RESUMO
Dendritic cells (DC) are promising targets for immunotherapy of cancer. Clinically, immunization against cancer antigens by means of the most potent antigen-presenting cells, that is DC, remains an important treatment option in combination with the modern immune checkpoint approaches. Instead of adoptively transferring in vitro monocyte-derived DC, they can also be loaded in situ by antibody-mediated targeting of antigen. Conventionally, these vaccines are delivered by classical intradermal injections. Here, we tested an alternative approach, namely laser-assisted epicutaneous immunization. With an infrared laser ("Precise Laser Epidermal System"/P.L.E.A.S.E.® Laser System), we created micropores in human skin and applied monoclonal antibodies (mAbs) against C-type lectins, for example DEC-205/CD205 and Langerin/CD207. Optimal parameters for formation of pores in epidermis and dermis were determined. We could induce pores of defined depths without enhanced apoptosis around them. Antibodies applied epicutaneously to the laser-porated skin could be detected both in Langerhans cells (LC) in situ in the epidermis and in migratory skin DC subsets from short term human skin explant culture, demonstrating uptake and transport of Langerin and DEC-205 mAbs. Efficacy of targeting was similar between the different laser treatments and pore depths. Thus, laser-assisted epicutaneous immunization may be a valuable alternative to intradermal injection, yet the loading efficacy of DC needs to be further improved.
Assuntos
Administração Cutânea , Anticorpos/imunologia , Antígenos CD/imunologia , Células Dendríticas/imunologia , Imunização/métodos , Células de Langerhans/imunologia , Lasers , Lectinas Tipo C/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Receptores de Superfície Celular/imunologia , Adulto , Idoso , Feminino , Humanos , Masculino , Adulto JovemRESUMO
Basal cell carcinoma (BCC) is the most common malignant tumor in light-skinned people and amounts to about 75 % of all cases of skin cancer. Increasing incidence rates have been reported for decades all over the world. The main risk factors include UV radiation, male sex, light skin type, advanced age, long-term immunosuppression, a positive individual or family history, and certain genodermatoses. BCC metastasizes only rarely, and its mortality is low, but it is associated with significant morbidity. Genetic mutations especially in the hedgehog pathway play an important role in BCC pathogenesis. Non-invasive procedures such as optical coherence tomography or confocal laser scan microscopy are increasingly utilized for diagnostics in addition to visual inspection and dermatoscopy, but only in exceptional cases can histological confirmation of the diagnosis be dispensed with. Various clinical and histological subtypes have been defined. Differentiating between BCC with high and low risk of recurrence has a significant influence on the choice of treatment. Most BCC can be treated effectively and safely with standard surgery, or in selected cases with topical treatment. Locally advanced and metastasized BCC must be treated with radiation or systemic therapy. Radiation is also an option for older patients with contraindications for surgery. The hedgehog inhibitors vismodegib and sonidegib are currently approved for systemic therapy of BCC in Europe. Approval for the PD1 inhibitor cemiplimab as second-line therapy is expected in the near future.
