An experimental subunit vaccine based on Bluetongue virus 4 VP2 protein fused to an antigen-presenting cells single chain antibody elicits cellular and humoral immune responses in cattle, guinea pigs and IFNAR(-/-) mice.

Bluetongue virus (BTV), the causative agent of bluetongue disease (BT) in domestic and wild ruminants, is worldwide distributed. A total of 27 serotypes have been described so far, and several outbreaks have been reported. Vaccination is critical for controlling the spread of BTV. In the last years, subunit vaccines, viral vector vaccines and reverse genetic-based vaccines have emerged as new alternatives to conventional ones. In this study, we developed an experimental subunit vaccine against BTV4, with the benefit of targeting the recombinant protein to antigen-presenting cells. The VP2 protein from an Argentine BTV4 isolate was expressed alone or fused to the antigen presenting cell homing (APCH) molecule, in the baculovirus insect cell expression system. The immunogenicity of both proteins was evaluated in guinea pigs and cattle. Titers of specific neutralizing antibodies in guinea pigs and cattle immunized with VP2 or APCH-VP2 were high and similar to those induced by a conventional inactivated vaccine. The immunogenicity of recombinant proteins was further studied in the IFNAR(-/-) mouse model where the fusion of VP2 to APCH enhanced the cellular immune response and the neutralizing activity induced by VP2.

Evaluación del coste económico de la técnica de la biopsia selectiva del ganglio centinela en melanoma / Cost Analysis of Sentinel Lymph Node Biopsy in Melanoma

INTRODUCCIÓN Y OBJETIVO: La técnica de la biopsia selectiva del ganglio centinela (BSGC) es la mejor herramienta para la estadificación ganglionar en el melanoma, permitiendo la realización de una linfadenectomía selectiva, es decir, reservada solo a aquellos pacientes que muestran el GC positivo para metástasis. Nuestro objetivo fue evaluar el coste económico de la técnica de la BSGC, ya que se ha convertido en el procedimiento recomendado como estándar en la atención al paciente con melanoma, y es necesaria para la inclusión de los pacientes en los ensayos clínicos. Existe además escasa bibliografía en nuestro medio sobre su relevancia económica. MÉTODO: De forma prospectiva se recogieron 100 pacientes a los que se realizó la técnica entre los años 2007-2010 con un procesamiento histológico transhiliar bivalvo multisecciones. Realizamos un cálculo aproximado del precio de la técnica utilizando las tarifas de precios oficiales de la Región de Murcia. RESULTADOS: El porcentaje de positividad de nuestra serie fue del 20%, con un número medio de ganglios de 1,96 y un 44% de melanomas delgados. El precio total de la técnica es de 9.486,57- 10.471,29 euros, siendo una parte muy importante de la misma atribuible al procesamiento histopatológico (5.769,36 euros). DISCUSIÓN: La técnica de la BSGC tiene un precio muy considerable, aunque en consonancia con otras referencias americanas previamente descritas. La optimización de la técnica vendrá dada en función de la selección cada vez más adecuada de los pacientes que deben someterse a ella, y a la estandarización de un modelo histopatológico sensible en la detección, pero a la vez sencillo en el procesamiento

INTRODUCTION AND OBJECTIVE: Sentinel lymph node biopsy (SLNB) is the most useful tool for node staging in melanoma. SLNB facilitates selective dissection of lymph nodes, that is, the performance of lymphadenectomy only in patients with sentinel nodes positive for metastasis. Our aim was to assess the cost of SLNB, given that this procedure has become the standard of care for patients with melanoma and must be performed whenever patients are to be enrolled in clinical trials. Furthermore, the literature on the economic impact of SLNB in Spain is scarce. METHOD: From 2007 to 2010, we prospectively collected data for 100 patients undergoing SLNB followed by transhilar bivalving and multiple-level sectioning of the node for histology. Our estimation of the cost of the technique was based on official pricing and fee schedules for the Spanish region of Murcia. RESULTS: The rate of node-positive cases in our series was 20%, and the mean number of nodes biopsied was 1.96; 44% of the patients in the series had thin melanomas. The total cost was estimated at between D 9486.57 and D 10 471.29. Histopathology accounted for a considerable portion of the cost (D 5769.36). DISCUSSION: The cost of SLNB is high, consistent with amounts described for a US setting. Optimaluse of SLNB will come with the increasingly appropriate selection of patients who should undergo the procedure and the standardization of a protocol for histopathologic evaluation that is both sensitive and easy to perform

Cost analysis of sentinel lymph node biopsy in melanoma.

