Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways.

BACKGROUND: The malignant mechanisms that control the development of cutaneous T-cell lymphoma (CTCL) are beginning to be identified. Recent evidence suggests that disturbances in specific intracellular signalling pathways, such as RAS-mitogen-activated protein kinase, T-cell receptor (TCR)-phospholipase C gamma 1 (PLCG1)-nuclear factor of activated T cells (NFAT) and Janus kinase (JAK)-signal transducer and activator of transcription (STAT), may play an essential role in the pathogenesis of CTCL. OBJECTIVES: To investigate the mechanisms controlling disease development and progression in mycosis fungoides (MF), the most common form of CTCL. METHODS: We collected 100 samples that were submitted for diagnosis of, or a second opinion regarding, MF between 2001 and 2018, 80% of which were in the early clinical stages of the disease. Formalin-fixed paraffin-embedded tissues were used for histological review and to measure the expression by immunohistochemistry of surrogate markers of activation of the TCR-PLCG1-NFAT, JAK-STAT and NF-κB pathways. Folliculotropism and large-cell transformation were also examined. RESULTS: NFAT and nuclear factor kappa B (NF-κB) markers showed a comparable activation status in early and advanced stages, while STAT3 activation was more frequent in advanced stages and was associated with large-cell transformation. Consistently with this observation, STAT3 activation occurred in parallel with MF progression in two initially MF-negative cases. A significant association of NFAT with NF-κB markers was also found, reflecting a common mechanism of activation in the two pathways. Genomic studies identified nine mutations in seven genes known to play a potential role in tumorigenesis in T-cell leukaemia/lymphoma, including PLCG1, JAK3 and STAT3, which underlies the activation of these key cell-survival pathways. A higher mutational allele frequency was detected in advanced stages. CONCLUSIONS: Our results show that STAT3 is activated in advanced cases and is associated with large-cell transformation, while the activation of NFAT and NF-κB is maintained throughout the disease. These findings could have important diagnostic and therapeutic implications. What's already known about this topic? Mycosis fungoides is characterized by a clonal expansion of T cells in the skin. The mechanisms controlling disease development and progression are not fully understood. What does this study add? An association of the nuclear factor of activated T cells and nuclear factor kappa B pathways was found, which could reflect a common mechanism of activation. These pathways were activated in early and advanced stages at the same level. Signal transducer and activator of transcription 3 activation was associated with large-cell transformation and was more frequent in advanced stages. A genomic analysis of cutaneous T-cell lymphoma-associated genes was performed. Nine mutations were detected. What is the translational message? These results could have important implications for the treatment of MF in the near future.

Reconstructive surgery of the medial zygomatic region of the cheek: presentation of 5 cases.

The cheek is the largest anatomical subunit of the face. It is a bilateral structure and symmetry must therefore be preserved. Peripherally it is related to important natural orifices whose location must also be maintained during surgical reconstructions. This is particularly important in the medial zygomatic subunit, whose delicate junction with the lower eyelid means that care must be taken to avoid ectropion. We present 5 options for the reconstruction of surgical defects secondary to the excision of tumors in this region.

Circulating levels of adiponectin, leptin, resistin and visfatin in non-diabetics patients with hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease associated with insulin resistance (IR), metabolic syndrome and increased cardiovascular risk. Adipokines are biologically active, pleotropic molecules which have been involved in the development of IR and in the pathogenesis of several chronic inflammatory conditions. The aim of the present study was to analyze serum concentrations of adiponectin, leptin, resistin and visfatin in patients with HS, and investigate their possible associations with IR, HS risk and disease severity. This case-control study enrolled 137 non-diabetic individuals (76 HS-patients and 61 age and sex-matched controls). Serum concentrations of adiponectin, leptin, resistin and visfatin, and the homeostasis model assessment of IR (HOMA-IR) were measured in all the participants. Serum adiponectin concentrations were found to be significantly lower, and leptin, resistin and visfatin levels were significantly higher in HS-patients than in controls. These differences remained significant even after adjusting for age, sex and body mass index, except for leptin. In a multivariate regression analysis, HOMA-IR was inversely correlated with adiponectin and positively associated with resistin levels. Furthermore, serum levels of resistin and visfatin were independently associated with HS risk. However, we found no association between serum levels of adipokines and HS severity. Our results suggest that reduced adiponectin and increased resistin serum levels may be surrogate biomarkers for IR in patients with HS. Moreover, resistin and visfatin might be independent risk factors for the development of HS.

