Cronología del diagnóstico de la neurofibromatosis tipo 1 en la infancia / Neurofibromatosis Type 1: Diagnostic Timelines in Children

Antecedentes y objetivos El diagnóstico de la neurofibromatosis 1 (NF1) plantea dificultades en niños sin antecedentes familiares durante la primera infancia. En este estudio pretendemos estimar la demora diagnóstica de los pacientes sin antecedentes familiares de NF1 y definir la repercusión de considerar las manchas café con leche y las efélides como un único criterio diagnóstico. Pacientes y métodos Estudio observacional descriptivo retrospectivo en el que se revisaron los hitos diagnósticos de la NF1 en las historias clínicas de los pacientes menores de 18 años atendidos en nuestro centro. Distribuimos a los pacientes en dos grupos en función de la existencia de antecedentes de NF1 entre sus progenitores, considerando las manchas café con leche y las efélides como un único criterio y aceptando el estudio genético como criterio de confirmación en casos de elevada sospecha. Resultados Se incluyeron en el estudio 108 menores con diagnóstico de NF1. La edad media de diagnóstico en nuestra serie fue de 3,94 años (desviación estándar:±3,8 años). En el grupo 1, sin antecedentes, la edad media de diagnóstico fue de 4 años y 8 meses, mientras que en el grupo 2, con antecedentes, fue de 12 meses, siendo la demora en el diagnóstico de 3 años y 8 meses entre ambos grupos. Conclusión Las lesiones cutáneas representan, en la mayoría de los casos, las primeras manifestaciones clínicas de la enfermedad. Consideramos necesaria la actualización de los criterios diagnósticos del NIH con el fin de facilitar el diagnóstico en los primeros años de vida (AU)

background and objectives The neurofibromatosis 1 (NF1) diagnosis is challenging in young children without a family history of NF1. The aims of this study were to estimate diagnostic delays in children without a family history of NF1 and to examine the effects of using café au lait macules and skin fold freckling as a single diagnostic criterion. Patients and methods Retrospective, descriptive, observational study of all patients diagnosed with NF1 before the age of 18 years who were seen at our hospital. The medical records of those included were reviewed to identify the date on which the diagnostic criteria of NF1 were objectified. The patients were categorized into 2 groups: those with a known parental history of NF1 and those without. Café au lait macules and skin fold freckling were assessed as a single diagnostic criterion, and genetic evidence was considered to confirm highly suspicious cases. Results We studied 108 patients younger than the age of 18 years with a diagnosis of NF1. Mean (SD) age at diagnosis was 3.94 (±3.8) years for the overall group, 1 year for patients with a parental history of NF1, and 4 years and 8 months for those without. Diagnosis was therefore delayed by 3 years and 8 months in patients without a family history. Conclusion Skin lesions were the first clinical manifestation of NF1 in most patients. We believe that the National Institutes of Health's diagnostic criteria for NF1 should be updated to aid diagnosis in young children (AU)

[Translated article] Neurofibromatosis Type 1: Diagnostic Timelines in Children / Cronología del diagnóstico de la neurofibromatosis tipo 1 en la infancia

background and objectives The neurofibromatosis 1 (NF1) diagnosis is challenging in young children without a family history of NF1. The aims of this study were to estimate diagnostic delays in children without a family history of NF1 and to examine the effects of using café au lait macules and skin fold freckling as a single diagnostic criterion. Patients and methods Retrospective, descriptive, observational study of all patients diagnosed with NF1 before the age of 18 years who were seen at our hospital. The medical records of those included were reviewed to identify the date on which the diagnostic criteria of NF1 were objectified. The patients were categorized into 2 groups: those with a known parental history of NF1 and those without. Café au lait macules and skin fold freckling were assessed as a single diagnostic criterion, and genetic evidence was considered to confirm highly suspicious cases. Results We studied 108 patients younger than the age of 18 years with a diagnosis of NF1. Mean (SD) age at diagnosis was 3.94 (±3.8) years for the overall group, 1 year for patients with a parental history of NF1, and 4 years and 8 months for those without. Diagnosis was therefore delayed by 3 years and 8 months in patients without a family history. Conclusion Skin lesions were the first clinical manifestation of NF1 in most patients. We believe that the National Institutes of Health's diagnostic criteria for NF1 should be updated to aid diagnosis in young children (AU)