INTRODUCTION AND OBJECTIVE: Sentinel lymph node biopsy (SLNB) is the most useful tool for node staging in melanoma. SLNB facilitates selective dissection of lymph nodes, that is, the performance of lymphadenectomy only in patients with sentinel nodes positive for metastasis. Our aim was to assess the cost of SLNB, given that this procedure has become the standard of care for patients with melanoma and must be performed whenever patients are to be enrolled in clinical trials. Furthermore, the literature on the economic impact of SLNB in Spain is scarce. METHOD: From 2007 to 2010, we prospectively collected data for 100 patients undergoing SLNB followed by transhilar bivalving and multiple-level sectioning of the node for histology. Our estimation of the cost of the technique was based on official pricing and fee schedules for the Spanish region of Murcia. RESULTS: The rate of node-positive cases in our series was 20%, and the mean number of nodes biopsied was 1.96; 44% of the patients in the series had thin melanomas. The total cost was estimated at between €9486.57 and €10471.29. Histopathology accounted for a considerable portion of the cost (€5769.36). DISCUSSION: The cost of SLNB is high, consistent with amounts described for a US setting. Optimal use of SLNB will come with the increasingly appropriate selection of patients who should undergo the procedure and the standardization of a protocol for histopathologic evaluation that is both sensitive and easy to perform.

Lesión pigmentada plantar asintomática en una mujer joven / Asymptomatic Pigmented Lesion on the Sole of a Young Woman

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'Bowenoid wart': wart with bowenoid histological changes? Report of 9 cases.

INTRODUCTION: Cases of lesions that simulate Bowen's disease have been previously described in the literature. CASE REPORT: Nine exophytic verruca-like lesions with histological findings of Bowen's disease (BD) are described. All cases had a rapid growth, and were located on the face and neck of elderly patients with chronic solar skin damage. We carried out p16 immunohistochemical staining using the immunoperoxidase technique, which was negative in all cases. DISCUSSION: We think that these 9 lesions are only histologically mimicking BD, and could be a subtype of verruca ('bowenoid wart'). These lesions could be provoked by nononcogenic human papillomavirus (HPV), as in other cases previously described. The p16 staining was negative in all cases, in contrast with most BD cases. It would be interesting to study whether positive p16 staining is related to oncogenic HPV, whereas negative p16 staining could be associated with low or nononcogenic HPV; thus, more studies are needed.

Las células tipo epidermodisplasia verruciforme como marcador histológico de inmunodepresión: revisión de 229 carcinomas espinocelulares / Epidermodysplasia verruciformis-like cells as histologic markers of immunosuppression: review of 229 squamous cell carcinomas

Introducción. La epidermodisplasia verruciforme (EV) es una enfermedad en la que existe una mayor susceptibilidad genética a la infección por determinados subtipos oncogénicos del virus del papiloma humano (VPH). Entre otros hallazgos histológicos, en la EV suelen observarse unas células claras, grandes, ovaladas o redondeadas (células EV) en la capa granulosa, que según algunos autores se podrían considerar como un marcador histológico de inmunodepresión. Material y métodos. Hemos estudiado 229 carcinomas espinocelulares (CE) para valorar si presentaban células EV y si se relacionaban con inmunodepresión, tanto localizada o cutánea (tumores con signos de intenso daño solar crónico o con una dermatitis de estasis intensa), como sistémica (pacientes inmunodeprimidos o ancianos). Resultados. Observamos células EV en 33 carcinomas. No hemos encontrado relación significativa entre la existencia de células EV e inmunodepresión. Realizamos reacción en cadena de la polimerasa (PCR) en 8 lesiones, pero los resultados no fueron valorables porque el ADN estaba desnaturalizado. Conclusiones. No hemos demostrado relación entre las células EV e inmunodepresión, localizada o sistémica, posiblemente porque la muestra no era adecuada (se podría considerar que prácticamente todos los CE estudiados se asociaban a signos de inmunodepresión, tanto aquellos que presentaban células EV como los que no). Serían necesarios más estudios que comparasen lesiones asociadas a inmunodepresión con otras que no. Es posible que estas células EV sean el resultado de los efectos citopáticos de determinados subtipos de VPH, como el VPH-5 o el VPH-8, aunque sería necesario demostrar esta hipótesis mediante técnicas de PCR o similar (AU)

