Experience With Bexarotene to Treat Cutaneous T-Cell Lymphomas: A Study of the Spanish Working Group of Cutaneous Lymphomas. / [Artículo traducido] Experiencia con bexaroteno en linfoma cutáneo de células T: un estudio del Grupo Español de Linfomas Cutáneos (GELC).

BACKGROUND AND OBJECTIVES: Bexarotene has been approved to treat advanced stage cutaneous T-cell lymphomas (CTCL) since 1999. However, very few data have been published on its long-term safety and efficacy profile. The aim of this study is to determine the tolerability to bexarotene and outcomes by collecting the 2nd largest case series to date on its long-term use vs CTCL. MATERIAL AND METHOD: This was a multicenter retrospective review of 216 patients with mycosis fungoides (174), or Sézary syndrome (42) on a 10-year course of bexarotene alone or in combination with other therapies at 19 tertiary referral teaching hospitals. RESULTS: A total of 133 men (62%) and 83 women (38%) were included, with a mean age of 63.5 year (27-95). A total of 45% were on bexarotene monotherapy for the entire study period, 22% started on bexarotene but eventually received an additional therapy, 13% were on another treatment but eventually received bexarotene while the remaining 20% received a combination therapy since the beginning. The median course of treatment was 20.78 months (1-114); and the overall response rate, 70.3%. Complete and partial response rates were achieved in 26% and 45% of the patients, respectively. Treatment was well tolerated, being the most common toxicities hypertriglyceridemia (79%), hypercholesterolemia (71%), and hypothyroidism (52%). No treatment-related grade 5 adverse events were reported. CONCLUSIONS: Our study confirms bexarotene is a safe and effective therapy for the long-term treatment of CTCL.

Experience With Bexarotene to Treat Cutaneous T-Cell Lymphomas: A Study of the Spanish Working Group of Cutaneous Lymphomas.

BACKGROUND AND OBJECTIVES: Bexarotene has been approved to treat advanced stage cutaneous T-cell lymphomas (CTCL) since 1999. However, very few data have been published on its long-term safety and efficacy profile. The aim of this study is to determine the tolerability to bexarotene and outcomes by collecting the 2nd largest case series to date on its long-term use vs CTCL. MATERIAL AND METHOD: This was a multicenter retrospective review of 216 patients with mycosis fungoides (174), or Sézary syndrome (42) on a 10-year course of bexarotene alone or in combination with other therapies at 19 tertiary referral teaching hospitals. RESULTS: A total of 133 men (62%) and 83 women (38%) were included, with a mean age of 63.5 year (27-95). A total of 45% were on bexarotene monotherapy for the entire study period, 22% started on bexarotene but eventually received an additional therapy, 13% were on another treatment but eventually received bexarotene while the remaining 20% received a combination therapy since the beginning. The median course of treatment was 20.78 months (1-114); and the overall response rate, 70.3%. Complete and partial response rates were achieved in 26% and 45% of the patients, respectively. Treatment was well tolerated, being the most common toxicities hypertriglyceridemia (79%), hypercholesterolemia (71%), and hypothyroidism (52%). No treatment-related grade 5 adverse events were reported. CONCLUSIONS: Our study confirms bexarotene is a safe and effective therapy for the long-term treatment of CTCL.

Cost of Treating Cutaneous T-Cell Lymphoma in Spain: Analysis of MICADOS Study Data by Disease Stage. / Evaluación de los costes asociados a la enfermedad de pacientes con linfoma cutáneo de células T en España: análisis en función del estadio clínico (estudio MICADOS).

