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The mechanisms that work alongside BRAFV600E oncogene in melanoma development, in addition to ultraviolet (UV) radiation (UVR), are of great interest. Analysis of human melanoma tumors [data from The Cancer Genome Atlas (TCGA)] revealed that 50% or more of the samples expressed no or low amounts of serine/threonine protein kinase STK11 (also known as LKB1) protein. Here, we report that, in a mouse model, concomitant neonatal BrafV600E activation and Lkb1 tumor suppressor ablation in melanocytes led to full melanoma development. A single postnatal dose of UVB radiation had no effect on melanoma onset in Lkb1-depleted mice compared with BrafV600E-irradiated mice, but increased tumor multiplicity. In concordance with these findings and previous reports, Lkb1-null irradiated mice exhibited deficient DNA damage repair (DDR). Histologically, tumors lacking Lkb1 were enriched in neural-like tumor morphology. Genetic profiling and gene set enrichment analyses of tumor sample mutated genes indicated that loss of Lkb1 promoted the selection of altered genes associated with neural differentiation processes. Thus, these results suggest that the loss of Lkb1 cooperates with BrafV600E and UVR, impairing the DDR and increasing melanoma multiplicity and neural-like dedifferentiation.
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BACKGROUND: Management of syphilis, a sexually transmitted infection (STI) with increasing incidence, is challenged by drug shortages, scarcity of randomised trial data, an absence of non-penicillin alternatives for pregnant women with penicillin allergy (other than desensitisation), extended parenteral administration for neurosyphilis and congenital syphilis, and macrolide resistance. Linezolid was shown to be active against Treponema pallidum, the causative agent of syphilis, in vitro and in the rabbit model. We aimed to assess the efficacy of linezolid for treating early syphilis in adults compared with the standard of care benzathine penicillin G (BPG). METHODS: We did a multicentre, open-label, non-inferiority, randomised controlled trial to assess the efficacy of linezolid for treating early syphilis compared with BPG. We recruited participants with serological or molecular confirmation of syphilis (either primary, secondary, or early latent) at one STI unit in a public hospital and two STI community clinics in Catalonia (Spain). Participants were randomly allocated in a 1:1 ratio using a computer-generated block randomisation list with six participants per block, to receive either oral linezolid (600 mg once per day for 5 days) or intramuscular BPG (single dose of 2·4 million international units) and were assessed for signs and symptoms (once per week until week 6 and at week 12, week 24, and week 48) and reagin titres of non-treponemal antibodies (week 12, week 24, and week 48). The primary endpoint was treatment response, assessed using a composite endpoint that included clinical response, serological response, and absence of relapse. Clinical response was assessed at 2 weeks for primary syphilis and at 6 weeks for secondary syphilis following treatment initiation. Serological cure was defined as a four-fold decline in rapid plasma reagin titre or seroreversion at any of the 12-week, 24-week, or 48-week timepoints. The absence of relapse was defined as the presence of different molecular sequence types of T pallidum in recurrent syphilis. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference in rates of treatment response was higher than -10%. The primary analysis was done in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05069974) and was stopped for futility after interim analysis. FINDINGS: Between Oct 20, 2021, and Sept 15, 2022, 62 patients were assessed for eligibility, and 59 were randomly assigned to linezolid (n=29) or BPG (n=30). In the per-protocol population, after 48 weeks' follow-up, 19 (70%) of 27 participants (95% CI 49·8 to 86·2) in the linezolid group had responded to treatment and 28 (100%) of 28 participants (87·7 to 100·0) in the BPG group (treatment difference -29·6, 95% CI -50·5 to -8·8), which did not meet the non-inferiority criterion. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (five [17%] of 29, 95% CI 5·8 to 35·8 in the linezolid group vs five [17%] of 30, 5·6 to 34·7, in the BPG group). No serious adverse events were reported during follow-up. INTERPRETATION: The efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis. FUNDING: European Research Council and Fondo de Investigaciones Sanitarias.
