RESUMEN
In addition to approved indications in non-melanoma skin cancer in immunocompetent patients, topical photodynamic therapy (PDT) has also been studied for its place in the treatment of, as well as its potential to prevent, superficial skin cancers in immune-suppressed patients, although sustained clearance rates are lower than for immune-competent individuals. PDT using a nanoemulsion of ALA in a daylight or conventional PDT protocol has been approved for use in field cancerization, although evidence of the potential of the treatment to prevent new SCC remained limited. High-quality evidence supports a strong recommendation for the use of topical PDT in photorejuvenation as well as for acne, refractory warts, cutaneous leishmaniasis and in onychomycosis, although these indications currently lack approvals for use and protocols remain to be optimized, with more comparative evidence with established therapies required to establish its place in practice. Adverse events across all indications for PDT can be minimized through the use of modified and low-irradiance regimens, with a low risk of contact allergy to photosensitizer prodrugs, and no other significant documented longer-term risks with no current evidence of cumulative toxicity or photocarcinogenic risk. The literature on the pharmacoeconomics for using PDT is also reviewed, although accurate comparisons are difficult to establish in different healthcare settings, comparing hospital/office-based therapies of PDT and surgery with topical ointments, requiring inclusion of number of visits, real-world efficacy as well as considering the value to be placed on cosmetic outcome and patient preference. This guideline, published over two parts, considers all current approved and emerging indications for the use of topical photodynamic therapy in Dermatology prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence.
Asunto(s)
Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Enfermedades de la Piel/terapia , Administración Tópica , Europa (Continente) , Humanos , Selección de Paciente , Guías de Práctica Clínica como Asunto , Rejuvenecimiento , Enfermedades de la Piel/etiología , Enfermedades de la Piel/patologíaRESUMEN
Topical photodynamic therapy (PDT) is a widely approved therapy for actinic keratoses, Bowen's disease (squamous cell carcinoma in situ), superficial and certain thin basal cell carcinomas. Recurrence rates when standard treatment protocols are used are typically equivalent to existing therapies, although inferior to surgery for nodular basal cell carcinoma. PDT can be used both as lesional and field therapies and has the potential to delay/reduce the development of new lesions. A protocol using daylight to treat actinic keratoses is widely practised, with conventional PDT using a red light after typically a 3-h period of occlusion employed for other superficial skin cancer indications as well as for actinic keratoses when daylight therapy is not feasible. PDT is a well-tolerated therapy although discomfort associated with conventional protocol may require pain-reduction measures. PDT using daylight is associated with no or minimal pain and preferred by patient. There is an emerging literature on enhancing conventional PDT protocols or combined PDT with another treatment to increase response rates. This guideline, published over two parts, considers all current approved and emerging indications for the use of topical PDT in dermatology, prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence.
Asunto(s)
Enfermedad de Bowen/tratamiento farmacológico , Carcinoma Basocelular/tratamiento farmacológico , Queratosis Actínica/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Neoplasias Cutáneas/tratamiento farmacológico , Europa (Continente) , Humanos , Fármacos Fotosensibilizantes/uso terapéutico , Sociedades MédicasRESUMEN
BACKGROUND: Topical immune response modifiers are established for actinic keratosis (AK) treatment and efforts are underway to make further improvements to their efficacy and safety. OBJECTIVES: To investigate the optimal dosing regimens of the Toll-like receptor 7/8 agonist resiquimod in terms of efficacy, safety and tolerability. METHODS: In a multicentre, partly placebo-controlled, double-blind clinical trial, we randomized 217 patients with AK lesions to 0·03% resiquimod gel once-daily application three times per week for 4 weeks or seven times within 2 weeks or five times for 1 week (arms 1/2/3) followed by a treatment-free interval of 8 weeks and one repetition of the cycle. In two additional arms (arms 4/5), patients applied either resiquimod gel 0·01% or 0·03% three times per week up to a biological end point defined by skin erosion or for a maximum duration of 8 weeks. Clearance was assessed clinically and histologically. RESULTS: Complete clinical clearance ranged from 56% to 85% with the highest rate observed in arm 2. Resiquimod 0·03% gel was more effective than 0·01% gel. Clearance rates in arms 1/2/3 were comparable and higher than with placebo and were reached with 24, 14 and 10 gel applications, respectively. Overall, 128 patients (59%) experienced treatment-related adverse reactions. CONCLUSIONS: Resiquimod 0·03% gel is more effective than 0·01% gel. From the perspectives of safety and tolerability, the lower concentration and shorter duration are preferable. The clinical response in arms 2/3 was reached with fewer gel applications. The dosing regimens that used the biological end point (arms 4/5) proved equally efficacious as predefined treatment durations and may therefore be suitable for personalized AK treatment.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Imidazoles/administración & dosificación , Queratosis Actínica/tratamiento farmacológico , Adyuvantes Inmunológicos/efectos adversos , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Imidazoles/efectos adversos , Queratosis Actínica/inmunología , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Placebos/efectos adversos , Factores de Tiempo , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 7/inmunología , Receptor Toll-Like 8/agonistas , Receptor Toll-Like 8/inmunología , Resultado del TratamientoRESUMEN