BACKGROUND AND OBJECTIVE: The cost of treating cutaneous T-cell lymphoma (CTCL) in Spain is unknown. With the advent of new treatments, it is more important than ever to gain an accurate picture of the true costs involved. The MICADOS study had 2 primary objectives: 1)to evaluate the impact of CTCL on patient quality of life, and 2)to evaluate the costs associated with the disease. This article reports the results of the cost analysis. METHODS: We estimated the cost of treating CTCL over a period of 1year from the perspective of the Spanish National Health System. Twenty-three dermatologists and hematologists from 15 public hospitals analyzed data for adult patients with mycosis fungoides (MF) or Sézary syndrome (SS). RESULTS: A total of 141 patients (57.4% male) with a mean age of 63.6 years (95%CI: 61.4-65.7 years) were included. The mean direct annual cost of treating CTCL was €34,214 per patient. The corresponding costs by stage were €11,952.47 for stageI disease, €23,506.21 for stageII disease, €38,771.81 for stageIII disease, and €72,748.84 for stageIV disease. The total direct annual cost of treating MF/SS in public hospitals in Spain was estimated at €78,301,171; stageI disease accounted for 81% of all costs, stageII for 7%, and stagesIII andIV for 6% each. CONCLUSIONS: The MICADOS study offers an accurate picture of the direct cost of treating CTCL in patients with MF/SS in Spain and shows that costs vary significantly according to disease stage. Patient-borne and indirect costs should be analyzed in future studies.

[Translated article] Cost of Treating Cutaneous T-Cell Lymphoma in Spain: Analysis of MICADOS Study Data by Disease Stage.

BACKGROUND AND OBJECTIVE: The cost of treating cutaneous T-cell lymphoma (CTCL) in Spain is unknown. With the advent of new treatments, it is more important than ever to gain an accurate picture of the true costs involved. The MICADOS study had 2 primary objectives: 1)to evaluate the impact of CTCL on patient quality of life, and 2)to evaluate the costs associated with the disease. This article reports the results of the cost analysis. METHODS: We estimated the cost of treating CTCL over a period of 1year from the perspective of the Spanish National Health System. Twenty-three dermatologists and hematologists from 15 public hospitals analyzed data for adult patients with mycosis fungoides (MF) or Sézary syndrome (SS). RESULTS: A total of 141 patients (57.4% male) with a mean age of 63.6 years (95%CI: 61.4-65.7 years) were included. The mean direct annual cost of treating CTCL was €34,214 per patient. The corresponding costs by stage were €11,952.47 for stageI disease, €23,506.21 for stageII disease, €38,771.81 for stageIII disease, and €72,748.84 for stageIV disease. The total direct annual cost of treating MF/SS in public hospitals in Spain was estimated at €78,301,171; stageI disease accounted for 81% of all costs, stageII for 7%, and stagesIII andIV for 6% each. CONCLUSIONS: The MICADOS study offers an accurate picture of the direct cost of treating CTCL in patients with MF/SS in Spain and shows that costs vary significantly according to disease stage. Patient-borne and indirect costs should be analyzed in future studies.

Characterization of the Electrophysiological Characteristics of Chronic Atrial Fibrillation for Efficient Simulations.

Atrial biophysical simulations have the potential to enhance outcomes by enabling the simulation of pharmacological and ablative strategies. However, the high computational times associated with such simulations render them unsuitable for diagnostic purposes. To address this challenge, discrete models such as cellular automata (CA) have been developed, which consider a finite number of states, thus significantly reducing computational times. Yet, there is a pressing need to determine whether CA can replicate pathological simulations with accuracy. The analysis of simulations under different degrees of electrical remodeling shows an expected increase of Action Potential Duration (APD) with the previous Diastolic Interval (DI) interval, indicating short-term memory of atrial cardiomyocytes: shorter APD0 provoked shorter APD+1, and previous DI has a similar effect on APD+1. Independent prediction using both APD0 and DI was found to provide a far better estimation of APD+1 values, compared to relying on DI alone (p<<0.01). Finally, the CA models were able to replicate reentrant patterns and cycle lengths of different states of atrial remodeling with a high degree of accuracy when compared to biophysical simulations. Overall, the use of atrial CA with short-term memory allows accurate reproduction of arrhythmic behavior in pathological tissue within a clinically relevant timeframe.Clinical Relevance- Discrete electrophysiological models simulate pathological self-sustained arrhythmias in diagnostic times.

Assessment of Risk for Ventricular Tachycardia based on Extensive Electrophysiology Simulations.