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Penicilina G Benzatina , Sífilis , Adulto , Humanos , Antibacterianos , Farmacorresistencia Bacteriana , Linezolid/uso terapéutico , Macrólidos/farmacología , Penicilina G Benzatina/uso terapéutico , Estudios Prospectivos , Reaginas , Recurrencia , España , Sífilis/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Mucosal melanoma (MM) is an uncommon melanoma subtype affecting mucosal surfaces of the head and neck, anorectal region, and vulvovaginal area. We aimed to present our experience at a tertiary-level hospital regarding MM diagnosis, management, monitoring of progression, mutations, and outcome predictors. We performed a registry-based cohort study including MM cases diagnosed from 2012 to 2022 and retrospectively characterized somatic mutations on BRAF, NRAS and c-KIT. We employed Kaplan-Meier curves, log-rank tests, and Cox regression analysis to explore prognostic factors and survival outcomes in a cohort of 35 patients, mainly women (63%) with a median age of 70 years. Predominantly, MM occurred in the vulvovaginal region (48.6%). At diagnosis, 28.6% had lymph node involvement, and 31.4% also had distant metastasis. Mutations in BRAF and c-KIT were identified in 3/35 (9%) and 2/6 patients (33%), respectively. Surgery was performed in 71.4% of patients, and most received systemic treatment (65.7%). Lower disease stage, thinner Breslow depth, and surgical resection were associated with improved overall survival. Notably, age, sex, radiotherapy, and BRAF mutant status did not affect survival. Standard management typically involves immunotherapy. Cases with BRAF or c-KIT mutations may be considered for targeted therapies. Unfortunately, MM prognosis remains unfavorable, with a less than 50% survival rate at 2 years.
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Acute and chronic cutaneous graft-versus-host disease (GVHD) are common complications following hematopoietic stem cell transplantation (HSCT) in pediatric patients. In this retrospective study, we explored the risk factors and clinical characteristics of acute and chronic cutaneous GVHD in a case series of children undergoing HSCT at a tertiary referral hospital. We found that 36% of acute cutaneous GVHD was severe and these patients were more likely to have an unrelated donor, and that children with acute cutaneous GVHD who progressed to chronic cutaneous GVHD had a higher proportion of malignant diseases, total body irradiation, and bronchiolitis obliterans compared to those who did not progress to chronic cutaneous GVHD. Our study highlights the importance of identifying and monitoring these high-risk patients to improve the clinical management and outcomes of cutaneous GVHD in pediatric HSCT recipients.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedades de la Piel , Humanos , Niño , Estudios Retrospectivos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedades de la Piel/epidemiología , Enfermedades de la Piel/etiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/complicaciones , Factores de RiesgoRESUMEN
BACKGROUND: Monkeypox DNA has been detected in skin lesions, saliva, oropharynx, urine, semen, and stool of patients infected during the 2022 clade IIb outbreak; however, the viral dynamics within these compartments remain unknown. We aimed to characterise the viral load kinetics over time in various parts of the body. METHODS: This was an observational, prospective, multicentre study of outpatients diagnosed with monkeypox in two hospitals and two sexual health clinics in Spain between June 28, 2022, and Sept 22, 2022. Men and women aged over 18 years were eligible if they reported having symptom onset within the previous 10 days of presentation, and were ineligible if disease was severe enough to be admitted to hospital. Samples were collected from five body locations (skin lesions, oropharynx, rectum, semen or vagina, and a dried blood spot) at six time points up to 57 days after the screening visit. Samples were analysed by quantitative PCR and a subset by cell culture. The primary endpoint was time from symptom onset to viral DNA clearance. FINDINGS: Overall, 1663 samples were collected from 77 study participants. 75 (97%) participants were men, the median age was 35·0 years (IQR 29·0-46·0), and 39 (51%) participants were living with HIV. The median time from symptom onset to viral clearance was 25 days (95% CI 23-28) in the skin lesions, 16 days (13-19) in the oropharynx, 16 days (13-23) in the rectum, 13 days in semen (9-18), and 1 day in blood (0-5). The time from symptom onset to viral clearance for 90% of cases was 41 days (95% CI 34-47) in skin lesions and 39 days (27-56) in semen. The median viral load in skin lesions was 7·3 log10 copies per mL (IQR 6·5-8·2) at baseline, compared with 4·6 log10 copies per mL (2·9-5·8) in oropharyngeal samples, 5·0 log10 copies per mL (2·9-7·5) in rectal samples, 3·5 log10 copies per mL (2·9-4·7) in semen samples, and 4·0 log10 copies per mL (4·0-4·0) in blood specimens. Replication-competent viruses were isolated in samples with high DNA levels (>6·5 log10 copies per mL). INTERPRETATION: In immunocompetent patients with mild monkeypox disease, PCR data alone would suggest a contact isolation period of 3 to 6 weeks but, based on detection of replication-competent virus, this time could be reduced. Based on findings from this cohort of patients, semen testing and prolonged use of condoms after recovery from monkeypox might not be necessary. FUNDING: University Hospital Germans Trias i Pujol and the YoMeCorono. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.