Antecedentes y objetivos El diagnóstico de la neurofibromatosis 1 (NF1) plantea dificultades en niños sin antecedentes familiares durante la primera infancia. En este estudio pretendemos estimar la demora diagnóstica de los pacientes sin antecedentes familiares de NF1 y definir la repercusión de considerar las manchas café con leche y las efélides como un único criterio diagnóstico. Pacientes y métodos Estudio observacional descriptivo retrospectivo en el que se revisaron los hitos diagnósticos de la NF1 en las historias clínicas de los pacientes menores de 18 años atendidos en nuestro centro. Distribuimos a los pacientes en dos grupos en función de la existencia de antecedentes de NF1 entre sus progenitores, considerando las manchas café con leche y las efélides como un único criterio y aceptando el estudio genético como criterio de confirmación en casos de elevada sospecha. Resultados Se incluyeron en el estudio 108 menores con diagnóstico de NF1. La edad media de diagnóstico en nuestra serie fue de 3,94 años (desviación estándar:±3,8 años). En el grupo 1, sin antecedentes, la edad media de diagnóstico fue de 4 años y 8 meses, mientras que en el grupo 2, con antecedentes, fue de 12 meses, siendo la demora en el diagnóstico de 3 años y 8 meses entre ambos grupos. Conclusión Las lesiones cutáneas representan, en la mayoría de los casos, las primeras manifestaciones clínicas de la enfermedad. Consideramos necesaria la actualización de los criterios diagnósticos del NIH con el fin de facilitar el diagnóstico en los primeros años de vida (AU)

Neurofibromatosis Type 1: Diagnostic Timelines in Children. / Cronología del diagnóstico de la neurofibromatosis tipo 1 en la infancia.

BACKGROUND AND OBJECTIVES: The neurofibromatosis 1 (NF1) diagnosis is challenging in young children without a family history of NF1. The aims of this study were to estimate diagnostic delays in children without a family history of NF1 and to examine the effects of using café au lait macules and skin fold freckling as a single diagnostic criterion. PATIENTS AND METHODS: Retrospective, descriptive, observational study of all patients diagnosed with NF1 before the age of 18 years who were seen at our hospital. The medical records of those included were reviewed to identify the date on which the diagnostic criteria of NF1 were objectified. The patients were categorized into 2 groups: those with a known parental history of NF1 and those without. Café au lait macules and skin fold freckling were assessed as a single diagnostic criterion, and genetic evidence was considered to confirm highly suspicious cases. RESULTS: We studied 108 patients younger than the age of 18 years with a diagnosis of NF1. Mean (SD) age at diagnosis was 3.94 (±3.8) years for the overall group, 1 year for patients with a parental history of NF1, and 4 years and 8 months for those without. Diagnosis was therefore delayed by 3 years and 8 months in patients without a family history. CONCLUSION: Skin lesions were the first clinical manifestation of NF1 in most patients. We believe that the National Institutes of Health's diagnostic criteria for NF1 should be updated to aid diagnosis in young children.

Cutaneous Manifestations not Considered Diagnostic Criteria for Neurofibromatosis Type 1. A Case–Control Study / Hallazgos cutáneos no considerados criterios diagnósticos de la NF1. Estudio de casos y controles

Background The diagnosis of Neurofibromatosis type 1 (NF1) is usually delayed in children without a family history. We aimed to define the prevalence and characteristics of prevalent skin manifestations in NF1 compared to the general population, which continue to be excluded from the diagnostic criteria for NF1. Patients and methods Case–control study, matched by age groups, in which 108 patients with a diagnosis of NF1 and 137 healthy controls were included. Results The prevalence of nevus anemicus (NA) (p<0.001) and juvenile xanthogranulomas (JXG) (p<0.001) was significantly higher in the population affected by NF1 than in the control population. A specificity of 99.27% [confidence interval (CI): 95.4–99.96%] and a positive predictive value (PPV) of 98.80% [92.54–99.94%] were estimated for NA and a specificity of 99.27% [95.4–99.96%] and a PPV of 92.86% [64.17–99.63%] for JXG in the diagnosis of NF1 in children who present 6 or more Café-au-lait macules. Statistically significant differences were also evidenced in the distribution by phototypes (p 0.025) and in relation to generalized itching with no other cause (p<0.001). Conclusions NA and JXG are relevant clinical findings for the diagnosis of NF1, especially during the first years of life. We consider that its inclusion among the diagnostic criteria of the disease should be evaluated (AU)

