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.

Daylight photodynamic therapy is an option for the treatment of actinic keratosis in patients with xeroderma pigmentosum in Africa.

BACKGROUND: Xeroderma pigmentosum (XP) is a very rare and severe genetic disorder with a DNA repair defect of ultraviolet (UV)-induced damage. Photodynamic therapy (PDT) has been successfully used in XP patients to treat actinic keratosis (AK) and daylight PDT (DL-PDT) has demonstrated similar efficacy to conventional PDT (C-PDT) for AK. OBJECTIVES: To assess DL-PDT for the treatment of AK in patients with XP. METHODS: Patients with XP were evaluated by a group of Spanish and African dermatologists. Clinical characteristics of the patients were assessed and divided in mild, severe or moderate affectation of AK in the face. A topical photosensitizer was extended on the patients' faces and after two hours of indoor light exposure, fluorescence was assessed and the cream was removed. Patients were examined two and seven days later to assess the reaction to PDT and followed up three months later. RESULTS: A total of 13 patients were treated on the whole face. Three were classified as severe AK, six as moderate AK and four as mild AK. Fluorescence assessment showed a soft yellow-green colour and a pink-color delineating the AK. Two days after treatment patients presented a scaly reaction. After one week the reaction healed, there was improvement and after three months no adverse events were noticed. CONCLUSIONS: PDT is an option for treatment of AK in patients with XP.

Generalized Licen Planus Treated With Narrowband UV-B Phototherapy: Results From 10 Patients and a Review of the Literature. / Liquen plano generalizado tratado con ultravioleta B de banda estrecha: resultados en 10 pacientes y revisión de la literatura.

Generalized lichen planus can be difficult to treat. One alternative for patients who do not respond to common topical and systemic treatments, such as corticosteroids and oral antihistamines, is phototherapy. Narrowband UV-B phototherapy offers several advantages and is currently the main treatment modality. In this study, we present the results corresponding to 10 patients with generalized lichen planus treated with narrowband UV-B phototherapy. We performed a prospective study of adult patients with generalized lichen planus affecting more than 20% of their body surface area. A complete response was observed in 8 patients (80%) and the disease recurred in 2 of these (recurrence rate, 25%). These rates are similar to those reported in the literature reviewed. Narrowband UV-B phototherapy is a widely used alternative to systemic treatments in GLP, but there are very few reports of its results in the literature.

Split-face study comparing conventional MAL photodynamic therapy in multiple actinic keratosis with complete time vs. half-time red light LED conventional illumination.

BACKGROUND: Conventional photodynamic therapy (PDT) with methylaminolevulinic acid (MAL) and daylight PDT have demonstrated similar efficacy in the treatment of actinic keratosis (AK). The reason for the use of daylight is to reduce pain during illumination but daylight has the limitation of the weather conditions. The difference in the doses of red light applied between these two methods suggests that an intermediate dose with red light conventional illumination could be effective in PDT of AK. OBJECTIVE: To compare the efficiency of conventional MAL-PDT with half-time conventional red light illumination in patients with multiple AK. MATERIAL AND METHODS: Adult patients with more than five symmetrically distributed AK were selected. After randomization, one area was treated with conventional PDT (Aktilite® , 630 nm, 37 J/cm2 , 8 min), while the contralateral was illuminated half time (Aktilite® , 630 nm, 37 J/cm2 , 4 min). Patients evaluated pain in each different side. Patients were evaluated at baseline, 3 and 6 months after PDT treatment by a blinded dermatologist. A questionnaire to be done at home 24 h after completing treatment was deliver to the patients to evaluate any side-effects. RESULTS: A total of 774 lesions were treated, 385 with conventional PDT and 389 with half-time PDT (P > 0.05). Conventional PDT was 85% of complete response of AK (327/385) at 3 months, and half-time PDT was 82% (319/389). At 6 months, conventional PDT was 70% (268/385) of complete response and half-time PDT was 65% (252/389). Pain during illumination was significantly lower in the VAS with the half-time protocol with a mean of 5.59 (SD 1.48) vs. 6.41 (SD 1.66) in conventional PDT. No difference in adverse effects was found between protocols. CONCLUSION: Conventional PDT with half-time illumination in multiple actinic keratosis is as effective as complete time illumination and decreased pain significantly.

Sex and acute oesophageal variceal bleeding-related in-hospital mortality: a 15-year retrospective study.