Transesophageal access to the cardiac cavities and descending thoracic aorta via echoendoscopy. An experimental study.

OBJECTIVE: The applications of endoscopic ultrasonography have diversified over recent years. The possibility of reaching cardiac territory has been successfully explored in experimental models, opening up a new field of possibilities for diagnostic and therapeutic interventions that were unthinkable until very recently. The aims set out in this study are to evaluate cardiac anatomy, its approach, the safety of the experimental procedure and the resulting morphological and histological changes after the procedure. MATERIAL AND METHODS: The study has been performed on two adult pigs. They have undergone different surgical approaches to the cardiac cavities and descending thoracic aorta with excellent results. RESULTS: Different cardiac structures have been identified and operated upon (right auricle, left auricle, left ventricle, cardiac valves), as well as major vessels. The use of contrast, both intracavitary and from a peripheral vein, enabled us to verify the anatomical spaces studied. During the procedures we monitored for arrhythmias, hemodynamic behavior, possibility of infection by obtaining sample hemocultures before and after procedures, and response to punctures. CONCLUSIONS: The present study has enabled us to evaluate access to the heart from the esophageal lumen using endoscopic ultrasonography, with results that are very similar to those described in the current bibliography. However, we offer two novelties: puncture of the right auricle through the interauricular partition and puncture of the descending thoracic aorta, both performed with ease and apparent safety.

Role of endogenous opioids in syncope induced by head-up tilt test and its relationship with isoproterenol-dependent and isoproterenol-independent neurally-mediated syncope.

This study was designed to evaluate the role of endogenous opioids in neurally-mediated syncope. Head-up tilt test was performed on 35 patients with syncope of unknown origin. Plasma beta-endorphin was measured (1) at baseline, (2) at the end of tilt test or at time of syncope, (3) 15 min before isoproterenol-test, (4) at the end of the isoproterenol-test or at time of syncope. Subjects with a positive tilt testing showed a larger rise in plasma beta-endorphin concentrations at time of syncope (baseline 13.7+/-8.0 vs. syncope 41.4+/-26.4 pmol l(-1); P<0.01). On the contrary, patients with a positive isoproterenol-test showed no rise in plasma beta-endorphin levels (baseline 7.9+/-3.6 vs. syncope 7.4+/-2.7 pmol l(-1); P=ns). Patients with a passive negative tilt test (baseline 6.7+/-2.8 vs. end of test 7.0+/-3.3 pmol l(-1); P=ns) and negative isoproterenol tilt test (baseline 7.4+/-3.8 vs. end of test 8.1+/-3.4 pmol l(-1); P=ns) showed no changes in beta-endorphin concentrations. To further examine the efficacy of i.v. naloxone to prevent syncope, 10 patients were randomized to naloxone (0.02 mg/kg) or placebo. Second head-up tilt testing was negative in 1/5 patients with naloxone and in 2/5 patients with placebo. We conclude that, (1) endogenous opioids seem to be involved in vasovagal syncope induced by baseline head-up tilt test, (2) changes in plasma beta-endorphin concentrations show significant differences between patients who have isoproterenol-dependent and isoproterenol-independent syncope, this finding might occur in the setting of different pathophysiologic mechanisms, and (3) intravenous naloxone at a dose of 0.02 mg/kg was not superior to placebo in order to prevent positive responses to baseline tilt test.

[Isolated pulmonary endocarditis on native valve in elderly patient without predisposing factors]. / Endocarditis pulmonar aislada sobre válvula nativa en un paciente anciano sin factores predisponentes.

