also affects the management plan in LAHNC patients.

Influencia de 2 dentífricos con agentes desensibilizantes en la conductabilidad hidráulica dentinaria / Influence of two agents desensitizing toothpastes in hydraulic conductance dentin

El objetivo del estudio fue determinar in vitro los efectos de agentes desensibilizantes de dentífricos sobre la conductancia hidráulica de la dentina. Se seleccionaron 60 terceros molares humanos sanos, recientemente extraídos, sin contacto oclusal, de pacientes entre 15-30 años, los cuales fueron limpiados, desinfectados (Tymol 0,1% durante 24 h) y conservados a temperatura ambiente en solución HBSS. Las coronas fueron seccionadas perpendicular al eje dentario mayor bajo abundante refrigeración, obteniendo un disco de 1 mm ± 0,1 mm de espesor por cada corona. Se trataron ambas superficies del disco con ácido ortofosfórico al 35% por 15 segundos. Los discos se separaron en los siguientes 3 grupos de tratamiento, de 20 discos cada uno: los que fueron cepillados (cepillo eléctrico Oral-B® Pro Salud Power) durante 2 minutos solo por su cara oclusal con a) Colgate® Sensitive Pro Alivio con tecnología pro arginina (Colgate-Palmolive, Estados Unidos); b) Sensodyne® Rápido Alivio (GlaxoSmitheKline, Reino Unidio), y c) agua destilada como control negativo. Los datos fueron analizados estadísticamente por medio de las pruebas de Kruskall-Wallis y Mann-Whitney. Los resultados expresados en µl*cm−2*min−1cm*H²O−1 como medias, separados por grupo fueron: a) 0,00650 (± 0,00384); b) 0,00800 (± 0,00472), y c) 0,03649 (± 0,03042). Con el estudio se pudo concluir que los 2 agentes desensibilizantes dentinarios presentan significativa disminución de la conductabilidad hidráulica en dentina. Se encontraron diferencias estadísticamente significativas entre el grupo control y Sensodyne® Rápido Alivio (p = 0,000) y entre el grupo control y Colgate® Sensitive Pro Alivio (p = 0,000). No se observó diferencia entre las 2 pastas dentales (p = 0,317).

The aim of the study was to determine the effects of agents toothpastes on the hydraulic conductance of dentin desensitizers "in vitro". We selected 60 third molars healthy humans, recently extracted without occlusal contact, of patients between 15-30 years, which were cleaned, disinfected (Tymol 0.1% per 24 hours) and preserved at T atmosphere solution for a maximum of 14 days. The crowns were sectioned perpendicular to the tooth axis under abundant refrigeration, obtaining a disc of 1 mm +/-0.1 mm. thickness for each Crown. Disks were separated into the following three groups of treatment, of 20 discs each, which were brushings (brush electrical Oral-B Pro health Power) for 2 minutes only by your face occlusal with; a) Colgate® Sensitive Pro relief with technology Pro arginine (Colgate-Palmolive, USA), b) Sensodyne® quick-relief (GlaxoSmitheKline, UK), and c) distilled water as a negative control. The data were statistically analyzed by Kruskall Wallis and Mann Whitney tests. The results expressed in µl*cm−2*min−1cm*H²O−1as stockings, separated by group were; a) 0,00650 (±0.00384), b) 0,00800 (±0,00472), c) 0 and 03649 (±0,03042). You could be concluded with the study that two dentin desensitizers agents present significant decrease in hydraulic conductance in dentin. Statistically significant differences were found between the group control and Sensodyne® fast relief (p = 0,000) and between group control and Colgate® Sensitive Pro relief (p = 0,000). There was no difference between the two toothpastes (p = 0,317).