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Papers by Pablo Fernandez Peñas
INTRODUCTION: Although 65 % of the deaths caused by skin cancer are due to melanomas, the possibl... more INTRODUCTION: Although 65 % of the deaths caused by skin cancer are due to melanomas, the possible causes that may explain the aggressiveness of this type of tumor are still unknown. Different approaches have been used to try to find an effective treatment, but they have been unsuccessful. Interference RNA (iRNA) is an essential technique for this research. With this technique, we can selectively "knock down" or silence protein expression. The tetraspanins CD9 and CD151 are molecules involved in cell motility, including melanoma cells.MATERIAL AND METHODS: A375 melanoma cell line, anti-CD9 and anti-CD151 monoclonal antibodies, and iRNA against CD9 and CD151. Immunofluorescence techniques, flow cytometry, cell transfection, cell selection with magnetic beads and evaluation of cell migration in a wound-healing model.RESULTS: The A375 cells express CD9 and CD151. By using iRNA against CD9 and CD151, we managed to inhibit the expression of these proteins. The cells transfected with iRNA against CD9 showed significant inhibition of their motility.DISCUSSION: We managed to silence the expression of CD9 and CD151 using iRNA techniques in the A375 melanoma cell line. The reduction in CD9 caused the inhibition of cell motility, while the interference with CD151 expression had a more moderate effect. This data indicates that the knockdown of tetraspanins may be a future target for the treatment of melanoma.
We report the case of a 56-year-old woman with reticular erythematous mucinosis (REM). During her... more We report the case of a 56-year-old woman with reticular erythematous mucinosis (REM). During her workup infection with the human immunodeficiency virus (HIV) was detected. She developed a cerebral toxoplasmosis, salmonella sp. bacteremia and oral ulcerations with the presence of type I herpes simplex virus and cytomegalovirus. The relation of REM with the deposition of mucin in AIDS patients' bone marrow and HIV infection is discussed. To our knowledge, this is the first report where REM is associated with HIV disease.
Pseudoxanthoma elasticum-like papillary dermal elastolysis is a peculiar idiopathic elastolytic d... more Pseudoxanthoma elasticum-like papillary dermal elastolysis is a peculiar idiopathic elastolytic disorder with cutaneous lesions clinically resembling pseudoxanthoma elasticum with partial or total band-like elastolysis of the papillary dermis histopathologically, and without systemic complications. We here report 2 new cases and review the clinicopathological features of patients with this diagnosis in the literature. The possible pathogenesis of this recently described entity is discussed.
BACKGROUND: Early detection of melanomas by means of diverse screening campaigns is an important ... more BACKGROUND: Early detection of melanomas by means of diverse screening campaigns is an important step towards a reduction in mortality. Computer-aided analysis of digital images obtained by dermoscopy has been reported to be an accurate, practical and time-saving tool for the evaluation of pigmented skin lesions (PSLs). A prototype for the computer-aided diagnosis of PSLs using artificial neural networks (NNs) has recently been developed: diagnostic and neural analysis of skin cancer (DANAOS).OBJECTIVES: To demonstrate the accuracy of PSL diagnosis by the DANAOS expert system, a multicentre study on a diverse multinational population was conducted.METHODS: A calibrated camera system was developed and used to collect images of PSLs in a multicentre study in 13 dermatology centres in nine European countries. The dataset was used to train an NN expert system for the computer-aided diagnosis of melanoma. We analysed different aspects of the data collection and its influence on the performance of the expert system. The NN expert system was trained with a dataset of 2218 dermoscopic images of PSLs.RESULTS: The resulting expert system showed a performance similar to that of dermatologists as published in the literature. The performance depended on the size and quality of the database and its selection.CONCLUSIONS: The need for a large database, the usefulness of multicentre data collection, as well as the benefit of a representative collection of cases from clinical practice, were demonstrated in this trial. Images that were difficult to classify using the NN expert system were not identical to those found difficult to classify by clinicians. We suggest therefore that the combination of clinician and computer may potentially increase the accuracy of PSL diagnosis. This may result in improved detection of melanoma and a reduction in unnecessary excisions.