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Mpox , Masculino , Humanos , Femenino , Adulto , Persona de Mediana Edad , Estudios Prospectivos , España/epidemiología , Semen , Saliva , Carga ViralRESUMEN
Importance: The Skin and UV Neoplasia Transplant Risk Assessment Calculator (SUNTRAC) tool has been developed in the US to facilitate the identification of solid organ transplant recipients (SOTRs) at a higher risk of developing skin cancer. However, it has not yet been validated in populations other than the one used for its creation. Objective: To provide an external validation of the SUNTRAC tool in different SOTR populations. Design, Setting, and Participants: This retrospective external validation prognostic study used data from a prospectively collected cohort of European SOTRs from transplant centers at teaching hospitals in the Netherlands (1995-2016) and Spain (2011-2021). Participants were screened and followed up at dermatology departments. Data were analyzed from September to October 2021. Main Outcomes and Measures: The discrimination ability of the SUNTRAC tool was assessed via a competing risk survival analysis, cumulative incidence plots, and Wolbers concordance index. Calibration of the SUNTRAC tool was assessed through comparison of projected skin cancer incidences. Skin cancer diagnoses included squamous cell carcinoma, basal cell carcinoma, melanoma, and Merkel cell carcinoma. Results: A total of 3421 SOTRs (median age at transplant, 53 [quartile 1: 42; quartile 3: 62] years; 2132 [62.3%] men) were assessed, including 72 Asian patients (2.1%), 137 Black patients (4.0%), 275 Latinx patients (8.0%), 109 Middle Eastern and North African patients (3.2%), and 2828 White patients (82.7%). With a total of 23â¯213 years of follow-up time, 603 patients developed skin cancer. The SUNTRAC tool classified patients into 4 groups with significantly different risks of developing skin cancer during follow-up. Overall, the relative rate for developing skin cancer estimated using subdistribution hazard ratios (SHRs) and using the low-risk group as the reference group, increased according to the proposed risk group (medium-risk group: SHR, 6.8 [95% CI, 3.8-12.1]; P < .001; high-risk group: SHR, 15.9 [95% CI, 8.9-28.4]; P < .001; very-high-risk group: SHR, 54.8 [95% CI, 29.1-102.9]; P < .001), with a concordance index of 0.72. Actual skin cancer incidences were similar to those predicted by the SUNTRAC tool (5-year skin cancer cumulative incidence for medium-risk group: predicted, 6.2%; observed, 7.0%). Conclusions and Relevance: The findings of this external validation prognostic study support the use of the SUNTRAC tool in European populations for stratifying SOTRs based on their skin cancer risk and also detecting patients at a high risk of developing skin cancer. This can be helpful in prioritizing and providing better screening and surveillance for these patients.
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Trasplante de Órganos , Neoplasias Cutáneas , Masculino , Humanos , Femenino , Estudios Retrospectivos , Trasplante de Órganos/efectos adversos , Estudios de Cohortes , Detección Precoz del Cáncer , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/etiología , Medición de Riesgo , Receptores de Trasplantes , Factores de RiesgoRESUMEN
BACKGROUND: There is no consensus for the best treatment of complex cutaneous leishmaniasis (CL). We aimed to describe a cohort of CL, focusing on liposomal amphotericin B (L-AmB) treatment outcome. METHODS: We performed a retrospective study in Vall d'Hebron University Hospital (Barcelona, Spain). All patients with parasitologically proven CL diagnosed from 2012 to 2018 were included. RESULTS: The analysis included 41 patients with CL. The median age was 39 years (IQR 12- 66); 12 (29%) were children, and 29 (71%) were men. Regarding treatment, 24 (59%) received local treatment, whereas 17 (41%) had complex CL and were offered intravenous systemic treatment. Sixteen patients received L-AmB; eight (50%) had adverse events, and three (19%) discontinued treatment for safety reasons. All cases were considered cured within the first year post-treatment. CONCLUSIONS: L-AmB for complex CL showed no treatment failures, offering an alternative treatment option for patients with complex CL. Clinicians should pay close attention to the potential adverse events of L-AmB and adopt an active drug safety surveillance scheme to rapidly detect reversible side effects.