OBJECTIVE: The relationship between in-hospital mortality (IHM) and acute oesophageal variceal bleeding (AOEVB) has not been fully assessed. The aim of this study was to establish the association between sex and mortality for patients hospitalized with AOEVB. PATIENTS AND METHODS: We analyzed hospitalizations from the Italian Health Ministry database by identifying all patients discharged with AOEVB from January 2001 to December 2015. A total of 144,943 hospitalizations were for oesophageal varices, but only 24,570 emergency admissions with AOEVB coded as the primary or secondary diagnosis were included for analysis. Factors independently associated with IHM were evaluated by multilevel logistic regression. RESULTS: Approximately half of the population was aged ≥ 65 years, and nearly 10% was diagnosed with hepatocellular carcinoma. Overall, the IHM was 11.8%, with 12.1% in males and 11.3% in females, increasing from 9.2% among subjects aged < 55 years to 18.9% among those aged ≥ 85 years. The crude risk of death was slightly higher among females; however, when age and clinical presentation were considered, female sex was associated with reduced mortality. For liver disease, the risk of death in women was lower only in those with non-alcoholic liver disease (odds ratio= 0.77, 0.66-0.89), but it was similar to that in men for unspecified, cancer and alcoholic liver disease. The risk declined over time and was increased in patients with multiple comorbidities. CONCLUSIONS: AOEVB-related IHM decreased from 2001-2005 to 2011-2015. Factors affecting mortality included liver disease, age, sex, development of hepatocellular carcinoma and comorbidities.

Non-steroidal anti-inflammatory drugs increase MRP4 expression in an endometriotic epithelial cell line in a PPARa dependent manner.

OBJECTIVE: Endometriosis is a debilitating disease characterized by chronic inflammation. The transporter multidrug resistance-associated protein 4 (MRP4/ABCC4) is expressed in human endometrial tissue; it is overexpressed in ectopic endometrial tissue, and is modulated by the anti-inflammatory lipid Lipoxin A4 (LXA4). Recently, it was demonstrated that aspirin induces platelet MRP4 over-expression, through genomic modulation in megakaryocytes. Since patients with endometriosis frequently use aspirin or other non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), the aim of this study was to verify whether aspirin and other NSAIDs enhance MRP4 expression in 12Z human endometriotic epithelial cells and whether this was peroxisome proliferator-activated receptor alpha (PPARa) dependent. MATERIALS AND METHODS: MRP4 and PPARa expression was analyzed by Q-RT-PCR using TaqMan® Master Mix and TaqMan® Assay Reagents (Life Technologies, Monza, Italy) and Western blot. RESULTS: In 12Z cells, aspirin and other NSAIDs enhanced MRP4 mRNA and protein expression; these treatments also induced PPARa expression. Aspirin and diclofenac-induced increases in MRP4 expression were not observed in cells where PPARa was knocked down using siRNA. NSAIDs-induced MRP4 expression was correlated with augmented PGE2 secretion, indicating functional relevance. CONCLUSIONS: MRP4 expression was increased in cells treated with NSAIDs and the nuclear receptor PPARa is involved. Elevated PGE2 levels in cell supernatants correlate with its increased transport by MRP4 after NSAID treatment. More importantly, we provide evidence that in endometriotic epithelial cells aspirin and non-aspirin NSAIDs treatments alter gene expression.

Immunohistochemical investigation of predictors of response or aggressiveness of bowen disease after photodynamic therapy.

BACKGROUND: Photodynamic therapy (PDT) is a good option for the treatment of Bowen's disease (BD). However, BD occasionally can progress into a squamous cell carcinoma (SCC) after PDT. OBJECTIVE: Find predictors of aggressiveness of BD after PDT METHODS: Two biopsies of patients with BD treated with PDT with progression to SCC within three months were selected for immunohistochemical (IHC) studies. Conventional PDT was applied. IHC analysis was performed together with hematoxylin-eosin in the biopsies prior to and after treatment with PDT. RESULTS: Among the IHC markers studied, none showed different expressions between pre-treatment and post-treatment biopsies except for HSP70 CONCLUSIONS: The expression of Hsp70 in BD may predict future aggressive behaviour in BD when treated with PDT. Nevertheless, due to the small number of biopsies studied, further investigations are required to draw conclusions.

New platelet functional method for identification of pathogenic antibodies in HIT patients.

Heparin-induced thrombocytopenia (HIT) is a thrombotic complication of heparin therapy. The most used functional method for HIT diagnosis is serotonin release assay (SRA). A different functional method based on ATP release with luciferin/luciferase long-life and stable luminescent signal is used here, which is shown to be comparable for accuracy with SRA in both negative (patients 4Ts ≤3, and negative for both anti-PF4/heparin immunoassay and SRA) and positive (4Ts >3, and positive for both PF4/heparin antibodies and SRA) patients. Our results show that ATP release is higher in washed platelets activated by sera from positive patients than in platelets activated by sera from negative patients. In conclusion, we demonstrate that ATP release assay is a valid alternative method to SRA for the identification of pathogenic anti-PF4/heparin antibodies.