Graft-versus-host disease (GVHD) is the main complication of allogeneic bone marrow transplantati... more Graft-versus-host disease (GVHD) is the main complication of allogeneic bone marrow transplantation and the skin is the most commonly involved organ. The clinical presentation is varied and may resemble autoimmune diseases, such as scleroderma, lichen planus or lichen sclerosus. Chronic GVHD presenting with a butterfly malar rash mimicking lupus erythematosus is uncommon. We report a series of five patients with cutaneous lichenoid GVHD that presented with a butterfly malar rash. Two of our patients had positive antinuclear antibody titres. The evolution was poor with development of sclerodermatous GVHD lesions in three patients and relapse of their haematological disease in two.
Keratosis punctata of the palmar creases (KPPC) is a variant of keratosis punctata of palms and s... more Keratosis punctata of the palmar creases (KPPC) is a variant of keratosis punctata of palms and soles in which lesions are confined to palmar creases. We present a patient with KPPC and study the prevalence of the disease in Caucasians. The survey included 1,001 white patients, that were examined for palmar lesions. We could not find any case that fulfilled the diagnostic criteria for KPPC. We conclude that KPPC is a rare disease among Caucasians but rather common in the black race.
A case of lichen amyloidosus in an HIV-infected patient is presented. To our knowledge, the assoc... more A case of lichen amyloidosus in an HIV-infected patient is presented. To our knowledge, the association between lichen amyloidosus and HIV infection has not been described previously. The possible relationship between both entities is discussed.
The recall phenomenon is an inflammatory reaction limited to a previously X-irradiated field when... more The recall phenomenon is an inflammatory reaction limited to a previously X-irradiated field when the patient is treated months or years later with certain drugs. Only a few cases have been reported in dermatological journals. We report a patient with lymphoma who was treated with low-dose abdominal irradiation and high-dose irradiation to the knees and who, 2 months later, when chemotherapy was started, developed a pronounced inflammatory reaction limited to the areas treated with high-dose irradiation. A skin biopsy specimen showed features of radiation damage, marked epidermal changes and extensive eccrine squamous syringometaplasia. This case of the recall phenomenon is of interest because we have found that there is apparently a radiation dose threshold for this event, and because this is the first report of its association with eccrine squamous syringometaplasia.
Three patients are described with leishmaniasis and AIDS, with cutaneous lesions mimicking dermat... more Three patients are described with leishmaniasis and AIDS, with cutaneous lesions mimicking dermatomyositis. Leishmania organisms were observed in great numbers in the dermis of lesional skin biopsy specimens. They were also present inside keratinocytes in all layers of the epidermis in one patient. Skin cultures from all patients and bone marrow culture in patients 1 and 3 revealed Leishmania infantum. Leishmania organisms were also found in nonlesional skin. The absence of proximal symmetric muscle weakness, elevated muscle enzymes, myopathic electromyograms, or characteristic histopathologic and immunologic features of dermatomyositis, and the rapid and complete clearance or marked improvement of the cutaneous lesions after treatment for leishmaniasis, make us consider true dermatomyositis unlikely. We suggest that leishmaniasis be included in the list of diseases capable of inducing a dermatomyositis-like eruption.
In the epidermis, beta1 integrin expression is normally confined to the basal layer; however, sup... more In the epidermis, beta1 integrin expression is normally confined to the basal layer; however, suprabasal expression of beta1 integrins in keratinocytes has been found in psoriasis, and it has been suggested that it could be a pathogenic factor of the disease. We have investigated herein the functional state of beta1 integrins of human keratinocytes in normal skin and psoriasis. The expression of beta1-activation-reporter epitopes was monitored with two monoclonal antibodies, HUTS-21 and MG5A7, that recognize epitopes whose expression parallels functional activity of beta1 integrins and correlates with the ligand binding activity of these heterodimeric glycoproteins. We have found that keratinocytes express activation epitopes of beta1 integrins, and that these epitopes can be modulated by manganese. The expression of activation epitopes of beta1 integrins was related to an enhanced adhesion to fibronectin and collagen. Immunohistochemical studies of normal and psoriatic skin with HUTS-21 and other monoclonal antibodies indicate that, although there is suprabasal expression of beta1 integrins in psoriasis, these molecules seem to be in an inactive state. Moreover, most beta1 integrins in lateral and apical surfaces of basal keratinocytes of psoriasis are also in a nonactive conformation, implying a decrease of activity compared with normal skin, in which active beta1 integrins are distributed all over the basal keratinocytes.
