Long-term efficacy of percutaneous tibial nerve stimulation for faecal incontinence and a new approach for partial responders.

BACKGROUND: The aim of the present study was to evaluate the long-term efficacy of percutaneous tibial nerve stimulation (PTNS) for patients with faecal incontinence (FI) refractory to conservative treatment. Secondary aims were to identify predictors of response and validate new treatment pathways for partial responders. METHODS: A prospective, interventional study was carried out in a specialist defecatory disorder unit from a university hospital between January 2010 and June 2017 on patients > 18 years old with FI refractory to conservative treatment. Thirty-minute PTNS sessions were performed in three phases (weekly, biweekly and monthly) up to a year, with clinical reassessment at 3, 6, 12 and 36 months. Patients were classified as optimal responders when their pretreatment Wexner score decreased > 50%; partial responders when it decreased 25-50%; and insufficient responders if it decreased < 25%. Only optimal and partial responders progressed into successive phases. RESULTS: Between 2010 and 2017, 139 patients (110 women, median age 63 years [range 22-82 years]) were recruited. After the first phase, 4 patients were optimal responders, 93 were partial responders and 36 were insufficient responders. At 6 and 12 months, 66 and 89 patients respectively were optimal responders, with an optimal response rate of 64% at the end of treatment. A total of 93.3% patients with a partial response initially finally became optimal responders. Furthermore, at 36 months, 71.9% of patients were still optimal responders without supplementary treatment, although their quality of life did not improve significantly. Baseline Wexner scores ≤ 10 and symptom duration < 1 year were identified as predictive factors for positive responses to PTNS. CONCLUSIONS: Patients undergoing PTNS for 1 year following this protocol had optimal long-term responses. PTNS sessions for up to 1 year in patients who were partial responders prevents a high percentage of them from needing more invasive treatments, and maintains long-term continence in patients who were optimal responders.

Setting up regional diagnostic reference levels for pediatric interventional cardiology in Latin America and the Caribbean countries: preliminary results and identified challenges.

The goal of the present study was to propose a set of preliminary regional diagnostic reference levels (DRLs) for pediatric interventional cardiology (IC) procedures in Latin America and the Caribbean countries, classified by age and weight groups. The study was conducted in the framework of the Optimization of Protection in Pediatric Interventional Radiology in Latin America and the Caribbean program coordinated by the World Health Organization and the Pan American Health Organization in cooperation with the International Atomic Energy Agency. The first step of the program was focused on pediatric IC. Dose data from diagnostic and therapeutic procedures were collected between December 2020 and December 2021. Regional DRLs were set as the third quartile of patient dose data (kerma area product) collected in 18 hospitals from 10 countries in an initial sample of 968 procedures. DRLs were set for four age bands and five weight ranges. The values obtained for the four age bands (<1 yr, 1 to <5 yr, 5 to <10 yr and 10 to <16 yr) were 2.9, 6.1, 8.8 and 14.4 Gy cm2for diagnostic procedures, and 4.0, 5.0, 10.0 and 38.1 Gy cm2for therapeutic procedures, respectively. The values obtained for the five weight bands (<5 kg, 5 to <15 kg, 15 to <30 kg, 30 to <50 kg and 50 to <80 kg) were 3.0, 4.5, 8.1, 9.2 and 26.8 Gy cm2for diagnostic procedures and 3.7, 4,3, 7.3, 16.1 and 53.4 Gy cm2for therapeutic procedures, respectively. While initial data were collected manually as patient dose management systems (DMSs) were not available in most of the hospitals involved in the program, a centralized automatic DMS for the collection and management of patient dose indicators has now been introduced and is envisaged to increase the sample size. The possibility of alerting on high dose values and introducing corrective actions will help in optimization.

A DNA Vaccine Delivery Platform Based on Elastin-Like Recombinamer Nanosystems for Rift Valley Fever Virus.