The pathogenesis of keratinocyte carcinoma following organ transplantation is multifactorial, and recent evidence suggests a complex and often synergistic interplay between the carcinogenic effects of ultraviolet radiation, compromised immune surveillance, direct pro- and anticarcinogenic effects of drugs, oncogenic viruses (in particular, beta-genus human papillomaviruses) and host genetic susceptibility factors. We present an overview of those factors for which there is currently the most convincing evidence and highlight important gaps in our knowledge. In particular, a clear understanding of the interdependence and relative contributions of these co-factors is currently lacking, yet has important implications for rational development of clinically relevant biomarkers and targeted strategies for treatment and prevention of post-transplant keratinocyte cancers.
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Carcinoma de Células Escamosas/etiología , Trasplante de Órganos/efectos adversos , Neoplasias Cutáneas/etiología , Carcinógenos , Epigénesis Genética/fisiología , Humanos , Inmunosupresores/efectos adversos , Infecciones por Papillomavirus/complicaciones , Trastornos por Fotosensibilidad/inducido químicamente , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Microambiente Tumoral , Rayos Ultravioleta/efectos adversosRESUMEN
BACKGROUND: Organ transplant recipients (OTRs) have a highly increased risk of cutaneous squamous cell carcinomas (SCCs). Sensation of pain in cutaneous tumours is a powerful patient-reported warning signal for invasive SCCs in OTRs. OBJECTIVES: To investigate the impact of painful vs. painless skin lesions and SCC vs. other skin lesions on the overall mortality risk in OTRs. METHODS: We followed 410 OTRs from 10 different centres across Europe and North America between 2008 and 2015. These patients had been enrolled in an earlier study to define clinically meaningful patient-reported warning signals predicting the presence of SCC, and had been included if they had a lesion requiring histological diagnosis. Cumulative incidences of overall mortality were calculated using Kaplan-Meier survival analysis, and risk factors were analysed with Cox proportional hazard analysis. RESULTS: There was an increased overall mortality risk in OTRs who reported painful vs. painless skin lesions, with a hazard ratio (HR) of 1·6 [95% confidence interval (CI) 0·97-2·7], adjusted for age, sex and other relevant factors. There was also an increased overall mortality risk in OTRs diagnosed with SCC compared with other skin lesions, with an adjusted HR of 1·7 (95% CI 1·0-2·8). Mortality due to internal malignancies and systemic infections appeared to prevail in OTRs with SCC. CONCLUSIONS: We suggest that OTRs have an increased overall mortality risk if they develop painful skin lesions or are diagnosed with cutaneous SCC.
Asunto(s)
Carcinoma de Células Escamosas/mortalidad , Dolor/etiología , Neoplasias Cutáneas/mortalidad , Receptores de Trasplantes , Adulto , Anciano , Carcinoma de Células Escamosas/etiología , Europa (Continente)/epidemiología , Femenino , Humanos , Estimación de Kaplan-Meier , Queratoacantoma , Masculino , Persona de Mediana Edad , América del Norte/epidemiología , Dolor/mortalidad , Percepción del Dolor/fisiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/mortalidad , Factores de Riesgo , Neoplasias Cutáneas/etiologíaRESUMEN
BACKGROUND: Lung transplant recipients (LTR) are at increased risk for squamous cell carcinoma of the skin (SCC), but risk factors (RF) are incompletely understood. OBJECTIVE: To assess associations between exposure to certain medications and viral infections, and subsequent SCC development. METHODS: Retrospective study examining incidence and potential RF for SCC in LTR transplanted from 1992 to 2010 followed up at one centre. Cumulative incidence and Cox proportional hazards regression models were used to evaluate RF in the first year post-transplant for SCC formation during the follow-up. RESULTS: In 205 analysed LTR, 46 patients were diagnosed with SCC during a median follow-up of 4.9 years. The cumulative incidences of first SCC were 16.7% and 34.1%, for 5 and 10 years post-transplantation respectively. Multivariable analysis identified CMV replication (HR 7.69, 95% CI 2.93-20.2, P < 0.001) and moxifloxacin exposure (HR 2.35, 95% CI 1.15-4.81, P = 0.020) during the first year post-transplantation as independent RF for SCC development during follow-up. CONCLUSION: In our cohort, moxifloxacin use and CMV replication during the first year post-transplantation were associated with increased risk for SCC. These two factors could be indicators of over-immunosuppression. Their role in SCC development requires investigations in larger cohorts and prospective studies.