Treatment of adult diffuse pityriasis lichenoides chronica with narrowband ultraviolet B: experience and literature review.

Pityriasis lichenoides chronica (PLC) is an infrequent dermatosis of unknown aetiology, wholse evolution and response to treatment differs between children and adults. When PLC is recalcitrant or unresponsive to topical treatment, phototherapy is one of the main treatments used. We carried out a prospective study of adult diffuse PLC treated with narrowband ultraviolet B (NB-UVB). We treated eight patients whose disease showed no response to topical therapy, and obtained a complete response rate of 88% in a mean of 23 sessions (cumulative dose 16.99 J/cm2 ). However, the relapse rate was 43% in the first 6 months. Our results are similar to those of other published studies but there is much variability between them in the doses applied and the number of sessions needed. Further studies are necessary to devise a protocol for NB-UVB treatment of PLC.

Downregulation of neuronal vasoactive intestinal polypeptide in Parkinson's disease and chronic constipation.

BACKGROUND: Chronic constipation (CC) is a common and severe gastrointestinal complaint in Parkinson's disease (PD), but its pathogenesis remains poorly understood. This study evaluated functionally distinct submucosal neurons in relation to colonic motility and anorectal function in PD patients with constipation (PD/CC) vs both CC and controls. METHODS: Twenty-nine PD/CC and 10 Rome III-defined CC patients were enrolled. Twenty asymptomatic age-sex matched subjects served as controls. Colonic transit time measurement and conventional anorectal manometry were evaluated in PD/CC and CC patients. Colonoscopy was performed in all three groups. Colonic submucosal whole mounts from PD/CC, CC, and controls were processed for immunohistochemistry with antibodies for vasoactive intestinal polypeptide (VIP) and peripheral choline acetyltransferase, markers for functionally distinct submucosal neurons. The mRNA expression of VIP and its receptors were also assessed. KEY RESULTS: Four subgroups of PD/CC patients were identified: delayed colonic transit plus altered anorectal manometry (65%); delayed colonic transit (13%); altered manometric pattern (13%); and no transit and manometric impairment (9%). There were no differences in the number of neurons/ganglion between PD/CC vs CC or vs controls. A reduced number of submucosal neurons containing VIP immunoreactivity was found in PD/CC vs controls (P<.05). VIP, VIPR1, and VIPR2 mRNA expression was significantly reduced in PD/CC vs CC and controls (P<.05). CONCLUSIONS AND INFERENCES: Colonic motor and rectal sensory functions are impaired in most PD/CC patients. These abnormalities are associated with a decreased VIP expression in submucosal neurons. Both sensory-motor abnormalities and neurally mediated motor and secretory mechanisms are likely to contribute to PD/CC pathophysiology.

Osteoporosis across chronic liver disease.

Osteoporosis is a complication of chronic liver disease, with impact on morbidity, quality of life, and survival. The progress of medicine and the new therapies stretched the disease's natural history and improved the survival of patients with liver disease. So, it is fundamental to make better the quality of life and to prevent complications. Metabolic bone disorders are common complications of chronic liver disease (CLD). Patients with CLD have an increased risk of bone fractures, with significant impact on morbidity, quality of life, and even on survival. Bone diseases, including osteomalacia, osteoporosis, and osteopenia, are frequently observed in many types of liver disease. The pathogenesis of damage and the mechanisms of bone loss are different in relation to the specific liver disease. The relevance of these conditions induced many authors to create a new nosographic entity known as "hepatic osteodystrophy", although this term is rarely used anymore and it is now commonly referred to as osteopenia or osteoporosis associated with chronic liver disease. This review is based on the personal experiences of the authors and upon research done of the available literature on this subject matter. The authors searched the PubMed database for publications containing the term "liver disease" in combination with "bone disease", "hepatic osteodistrophy", "osteoporosis", "osteopenia", "osteomalacia", and "fractures". They selected publications from the past 10 years but did not exclude older seminal publications, especially for colestatic liver diseases. This review of literature shows that osteoporosis crosses all CLD. It is important to underline that the progress of medicine and the new therapies stretched the disease's natural history and improved the survival of patients with CLD. It is fundamental to make better the quality of life and it is mandatory to prevent complications and in particular the osteoporotic ones, especially fractures.

Experimental protocol of dental procedures In patients with hereditary angioedema: the role of anxiety and the use of nitrogen oxide.