Antecedentes El diagnóstico de la neurofibromatosis tipo 1 (NF1) se demora normalmente en niños sin antecedentes familiares. Nuestro objetivo fue definir la prevalencia y características de las manifestaciones cutáneas prevalentes en NF1, en comparación con la población general, que siguen siendo excluidas de los criterios diagnósticos para NF1. Pacientes y métodos Estudio de casos y controles, pareado por grupos de edad, en el que se incluyeron 108 pacientes diagnosticados de NF1 y 137 controles sanos. Resultados La prevalencia de nevus anemicus (NA) (p < 0,001) y xantogranuloma juvenil (XJ) (p < 0,001) fue significativamente superior en la población afectada de NF1, en comparación con el grupo control. Se estimaron una especificidad del 99,27% [Intervalo de confianza (IC): 95,4-99,96%] y un valor predictivo positivo (VPP) del 98,80% [92,54-99,94%] para NA, y una especificidad del 99,27% [95,4-99,96%] y VPP del 92,86% [64,17-99,63%] para XJ en el diagnóstico de NF1 en niños que presentan 6 o más manchas café con leche. También se evidenciaron diferencias estadísticamente significativas en la distribución por fototipos (p 0,025), y con relación al prurito generalizado sin ninguna otra causa (p <,001). Conclusiones Los NA y los XJ son hallazgos clínicos relevantes para el diagnóstico de NF1, especialmente durante los primeros años de vida. Consideramos que debería evaluarse su inclusión en los criterios diagnósticos de la enfermedad (AU)

Hallazgos cutáneos no considerados criterios diagnósticos de la NF1. Estudio de casos y controles / Cutaneous Manifestations not Considered Diagnostic Criteria for Neurofibromatosis Type 1. A Case-Control Study

Antecedentes El diagnóstico de la neurofibromatosis tipo 1 (NF1) se demora normalmente en niños sin antecedentes familiares. Nuestro objetivo fue definir la prevalencia y características de las manifestaciones cutáneas prevalentes en NF1, en comparación con la población general, que siguen siendo excluidas de los criterios diagnósticos para NF1. Pacientes y métodos Estudio de casos y controles, pareado por grupos de edad, en el que se incluyeron 108 pacientes diagnosticados de NF1 y 137 controles sanos. Resultados La prevalencia de nevus anemicus (NA) (p < 0,001) y xantogranuloma juvenil (XJ) (p < 0,001) fue significativamente superior en la población afectada de NF1, en comparación con el grupo control. Se estimaron una especificidad del 99,27% [Intervalo de confianza (IC): 95,4-99,96%] y un valor predictivo positivo (VPP) del 98,80% [92,54-99,94%] para NA, y una especificidad del 99,27% [95,4-99,96%] y VPP del 92,86% [64,17-99,63%] para XJ en el diagnóstico de NF1 en niños que presentan 6 o más manchas café con leche. También se evidenciaron diferencias estadísticamente significativas en la distribución por fototipos (p 0,025), y con relación al prurito generalizado sin ninguna otra causa (p <,001). Conclusiones Los NA y los XJ son hallazgos clínicos relevantes para el diagnóstico de NF1, especialmente durante los primeros años de vida. Consideramos que debería evaluarse su inclusión en los criterios diagnósticos de la enfermedad (AU)

Background The diagnosis of Neurofibromatosis type 1 (NF1) is usually delayed in children without a family history. We aimed to define the prevalence and characteristics of prevalent skin manifestations in NF1 compared to the general population, which continue to be excluded from the diagnostic criteria for NF1. Patients and methods Case–control study, matched by age groups, in which 108 patients with a diagnosis of NF1 and 137 healthy controls were included. Results The prevalence of nevus anemicus (NA) (p<0.001) and juvenile xanthogranulomas (JXG) (p<0.001) was significantly higher in the population affected by NF1 than in the control population. A specificity of 99.27% [confidence interval (CI): 95.4–99.96%] and a positive predictive value (PPV) of 98.80% [92.54–99.94%] were estimated for NA and a specificity of 99.27% [95.4–99.96%] and a PPV of 92.86% [64.17–99.63%] for JXG in the diagnosis of NF1 in children who present 6 or more Café-au-lait macules. Statistically significant differences were also evidenced in the distribution by phototypes (p 0.025) and in relation to generalized itching with no other cause (p<0.001). Conclusions NA and JXG are relevant clinical findings for the diagnosis of NF1, especially during the first years of life. We consider that its inclusion among the diagnostic criteria of the disease should be evaluated (AU)

Cutaneous Manifestations not Considered Diagnostic Criteria for Neurofibromatosis Type 1. A Case-Control Study. / Hallazgos cutáneos no considerados criterios diagnósticos de la NF1. Estudio de casos y controles.