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Antibacterianos/uso terapéutico , Carcinoma de Células Escamosas/epidemiología , Infecciones por Citomegalovirus/epidemiología , Fluoroquinolonas/uso terapéutico , Trasplante de Pulmón , Neoplasias Cutáneas/epidemiología , Adulto , Carcinoma de Células Escamosas/etiología , Citomegalovirus/fisiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Moxifloxacino , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Cutáneas/etiología , Replicación ViralRESUMEN
BACKGROUND: SIAscopy (Spectrophotometric Intracutaneous Analysis) enables non-invasive analysis of the skin. OBJECTIVE: We wanted to determine whether SIAscopy is able to detect and differentiate the skin chromophores melanin, collagen and haemoglobin and the influence of immunosuppressive drugs and other known risk factors for non-melanoma skin cancer (NMSC). METHODS: Volunteers and patients were measured by SIAscopy at six spots on sun-exposed and two spots on sun-protected skin. Measurements were transformed by SIAmetrics into arbitrary units and statistically analysed. RESULTS: Melanin was shown to be higher with age (+1.73759 a.u.; P < 0.0001), sun exposure (+47.03998 a.u.; P < 0.0001), immunosuppression (+10.48526 a.u.; P < 0.0001) and lower in males (-26.50952 a.u.; P < 0.0001). Collagen was lower with increasing age (-0.29162 a.u.; P < 0.0001) and sun exposure (-6.85586 a.u.; P < 0.0001) but higher with male sex (+8.34251 a.u.; P < 0.0001) and immunosuppression (+5.79171 a.u.; P = 0.0001). Haemoglobin was lower with increasing age (-0.23833 a.u.; P = 0.0005), but higher with male sex (+18.51976 a.u.; P < 0.0001) and sun exposure (+13.74523 a.u.; P < 0.0001). Haemoglobin content was not associated to immunosuppression. CONCLUSION: Our results encourage the use of SIAscopy as a tool to better gauge an individual patient's NMSC risk factors. Further studies should help to better delineate SIAscopy as a prognostic tool.
Asunto(s)
Colágeno/análisis , Hemoglobinas/análisis , Huésped Inmunocomprometido , Melaninas/análisis , Envejecimiento de la Piel , Piel/química , Adulto , Factores de Edad , Análisis de Varianza , Exposición a Riesgos Ambientales , Femenino , Humanos , Huésped Inmunocomprometido/fisiología , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Factores Sexuales , Envejecimiento de la Piel/fisiología , Espectrofotometría/métodos , Rayos Ultravioleta , Población Blanca , Adulto JovenRESUMEN
BACKGROUND: General practitioners (GPs) play crucial roles in early detection of skin cancer. A pilot-study found a positive short-term effect of a 1-day dermatologic education programme on GPs' diagnostic competence. OBJECTIVE: To determine effects of a multifaceted intervention, including technical equipment and continuing feedback by a dermatologist, on GPs' diagnostic skills regarding skin cancer. METHODS: Randomized controlled trial with 78 GPs of the Canton of Zurich, Switzerland. INTERVENTION: GPs in intervention group received a 1-day training, a Lumio (magnifying glass with polarized light, 3Gen), a Nikon digital camera and - during 1 year - feedback on skin lesion pictures sent to the dermatologist. GPs in control group only received the 1-day training. PRIMARY OUTCOME: structured assessment of GP's diagnostic skills in correctly diagnosing images of skin lesions regarding skin cancer. At baseline prior to intervention (T0), after the full-day training course in both groups (T1), and after 1 year of continuing feedback (T2) to the intervention group. MEASURES: Non-parametric unpaired (Wilcoxon-Mann-Whitney) tests were used to compare numbers of correctly classified skin lesions between both groups at T2 and for the change between T1 and T2. RESULTS: At T0, both groups classified a median of 23 skin lesions of the 36 images correctly. This value rose to 28 for both groups at T1 and fell to 24 for both groups at T2. No difference between control and intervention group at T2. Furthermore, we compared differences in the sum scores per GP between T1 and T2 for each group. Also in this comparison, no difference between control and intervention group was found. CONCLUSION AND RELEVANCE: No long-term effect of the multifaceted intervention was found on the competence to diagnose skin cancer by GPs. The positive short-term effect of the 1-day dermatologic education programme did not persist over 12 months.