Cutaneous involvement in graft versus host disease (GVHD) after allogeneic hematopoietic cell tra... more Cutaneous involvement in graft versus host disease (GVHD) after allogeneic hematopoietic cell transplant can be separated into acute GVHD (aGVHD), lichenoid chronic GVHD (cGVHD) and sclerodermatous cGVHD. It seems clear that these syndromes result from different mechanisms and entail different treatment approaches. Standard treatment of cutaneous aGVHD involves the intensification of immunosuppressive therapy with adequate topical supportive management. In skin-limited disease, phototherapy has shown promising results. In cutaneous cGVHD, the combination of corticosteroids and cyclosporine (ciclosporin) is the recommended therapy, and other immunosuppressants may be added depending on whether lichenoid or sclerodermatous lesions are present. High response rates to phototherapy have been found in lichenoid disease, while sclerodermatous disease responds better to etretinate or extracorporeal photochemotherapy. Localized cutaneous cGVHD may be treated with topical corticosteroids alone. Few reports on the effect of treatments in GVHD clearly describe the cutaneous involvement and the influence of the treatment on the skin. Therefore, dermatologists should be deeply involved in the diagnosis and treatment of GVHD, and good dermatologic grading systems should be developed. Theses changes will increase our knowledge of cutaneous GVHD, and relevant data in the evaluation of the effect of therapy in the disease will be obtained.
BACKGROUND: Metalloproteinases (MMPs) are proteins involved in extracellular matrix breakdown and... more BACKGROUND: Metalloproteinases (MMPs) are proteins involved in extracellular matrix breakdown and have been implicated in stages of migration and metastasis. MT1-MMP is an MMP anchored to the cell membrane. During maturation, melanocytic nevi penetrate the extracellular matrix and express MMPs.METHODS: We studied 10 junctional, 10 compound, and 10 intradermal nevi diagnosed by clinical and histological studies and by performing immunohistochemical study to assess MT1-MMP activity.RESULTS: We found evidence of MT1-MMP expression in melanocytic nevus cells, particularly around the entire border of cell nests. Expression was more intense in junctional nevi and gradually decreased with acquisition of intradermal component and became nonexistent in nevi in the deep dermis.CONCLUSIONS: MT1-MMP is expressed in the membrane of nevus cells, with expression greater in nest cells in contact with the extracellular matrix. The intensity of expression correlated inversely with the maturation phase of the nevus, being very high in junctional nevi and low in intradermal nevi.
A young girl presented with a purpuric rash on lower limbs, fever, eosinophilia, peripheral neuro... more A young girl presented with a purpuric rash on lower limbs, fever, eosinophilia, peripheral neuropathy and progressive renal insufficiency. She developed vesicles, purpuric macules and papules on the head, several nodules on the palmar sides of hands and fingers, splinter haemorrhages, and a disfiguring, facial oedema. A renal biopsy specimen disclosed a focal and segmental necrotizing glomerulonephritis with crescents. Peripheral ANCA with antimyeloperoxidase specificity [P-ANCA (MPO)] was positive and cytoplasmic ANCA with PR3 specificity was negative. Treatment with prednisone and cyclophosphamide was started with a good clinical response, stabilization of renal insufficiency and disappearance of P-ANCA (MPO). Our case fulfils the diagnostic criteria for microscopic polyangiitis (microscopic polyarteritis, MPA), namely a segmental necrotizing and crescentic glomerulonephritis associated with extrarenal vasculitis involving small-sized vessels, without granulomas or asthma. This is a rare disease, which has a poor prognosis in the absence of aggressive therapy, and is infrequently reported in dermatological journals.