Patients that have suffered a myocardial infarction are at high risk of developing ventricular tachycardia. Patient stratification is often determined by characterization of the underlying myocardial substrate by cardiac imaging methods. In this study, we show that computer modeling of cardiac electrophysiology based on personalized fast 3D simulations can help to assess patient risk to arrhythmia. We perform a large simulation study on 21 patient digital twins and reproduce successfully the clinical outcomes. In addition, we provide the sites which are prone to sustain ventricular tachycardias, i.e, onset sites around the scar region, and validate if they colocalize with exit sites from slow conduction channels.Clinical relevance- Fast electrophysiological simulations can provide advanced patient stratification indices and predict arrhythmic susceptibility to suffer from ventricular tachycardia in patients that have suffered a myocardial infarction.

Mechanism of action of chlormethine gel in mycosis fungoides.

Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, is characterized by proliferation of malignant skin-tropic T cells. Progression from early-stage disease (skin patches and/or plaques) to more advanced stages (cutaneous tumours, erythroderma or extracutaneous involvement) occurs slowly and can be discontinuous. Prognosis is poor for the ~25% of patients who progress to advanced disease. Patients at any stage of MF may experience reduced health-related quality of life (QoL) via a spectrum of physically and psychologically debilitating symptoms that can impact many aspects of daily life. Allogeneic stem-cell transplantation is a curative treatment option for some patients with advanced disease, but otherwise there is currently no cure for MF; patients are often refractory to several treatments and require lifelong management. The goals of therapy are symptom control, prevention of disease progression, avoidance of treatment-related toxicity and maintenance/improvement of QoL. Although treatment regimens exist it can be difficult to know how to prioritize them, hence therapies are tailored according to patient needs and drug availabilities, following clinical recommendations. International consensus guidelines recommend skin-directed therapies (SDTs) as first-line treatment for early-stage disease, and SDTs combined with systemic therapy for advanced stages. Chlormethine (CL), also known as mechlorethamine, chlorethazine, mustine, HN2, caryolysine and embichin, is a synthetic deoxyribonucleic acid-alkylating agent that was used as a chemical weapon (mustard gas) during the First World War. Subsequent investigation revealed that survivors of mustard gas exposure had lymphocytopenia, and that CL could inhibit rapidly proliferating malignant T cells. CL has since been developed as a topical treatment for MF and prescribed as such for over 70 years. This review aims to summarize the current knowledge regarding the mechanism of action of CL in the cutaneous micro-environment, in the specific context of MF treatment.

Evaluating the effect of phenolic compounds as hydrogen acceptors when ruminal methanogenesis is inhibited in vitro - Part 1. Dairy cows.

Some antimethanogenic feed additives for ruminants promote rumen dihydrogen (H2) accumulation potentially affecting the optimal fermentation of diets. We hypothesised that combining an H2 acceptor with a methanogenesis inhibitor can decrease rumen H2 build-up and improve the production of metabolites that can be useful for the host ruminant. We performed three in vitro incubation experiments using rumen fluid from lactating Holstein cows: Experiment 1 examined the effect of phenolic compounds (phenol, catechol, resorcinol, hydroquinone, pyrogallol, phloroglucinol, and gallic acid) at 0, 2, 4, and 6 mM on ruminal fermentation for 24 h; Experiment 2 examined the combined effect of each phenolic compound from Experiment 1 at 6 mM with two different methanogenesis inhibitors (Asparagopsis taxiformis or 2-bromoethanesulfonate (BES)) for 24 h incubation; Experiment 3 examined the effect of a selected phenolic compound, phloroglucinol, with or without BES over a longer term using sequential incubations for seven days. Results from Experiment 1 showed that phenolic compounds, independently of the dose, did not negatively affect rumen fermentation, whereas results from Experiment 2 showed that phenolic compounds did not decrease H2 accumulation or modify CH4 production when methanogenesis was decreased by up to 75% by inhibitors. In Experiment 3, after three sequential incubations, phloroglucinol combined with BES decreased H2 accumulation by 72% and further inhibited CH4 production, compared to BES alone. Interestingly, supplementation with phloroglucinol (alone or in combination with the CH4 inhibitor) decreased CH4 production by 99% and the abundance of methanogenic archaea, with just a nominal increase in H2 accumulation. Supplementation of phloroglucinol also increased total volatile fatty acid (VFA), acetate, butyrate, and total gas production, and decreased ammonia concentration. This study indicates that some phenolic compounds, particularly phloroglucinol, which are naturally found in plants, could improve VFA production, decrease H2 accumulation and synergistically decrease CH4 production in the presence of antimethanogenic compounds.

