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1.
Cancer Immunol Immunother ; 69(3): 477-488, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31980913

RESUMEN

BACKGROUND: Autologous dendritic cell (DC) vaccines can induce tumor-specific T cells, but their effect can be counteracted by immunosuppressive mechanisms. Cisplatin has shown immunomodulatory effects in vivo which may enhance efficacy of DC vaccination. METHODS: This is a prospective, randomized, open-label phase 2 study (NCT02285413) including stage III and IV melanoma patients receiving 3 biweekly vaccinations of gp100 and tyrosinase mRNA-loaded monocyte-derived DCs with or without cisplatin. Primary objectives were to study immunogenicity and feasibility, and secondary objectives were to assess toxicity and survival. RESULTS: Twenty-two stage III and 32 stage IV melanoma patients were analyzed. Antigen-specific CD8+ T cells were found in 44% versus 67% and functional T cell responses in 28% versus 19% of skin-test infiltrating lymphocytes in patients receiving DC vaccination with and without cisplatin, respectively. Four patients stopped cisplatin because of toxicity and continued DC monotherapy. No therapy-related grade 3 or 4 adverse events occurred due to DC monotherapy. During combination therapy, one therapy-related grade 3 adverse event, decompensated heart failure due to fluid overload, occurred. The clinical outcome parameters did not clearly suggest significant differences. CONCLUSIONS: Combination of DC vaccination and cisplatin in melanoma patients is feasible and safe, but does not seem to result in more tumor-specific T cell responses or improved clinical outcome, when compared to DC vaccination monotherapy.


Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Cisplatino/uso terapéutico , Células Dendríticas/inmunología , Melanoma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Vacunas contra el Cáncer/farmacología , Cisplatino/farmacología , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Monocitos/inmunología , Estadificación de Neoplasias , Estudios Prospectivos , Vacunación , Adulto Joven
2.
Hum Genet ; 137(5): 389-400, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29754270

RESUMEN

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.


Asunto(s)
Pérdida Auditiva/genética , Heterocigoto , Proteínas con Homeodominio LIM/genética , Mutación Missense , Factores de Transcripción/genética , Enfermedades Vestibulares/genética , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad
3.
Am J Hum Genet ; 97(5): 647-60, 2015 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-26522471

RESUMEN

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.


Asunto(s)
Ligamiento Genético , Pérdida Auditiva Unilateral/genética , Mutación/genética , Factor de Células Madre/genética , Síndrome de Waardenburg/genética , Alelos , Animales , Femenino , Técnica del Anticuerpo Fluorescente , Pérdida Auditiva Unilateral/metabolismo , Pérdida Auditiva Unilateral/patología , Humanos , Masculino , Ratones , Células 3T3 NIH , Linaje , Fenotipo , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Síndrome de Waardenburg/metabolismo , Síndrome de Waardenburg/patología
5.
J Low Genit Tract Dis ; 21(1): 33-36, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27741039

RESUMEN

OBJECTIVES: Female renal transplant recipients (RTRs) have increased risk for developing human papillomavirus (HPV)-related (pre)malignancies of the lower genital tract. Annual cervical screening is advised for RTRs, but the participation rate is low. The aim of this study is to investigate whether HPV self-sampling is suitable for gynecological screening of RTRs to increase participation rate. METHODS: A large cohort of 253 RTRs was investigated for the prevalence of HPV. All participants received a device for a cervicovaginal self-sample. Questionnaires were sent to assess the experience with this device. High-risk (hrHPV) presence was determined with the SPF10-LiPA25 system and GP5+/6+ PCR. HrHPV-positive patients underwent gynecological examination. RESULTS: More than 90% of the patients rated their experience with the self-sample device as good to excellent, and 77% preferred self-sampling over a physician taken sample. Approximately thirty-five of 217 women tested hrHPV positive with SPF10- LiPA25, and 22 tested positive with the GP5+/6+ PCR. Eleven hrHPV-positive patients had clinically relevant gynecological abnormalities, and they all tested positive with GP5+/6+ PCR. CONCLUSIONS: Self-sampling is clinically applicable in a gynecological screening and is preferred by female RTRs. Therefore, self-sampling could be implemented with the aim to increase the participation rate of female RTRs in yearly gynecological screening.