BACKGROUND: The diagnosis of Neurofibromatosis type 1 (NF1) is usually delayed in children without a family history. We aimed to define the prevalence and characteristics of prevalent skin manifestations in NF1 compared to the general population, which continue to be excluded from the diagnostic criteria for NF1. PATIENTS AND METHODS: Case-control study, matched by age groups, in which 108 patients with a diagnosis of NF1 and 137 healthy controls were included. RESULTS: The prevalence of nevus anemicus (NA) (P<.001) and juvenile xanthogranulomas (JXG) (P<.001) was significantly higher in the population affected by NF1 than in the control population. A specificity of 99.27% (confidence interval): 95.4-99.96%] and a positive predictive value (PPV) of 98.80% [92.54-99.94%] were estimated for NA and a specificity of 99.27% [95.4-99.96%] and a PPV of 92.86% [64.17-99.63%] for JXG in the diagnosis of NF1 in children who present 6 or more Café-au-lait macules. Statistically significant differences were also evidenced in the distribution by phototypes (P=.025) and in relation to generalized itching with no other cause (P<.001). CONCLUSIONS: NA and JXG are relevant clinical findings for the diagnosis of NF1, especially during the first years of life. We consider that its inclusion among the diagnostic criteria of the disease should be evaluated.

Cutaneous Manifestations not Considered Diagnostic Criteria for Neurofibromatosis Type 1. A Case-Control Study.

BACKGROUND: The diagnosis of Neurofibromatosis type 1 (NF1) is usually delayed in children without a family history. We aimed to define the prevalence and characteristics of prevalent skin manifestations in NF1 compared to the general population, which continue to be excluded from the diagnostic criteria for NF1. PATIENTS AND METHODS: Case-control study, matched by age groups, in which 108 patients with a diagnosis of NF1 and 137 healthy controls were included. RESULTS: The prevalence of nevus anemicus (NA) (p<0.001) and juvenile xanthogranulomas (JXG) (p<0.001) was significantly higher in the population affected by NF1 than in the control population. A specificity of 99.27% [confidence interval (CI): 95.4-99.96%] and a positive predictive value (PPV) of 98.80% [92.54-99.94%] were estimated for NA and a specificity of 99.27% [95.4-99.96%] and a PPV of 92.86% [64.17-99.63%] for JXG in the diagnosis of NF1 in children who present 6 or more Café-au-lait macules. Statistically significant differences were also evidenced in the distribution by phototypes (p 0.025) and in relation to generalized itching with no other cause (p<0.001). CONCLUSIONS: NA and JXG are relevant clinical findings for the diagnosis of NF1, especially during the first years of life. We consider that its inclusion among the diagnostic criteria of the disease should be evaluated.

Split-thickness skin grafts obtained from adjacent hairy skin for reconstructing auricular concave surfaces after Mohs surgery.

BACKGROUND: Reconstruction of large auricular defects with full-thickness skin grafts (FTSG) is a commonly reported option, but less attention has focused on the advantages and indications of using split-thickness skin grafts (STSG) in the ear. OBJECTIVE: We sought to report our experience using STSG for repair of defects located on the auricular concave surfaces, highlighting the utility of choosing the adjacent hairy skin as donor site. METHODS: We performed a retrospective review of all Mohs micrographic defects on the auricular concave surfaces repaired with STSG obtained from the adjacent hairy skin, between January 2017 and July 2018 at our institution. RESULTS: A total of 16 patients with defects on the auricular concavities resulting from removal of non-melanoma skin cancer were reconstructed with STSG taken from the adjacent hairy skin. Only one patient experienced partial graft failure and no other complications were observed after 6-month follow-up. CONCLUSION: Split-thickness skin grafts are suitable for reconstructing concave areas in the ear, providing good cosmetic results with a simple, cost-effective and easily reproducible technique. Choosing the adjacent hairy skin as a donor area shortens the operative and postoperative time, and allows the procedure to be performed in a single surgical field.