Associated with greater susceptibility to infection by certain oncogenic subtypes of human papillomavirus (HPV). Among other histologic findings, large, clear, oval or rounded cells (EV cells) are observed in the granular layer in EV, and some authors consider these cells to be markers of immunosuppression. Material and Methods. We analyzed 229 squamous cell carcinomas (SCC) to determine whether EV cells were present and to assess whether their presence was associated either with localized or cutaneous immunosuppression (tumors with signs of severe chronic actinic damage or severe stasis dermatitis) or with systemic immunosuppression (immunocompromised or elderly patients). Results. We observed EV cells in 33 SCC. No statistically significant relationship was observed between the presence of EV cells and immunosuppression. We performed polymerase chain reaction in 8 lesions, but the results were not informative as the DNA was denatured. Conclusions. We found no relationship between the presence of EV cells and localized or systemic immunosuppression, possibly because the sample was inadequate (almost all SCC studied were associated with signs of immunosuppression, irrespective of the presence or absence of EV cells). Further studies will be required to compare lesions associated with immunosuppression with those in which immunosuppression is absent. The presence of EV cells may be the result of cytopathic effects of certain HPV subtypes, such as HPV 5 or 8, but this will need to be demonstrated using techniques such as polymerase chain reaction (AU)

[Epidermodysplasia verruciformis-like cells as histologic markers of immunosuppression: review of 229 squamous cell carcinomas]. / Las células tipo epidermodisplasia verruciforme como marcador histológico de inmunodepresión: revisión de 229 carcinomas espinocelulares.

INTRODUCTION: Epidermodysplasia verruciformis (EV) is associated with greater susceptibility to infection by certain oncogenic subtypes of human papillomavirus (HPV). Among other histologic findings, large, clear, oval or rounded cells (EV cells) are observed in the granular layer in EV, and some authors consider these cells to be markers of immunosuppression. MATERIAL AND METHODS: We analyzed 229 squamous cell carcinomas (SCC) to determine whether EV cells were present and to assess whether their presence was associated either with localized or cutaneous immunosuppression (tumors with signs of severe chronic actinic damage or severe stasis dermatitis) or with systemic immunosuppression (immunocompromised or elderly patients). RESULTS: We observed EV cells in 33 SCC. No statistically significant relationship was observed between the presence of EV cells and immunosuppression. We performed polymerase chain reaction in 8 lesions, but the results were not informative as the DNA was denatured. CONCLUSIONS: We found no relationship between the presence of EV cells and localized or systemic immunosuppression, possibly because the sample was inadequate (almost all SCC studied were associated with signs of immunosuppression, irrespective of the presence or absence of EV cells). Further studies will be required to compare lesions associated with immunosuppression with those in which immunosuppression is absent. The presence of EV cells may be the result of cytopathic effects of certain HPV subtypes, such as HPV 5 or 8, but this will need to be demonstrated using techniques such as polymerase chain reaction.

Cutaneous hyperpigmentation induced by omeprazole mimicking ashy dermatosis.