Isolated infective endocarditis in the native pulmonary valve is an unusual clinical entity in patients without predisposing factors and in non-intravenous drugs users. We present the case of a 75-year-old patient, with a subacute clinical picture of fever and pulmonary cavity nodules, admitted to our hospital with an initial suspected diagnosis of pulmonary tuberculosis. The presence of Enterococcal bacteremia in hemocultive and the documentation of a large vegetation in pulmonary valve by transtoracic and transesophageal echocardiography were key factors for final diagnosis.

[Long-term prognosis of patients with syncope of unknown origin in prolonged asystole induced by the head-up tilt test]. / Pronóstico a largo plazo de pacientes con síncope de origen desconocido y asistolia prolongada inducida mediante test de basculación.

INTRODUCTION AND OBJECTIVES: Prognosis and therapeutic assessment of patients with syncope and prolonged asystole during head-up tilt test remain unclear. The aim of the present study was to analyze the clinical evolution of patients with syncope of unknown origin, no heart disease and severe cardioinhibitory response induced by head-up tilt. METHODS: A prospective follow-up study was performed in 12 patients (6 male and 6 female, mean age 31 +/- 20 years) with recurrent syncope, no heart disease and affected by severe cardioinhibitory syncope induced by head-up tilt test. This was defined as syncope or near-syncope induced by baseline or isoproterenol tilt with asystole of > or = 3 seconds. All patients were re-tilted twice: with salt and fluid and with metoprolol (25 mg/b.i.d). According to the results of these tests, 5 patients were discharged with dietetic measures (salt & fluid) and 5 with metoprolol. In 2 patients who showed recurrent prolonged asystole a DDD pacemaker was implanted. RESULTS: After follow-up of 34 +/- 20 months all patients ae alive. The number of recurrences was small (2 syncopes and 2 near-syncopes). No relationship was observed between the number of syncopal recurrences and the applied treatment. CONCLUSIONS: We conclude that prolonged asystole induced by head-up tilt test does not confer an adverse prognosis in patients with syncope of unknown origin and no heart disease, thus, the clinical evolution of these patients is benign.

[Use of transdermal scopolamine in the prevention of neuro-cardiogenic syncope induced by the tilt test]. / Uso de la escopolamina transdérmica en la prevención del síncope neurocardiogénico inducido mediante test de basculación.

INTRODUCTION AND OBJECTIVES: The underlying mechanism of syncope induced by head-up tilt test is still incompletely understood. It has been proposed a sudden increase in parasympathetic's activity induced by the excessive activation of the cardiac mechanoreceptors. The aim of our study was to evaluate the clinical, electrocardiographic and hemodynamic responses to head-up tilt test before and after treatment with transdermal Scopolamine (anticholinergic agent). METHODS: We studied 17 patients (8 females, 9 males; mean age 43 +/- 19 years) with > or = 2 syncopal episodes of unknown origin and a positive tilt test (a positive response to tilt testing alone or in conjunction with an infusion of isoproterenol was defined as the appearance of syncope or presyncope associated to hypotension and/or bradycardia). Symptoms developed in 12 patients during the baseline tilt (Group I) and in 5 patients after infusion of isoproterenol (Group II). Mean time to symptoms was 8.5 +/- 7.9 minutes in group I. All patients were them treated with transdermal Scopolamine (1.5 mg/24 hours) and 48 hours later tilt test was repeated. RESULTS: In group I, 8 patients (66.6%) became tilt test negative and in the remaining 4 patients mean time before the appearance of symptoms was increased (8.5 +/- 7.9 vs 16.2 +/- 2.5 minutes; p < 0.05). In group II, 3 patients (60%) became tilt test negative and in the remaining 2 patients symptoms developed after an infusion of higher doses of isoproterenol than in the first study. So, with transdermal scopolamine 11 out of 17 patients became tilt test negative and time to symptoms was increased in all of the remaining 6 patients. CONCLUSIONS: Our study suggest that transdermal scopolamine is an usefull treatment in the prevention of neuro-cardiogenic syncope induced by head-up tilt test.