Asunto(s)
Competencia Clínica , Dermatología , Medicina General/educación , Neoplasias Cutáneas/diagnóstico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Organ transplant recipients (OTR) are at high risk for cutaneous squamous cell carcinomas (SCC). We aimed to define clinically meaningful patient-reported warning signals predicting the presence of invasive SCC.Patient-reported signs and symptoms of 812 consecutively biopsied skin lesions from 410 OTR were determined by questionnaire and physical examination and related to the subsequent biopsy-proven diagnoses. Receiver-operating characteristic (ROC) curve analyses were used as a measure of distinction between the predictive values of patient-reported warning signals and the occurrence of SCC. Pain was an independent predictive patient-reported warning signal for a biopsy-proven invasive SCC. The odds ratio from the fully adjusted model predicting SCC was 4.4(95% confidence interval: 2.48.2). Higher scores on the visual analog scale (VAS) for pain were associated witha greater likelihood for the presence of SCC compared to none or mild pain. The for scores on the VAS from 1to 3, 4 to 6 and 7 to 10 were 4.9 (2.210.5), 2.3 (0.965.5)and 16.5 (3.675.8), respectively. Pain is the most powerful patient-reported warning signal for invasive cutaneous SCC in OTR. Empowerment of patients by education could accelerate diagnosis and treatment of cutaneous SCC.
Asunto(s)
Carcinoma de Células Escamosas/diagnóstico , Trasplante de Órganos/efectos adversos , Dolor/diagnóstico , Neoplasias Cutáneas/diagnóstico , Adulto , Anciano , Carcinoma de Células Escamosas/etiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Neoplasias Cutáneas/etiología , Encuestas y CuestionariosAsunto(s)
Fototerapia/efectos adversos , Enfermedades de la Piel/terapia , Rayos Ultravioleta , Adulto , Femenino , Humanos , Adulto JovenRESUMEN
BACKGROUND: The origin of collagen autoimmune diseases is not fully understood. Some studies postulate a mechanism of molecular mimicry or heterologous immunity following viral infections triggering autoimmunity. Apart from infections, other exogenous factors such as visible light or X-rays have been reported to incite autoimmunity. CASE REPORT: We report a case of histologically and serologically confirmed subacute lupus erythematosus (SCLE) following radiotherapy for breast cancer. DISCUSSION: The close temporal and spatial correlation between radiotherapy and onset of SCLE in this patient suggests that an autoimmune reaction may have been triggered locally by functionally altering the immune system and breaking self-tolerance.
RESUMEN
BACKGROUND: Lichen planus is a common skin disorder of unknown etiology. Most cases are idiopathic, but substances such as gold, antimalarials, penicillamine, thiazide diuretics, ß-blockers, arsenic and nonsteroidal anti-inflammatory drugs have been implicated as trigger factors. CASE PRESENTATION: We report the case of a lichenoid eruption in a male drug addict who administered oral heroin (diamorphine) intravenously. Diamorphine was stopped immediately. Following topical steroids, phototherapy and oral acitretin, the lesions gradually disappeared. A lymphocyte transformation test was negative for pure morphine and codeine. DISCUSSION: A coincidental association between the intravenous application of orally formulated semisynthetic heroin and the lichenoid eruption cannot be completely ruled out. However, the diagnosis of a lichenoid drug eruption is favoured over idiopathic lichen planus because of the clear chronological correlation between drug use and appearance as well as drug withdrawal and disappearance of the skin lesions, and because of a flare-up following repeated intravenous application of diamorphine.