BACKGROUND: Omeprazole has been associated with multiple adverse effects including skin reactions but, to date, cutaneous hyperpigmentation has not been described as an adverse effect of this drug. OBSERVATIONS: We describe a case of a 52-year-old Caucasian woman who developed skin hyperpigmentation in the upper trunk, mimicking ashy dermatosis, 2 months after initiating omeprazole treatment. Histopathologic examination of a skin biopsy taken from a pigmented macule showed dermal macrophages containing golden-brown granules, which also displayed a sulphur peak on energy-dispersive X-ray microanalysis. High-performance liquid chromatography (HPLC) and mass spectrometry were also performed on the drug and on a biopsy specimen revealing the same chromatograms as well as the same mass spectra. CONCLUSIONS: According to our results, omeprazole itself may induce cutaneous pigmentation and, to our knowledge, this is the first report of this finding.

Interleukin-10, interleukin-6 and interferon-gamma gene polymorphisms in melanoma patients.

The immune response against melanoma can be influenced by cytokines with potentially opposite effects on tumour cell growth, such as interleukin-10 (IL10), interleukin-6 (IL6) and interferon-gamma (IFNgamma). Our objective in this study was to investigate whether polymorphisms in the regulatory regions of IL10, IL6 and IFNgamma genes are associated with the development of primary cutaneous melanoma and/or the prognosis of this tumour. We studied genotypic variations at positions -1082, -819 and -592 in the IL10 promoter, -174 in the IL6 promoter and +874 in the IFNgamma intron 1 in 42 melanoma patients and 48 healthy controls. These two populations showed very similar genotypic frequencies for IL10, IL6 and IFNgamma gene polymorphisms. There was a significant increase in the prevalence of IL10 low expression genotypes, specially the ACC/ATA genotype, among patients with a poorer prognosis. In contrast, IL6 promoter and IFNgamma intron 1 gene polymorphisms did not correlate with melanoma prognosis. These data indicate that investigation of polymorphisms in the regulatory regions of IL10, IL6 and INFgamma genes does not seem to be useful for predicting the risk of development of primary cutaneous melanoma. However, IL10 low expression genotypes may be associated with a poorer outcome in melanoma patients.

Does injection distance of the radiocolloid modify lymphatic mapping in melanoma?

BACKGROUND: An important factor to be considered when performing lymphogammagraphy in melanoma patients is the adequate distance of injection of the radiopharmaceutical from the biopsy excision site or the primary lesion. OBJECTIVE: To test the reproducibility of lymphatic mapping in patients with primary cutaneous melanoma who had undergone narrow excisional biopsy by injecting a technetium marker at different distances from the biopsy scar. METHODS: After informed consent, two lymphoscintigraphies were performed on each of 19 melanoma patients, following narrow excisional biopsy. Four aliquots of the radiocolloid were intradermally injected in each procedure, surrounding the biopsy excision site at 1.5 and 0.5 cm, respectively. RESULTS: Both lymphoscintigraphies showed similar lymph channels and sentinel node(s). CONCLUSION: In melanoma patients who have undergone narrow excisional biopsy, lymphoscintigraphy marks with accuracy the sentinel node, at least when the radiopharmaceutical is injected at a distance of less than 1.5 cm from the limits of the biopsy scar.

[Selective sentinel node biopsy in melanoma using preoperative lymphoscintigraphy location and intraoperative detection gamma probe]. / Biopsia selectiva del ganglio centinela en el melanoma mediante localización con linfogammagrafía preoperatoria y sonda de detección gamma intraoperatoria.

BACKGROUND: The experience in detection of sentinel lymph node in melanoma using preoperative scintigraphy and intraoperative gamma probe is referred. PATIENTS AND METHODS: We studied 60 patients with stage I-II melanoma who underwent sentinel lymph node biopsy performed using 99m-Tc-labelled sulphur colloid as radioactive tracer. A preoperative scintigraphy was performed and intraoperative gamma probe was used to localize the sentinel node in all cases. Scintigraphy results, effectiveness of intraoperative detection (technical efficacy), pathological results, and follow-up have been studied. RESULTS: Preoperative detection was 98.3% and the mean basin detected was 1.17. There were multiple basins especially when melanomas were on the trunk. Technical efficacy was 98.4% and intraoperative detection was more difficult in parotid gland region. HMB-45 immunohistochemical staining was essential in pathological studies, in whom 10% were positives. Lymphadenectomy could be avoided in 90% of the patients. Recurrences were not detected during follow-up and metastases were found only in non biopsied cases. Sentinel node biopsy morbidity was significative lesser than that of lymphadenectomy. CONCLUSIONS: Preoperative scintigraphy and intraoperative gamma probe use to localize sentinel node in melanoma have a high efficacy. They can reveal multiple basins and they allow a more selective surgical approach and a minimal dissection.