This work analyzes the immunogenicity of six genetically engineered constructs based on elastin-like recombinamers (ELRs) fused to the Gn glycoprotein from Rift Valley fever virus (RVFV). Upon transfection, all constructs showed no effect on cell viability. While fusion constructs including ELR blocks containing hydrophobic amino acids (alanine or isoleucine) did not increase the expression of viral Gn in eukaryotic cells, glutamic acid- or valine-rich fusion proteins showed enhanced expression levels compared with the constructs encoding the viral antigen alone. However, in vivo DNA plasmid immunization assays determined that the more hydrophobic constructs reduced viremia levels after RVFV challenge to a higher extent than glutamic- or valine-rich encoding plasmids and were better inducers of cellular immunity as judged by in vitro restimulation experiments. Although the Gn-ELR fusion constructs did not surpass the protective efficacy of a plasmid vaccine expressing nonfused Gn, our results warrant further experiments directed to take advantage of the immunomodulatory potential of ELR biomaterials for improving vaccines against infectious diseases.

High-pressure homogenization and high hydrostatic pressure processing of human milk: Preservation of immunological components for human milk banks.

Human milk (HM) constitutes the first immunological barrier and the main source of nutrients and bioactive components for newborns. Immune factors comprise up to 10% of the protein content in HM, where antibodies are the major components (mainly IgA, IgG, and IgM). In addition, antibacterial enzymes such as lysozyme and immunoregulatory factors such as soluble cluster of differentiation 14 (sCD14) and transforming growth factor ß2 (TGF-ß2) are also present and play important roles in the protection of the infant's health. Donor milk processed in HM banks by Holder pasteurization (HoP; 62.5°C, 30 min) is a safe and valuable resource for preterm newborns that are hospitalized, but is reduced in major immunological components due to thermal inactivation. We hypothesized that high hydrostatic pressure (HHP) and high-pressure homogenization (HPH) are 2 processes that can be used on HM to reduce total bacteria counts while retaining immunological components. We studied the effects of HHP (400, 450, and 500 MPa for 5 min applied at 20°C) and HPH (200, 250, and 300 MPa, milk inlet temperature of 20°C) applied to mature HM, on microbiological and immunological markers (IgA, IgG, IgM, sCD14, and TGF-ß2), and compared them with those of traditional HoP in HM samples from healthy donors. The HHP processing between 400 and 500 MPa at 20°C reduced counts of coliform and total aerobic bacteria to undetectable levels (<1.0 log cfu/mL) while achieving approximately 100% of immunological component retention. In particular, comparing median percentages of retention of immunological components for 450 MPa versus HoP, we found 101.5 versus 50.5% for IgA, 89.5 versus 26.0% for IgM, 104.5 versus 75.5% for IgG, 125.0 versus 72.5% for lysozyme, 50.6 versus 0.1% for sCD14, and 88.5 versus 61.1% for TGF-ß2, respectively. Regarding HPH processing, at a pressure of 250 MPa and inlet temperature of 20°C, the process showed good potential to reduce coliforms to undetectable levels and total aerobic bacteria to levels slightly above those obtained by HoP. The median percentages of retention of immunological markers for HPH versus HoP were 71.5 versus 52.0%, 71.0 versus 27.0%, 104.0 versus 66.5%, and 30.9 versus 0.2%, for IgA, IgM, IgG, and sCD14, respectively; results did not significantly differ for lysozyme and TGF-ß2. The HPH at 300 MPa produced higher inactivation of immunological components, similar to values achieved with HoP.

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.

Lactobacillus spp. impair the ability of Listeria monocytogenes FBUNT to adhere to and invade Caco-2 cells.

OBJECTIVES: The objective of this study was to evaluate the ability of Lactobacillus curvatus CRL705, CRL1532, and CRL1533 and Lactobacillus sakei CRL1613 to survive under simulated gastrointestinal conditions. Moreover, a microencapsulation approach was proposed to improve gastrointestinal survival. Finally, experiments were performed to demonstrate that Lactobacillus spp. can modulate the ability of Listeria monocytogenes FBUNT to adhere to and invade Caco-2 cells. RESULTS: Lactobacillus strains were encapsulated in alginate beads to enhance the survival of bacteria under in vitro gastrointestinal conditions. All strains hydrolyzed bile salts using chenodeoxycholic acid as a substrate and adhered to Caco-2 cells. Cell-free supernatants (CFSs) showed antimicrobial activity against L. monocytogenes as demonstrated by agar diffusion assays. The average percentages of L. monocytogenes adhesion decreased from 67.74 to 41.75 and 38.7% in the presence of 50 and 90% (v/v), respectively, for all CFSs tested. The highest concentrations of CFSs completely inhibited the L. monocytogenes invasion of Caco-2 cells. CONCLUSIONS: The studied Lactobacillus strains have protective effects against the adhesion and invasion of L. monocytogenes FBUNT. Alginate encapsulation of these bacteria improved gastrointestinal tolerance such that they could be further studied as potential probiotics against intestinal pathogenic bacteria.