INTRODUCTION: Although 65 % of the deaths caused by skin cancer are due to melanomas, the possibl... more INTRODUCTION: Although 65 % of the deaths caused by skin cancer are due to melanomas, the possible causes that may explain the aggressiveness of this type of tumor are still unknown. Different approaches have been used to try to find an effective treatment, but they have been unsuccessful. Interference RNA (iRNA) is an essential technique for this research. With this technique, we can selectively "knock down" or silence protein expression. The tetraspanins CD9 and CD151 are molecules involved in cell motility, including melanoma cells.MATERIAL AND METHODS: A375 melanoma cell line, anti-CD9 and anti-CD151 monoclonal antibodies, and iRNA against CD9 and CD151. Immunofluorescence techniques, flow cytometry, cell transfection, cell selection with magnetic beads and evaluation of cell migration in a wound-healing model.RESULTS: The A375 cells express CD9 and CD151. By using iRNA against CD9 and CD151, we managed to inhibit the expression of these proteins. The cells transfected with iRNA against CD9 showed significant inhibition of their motility.DISCUSSION: We managed to silence the expression of CD9 and CD151 using iRNA techniques in the A375 melanoma cell line. The reduction in CD9 caused the inhibition of cell motility, while the interference with CD151 expression had a more moderate effect. This data indicates that the knockdown of tetraspanins may be a future target for the treatment of melanoma.
We report the case of a 56-year-old woman with reticular erythematous mucinosis (REM). During her... more We report the case of a 56-year-old woman with reticular erythematous mucinosis (REM). During her workup infection with the human immunodeficiency virus (HIV) was detected. She developed a cerebral toxoplasmosis, salmonella sp. bacteremia and oral ulcerations with the presence of type I herpes simplex virus and cytomegalovirus. The relation of REM with the deposition of mucin in AIDS patients' bone marrow and HIV infection is discussed. To our knowledge, this is the first report where REM is associated with HIV disease.
Pseudoxanthoma elasticum-like papillary dermal elastolysis is a peculiar idiopathic elastolytic d... more Pseudoxanthoma elasticum-like papillary dermal elastolysis is a peculiar idiopathic elastolytic disorder with cutaneous lesions clinically resembling pseudoxanthoma elasticum with partial or total band-like elastolysis of the papillary dermis histopathologically, and without systemic complications. We here report 2 new cases and review the clinicopathological features of patients with this diagnosis in the literature. The possible pathogenesis of this recently described entity is discussed.
BACKGROUND: Early detection of melanomas by means of diverse screening campaigns is an important ... more BACKGROUND: Early detection of melanomas by means of diverse screening campaigns is an important step towards a reduction in mortality. Computer-aided analysis of digital images obtained by dermoscopy has been reported to be an accurate, practical and time-saving tool for the evaluation of pigmented skin lesions (PSLs). A prototype for the computer-aided diagnosis of PSLs using artificial neural networks (NNs) has recently been developed: diagnostic and neural analysis of skin cancer (DANAOS).OBJECTIVES: To demonstrate the accuracy of PSL diagnosis by the DANAOS expert system, a multicentre study on a diverse multinational population was conducted.METHODS: A calibrated camera system was developed and used to collect images of PSLs in a multicentre study in 13 dermatology centres in nine European countries. The dataset was used to train an NN expert system for the computer-aided diagnosis of melanoma. We analysed different aspects of the data collection and its influence on the performance of the expert system. The NN expert system was trained with a dataset of 2218 dermoscopic images of PSLs.RESULTS: The resulting expert system showed a performance similar to that of dermatologists as published in the literature. The performance depended on the size and quality of the database and its selection.CONCLUSIONS: The need for a large database, the usefulness of multicentre data collection, as well as the benefit of a representative collection of cases from clinical practice, were demonstrated in this trial. Images that were difficult to classify using the NN expert system were not identical to those found difficult to classify by clinicians. We suggest therefore that the combination of clinician and computer may potentially increase the accuracy of PSL diagnosis. This may result in improved detection of melanoma and a reduction in unnecessary excisions.