Dermatosis y hepatitis / Dermatosis and hepatitis

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Positividad de la prueba del parche con fenitoína en un caso de síndromede Stevens-Johnson / Positive patch test with phenytoin in a case of Stevens-Johnson syndrome

El síndrome de Stevens-Johnson (SJS) o eritema multiforme mayor es una reacción de posible mecanismo inmunológico poco frecuente, con una incidencia media anual estimada de 1-2 casos por millón de habitantes. La fenitoína y otros anticonvulsivantes, tales como fenobarbital y carbamnacepina, se han asociado con casos de SJS. Se describe el caso de una mujer de 40 arios de edad, diagnosticada de un tumor cerebral (oligodendroglloma), que presentó un cuadro clínico compatible con SJS, 48 horcas después de administrarle metamizol magnésico y fenitoína, por vía intravenosa (la paciente había realizado previamente un ciclo de tratamiento con buena tolerancia a dichos fármacos). Se realizaron pruebas cutáncas (1prick test) con los preparados comerciales de fenitoína (50 mg/ml) y metamizol (400 mg/ml), que frieron negativas en ambos casos. Se llevaron a cabo pruebas epicutáneas con los preparados comerciales de los fármacos implicados que resultaron positivas a fenitoína, a las 48 y 96 horas con persistencia de la lesión resultante incluso una semana después, y negativas en el caso del metamizol. La provocación oral hasta alcanzar la dosis terapéutica con metamizol fue tolerada. La provocación con fenitoína no se realizó, por el riesgo de una reacción potencialmente grave. Este caso puede servir como ejemplo de la utilidad de las pruebas epicutáneas para llegas- a identificar al agente causal, en casos de SJS relacionados con la toma de varios medicamentos (AU)

Subcutaneous nodules following treatment with aluminium-containing allergen extracts.

We describe two patients who developed multiple itching nodules following immunization with vaccines adsorbed on aluminium hydroxide. Both patients had been treated with vaccines for extrinsic asthma and rhinitis for 4 and 10 years respectively. The lesions were persistent and lasted for several years. Histopathological findings were those of a foreign body reaction. Aluminium was most probably involved in the pathogenesis of these lesions because its presence could be demonstrated in macrophages using energy-dispersive X-ray microanalysis. Although some symptomatic relief was achieved with topical corticosteroids and oral antihistamines, treatment was unsuccessful.

Efficacy of lipectomy and liposuction in the treatment of multiple symmetric lipomatosis.

BACKGROUND: Multiple symmetric lipomatosis (MSL) is a rare disease characterized by enlarging, symmetric, nonencapsulated, fat deposits mainly on the neck and upper trunk. Liposuction and lipectomy, although palliative, are the treatments of choice, especially indicated when vital structures are compromised. OBJECTIVE: Our purpose was to evaluate the efficacy and safety of liposuction and lipectomy in the treatment of MSL. METHODS: We have examined two patients diagnosed with MSL who presented with symptoms derived from the compression of vascular, nervous, and/or respiratory tract structures. One was treated with lipectomy and the other with liposuction. RESULTS: A rapid resolution of the clinical symptoms was achieved with both therapies. The patient who was treated with lipectomy suffered from a compression of the left brachial plexus by scar tissue as an adverse effect, requiring a second surgical procedure. Liposuction only provoked a mild autoinvolutive hematoma in the other case. No clinical recurrences were observed at 3 and 2 years of follow-up respectively. CONCLUSIONS: We consider both lipectomy and liposuction as safe and effective techniques for the treatment of MSL patients. Although liposuction is usually associated with less adverse effects than lipectomy, location of the lipomas must be carefully considered before choosing one technique over another.