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.

Self-Assembling Elastin-Like Hydrogels for Timolol Delivery: Development of an Ophthalmic Formulation Against Glaucoma.

This work focuses on improving the effectiveness of current therapies against glaucoma by incorporating self-assembled polymers into the ophthalmic formulation. To that end, we first studied the influence of the dispersing medium on the mechanical performance of self-assembling elastin-like (EL) and silk-elastin-like (SEL) hydrogels by conducting rheological tests. These polymers were subsequently incorporated into the antiglaucoma formulation, which contains timolol maleate (TM) as active ingredient, and in vivo tests, namely adhesion tests and intraocular pressure measurements (IOP), were performed in New Zealand rabbits. An enhanced reduction in IOP due to the presence of the polymers was observed. Moreover, differences in the effectiveness between both EL- and SEL-hydrogels, which can be explained on the basis of the different rheological properties displayed by these two systems, were also encountered. The results point to the potential of this system as a basis for the development of an ophthalmic formulation against glaucoma.

Effectiveness and Safety of CT-P13 (Biosimilar Infliximab) in Patients with Inflammatory Bowel Disease in Real Life at 6 Months.

BACKGROUND: CT-P13 is a biosimilar of Remicade®, an agent approved in some countries for use in inflammatory bowel disease (IBD). Controlled clinical trials have demonstrated the efficacy and safety of CT-P13 in rheumatic diseases, but not in IBD. AIMS: To assess the effectiveness and safety of CT-P13 in IBD patients in real clinical practice. METHODS: This is a prospective observational study in patients with moderate to severe Crohn's disease or ulcerative colitis treated with CT-P13. The study was performed in one single center. Patients included were naive or switched to anti-TNF treatment from the reference infliximab (Remicade®) to CT-P13. Efficacy and safety were assessed in naive and switched patients who were in remission at the time of the switch at months 3 and 6 of therapy. RESULTS: 87.5 and 83.9% of switched CD patients who were in remission at the time of the switch continued in remission, and 66.7 and 50% of naive CD patients reached remission, at months 3 and 6. In UC switched cases, 92 and 91.3% of patients in remission at the time of the switch continued in remission, at 3 and 6 months. In naive UC patients, the remission rates were 44.4 and 66.7%, at months 3 and 6. Adverse events occurred in 7.5% of patients during 6 months of study. CONCLUSIONS: CT-P13 was efficacious and well tolerated in patients with CD or UC.

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.

Amphiphilic Elastin-Like Block Co-Recombinamers Containing Leucine Zippers: Cooperative Interplay between Both Domains Results in Injectable and Stable Hydrogels.

Many biological processes are regulated by reversible binding events, with these interactions between macromolecules representing the core of dynamic chemistry. As such, any attempt to gain a better understanding of such interactions, which would pave the way to the extrapolation of natural designs to create new advanced systems, is clearly of interest. This work focuses on the development of a leucine zipper-elastin-like recombinamer (ZELR) in order to elucidate the behavior of such domains when coexisting along the same molecule and to engineer reversible, injectable and stable hydrogels. The unique propensity of the Z-moiety selected to dimerize, together with the thermosensitive behavior of the ELR, which has been constructed as a thermosensitive amphiphilic tetrablock, has been engineered into a single recombinant molecule. In this molecular design, the Z-moieties are unable to form a network, while the ELR is below its Tt, thus, guaranteeing the liquid-like state of the system. However, this situation changes rapidly as the temperature increases above Tt, where a stable hydrogel is formed, as demostrated by rheological tests. The inability of the ELR molecule (without Z-domains) to form such a stable hydrogel above Tt clearly points to a positive cooperative effect between these two domains (Z and EL), and no conformational changes in the former are involved, as demonstrated by circular dichroism analysis. AFM shows that Z-motifs seem to induce the aggregation of micelles, which supports the enhanced stability displayed by ZELRs when compared to ELR at the macroscale level. To the best of our knowledge, this is the first time that such an interplay between these two domains has been reported. Furthermore, the cytocompatibility of the resulting hydrogels opens the door to their use in biomedical applications.