RESUMEN
Primary cutaneous posttransplant lymphoproliferative disorders (PTLD) are rare. This retrospective, multicenter study of 35 cases aimed to better describe this entity. Cases were (re)-classified according to the WHO-EORTC or the WHO 2008 classifications of lymphomas. Median interval between first transplantation and diagnosis was 85 months. Fifty-seven percent of patients had a kidney transplant. Twenty-four cases (68.6%) were classified as primary cutaneous T cell lymphoma (CTCL) and 11 (31.4%) as primary cutaneous B cell PTLD. Mycosis fungoides (MF) was the most common (50%) CTCL subtype. Ten (90.9%) cutaneous B cell PTLD cases were classified as EBV-associated B cell lymphoproliferations (including one plasmablastic lymphoma and one lymphomatoid granulomatosis) and one as diffuse large B cell lymphoma, other, that was EBV-negative. Sixteen (45.7%) patients died after a median follow-up of 19.5 months (11 [68.8%] with CTCL [6 of whom had CD30(+) lymphoproliferative disorders (LPD)] and 5 [31.2%] with cutaneous B cell PTLD. Median survival times for all patients, CTCL and cutaneous B cell PTLD subgroups were 93, 93, and 112 months, respectively. Survival rates for MF were higher than those for CD30(+) LPD. The spectrum of primary CTCL in organ transplant recipients (OTR) is similar to that in the general population. The prognosis of posttransplant primary cutaneous CD30(+) LPD is worse than posttransplant MF and than its counterpart in the immunocompetent population. EBV-associated cutaneous B cell LPD predominates in OTR.
Asunto(s)
Linfoma Cutáneo de Células T/etiología , Trastornos Linfoproliferativos/etiología , Micosis Fungoide/etiología , Trasplante de Órganos/efectos adversos , Complicaciones Posoperatorias , Neoplasias Cutáneas/etiología , Femenino , Estudios de Seguimiento , Humanos , Agencias Internacionales , Linfoma Cutáneo de Células T/diagnóstico , Linfoma Cutáneo de Células T/mortalidad , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/mortalidad , Masculino , Persona de Mediana Edad , Micosis Fungoide/diagnóstico , Micosis Fungoide/mortalidad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/mortalidad , Tasa de SupervivenciaAsunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Enfermedad de Crohn/tratamiento farmacológico , Eritema Nudoso/inducido químicamente , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Fragmentos Fab de Inmunoglobulinas/efectos adversos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Certolizumab Pegol , Eritema Nudoso/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , PronósticoRESUMEN
BACKGROUND: The incidence of actinic keratoses (AK) and non-melanoma skin cancer (NMSC) in organ transplant recipients (OTRs) is significantly higher than in immunocompetent patients. Rates of progression and recurrence following treatment are higher too, in part due to the effects of the immunosuppressant drugs. Conventional therapies for AK, using curettage, cryotherapy, surgical excision, topical therapies and photodynamic therapy (PDT), are often less effective, and may be inappropriate, for treating the greater numbers and extent of lesions in OTRs. Moreover, there are no specific protocols for treating this patient population that take into account the need for more frequent treatment and the increased pain associated with treating larger areas. OBJECTIVES: Recently, a pan-European group of dermatologists with expertise in this area met to share current best practice in PDT for the treatment of AK in OTRs. METHODS: The group identified areas where PDT currently is not meeting the needs of these patients and discussed how these gaps might be addressed. RESULTS/CONCLUSIONS: This position article summarizes those discussions and makes recommendations concerning a standardized protocol for treating OTRs, for a large randomized controlled trial to provide robust data on safety, efficacy and optimal pain control, and to provide pharmaco-economics data that can be used to support extended reimbursement in this patient group. The authors also recommend a second clinical trial to further investigate induced immunosuppression with PDT in healthy volunteers.
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Huésped Inmunocomprometido , Queratosis Actínica/tratamiento farmacológico , Trasplante de Órganos/estadística & datos numéricos , Fotoquimioterapia/métodos , Adulto , Factores de Edad , Anciano , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Queratosis Actínica/epidemiología , Queratosis Actínica/inmunología , Masculino , Persona de Mediana Edad , Fotoquimioterapia/efectos adversos , Guías de Práctica Clínica como Asunto , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Inmunología del Trasplante/fisiología , Resultado del Tratamiento , Procedimientos InnecesariosRESUMEN
Kaposi sarcoma (KS) is a vascular neoplasm pathogenetically linked to human herpesvirus 8. Transplant recipients, in particular renal-transplant recipients (RTRs) are at higher risk for post-transplant (P)-KS which affects 0.2-11% of RTRs. The course of P-KS is influenced by the post-transplantation immunosuppressive treatment. Reduction of immunosuppressive drugs can result in tumour regression, and is the treatment of choice for P-KS, but is associated with the risk for transplant rejection. Imiquimod is a topically applied immunomodulator without relevant systemic absorption, and may thus represent a promising treatment for cutaneous KS in RTRs. The aim of this study was to investigate the clinical and histological effects of imiquimod in two RTRs with cutaneous KS. Imiquimod resulted in complete clinical and histologically proven remission in one patient, but in the second patient, although there was clinical remission, histological persistence of KS was found. Imiquimod may represent an effective treatment for RTRs with cutaneous P-KS. However, clinical remission does not necessarily indicate complete tumour regression, as shown in one of our patients, who had a persisting tumour, as shown by biopsy examination. Thus, histological confirmation is crucial to confirm complete response.