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Drug-induced sarcoidosis-like reactions (DISRs) are systemic granulomatous diseases that develop in the context of a new drug onset. Ipilimumab is an immune checkpoint inhibitor (ICI) approved for the treatment of advanced melanoma which has been associated with DISR. Differential diagnosis between tumour progression and DISR by positron emission tomography/computed tomography (PET/CT) in patients treated with an ICI can be a challenge. A 31-year-old woman was diagnosed with a stage IIIB melanoma in her back. Ipilimumab 10 mg/kg was initiated. After 1 month of finishing the treatment a routine, PET/CT showed multiple enlarged mediastinal and hilar lymph nodes FDG-positive. A transbronchial biopsy showed sarcoid-like granulomatous infiltration which favoured the diagnosis of DISR related to ipilimumab. The patient remained asymptomatic and lymphadenopathy regressed progressively after 11 months. Our work highlights the importance of differentiating DISR from tumour progression, before unnecessary changes in therapeutic strategies. PET/CT is a useful diagnostic tool for its follow-up.
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Granuloma/inducido químicamente , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Ipilimumab/efectos adversos , Linfadenopatía/inducido químicamente , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Dorso , Biopsia , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Fluorodesoxiglucosa F18 , Granuloma/diagnóstico por imagen , Granuloma/patología , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Linfadenopatía/diagnóstico por imagen , Linfadenopatía/patología , Mediastino , Melanoma/diagnóstico por imagen , Melanoma/patología , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Neoplasias Cutáneas/patologíaRESUMEN
Autoinflammatory diseases (AIDs) were first described as clinical disorders characterized by recurrent episodes of seemingly unprovoked sterile inflammation. In the past few years, the identification of novel AIDs expanded their phenotypes toward more complex clinical pictures associating vasculopathy, autoimmunity, or immunodeficiency. Herein, we describe two unrelated patients suffering since the neonatal period from a complex disease mainly characterized by severe sterile inflammation, recurrent bacterial infections, and marked humoral immunodeficiency. Whole-exome sequencing detected a novel, de novo heterozygous PLCG2 variant in each patient (p.Ala708Pro and p.Leu845_Leu848del). A clear enhanced PLCγ2 activity for both variants was demonstrated by both ex vivo calcium responses of the patient's B cells to IgM stimulation and in vitro assessment of PLC activity. These data supported the autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) diagnosis in both patients. Immunological evaluation revealed a severe decrease of immunoglobulins and B cells, especially class-switched memory B cells, with normal T and NK cell counts. Analysis of bone marrow of one patient revealed a reduced immature B cell fraction compared with controls. Additional investigations showed that both PLCG2 variants activate the NLRP3-inflammasome through the alternative pathway instead of the canonical pathway. Collectively, the evidences here shown expand APLAID diversity toward more severe phenotypes than previously reported including dominantly inherited agammaglobulinemia, add novel data about its genetic basis, and implicate the alternative NLRP3-inflammasome activation pathway in the basis of sterile inflammation.