Self-organized ECM-mimetic model based on an amphiphilic multiblock silk-elastin-like corecombinamer with a concomitant dual physical gelation process.

Although significant progress has been made in the area of injectable hydrogels for biomedical applications and model cell niches, further improvements are still needed, especially in terms of mechanical performance, stability, and biomimicry of the native fibrillar architecture found in the extracellular matrix (ECM). This work focuses on the design and production of a silk-elastin-based injectable multiblock corecombinamer that spontaneously forms a stable physical nanofibrillar hydrogel under physiological conditions. That differs from previously reported silk-elastin-like polymers on a major content and predominance of the elastin-like part, as well as a more complex structure and behavior of such a part of the molecule, which is aimed to obtain well-defined hydrogels. Rheological and DSC experiments showed that this system displays a coordinated and concomitant dual gelation mechanism. In a first stage, a rapid, thermally driven gelation of the corecombinamer solution takes place once the system reaches body temperature due to the thermal responsiveness of the elastin-like (EL) parts and the amphiphilic multiblock design of the corecombinamer. A bridged micellar structure is the dominant microscopic feature of this stage, as demonstrated by AFM and TEM. Completion of the initial stage triggers the second, which is comprised of a stabilization, reinforcement, and microstructuring of the gel. FTIR analysis shows that these events involve the formation of ß-sheets around the silk motifs. The emergence of such ß-sheet structures leads to the spontaneous self-organization of the gel into the final fibrous structure. Despite the absence of biological cues, here we set the basis of the minimal structure that is able to display such a set of physical properties and undergo microscopic transformation from a solution to a fibrous hydrogel. The results point to the potential of this system as a basis for the development of injectable fibrillar biomaterial platforms toward a fully functional, biomimetic, artificial extracellular matrix, and cell niches.

Adjuvant therapy with cetuximab for locally advanced squamous cell carcinoma of the oropharynx: results from a randomized, phase II prospective trial.

BACKGROUND: Cetuximab combined with radiotherapy (RT) is a treatment option for head and neck cancer. The objectives of this randomized, phase II trial were to evaluate the efficacy and safety of cetuximab maintenance therapy following definitive RT with concomitant cetuximab in patients with oropharyngeal cancer. PATIENTS AND METHODS: Ninety-one patients with stage III-IV M0 oropharyngeal tumors were randomly assigned to the treatment with accelerated concomitant boost RT (69.9 Gy) + cetuximab or the same treatment with the addition of 12 consecutive weeks of cetuximab maintenance therapy. The primary end point was locoregional control (LRC) at 1 year. RESULTS: LRC at 1 year was superior among patients in the experimental arm, treated with cetuximab maintenance (59% versus 47%). However, LRC was similar between both arms after 2 years of follow-up, as a result of increased locoregional recurrences after the first year in the maintenance group. Patients treated with adjuvant cetuximab do recover very soon from toxic effect after combined treatment. CONCLUSIONS: Twelve weeks of cetuximab maintenance therapy after concomitant cetuximab + RT in locally advanced oropharyngeal carcinoma is feasible and improves clinical outcomes measured at 1 year. This improvement is not maintained after the second year suggesting that epidermal growth factor receptor blockade is not sufficient to completely eliminate the minimal residual disease.

Immunomodulatory nanoparticles from elastin-like recombinamers: single-molecules for tuberculosis vaccine development.