Evaluating the effect of phenolic compounds as hydrogen acceptors when ruminal methanogenesis is inhibited in vitro - Part 2. Dairy goats.

Most mitigation strategies to reduce enteric methane (CH4) production in the rumen induce an excess of rumen dihydrogen (H2) that is expelled and consequently not redirected to the synthesis of metabolites that can be utilised by the ruminant. We hypothesised that phenolic compounds can be potential H2 acceptors when added to the diet, as they can be degraded to compounds that may be beneficial for the animal, using part of the H2 available when ruminal methanogenesis is inhibited. We performed four in vitro incubation experiments using rumen inoculum from Murciano-Granadina adult goats: Experiment 1 examined the inhibitory potential of Asparagopsis taxiformis (AT) at different concentrations (0, 1, 2, 3, 4 and 5% of the substrate on a DM basis) in 24 h incubations; Experiment 2 investigated the effect of a wide range of phenolic compounds (phenol, catechol, resorcinol, hydroquinone, pyrogallol, phloroglucinol, gallic acid and formic acid) at different doses (0, 2, 4, and 6 mM) on rumen fermentation for 24 h; Experiment 3 evaluated the combined effect of each phenolic compound at 6 mM with AT at 2% DM in sequential batch cultures for 5 days; and Experiment 4 examined the dose-response effect of phloroglucinol at different concentrations (0, 6, 16, 26 and 36 mM) combined with AT in sequential batch cultures for 5 days. Results from Experiment 1 confirmed that AT at 2% DM substantially inhibited CH4 production while significantly increasing H2 accumulation and decreasing the acetate:propionate ratio. Results from Experiment 2 showed that phenolic compounds did not negatively affect rumen fermentation at any dose. In Experiment 3, each phenolic compound at 6 mM combined with AT at 2% DM inhibited CH4 production. Phloroglucinol numerically decreased H2 accumulation and significantly increased total gas production (TGP), volatile fatty acid (VFA) production and the acetate:propionate ratio. In Experiment 4, phloroglucinol at increasing doses supplemented with AT at 2% DM significantly decreased H2 accumulation and the abundances of archaea, protozoa and fungi abundances, and increased TGP, total VFA production and the acetate:propionate ratio in a dose-dependent way. In conclusion, combined treatment with AT and phloroglucinol was successful to mitigate CH4 production while preventing the accumulation of H2, leading to an increase in acetate and total VFA production and therefore an improvement in rumen fermentation in goats.

Spanish Version of the RECAP Questionnaire to Assess Control of Atopic Eczema: Translation, Cultural Adaptation, Validation, and Correlations with Other Patient-Reported Outcome Measures. / Traducción, adaptación transcultural, correlación con otros PRO y validación del cuestionario RECAP sobre el grado de control de la dermatitis atópica.

BACKGROUND: The 7-item RECAP (Recap of Atopic Eczema) questionnaire is used to assess the control of different degrees of eczema severity in patients of all ages. Long-term control of eczema is one of the 4 core outcome domains to be assessed in clinical trials of eczema therapies. After the RECAP was developed in the United Kingdom, it was translated into Chinese, German, Dutch, and French. OBJECTIVES: To produce a validated Spanish version of the RECAP questionnaire and, secondarily, to test its content validity in a group of Spanish patients with atopic eczema. MATERIAL AND METHODS: In a 7-step process we produced 2forward translations and 1back translation of the RECAP questionnaire. Experts then held two meetings to reach consensus and draft a Spanish version of the questionnaire. Fifteen adult patients with atopic eczema were interviewed to evaluate the comprehensibility, comprehensiveness, and relevance of the drafted items. These patients also completed the Atopic Dermatitis Control Tool (ADCT), the Dermatology Life Quality Index (DLQI), and the Patient-Oriented Eczema Measure (POEM). Stata software (version 16) was then used to explore the correlations between the patients' scores on these tools and the RECAP. RESULTS: The patients found the Spanish version of the RECAP to be comprehensible and easy to answer. We observed a strong correlation between results on the Spanish RECAP and the ADCT, and highly significant correlations between the RECAP and the DLQI and POEM tools. CONCLUSIONS: The culturally adapted Spanish version of the RECAP is linguistically equivalent to the original version of the questionnaire. RECAP scores correlate highly with other patient-reported outcome measures.