Asunto(s)
Detección Precoz del Cáncer/métodos , Trasplante de Riñón , Infecciones por Papillomavirus/diagnóstico , Autoexamen/métodos , Manejo de Especímenes/métodos , Receptores de Trasplantes , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Aceptación de la Atención de Salud , Encuestas y Cuestionarios , Adulto Joven
6.
Cancer Immunol Immunother ; 65(3): 327-39, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26861670

RESUMEN

Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRNA encoding tumor antigens gp100 and tyrosinase. Tumor antigen-specific T cell responses were monitored in blood and skin-test infiltrating-lymphocyte cultures. Almost all patients mounted prophylactic vaccine- or KLH-specific immune responses. Both after intranodal injection and after intradermal/intravenous injection, tumor antigen-specific immune responses were detected, which coincide with longer overall survival in stage IV melanoma patients. VAC-DC induce local and systemic CTC grade 2 and 3 toxicity, which is most likely caused by BCG in the maturation cocktail. The side effects were self-limiting or resolved upon a short period of systemic steroid therapy. We conclude that VAC-DC can induce functional tumor-specific responses. Unfortunately, toxicity observed after vaccination precludes the general application of VAC-DC, since in DC maturated with prophylactic vaccines BCG appears to be essential in the maturation cocktail.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Células Dendríticas/inmunología , Melanoma/terapia , Monocitos/citología , Adulto , Anciano , Vacuna BCG/inmunología , Vacunas contra el Cáncer/efectos adversos , Dinoprostona/farmacología , Femenino , Hemocianinas/inmunología , Humanos , Masculino , Melanoma/inmunología , Persona de Mediana Edad , Monofenol Monooxigenasa/genética , Monofenol Monooxigenasa/inmunología , Linfocitos T/inmunología , Vacunación , Antígeno gp100 del Melanoma/genética , Antígeno gp100 del Melanoma/inmunología
7.
Acta Derm Venereol ; 95(2): 211-6, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24806592

RESUMEN

Genital psoriasis is a neglected manifestation of psoriasis, although it affects numerous patients and has major effects on sexual quality of life (SQoL). We aimed to assess the value of specialised care for patients with genital psoriasis. Patients were treated for at least one year at a specialised research outpatient clinic with extensive attention for genital lesions and SQoL. The genital lesions were treated according to a stepwise algorithm. First follow-up was planned after 6 weeks; subsequent follow-up visits were scheduled every 3 months. At every visit, psoriasis severity and SQoL were measured with validated tools. Differences in scores between visits were analysed by a mixed model for repeated measures. Forty-two patients were included (M:F = 25:17). All objective and subjective genital psoriasis severity and QoL parameters improved significantly within the first follow-up period of approximately 6 weeks. In female patients, SQoL also significantly improved. In conclusion, genital psoriasis can relatively easy be treated within limited time exposure, resulting in significant improvement of QoL. Prompt and simple adjustments in the provided care are enough to accomplish this.


Asunto(s)
Fármacos Dermatológicos/administración & dosificación , Enfermedades de los Genitales Femeninos/tratamiento farmacológico , Enfermedades de los Genitales Masculinos/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Corticoesteroides/administración & dosificación , Algoritmos , Inhibidores de la Calcineurina/administración & dosificación , Estudios de Cohortes , Vías Clínicas , Esquema de Medicación , Quimioterapia Combinada , Femenino , Enfermedades de los Genitales Femeninos/diagnóstico , Enfermedades de los Genitales Femeninos/psicología , Enfermedades de los Genitales Masculinos/diagnóstico , Enfermedades de los Genitales Masculinos/psicología , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Servicio Ambulatorio en Hospital , Psoriasis/diagnóstico , Psoriasis/psicología , Calidad de Vida , Índice de Severidad de la Enfermedad , Conducta Sexual , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Vitamina D/administración & dosificación , Vitamina D/análogos & derivados
8.
Proc Natl Acad Sci U S A ; 108(45): 18396-9, 2011 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-22025695