Graft-versus-host disease (GVHD) is the main complication of allogeneic bone marrow transplantati... more Graft-versus-host disease (GVHD) is the main complication of allogeneic bone marrow transplantation and the skin is the most commonly involved organ. The clinical presentation is varied and may resemble autoimmune diseases, such as scleroderma, lichen planus or lichen sclerosus. Chronic GVHD presenting with a butterfly malar rash mimicking lupus erythematosus is uncommon. We report a series of five patients with cutaneous lichenoid GVHD that presented with a butterfly malar rash. Two of our patients had positive antinuclear antibody titres. The evolution was poor with development of sclerodermatous GVHD lesions in three patients and relapse of their haematological disease in two.
Keratosis punctata of the palmar creases (KPPC) is a variant of keratosis punctata of palms and s... more Keratosis punctata of the palmar creases (KPPC) is a variant of keratosis punctata of palms and soles in which lesions are confined to palmar creases. We present a patient with KPPC and study the prevalence of the disease in Caucasians. The survey included 1,001 white patients, that were examined for palmar lesions. We could not find any case that fulfilled the diagnostic criteria for KPPC. We conclude that KPPC is a rare disease among Caucasians but rather common in the black race.
A case of lichen amyloidosus in an HIV-infected patient is presented. To our knowledge, the assoc... more A case of lichen amyloidosus in an HIV-infected patient is presented. To our knowledge, the association between lichen amyloidosus and HIV infection has not been described previously. The possible relationship between both entities is discussed.
The recall phenomenon is an inflammatory reaction limited to a previously X-irradiated field when... more The recall phenomenon is an inflammatory reaction limited to a previously X-irradiated field when the patient is treated months or years later with certain drugs. Only a few cases have been reported in dermatological journals. We report a patient with lymphoma who was treated with low-dose abdominal irradiation and high-dose irradiation to the knees and who, 2 months later, when chemotherapy was started, developed a pronounced inflammatory reaction limited to the areas treated with high-dose irradiation. A skin biopsy specimen showed features of radiation damage, marked epidermal changes and extensive eccrine squamous syringometaplasia. This case of the recall phenomenon is of interest because we have found that there is apparently a radiation dose threshold for this event, and because this is the first report of its association with eccrine squamous syringometaplasia.
Three patients are described with leishmaniasis and AIDS, with cutaneous lesions mimicking dermat... more Three patients are described with leishmaniasis and AIDS, with cutaneous lesions mimicking dermatomyositis. Leishmania organisms were observed in great numbers in the dermis of lesional skin biopsy specimens. They were also present inside keratinocytes in all layers of the epidermis in one patient. Skin cultures from all patients and bone marrow culture in patients 1 and 3 revealed Leishmania infantum. Leishmania organisms were also found in nonlesional skin. The absence of proximal symmetric muscle weakness, elevated muscle enzymes, myopathic electromyograms, or characteristic histopathologic and immunologic features of dermatomyositis, and the rapid and complete clearance or marked improvement of the cutaneous lesions after treatment for leishmaniasis, make us consider true dermatomyositis unlikely. We suggest that leishmaniasis be included in the list of diseases capable of inducing a dermatomyositis-like eruption.
In the epidermis, beta1 integrin expression is normally confined to the basal layer; however, sup... more In the epidermis, beta1 integrin expression is normally confined to the basal layer; however, suprabasal expression of beta1 integrins in keratinocytes has been found in psoriasis, and it has been suggested that it could be a pathogenic factor of the disease. We have investigated herein the functional state of beta1 integrins of human keratinocytes in normal skin and psoriasis. The expression of beta1-activation-reporter epitopes was monitored with two monoclonal antibodies, HUTS-21 and MG5A7, that recognize epitopes whose expression parallels functional activity of beta1 integrins and correlates with the ligand binding activity of these heterodimeric glycoproteins. We have found that keratinocytes express activation epitopes of beta1 integrins, and that these epitopes can be modulated by manganese. The expression of activation epitopes of beta1 integrins was related to an enhanced adhesion to fibronectin and collagen. Immunohistochemical studies of normal and psoriatic skin with HUTS-21 and other monoclonal antibodies indicate that, although there is suprabasal expression of beta1 integrins in psoriasis, these molecules seem to be in an inactive state. Moreover, most beta1 integrins in lateral and apical surfaces of basal keratinocytes of psoriasis are also in a nonactive conformation, implying a decrease of activity compared with normal skin, in which active beta1 integrins are distributed all over the basal keratinocytes.