This study investigates both the physicochemical properties and immunogenicity of a genetically engineered elastin-like block corecombinamer (ELbcR) containing a major membrane protein sequence from Mycobacterium tuberculosis. The recombinant production of this ELbcR allows the production of large quantities of safe, antigenic particle-based constructs that directly and reversibly self-assemble into highly biocompatible, multivalent, monodisperse, and stable nanovesicles with a diameter of 55 nm from the same gene product using a highly efficient and cost-effective inverse transition cycling (ITC) procedure. The compositional complexity of these vesicles is retained after secondary processes such as endotoxin removal, sterilization, and lyophilization. An initial pro-chemotactic cytokine response (IL-1ß) followed by a pro-Th2/IL-5 response was observed in mice plasma following subcutaneous administration of the antigen-loaded nanovesicles in mice. This biphasic model of cytokine production was coupled with humoral isotype switching from IgM- to IgG-specific antibodies against the antigen, which was only observed in the presence of both the antigen and the polymer in the same construct and in the absence of additional adjuvants.

Multifunctional compartmentalized capsules with a hierarchical organization from the nano to the macro scales.

Inspired by the cells' structure, we present compartmentalized capsules with temperature and magnetic-based responsiveness and hierarchical organization ranging from the nano- to the visible scales. Liquefied alginate macroscopic beads coated with a layer-by-layer (LbL) chitosan/alginate shell served as containers both for model fluorophores and microcapsules, which in their turn encapsulated either another fluorophore or magnetic nanoparticles (MNPs). The microcapsules were coated with a temperature-responsive chitosan/elastin-like recombinamer (ELR) nanostructured shell. By varying the temperature from 25 to 37 °C, the two-hour release of rhodamine encapsulated within the microcapsules and its diffusion through the external compartment decreased from 84% and 71%. The devices could withstand handling and centrifugal stress, with 50% remaining intact at a rotation speed of 2000g. MNPs attributed magnetic responsiveness toward external magnetic fields. Such a customizable system can be envisaged to transport bioactive agents and cells in tissue engineering applications.

Prognostic significance of thymidylate synthase polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy.

AIM: There is a lack of prognostic factors of preoperative chemoradiation for locally advanced rectal cancer. Thymidylate synthase (TS) is the most important target of 5-fluorouracil; three main genetic polymorphisms of TS have been described. We analysed the prognostic value of these in patients with locally advanced rectal cancer treated with fluoropyrimidine-based chemoradiation. METHOD: Ninety-nine patients treated between November 2001 and March 2009 were included. All were treated by radiotherapy (5040 cGy) and concomitant fluoropyrimidine-based chemotherapy. Three polymorphisms were analysed: (i) a double (2R) or triple (3R) repeat of a 28 base pair (bp) tandem sequence upstream of the ATG codon initiation site in the 5'-terminal regulatory region, (ii) a functional G > C single nucleotide polymorphism present in the second repeat of the 3R alleles and (iii) a 6 bp deletion at nucleotide 1494 in the 3'-untranslated region. DNA was extracted from paraffin-embedded core biopsies taken from the tumour and the genotype was analysed using polymerase chain reaction restriction fragment length polymorphism. RESULTS: The 6 bp polymorphism was significantly associated with disease-free survival (+ 6 bp/+ 6 bp vs-6 bp/-6 bp, P = 0.032 logistic regression). No differences were found in disease-free survival according to the other polymorphisms studied. No relationship was observed between the different TS genotypes and pathological regression. CONCLUSION: The study suggests that the TS 6 bp polymorphism may be a predictor of disease-free survival in patients with locally advanced rectal cancer treated with fluoropyrimidine-based chemoradiation.

Characteristics and treatment of pyoderma gangrenosum in inflammatory bowel disease.