Primary Cutaneous Lymphoma Registry of the Spanish Academy of Dermatology and Venereology (AEDV): Data for the First 5 Years. / Registro de linfomas cutáneos primarios (RELCP) de la AEDV: datos tras 5 años de funcionamiento.

BACKGROUND AND OBJECTIVE: Primary cutaneous lymphomas (PCL) are uncommon. Observations based on the first year of data from the Spanish Registry of Primary Cutaneous Lymphomas (RELCP, in its Spanish abbreviation) of the Spanish Academy of Dermatology and Venereology (AEDV) were published in February 2018. This report covers RELCP data for the first 5 years. PATIENTS AND METHODS: RELCP data were collected prospectively and included diagnosis, treatments, tests, and the current status of patients. We compiled descriptive statistics of the data registered during the first 5 years. RESULTS: Information on 2020 patients treated at 33 Spanish hospitals had been included in the RELCP by December 2021. Fifty-nine percent of the patients were men; the mean age was 62.2 years. The lymphomas were grouped into 4 large diagnostic categories: mycosis fungoides/Sézary syndrome, 1112 patients (55%); primary B-cell cutaneous lymphoma, 547 patients (27.1%); primary CD30+lymphoproliferative disorders, 222 patients (11%), and other T-cell lymphomas, 116 patients (5.8%). Nearly 75% of the tumors were registered in stage I. After treatment, 43.5% achieved complete remission and 27% were stable at the time of writing. Treatments prescribed were topical corticosteroids (1369 [67.8%]), phototherapy (890 patients [44.1%]), surgery (412 patients [20.4%]), and radiotherapy (384 patients [19%]). CONCLUSION: The characteristics of cutaneous lymphomas in Spain are similar to those reported for other series. The large size of the RELCP registry at 5 years has allowed us to give more precise descriptive statistics than in the first year. This registry facilitates the clinical research of the AEDV's lymphoma interest group, which has already published articles based on the RELCP data.

Epidemiology of Melanoma in Spain: Estimation of Number of Patients With Stage III Disease Eligible for Adjuvant Therapies. / Epidemiología del melanoma en España: estimación de los pacientes con melanoma con estadio III candidatos al tratamiento adyuvante.

BACKGROUND AND OBJECTIVE: Accurate information on the incidence of melanoma by stage and a better understanding of transition between stages are important for determining the burden of disease and assessing the impact of new adjuvant therapies on recurrence and survival. The aim of this study was to estimate the incidence rates of the various stages of melanoma in Spain and to estimate the number of patients with stage III disease who are eligible for adjuvant systemic therapies. MATERIALS AND METHOD: We built an epidemiological model using prospectively collected data from patients diagnosed with de novo or recurrent melanoma between 2012 and 2016 in the melanoma units of 4 public hospitals. RESULTS: The estimated crude incidence rates for stage I and II melanoma were 7 and 2.9 cases per 100,000 person-years, respectively. The corresponding rates for stage III and IV melanoma were 1.9 and 1.3 cases per 100,000 person-years; 25.8% of patients with stage III melanoma were stage IIIA, 47% were stage IIIB, and 27.3% were stage IIIC. The respective estimated incidence rates for recurrent stage III and IV melanoma were 1.1 and 0.9 cases per 100,000 person-years. Overall, 54% of patients with recurrent stage III melanoma had progressed from stage I or II; the other cases corresponded to changes in substage. Of the patients with stage III melanoma, 85% of those with a de novo diagnosis and 80% of those who had relapsed had resectable disease, meaning they were eligible for adjuvant therapy; 47% of these patients had a BRAF mutation. CONCLUSIONS: The above estimates could have a major impact on health care resource planning. Assessing the number of patients with melanoma who are eligible for adjuvant therapies in melanoma could help decision-makers and clinicians anticipate future needs for the management of this disease.