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Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Mutación , Fosfolipasa C gamma/genética , Adolescente , Agammaglobulinemia/terapia , Autoinmunidad/genética , Biomarcadores , Caspasa 1/metabolismo , Niño , Citocinas/metabolismo , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Enfermedades Autoinflamatorias Hereditarias/terapia , Humanos , Inflamasomas/metabolismo , Masculino , Linaje , Fenotipo , Fosfolipasa C gamma/química , Fosfolipasa C gamma/metabolismo , Relación Estructura-ActividadRESUMEN
Although desmoplasia has been associated with poor prognoses in cutaneous squamous cell carcinoma, little attention has been paid to the patterns of fibrosis. This study aimed to examine the different stromal fibrotic patterns as markers of metastatic risk. We performed a multicenter retrospective study that included 102 cutaneous squamous cell carcinomas (52 non-metastatic and 50 metastatic carcinomas). Clinical and histopathological data were registered. The fibrotic reaction pattern was classified as mature, intermediate or immature depending on the presence of keloid-like collagen and myxoid stroma. The immature pattern (areas characterized by myxoid changes with no inflammation) was observed in 18 samples and its presence was significantly associated with immunosuppression, budding, desmoplasia, perineural invasion, anatomic level, tumoural depth and metastatic risk in the multivariate analysis. Our findings suggest that the presence of an immature myxoid fibrotic pattern, which can be easily identified by routine hematoxylin-eosin staining, is strongly associated with metastatic risk.
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Carcinoma de Células Escamosas/secundario , Neoplasias Cutáneas/patología , Células del Estroma/patología , Anciano , Anciano de 80 o más Años , Biopsia , Colorantes , Eosina Amarillenta-(YS) , Femenino , Fibrosis , Hematoxilina , Humanos , Masculino , Fenotipo , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , España , Coloración y Etiquetado/métodos , Microambiente TumoralRESUMEN
BACKGROUND: The incidence of cutaneous infections by dematiaceous fungi is rising in our environment due to the high number of solid organ transplant recipients (SOTR). OBJECTIVE: To review our experience in the management of cutaneous phaeohyphomycoses in a Spanish reference centre for dermatological care of SOTR. METHODS: Retrospective clinical, histopathological and microbiological review of all SOTR diagnosed of a phaeohyphomycosis in a 7-year period. RESULTS: Eleven SOTR were identified (8 lung and 3 kidney). The lesions were solitary in six patients and multiple in five, affecting mostly the lower extremities. Early lesions showed epidermal hyperplasia and a diffuse dermal suppurative granulomatous infiltrate that was progressively substituted by fibrosis when the lesions were treated. Septated fungal structures with refractile walls were identified. DNA sequencing confirmed the presence of Alternaria spp (8 cases), Cladosporium cladosporioides, Microsphaeropsis arundinis and Exophiala oligosperma. Three patients with single lesions were treated with surgery, while the other 8 required long-term antifungal therapy, including itraconazole, voriconazole and/or terbinafine, combined with surgery and reduction in tacrolimus doses. CONCLUSION: A clinical, histopathological and microbiological correlation is essential to corroborate this diagnosis. Solitary lesions are easily treated with surgery, but larger or multiple lesions may require long medical treatments combined with surgery and modification of immunosuppressive medication. The list of dematiaceous fungi implicated in cutaneous infections is expanding, in line with the availability of more sophisticated identification methods and the increasing number of immunosuppressed patients.
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Manejo de la Enfermedad , Feohifomicosis/diagnóstico , Feohifomicosis/terapia , Receptores de Trasplantes , Adulto , Anciano , Antifúngicos/uso terapéutico , Ascomicetos/clasificación , Ascomicetos/genética , Ascomicetos/aislamiento & purificación , Desbridamiento , Femenino , Histocitoquímica , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Feohifomicosis/epidemiología , Feohifomicosis/patología , Estudios Retrospectivos , Piel/microbiología , Piel/patología , España/epidemiología , TrasplantesRESUMEN
BACKGROUND: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous lymphoma of mature cytotoxic T cells. Initially, patients with SPTCL were treated with doxorubicin-based polychemotherapy. OBJECTIVE: To analyze clinical, biologic, immunophenotypical, molecular, imaging, treatment, and outcome data reflecting the current state of knowledge. METHODS: A retrospective multicenter study of 16 patients with SPTCL that was diagnosed between 1996 and 2016. RESULTS: The female-to-male ratio was 1.7. The median age at diagnosis was 46.5 years. Patients presented with multiple nodular or plaque-like lesions preferentially affecting the legs and/or trunk. Histopathology typically showed a lobular panniculitis with individual adipocytes surrounded by atypical lymphocytes, usually with a CD3+, CD4-, CD8+, CD56-, TIA1 cytotoxic granule associated RNA binding protein 1-positive phenotype and high proliferation rate. SPTCL was associated with autoimmune diseases in 25% of patients, and with the development of hemophagocytic syndrome in 18% of patients. Oral steroids alone or in combination with low-dose methotrexate or cyclosporine A were the most common initial treatment, achieving a complete response in 85% of the treated patients. The median follow-up time was 14 months. The 5-year disease-specific survival rate was 85.7%. LIMITATIONS: This was a retrospective study. CONCLUSIONS: SPTCL has an excellent prognosis. Immunosuppressive agents can be considered for first-line treatment.