Cutaneous involvement in graft versus host disease (GVHD) after allogeneic hematopoietic cell tra... more Cutaneous involvement in graft versus host disease (GVHD) after allogeneic hematopoietic cell transplant can be separated into acute GVHD (aGVHD), lichenoid chronic GVHD (cGVHD) and sclerodermatous cGVHD. It seems clear that these syndromes result from different mechanisms and entail different treatment approaches. Standard treatment of cutaneous aGVHD involves the intensification of immunosuppressive therapy with adequate topical supportive management. In skin-limited disease, phototherapy has shown promising results. In cutaneous cGVHD, the combination of corticosteroids and cyclosporine (ciclosporin) is the recommended therapy, and other immunosuppressants may be added depending on whether lichenoid or sclerodermatous lesions are present. High response rates to phototherapy have been found in lichenoid disease, while sclerodermatous disease responds better to etretinate or extracorporeal photochemotherapy. Localized cutaneous cGVHD may be treated with topical corticosteroids alone. Few reports on the effect of treatments in GVHD clearly describe the cutaneous involvement and the influence of the treatment on the skin. Therefore, dermatologists should be deeply involved in the diagnosis and treatment of GVHD, and good dermatologic grading systems should be developed. Theses changes will increase our knowledge of cutaneous GVHD, and relevant data in the evaluation of the effect of therapy in the disease will be obtained.
BACKGROUND: Metalloproteinases (MMPs) are proteins involved in extracellular matrix breakdown and... more BACKGROUND: Metalloproteinases (MMPs) are proteins involved in extracellular matrix breakdown and have been implicated in stages of migration and metastasis. MT1-MMP is an MMP anchored to the cell membrane. During maturation, melanocytic nevi penetrate the extracellular matrix and express MMPs.METHODS: We studied 10 junctional, 10 compound, and 10 intradermal nevi diagnosed by clinical and histological studies and by performing immunohistochemical study to assess MT1-MMP activity.RESULTS: We found evidence of MT1-MMP expression in melanocytic nevus cells, particularly around the entire border of cell nests. Expression was more intense in junctional nevi and gradually decreased with acquisition of intradermal component and became nonexistent in nevi in the deep dermis.CONCLUSIONS: MT1-MMP is expressed in the membrane of nevus cells, with expression greater in nest cells in contact with the extracellular matrix. The intensity of expression correlated inversely with the maturation phase of the nevus, being very high in junctional nevi and low in intradermal nevi.
A young girl presented with a purpuric rash on lower limbs, fever, eosinophilia, peripheral neuro... more A young girl presented with a purpuric rash on lower limbs, fever, eosinophilia, peripheral neuropathy and progressive renal insufficiency. She developed vesicles, purpuric macules and papules on the head, several nodules on the palmar sides of hands and fingers, splinter haemorrhages, and a disfiguring, facial oedema. A renal biopsy specimen disclosed a focal and segmental necrotizing glomerulonephritis with crescents. Peripheral ANCA with antimyeloperoxidase specificity [P-ANCA (MPO)] was positive and cytoplasmic ANCA with PR3 specificity was negative. Treatment with prednisone and cyclophosphamide was started with a good clinical response, stabilization of renal insufficiency and disappearance of P-ANCA (MPO). Our case fulfils the diagnostic criteria for microscopic polyangiitis (microscopic polyarteritis, MPA), namely a segmental necrotizing and crescentic glomerulonephritis associated with extrarenal vasculitis involving small-sized vessels, without granulomas or asthma. This is a rare disease, which has a poor prognosis in the absence of aggressive therapy, and is infrequently reported in dermatological journals.