BACKGROUND: Pyoderma gangrenosum is a serious cutaneous complication seen in approximately 1 % of patients with inflammatory bowel disease (IBD). Oral corticosteroids are the mainstay treatment, although the evidence supporting their use is weak. AIMS: The purpose of this study was to investigate the characteristics of pyoderma gangrenosum associated with Crohn's disease or ulcerative colitis and which treatments are prescribed in Spanish clinical practice. METHODS: In this retrospective, observational study, the medical records from all patients with IBD and a diagnosis of pyoderma gangrenosum attended by the gastroenterology departments of 12 Spanish hospitals were reviewed. Data on patient demographics and characteristics, underlying IBD and treatment, and pyoderma gangrenosum characteristics, treatment, and outcome were collected and analyzed. RESULTS: The data from 67 patients were analyzed (41 [61.2 %] women, 41 [61.2 %] with Crohn's disease, 25 [37.3 %] with ulcerative colitis, and 1 [1.5 %] with indeterminate disease). The underlying disease was in remission in approximately one-third of patients at the time of presentation of pyoderma gangrenosum. Healing was achieved in all patients (in 3 without any systemic therapy). Oral corticosteroids were taken by 51 patients (76.1 %), almost always as first-line treatment, although definitive healing was attained in 19 (28.4 %). Biologic agents such as infliximab and adalimumab were taken by 31 patients (46.3 %) at some point (first-line in 6 patients [9.0 %]), with definitive healing in 29 patients (93.5 %). CONCLUSIONS: Oral corticosteroid therapy remains the most common treatment for pyoderma gangrenosum associated with inflammatory bowel disease. Biologic therapies such as infliximab and adalimumab should also be considered.

Dimethyl fumarate induced Wells syndrome. A case report. / Síndrome de Wells secundario a dimetilfumarato. A propósito de un caso clínico.

INTRODUCTION: Wells syndrome, also known as eosinophilic cellulitis, is a rare dermatosis with approximately 200 cases previously described in the literature. Here, we present a case of a patient with multiple sclerosis with Wells syndrome induced by dimethyl fumarate (DMF). CASE REPORT: A 41-year-old Caucasian woman was treated with DMF in July 2021. One week later, she experienced itching on her upper and lower right arm, followed by the appearance of erythematous plaques covered with vesicles. The complete blood count showed an increased eosinophil count of up to 2,000 µL. The histological images demonstrated dermal eosinophil infiltration concordant with Wells syndrome. The clinical course was benign, with complete resolution of the lesions and normalization of the eosinophil count within four weeks. Administration of corticosteroids was not necessary. CONCLUSIONS: Eosinophilia is rare in patients with multiple sclerosis treated with DMF and usually does not require dosage adjustments. Although clinical manifestations of eosinophilia in these patients are very rare, it is important for practitioners to recognize the symptoms. Many neuroleptic drugs can induce eosinophilia and systemic symptoms; therefore, physicians must be aware of the risks associated with DMF and neuroleptic drugs, particularly for quetiapine, which contains fumarate.

TITLE: Síndrome de Wells secundario a dimetilfumarato. A propósito de un caso clínico.Introducción. El síndrome de Wells, también conocido como celulitis eosinofílica, es una rara dermatosis con aproximadamente 200 casos descritos en la bibliografía. Aquí presentamos un caso clínico de un paciente con esclerosis múltiple y síndrome de Wells secundario a dimetilfumarato (DMF). Caso clínico. Mujer de 41 años que en julio de 2021 inició el tratamiento con DMF. Una semana más tarde, comenzó con prurito en las extremidades derechas, seguido por la aparición de zonas eritematosas con vesículas. El hemograma mostró elevación del recuento de los eosinófilos hasta 2.000 µL. El estudio anatomopatológico evidenció un infiltrado eosinófilo a nivel de la dermis compatible con síndrome de Wells. La evolución clínica fue favorable, con resolución de las lesiones y normalización de la eosinofilia aproximadamente en cuatro semanas. No fue necesario administrar corticoesteroides. Conclusiones. La eosinofilia es rara en los pacientes con EM tratados con DMF y generalmente no precisa ajuste de dosis. A pesar de que las manifestaciones clínicas de la eosinofilia en estos pacientes sean raras, es importante que el médico reconozca los síntomas. Numerosos neurolépticos pueden causar eosinofilia y síntomas sistémicos; por lo tanto, los facultativos deben conocer los riesgos de la asociación entre DMF y neurolépticos, en particular por la quetiapina, que contiene fumarato.