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Linfoma Cutáneo de Células T/patología , Linfoma Cutáneo de Células T/terapia , Linfoma de Células T/patología , Linfoma de Células T/terapia , Paniculitis/patología , Paniculitis/terapia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Adulto , Anciano , Quimioradioterapia/métodos , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma de Células T/diagnóstico por imagen , Linfoma de Células T/mortalidad , Linfoma Cutáneo de Células T/diagnóstico por imagen , Linfoma Cutáneo de Células T/mortalidad , Masculino , Persona de Mediana Edad , Paniculitis/diagnóstico por imagen , Paniculitis/mortalidad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos , Medición de Riesgo , Muestreo , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/mortalidad , España , Análisis de Supervivencia , Adulto JovenAsunto(s)
Carcinoma de Células Escamosas/genética , Epidermólisis Ampollosa Distrófica/genética , Proteínas Proto-Oncogénicas c-myc/genética , Receptores Notch/genética , Neoplasias Cutáneas/genética , Proteína p53 Supresora de Tumor/genética , Adulto , Animales , Biopsia , Carcinoma de Células Escamosas/complicaciones , Carcinoma de Células Escamosas/patología , Colágeno Tipo VII/genética , Variaciones en el Número de Copia de ADN , Epidermólisis Ampollosa Distrófica/complicaciones , Epidermólisis Ampollosa Distrófica/patología , Femenino , Genes Recesivos/genética , Perfil Genético , Humanos , Pérdida de Heterocigocidad , Masculino , Ratones , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Objectives: To analyse the influence of genetic alterations and differential expression of transcription intermediary factor 1 (TIF1) genes in the pathophysiology of cancer-associated myositis (CAM). Methods: Paired blood and tumour DNA samples from patients with anti-TIF1γ-positive CAM and from controls were analysed by whole-exome sequencing for the presence of somatic mutations and loss of heterozygosity (LOH) in their TIF1 genes. The genesis and maintenance of the autoimmune process were investigated immunohistochemically by studying TIF1γ expression in the different tissues involved in CAM (skin, muscle and tumour) based on the immunohistochemical H-score. Results: From seven patients with anti-TIF1γ-positive CAM, we detected one somatic mutation and five cases of LOH in one or more of the four TIF1 genes compared with just one case of LOH in tumours from TIF1γ-negative myositis patients (86% vs 17%; P = 0.03). Compared with type-matched control tumours from non-myositis patients, TIF1γ staining was more intense in tumours from anti-TIF1γ-positive patients (H-score 255 vs 196; P = 0.01). Also, TIF1γ staining in muscle was slightly more intense in anti-TIF1γ-positive than in anti-TIF1γ-negative myositis (H-score 22 vs 5; P = 0.03). In contrast, intense TIF1γ staining was detected in the skin of both myositis and control patients. Conclusion: Tumours from paraneoplastic anti-TIF1γ-positive patients showed an increased number of genetic alterations, such as mutations and LOH, in TIF1 genes. These genetic alterations, in the context of a high expression of TIF1γ in the tumour, muscle and skin of these patients may be key to understanding the genesis of paraneoplastic myositis.