Assuntos
Antineoplásicos , Carcinoma Basocelular , Neoplasias Cutâneas , Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/terapia , Proteínas Hedgehog , Humanos , Masculino , Recidiva Local de Neoplasia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/terapiaRESUMO
HINTERGRUND: Ichthyosen sind eine heterogene Gruppe von Krankheiten, deren klinische Klassifizierung schwierig ist. Hier wird die Ichthyosekohorte eines Expertisezentrums für Genodermatosen im Detail beschrieben. PATIENTEN UND METHODIK: Eingeschlossen wurden Patienten mit klinisch oder genetisch bestätigter Ichthyose, die zwischen 2004 und 2017 untersucht und in einer Datenbank aufgenommen wurden. Krankheitsbeginn, Phänotyp, Histologie, Komorbiditäten und Familienanamnese wurden detailliert beschrieben. Bei den genetisch getesteten Patienten wurden Jahr und Methode der genetischen Testung protokolliert und die Prävalenz der unterschiedlichen Autosomal-rezessive-kongenitale Ichthyose (ARCI)-Gene und -Phänotypen, die Prävalenz der syndromalen Ichthyosen und die Genotyp-Phänotyp-Korrelationen analysiert. ERGEBNISSE UND METHODIK: Von den insgesamt 198 eingeschlossenen Patienten wurden 151 genetisch getestet. 81 Patienten hatten eine Ichthyosis vulgaris (IV), 43 eine X-chromosomale Ichthyose (XLI), 38 eine ARCI, 9 eine keratinopathische Ichthyose (KPI) und ein Patient eine Exfoliative Ichthyose. 26 Patienten litten an einer syndromalen Ichthyose. Im Vergleich zu den syndromalen Ichthyosen wurde bei den häufigen Ichthyosen (IV, XLI) und KPI eine gute Phänotyp-Genotyp-Korrelation beobachtet. In 91 % der ARCI-Patienten konnte die exakte Diagnose durch genetische Testung gestellt werden. Lediglich bei 33 % der Patienten mit syndromaler Ichthyose bestand vor der genetischen Testung ein Verdacht auf die tatsächliche Diagnose. In 86 % der Fälle wurde eine kausale Mutation nachgewiesen. SCHLUSSFOLGERUNGEN: Die Arbeit beschreibt das Spektrum der Ichthyosen an einem Expertisezentrum und zeigt, dass für diese Gruppe die genetische Testung von Genodermatosen ein diagnostischer Standard werden sollte.
RESUMO
BACKGROUND: Ichthyoses are a heterogeneous disease group, which makes clinical classification challenging. An ichthyosis cohort at a center for genodermatoses is presented in detail. PATIENTS AND METHODS: Patients with clinically and/or genetically confirmed ichthyosis seen from 2004 to 2017 and listed in a database were included. Disease onset, phenotype, histology, comorbidities and family history were described in detail. In genetically tested patients, the prevalence of various ARCI genes, ARCI phenotypes and syndromic ichthyoses, as well as genotype-phenotype correlation and year/method of genetic testing was assessed. RESULTS: Of all 198 patients who were included in the cohort, 151 were genetically tested. 81 had ichthyosis vulgaris, 43 X-linked ichthyosis, 38 autosomal recessive congenital ichthyosis (ARCI), 9 keratinopathic ichthyosis (KPI) and one exfoliative ichthyosis. 26 individuals suffered from syndromic ichthyoses. A good genotype-phenotype correlation was observed for common ichthyoses and KPI; the correlation was less good in syndromic ichthyoses. In 91 % of ARCI patients an accurate diagnosis was obtained by genetic testing. In only 33 % of syndromic ichthyoses was the definitive diagnosis suspected before genetic testing, which revealed a causative mutation in 86 % of cases. CONCLUSION: This study describes the spectrum of ichthyoses in a center of expertise and shows that genetic testing should become a diagnostic standard for this disease group.
Assuntos
Testes Genéticos , Ictiose/genética , Fenótipo , Adolescente , Áustria , Feminino , Genótipo , Humanos , Ictiose/classificação , Ictiose/diagnóstico , Ictiose/patologia , Imuno-Histoquímica , Masculino , Microscopia Eletrônica de Transmissão , Mutação , Estudos RetrospectivosRESUMO
In this case report, we describe a patient with an inoperable mucosal melanoma of the sinonasal cavity who achieved an ongoing complete response to combined immunotherapy with ipilimumab and nivolumab after initial pseudoprogression. Despite massive enlargement of the tumor 9 weeks after treatment initiation, we decided to continue with checkpoint inhibitor immunotherapy because of lacking potent therapeutic alternatives and the possibility of pseudoprogression. In the computed tomography scan 3 months later, the tumor was no longer detectable. To date, the patient is still in remission. However, she developed severe immune-related thrombocytopenia and neutropenia that are rarely encountered with checkpoint inhibitor immunotherapy. Thrombocytopenia did not respond to corticosteroids, but rapidly improved after the administration of single-dose intravenous immunoglobulin. This exceptional case highlights the effectiveness of combined immunotherapy with ipilimumab and nivolumab in mucosal melanoma, the phenomenon of pseudoprogression, as well as the rare event of immune-related hematological side effects.