Management of cyclodialysis cleft with transscleral cryotherapy.

A cyclodialysis cleft is a rare disease that is produced as a result of a separation of the longitudinal fibers of the ciliary body muscle from the scleral spur. A stepwise approach is the best course of action to treat cyclodialysis, starting with medical therapy and continuing with more invasive surgical options. We report a case of ocular hypotony due a traumatic cyclodialysis successfully resolved with transscleral cryotherapy.

Survey of glaucoma surgical preferences among glaucoma specialists in Spain.

PURPOSE: To evaluate the spectrum of glaucoma surgery undertaken among members of the Spanish Glaucoma Society (SEG). METHODS: A 10 question web-based anonimous survey was mailed through the Annals of the Spanish Glaucoma Society to all its members on January, February and July 2019 to determine their preferred surgical approach. MAIN OUTCOME MEASURES: Age, type of Glaucoma, surgery undertaken, type of anti-scarring strategy and prothesis introduced for the last 10 surgeries since the survey was received. The surgeon experience was registered in years of practice. RESULTS: A total of 97 SEG members across the country answered the survey. Sixty-two (63.4%) responders had more than 10 years of experience. Primary open angle glaucoma was the most frequent type of glaucoma (60.6%). The most popular surgery was deep-sclerectomy (37.3%) followed by trabeculectomy (17,6%) and the collagen microshunt (XEN® Allergan Inc., Irvine, CA) (14.1%). Glaucoma drainage device (GDD) was used in 10.5% of the cases. Up to 21.7% of surgeries were reinterventions, where GDD was used in 27.3% and trabeculectomy in 20.3% of the cases. Glaucoma surgery was combined with phacoemulsification in 47.3% of the eyes. Mitomycin C (MMC) was used in 54,8% of the cases, collagen matrix (Ologen®, Aeon Astron Corporation, Taipei, Taiwan) was used alone in 8.2% of the cases and in 13,7% combined with MMC. MMC was used in a soaked sponge in 79% of cases (concentrations of 0.02% in 99% and 0.04% in 1%) and in 21% of cases MMC was injected subconjunctivally (concentrations of 0,01% in 81% and 0.02% in 19%). CONCLUSIONS: Although the glaucoma surgeon performs a wide range of surgical techniques, deep sclerectomy remains the most widely used surgical technique in Spain. Combined cataract and glaucoma surgery is performed almost in half of the patients and MMC is the most frequently selected antifibrotic agent, alone or combined with collagen matrix. The new minimal invasive surgical techniques represent the 20% of the total.

Ventilation conditions and their influence on thermal comfort in examination classrooms in times of COVID-19. A case study in a Spanish area with Mediterranean climate.

Current evidence and recent publications have led to the recognition that aerosol-borne transmission of COVID-19 is possible in indoor areas such as educational centers. A crucial measure to reduce the risk of infection in high occupancy indoors is ventilation. In this global pandemic context of SARS-CoV-2 virus infection, a study has been carried out with the main objective of analyzing the effects of natural ventilation conditions through windows on indoor air quality and thermal comfort during on-site examinations in higher education centers during the winter season, as this implies situations of unusual occupation and the impossibility in many cases of taking breaks or leaving classrooms, as well as the existence of unfavorable outdoor weather conditions in terms of low temperatures. For this purpose, in situ measurements of the environmental variables were taken during different evaluation tests. As the main results of the study, ventilation conditions were generally adequate in all the tests carried out, regardless of the ventilation strategy used, with average CO2 concentration levels of between 450 and 670 ppm. The maximum CO2 concentration value recorded in one of the tests was 808 ppm. On this basis, the limit for category IDA 2 buildings, corresponding to educational establishments, was not exceeded in any case. However, these measures affected the thermal comfort of the occupants, especially when the outside temperature was below 6 °C, with a dissatisfaction rate of between 25 and 72%. Examinations carried out with outside temperatures above 12 °C were conducted in acceptable comfort conditions regardless of outside air supply and classroom occupancy. In these cases, the dissatisfaction rate was less than 10%. The results obtained have made it possible to establish strategies for ventilation in the implementation of future exams, depending on the climatic conditions outside.