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Pérdida de Heterocigocidad/genética , Mutación , Miositis/genética , Neoplasias/genética , Factores de Transcripción/genética , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Piel/metabolismo , Secuenciación del ExomaRESUMEN
Introducció: les fitofotodermatitis són les reaccions cutànies induïdes pel contacte de certs vegetals amb la pell sumades a l'efecte de la radiació ultraviolada. Les substàncies que hi estan implicades més sovint solen ser les furocumarines, presents en rutàcies (llimoner, taronger i llima), moràcies (figuera) i umbellíferes (pastanaga, api i julivert), entre altres. Aquestes reaccions es manifesten amb plaques eritematoses urticariformes sobres les quals es poden arribar a formar vesícules i butllofes, simulant una cremada. Típicament, el contacte amb les plantes ocasiona lesions cutànies amb patrons lineals. Aquest treball permet desenvolupar les característiques clíniques de l'entitat partint d'un cas particular. Cas clínic: un nen de 9 anys va acudir a urgències per una placa eritematosa a la cama esquerra sobre la qual havien aparegut butllofes i en què s'intuïa una disposició lineal. Dos dies abans havia estat jugant al camp exposat al sol i amb pantalons curts. El pacient va ser hospitalitzat i es va procedir a la flictenectomia de les ampolles tenses més grans, a l'administració d'analgèsics, corticoides i antihis-tamínics per via endovenosa, i a cures amb foments de permanganat potàssic i crema de sulfadiazina argèntica. L'evolució va ser favorable i el nen va poder continuar amb les cures de forma ambulatòria. Revisant les plantes presents al camp que va visitar el pacient trobem algun exemplar d'umbellífera.Comentaris: la fitofotodermatitis és una condició infreqüent que generalment no suposa gravetat, però les lesions ampullars locals poden ser molt cridaneres ja que semblen una cremada. El diagnòstic és fonamentalment clínic, i és imprescindible mantenir un alt grau de sospita
Introducción. Las fitofotodermatitis son aquellas reacciones cutáneas inducidas por el contacto de ciertos vegetales con la piel sumadas a la radiación ultravioleta. Las sustancias más frecuentemente implicadas suelen ser furocumarinas, presentes en rutáceas (limonero, naranjo y lima), moráceas (higuera) y umbelíferas (zanahoria, apio y perejil), entre otras. Dichas reacciones se manifiestan con placas eritematosas urticariformes sobre las que pueden llegar a formarse vesículas y ampollas, simulando una quemadura. Típicamente, el contacto con las plantas ocasiona lesiones cutáneas con patrones lineales. Este trabajo permite desarrollar las características clínicas de la entidad partiendo de un caso particular. Caso clínico. Un niño de 9 años acudió a urgencias por una placa eritematosa en la pierna izquierda sobre la que habían aparecido ampollas, y en la que se intuía una disposición lineal. Dos días antes había estado jugando en el campo y, con pantalón corto, había estado también expuesto al sol. El paciente fue hospitalizado y se procedió a la flictenectomía de las ampollas tensas de mayor tamaño, a la administración de analgésicos, corticoides y antihistamínicos por vía endovenosa, y a curas con fomentos de permanganato potásico y crema de sulfadiazina argéntica. La evolución fue favorable y el niño pudo continuar con las curas de forma ambulatoria. Revisando las plantas presentes en el campo que visitó el paciente encontramos algún ejemplar de umbelífera. Comentarios. La fitofotodermatitis es una condición infrecuente que generalmente no supone gravedad, pero las lesiones ampollosas locales pueden ser muy llamativas simulando una quemadura. El diagnóstico es fundamentalmente clínico, siendo imprescindible mantener un alto grado de sospecha (AU)
Introduction. Phytophotodermatitis is a skin reaction occurring after contact of the skin with a plant in conjunction with exposure to UV irradiation. The substances most frequently involved are furocoumarines, which are usually present in Rutaceae (lemon, orange, and lime), Moraceae (fig), and Umbelliferae (carrot, celery, and parsley), among others. Such reactions manifest by erythematous urticarial plaques that can develop vesicles and blisters, simulating a burn. Contact with the plants usually causes skin lesions with linear patterns. In this report we present a clinical characterization of this condition. Case report. A 9 years old boy presented to the Emergency Department with an erythematous plaque and blisters in a linear pattern in his left leg. Two days earlier he had been playing in a field wearing shorts and exposed to the sun. The patient was admitted, the large blisters were drained and treated with potassium permanganate soaks and silver sulfadiazine cream, and he received intravenous analgesics, corticosteroids, and antihystaminics. The outcome was good and topical treatments were continued as outpatient. Evaluation of the plants in the playing field revealed the presence of Umbelliferae. Comments. Phytophotodermatitis is not a common or severe disease, but bullous lesions can be striking and mimic a burn. Diagnosis is clinical, and a high level of suspicion is required (AU)