[Update of hidradenitis suppurativa in Primary Care]. / Actualización en hidrosadenitis supurativa en Atención Primaria.

Hidradenitis suppurativa is a prevalent disease that is noted for its clinical variability and by its severe impact on quality of life. A meticulous scientific literature review is presented in this article in order to give an update on what is known on this condition. Primary Care physicians obviously play an important role in the early diagnosis and management of hidradenitis suppurativa. This review aims to provide a current and practical overview about this disease in order to optimise the healthcare for these patients by making the best use of available resources.

Pathogenesis: common pathways between hidradenitis suppurativa and Crohn disease. / Etiopatogenia: nexos en común entre la hidradenitis supurativa y la enfermedad de Crohn.

Both hidradenitis suppurativa and Crohn disease are considered chronic inflammatory diseases due to immune dysregulation. The high prevalence of Crohn disease patients diagnosed with hidradenitis suppurativa suggests the existence of common pathogenic links. The present literature review analyses the similarities and differences in the pathogenesis of the two diseases, in the search for new research and knowledge targets.

An Update on Hidradenitis Suppurativa (Part I): Epidemiology, Clinical Aspects, and Definition of Disease Severity.

Hidradenitis suppurativa is a chronic inflammatory disorder that has attracted increasing attention in recent years due to underestimations of prevalence and the considerable impact of the condition on interpersonal relationships, physical appearance, self-esteem, and body image. Although hidradenitis suppurative has a significant psychological impact on patients and can even cause physical limitations when thick scarring results in limb mobility limitation, until very recently little evidence was available relating to its epidemiology, etiology, or pathogenesis. In this review, we highlight the latest advances in our understanding of the epidemiological and clinical aspects of hidradenitis suppurativa. We will also look at the different classification systems for hidradenitis suppurativa and discuss the emergence of skin ultrasound as a promising technique for monitoring the course of this chronic inflammatory disease.

Asociación entre el síndrome de movilidad articular limitada y el riesgo de caídas accidentales en pacientes diabéticos / Association between limited joint mobility syndrome and risk of accidental falls in diabetic patients

Introducción: El síndrome de movilidad articular limitada (SMAL) aparece exclusivamente en pacientes con diabetes, tanto tipo 1 como tipo 2. Se manifiesta como una limitación en la movilidad articular que inicialmente afecta a las falanges proximales de las manos, seguidas, por orden de frecuencia, por muñecas, codos, hombros, rodillas y esqueleto axial. El diagnóstico se puede realizar mediante pruebas sencillas, como «el test de la oración». El objetivo fue conocer la prevalencia de pacientes diabéticos con SMAL, evaluar la asociación entre el SMAL y el grado de control glucémico y el riesgo de caídas accidentales. Pacientes y métodos: Estudio observacional transversal en el Centro de Salud de San Fernando II, Madrid (periferia). La muestra fueron 184 pacientes con un diagnóstico de diabetes superior a 5 años entre noviembre-marzo de 2013. Se utilizó el test de la oración para evaluar si los pacientes presentaban SMAL. El riesgo de caídas fue determinado según el test Timed Up & Go. Resultados: Un total de 99 pacientes (53,8%) (IC 95% 46,6-61) presentaron un test de la oración positivo. No se obtuvo una relación estadísticamente significativa con la HbA1c, en cambio, sí que se vio una asociación entre el test Timed Up & Go y el SMAL (p < 0,001) (IC 95% 1,173-1,611). Los pacientes con SMAL presentaban un riesgo moderado de caídas frente a aquellos sin SMAL, que presentaban un riesgo bajo. Conclusiones: Existe una alta prevalencia de SMAL en nuestro medio. Presentamos el primer estudio en donde se relaciona el SMAL con el riesgo de caídas en los pacientes diabéticos (AU)