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Adyuvantes Inmunológicos/administración & dosificación , Aminoquinolinas/administración & dosificación , Antineoplásicos/administración & dosificación , Trasplante de Riñón/efectos adversos , Sarcoma de Kaposi/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Administración Tópica , Anciano , Antígenos CD/metabolismo , Femenino , Humanos , Imiquimod , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Sarcoma de Kaposi/etiología , Sarcoma de Kaposi/inmunología , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/inmunologíaRESUMEN
BACKGROUND: Recent studies suggest that patients on mammalian target of rapamycin (mTOR) inhibitors experience a reduction in cutaneous carcinogenesis by an estimated 50% or more compared with calcineurin inhibitors. While randomized trials are running, organ transplant recipients are frequently switched from calcineurin inhibitors to mTOR inhibitors when cutaneous carcinogenesis increases. OBJECTIVES: To slow carcinogenesis in our patient, a heart transplant recipient with a neuropathic diabetic foot syndrome who had developed cutaneous carcinogenesis at a rate of more than 20 squamous cell carcinomas (SCC) annually. METHODS: The patient's immunosuppression was switched from the calcineurin inhibitor ciclosporin to the mTOR inhibitor everolimus. RESULTS: Carcinogenesis slowed to six SCC annually; however, he developed recalcitrant diabetic foot ulcers which were purely neuropathic and nonangiopathic, and a limb-threatening fistulating necrotic erysipelas of the right leg. Both sites responded poorly to antibiotic therapy, offloading and debridement. This skin fistula became chronic and some toes were at risk for minor amputation. In view of the propensity for mTOR inhibitors to impair would healing, immunosuppression was switched back to ciclosporin. All wounds healed rapidly, but skin carcinogenesis rose to former levels. CONCLUSIONS: This case impressively illustrates the clinical dilemma for mTOR inhibitor use where benefit in carcinogenesis is counterbalanced by impairment in wound healing. Changes in immunosuppressive regimens should thus be made on an individual basis with careful consideration of the relative risks.
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Pie Diabético/fisiopatología , Inmunosupresores/efectos adversos , Neoplasias Cutáneas/prevención & control , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Cicatrización de Heridas/efectos de los fármacos , Anciano , Inhibidores de la Calcineurina , Cardiomiopatía Dilatada/cirugía , Transformación Celular Neoplásica/efectos de los fármacos , Sustitución de Medicamentos , Everolimus , Trasplante de Corazón , Humanos , Masculino , Sirolimus/efectos adversos , Sirolimus/análogos & derivados , Sirolimus/antagonistas & inhibidores , Dedos del PieRESUMEN
Azathioprine is associated with enhanced skin photosensitivity to ultraviolet A (UVA) and leads to incorporation of 6-thioguanine (6-TG) into DNA of dividing cells. Unlike canonical DNA, 6-TG DNA is damaged by UVA, which comprises more than 90% of the ultraviolet reaching earth. Skin photosensitivity to UVA and UVB was measured in 48 kidney transplant patients immunosuppressed either by azathioprine (n = 32) or mycophenolate (n = 16). In 23 patients, azathioprine was subsequently replaced by mycophenolate and skin photosensitivity, DNA 6-TG content in peripheral blood mononuclear cells, and susceptibility to UVA-induced DNA damage were monitored for up to 2 years. The mean minimal erythema dose to UVA on azathioprine was twofold lower than on mycophenolate. Three months after replacing azathioprine by mycophenolate mofetil, the minimal erythema dose to UVA had increased from 15 to 25 J/cm(2) (p < 0.001) accompanied by reduced DNA 6-TG content. P53 protein expression in irradiated skin indicated reduced susceptibility to UVA-induced DNA damage. 6-TG DNA in peripheral blood mononuclear cells remained measurable for over 2 years. Replacing azathioprine selectively reduced the skin photosensitivity to UVA, attenuated UVA-induced skin DNA damage, and is likely based on incorporated 6-TG in DNA.