Hereditary angioedema (HAE) is a rare disease, little known to the medical and dental community, but with a growing rate of hospitalization over the years. HAE is due to a deficit/dysfunction of C1 esterase inhibitor which leads to an increase in vascular permeability and the appearance of edemas widespread in all body areas. The airways are the most affected and laryngeal swelling, which can occur, it is dangerous for the patient's life, is also a sensitive spot in our daily practice, therefore, it is also important to be aware of all the signs of this disease. Episodes of HAE have no obvious cause, but it can be triggered by anxiety, invasive procedures and trauma. So this disease is a major problem in oral and maxillofacial surgery, ENT, endoscopy, emergency medicine and anesthesia because even simple procedures can cause laryngeal edema. The recommendations on the management of HAE include long- and short-term prophylaxis and treatment for acute attacks, however, the importance of anxiety control during the operating phases is undervalued. The present work suggests an experimental protocol for the surgery management of HAE patients with the help of nitrous oxide, with a brief review of the literature on this topic.

Six years of experience in photodynamic therapy for Basal cell carcinoma: results and fluorescence diagnosis from 191 lesions.

Background. Photodynamic therapy (PDT) has become a therapeutic option for basal cell carcinoma (BCC) in the last decade. Objectives. To study the results and predictors of BCC response to treatment with PDT and to evaluate fluorescence diagnosis of BCC. Methods. A descriptive, retrospective, and observational study was carried out. Patients with biopsy-confirmed BCC who were treated with methyl aminolevulinate and red light according to standard treatment protocols (2 sessions separated by 2 weeks, 630 nm, 37 J/cm(2), 8 minutes, Aktilite) were selected. Response was scored as clinically complete and incomplete and the patients were followed up every three months. Results. Data from 191 BCC in 181 patients with a mean age of 69.55 years and a mean follow-up period of 34.4 months were collected. The overall response was 74% of the BCC treated, with the best response in superficial BCC with a 95% of complete response. The regression analysis revealed that the superficial histological type was the primary factor predictive of a complete response. Conclusions. In the treatment of BCC with PDT, the most significant factor for predicting response is the histological type.

Experimental evidence and mathematical modeling of thermal effects on human colonic smooth muscle contractility.

It has been shown, in animal models, that gastrointestinal tract (GIT) motility is influenced by temperature; nevertheless, the basic mechanism governing thermal GIT smooth muscle responses has not been fully investigated. Studies based on physiologically tuned mathematical models have predicted that thermal inhomogeneity may induce an electrochemical destabilization of peristaltic activity. In the present study, the effect of thermal cooling on human colonic muscle strip (HCMS) contractility was studied. HCMSs were obtained from disease-free margins of resected segments for cancer. After removal of the mucosa and serosa layers, strips were mounted in separate chambers. After 30 min, spontaneous contractions developed, which were measured using force displacement transducers. Temperature was changed every hour (37, 34, and 31°C). The effect of cooling was analyzed on mean contractile activity, oscillation amplitude, frequency, and contraction to ACh (10(-5) M). At 37°C, HCMSs developed a stable phasic contraction (~0.02 Hz) with a significant ACh-elicited mean contractile response (31% and 22% compared with baseline in the circular and longitudinal axis, respectively). At a lower bath temperature, higher mean contractile amplitude was observed, and it increased in the presence of ACh (78% and 43% higher than the basal tone in the circular and longitudinal axis, respectively, at 31°C). A simplified thermochemomechanical model was tuned on experimental data characterizing the stress state coupling the intracellular Ca(2+) concentration to tissue temperature. In conclusion, acute thermal cooling affects colonic muscular function. Further studies are needed to establish the exact mechanisms involved to better understand clinical consequences of hypothermia on intestinal contractile activity.

Restoration of peripheral blood natural killer and B cell levels in patients affected by rheumatoid and psoriatic arthritis during etanercept treatment.

Etanercept (ETN) is an anti-tumour necrosis factor (TNF)-α agent used in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Few studies focused on the effects of anti-TNF-α on peripheral blood cells. We aimed to evaluate peripheral blood cells in RA and PsA patients during ETN treatment and to explore their relationships with disease activity. RA (n = 82) and PsA (n = 32) patients who started ETN were included into the study and evaluated prospectively before the beginning of ETN therapy and after 14, 22, 54 and 102 weeks. Patients were studied in terms of disease activity score on 28 joints (DAS28), clinical response and laboratory findings. Natural killer (NK) cells, B cells and T cells were characterized by immunophenotyping. Both the RA and the PsA patients showed reduced NK and B cell count before ETN treatment compared with controls. A negative correlation was demonstrated between DAS28 and B cell count in RA patients at baseline. Sustained significant increase of NK and B cells up to normal levels was observed in RA and PsA patients along ETN treatment. Increase of NK cell count was associated with a good-moderate clinical response to ETN in both RA and PsA patients. During ETN treatment peripheral blood NK and B cells levels were restored in RA and PsA patients. Correlations between NK and B cells with disease activity were observed, suggesting that those effects could be mediated by ETN treatment.