Introduction: Limited joint mobility syndrome (LJMS) appears exclusively in both type 1 and type 2 diabetic patients. It is characterized by a limited range of digital motion, with involvement of small joints of the hands. It initially affects the proximal interphalangeal joints, followed by wrists, elbows, shoulders, knees, and axial skeleton. The diagnosis can be made by the simple «prayer sign» test. The objective was to study the prevalence of diabetic patients with LJMS, and to evaluate the association between LJMS and metabolic control, and the risk of accidental falls. Patients and methods: A cross-sectional study was conducted in the San Fernando II Health Centre, Madrid (suburbs). The sample consisted of 184 patients with a diagnosis of diabetes of over 5 years from November to March, 2013. The prayer sign was used to define which patients had LJMS. Fall risk was determined using the Timed Up & Go test. Results: A total of 99 patients (53.8%) (95% CI 46.6 to 61) had a positive prayer sign. No statistically significant relationship was found with HbA1c, but there was an association with the Timed Up & Go test (P < .001) (95% CI 1.173 to 1.611). The patients with LJMS had a moderate risk of falls compared with those without LJMS, which was of low risk. Conclusions: The prevalence of LJMS is high. This is the first study that shows a relationship between LJMS and the risk of falls in diabetic patients (AU)

[Association between limited joint mobility syndrome and risk of accidental falls in diabetic patients]. / Asociación entre el síndrome de movilidad articular limitada y el riesgo de caídas accidentales en pacientes diabéticos.

INTRODUCTION: Limited joint mobility syndrome (LJMS) appears exclusively in both type 1 and type 2 diabetic patients. It is characterized by a limited range of digital motion, with involvement of small joints of the hands. It initially affects the proximal interphalangeal joints, followed by wrists, elbows, shoulders, knees, and axial skeleton. The diagnosis can be made by the simple "prayer sign" test. The objective was to study the prevalence of diabetic patients with LJMS, and to evaluate the association between LJMS and metabolic control, and the risk of accidental falls. PATIENTS AND METHODS: A cross-sectional study was conducted in the San Fernando II Health Centre, Madrid (suburbs). The sample consisted of 184 patients with a diagnosis of diabetes of over 5 years from November to March, 2013. The prayer sign was used to define which patients had LJMS. Fall risk was determined using the Timed Up & Go test. RESULTS: A total of 99 patients (53.8%) (95% CI 46.6 to 61) had a positive prayer sign. No statistically significant relationship was found with HbA1c, but there was an association with the Timed Up & Go test (P<.001) (95% CI 1.173 to 1.611). The patients with LJMS had a moderate risk of falls compared with those without LJMS, which was of low risk. CONCLUSIONS: The prevalence of LJMS is high. This is the first study that shows a relationship between LJMS and the risk of falls in diabetic patients.

[Ultrasound in pediatric dermatology]. / Ecografía en dermatología pediátrica.

Cutaneous ultrasound is particularly useful in pediatric dermatology to diagnose numerous diseases without the need to use invasive tests. The present articles reviews some frequent dermatological entities in children whose study can be simplified through cutaneous ultrasound. This article also provides practical recommendations reported in the literature that may facilitate ultrasound examination, with special mention of benign tumoural disease, both congenital and acquired, and vascular anomalies.

Psoriasiform exfoliative erythroderma induced by golimumab.

Golimumab is a fully human anti-tumour necrosis factor (TNF)-α monoclonal antibody approved for use in the treatment of active rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Psoriasis induced by treatment with anti-TNF drugs is well documented, but to our knowledge, the development of clinical features of psoriasiform exfoliative erythroderma during treatment with golimumab has not been previously described.

Actualización en el tratamiento de las micosis cutáneas / Update on the Treatment of Superficial Mycoses

Se revisa la terapéutica disponible actualmente para el tratamiento de las micosis superficiales, las novedades existentes en el campo de la quimioterapia y los tratamientos coadyuvantes más útiles en este terreno. Se hace especial hincapié en el adecuado uso de los tratamientos convencionales y en algunos aspectos farmacoeconómicos relacionados con el tema. Se actualizan los procedimientos terapéuticos más adecuados en circunstancias especiales. Finalmente, se discuten algunas aportaciones novedosas encontradas en la literatura revisada (AU)

We review the current treatments available for superficial mycoses and discuss recent developments in pharmacotherapy and the most useful adjuvant treatments. Special emphasis is placed on the proper use of conventional therapies and a number of pharmacoeconomic issues. The review also offers an update on the best treatment choices in particular circumstances. Finally, we discuss some novel contributions found in the literature (AU)