RESUMEN

Current biomarkers are unable to adequately predict vaccine-induced immune protection in humans with infectious disease or cancer. However, timely and adequate assessment of antigen-specific immune responses is critical for successful vaccine development. Therefore, we have developed a method for the direct assessment of immune responses in vivo in a clinical setting. Melanoma patients with lymph node (LN) metastases received dendritic cell (DC) vaccine therapy, injected intranodally, followed by [(18)F]-labeled 3'-fluoro-3'-deoxy-thymidine ([(18)F]FLT) PET at varying time points after vaccination. Control LNs received saline or DCs without antigen. De novo immune responses were readily visualized in treated LNs early after the prime vaccination, and these signals persisted for up to 3 wk. This selective [(18)F]FLT uptake was markedly absent in control LNs, although tracer uptake in treated LNs increased profoundly with as little as 4.5 × 10(5) DCs. Immunohistochemical staining confirmed injected DC dispersion to T-cell areas and resultant activation of CD4(+) and CD8(+) T cells. The level of LN tracer uptake significantly correlates to the level of circulating antigen-specific IgG antibodies and antigen-specific proliferation of T cells in peripheral blood. Furthermore, this correlation was not observed with [(18)F]-labeled fluoro-2-deoxy-2-D-glucose. Therefore, [(18)F]FLT PET offers a sensitive tool to study the kinetics, localization, and involvement of lymphocyte subsets in response to vaccination. This technique allows for early discrimination of responding from nonresponding patients in anti-cancer vaccination and aid physicians in individualized decisionmaking.


Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/administración & dosificación , Didesoxinucleósidos , Fluorodesoxiglucosa F18 , Melanoma/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Humanos , Metástasis Linfática/diagnóstico por imagen , Metástasis Linfática/inmunología , Melanoma/inmunología , Melanoma/patología
9.
Nat Commun ; 15(1): 1632, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38395969

RESUMEN

Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88-1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73-2.38; p = 0.44). Grade 3-4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p < 0.001). In conclusion, while adjuvant nDC treatment in stage IIIB/C melanoma patients generated specific immune responses and was well tolerated, no benefit in RFS was observed.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Supervivencia sin Enfermedad , Adyuvantes Inmunológicos/uso terapéutico , Células Dendríticas/patología , Estadificación de Neoplasias
11.
Int J Dermatol ; 62(4): 508-513, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36539393

RESUMEN

BACKGROUND: Time trend analysis of cutaneous melanoma (CM) mortality in fair skin populations shows both a gradual decrease and/or an increase. To explain these differences, we analyzed long-term time trends in the incidence of the most common histological subtypes of CM: superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), and nodular melanoma (NM). METHODS: Using data from the Netherlands Cancer Registry and Statistics Netherlands, the number and rates of cases diagnosed with SSM, LLM, and NM from 1989 to 2016 were analyzed by age, calendar period, and birth cohort of people born in successive periods from 1925 to 1973. RESULTS: Primary CM was diagnosed in 52,000 men and 66,588 women in the study period. The annual age-standardized incidence rate increased three-fold from 14 to 42 per 100,000 person-years. The most common subtype was SSM (50%), followed by LMM (23%) and NM (14%). Age-specific subtype rates showed an upward trend over time for both men and women. Younger birth cohorts had higher rates of SSM and LMM diagnosis than older birth cohorts. This birth cohort pattern was not observed for NM. CONCLUSIONS: We observed a strong increase in the melanoma epidemic curves in the light-skinned Dutch population over the last three decades. This increase is explained by younger generations having higher rates of SSM and LMM than older generations.


Asunto(s)
Peca Melanótica de Hutchinson , Melanoma , Neoplasias Cutáneas , Masculino , Femenino , Humanos , Melanoma/patología , Neoplasias Cutáneas/patología , Países Bajos/epidemiología , Peca Melanótica de Hutchinson/patología , Melanoma Cutáneo Maligno
12.
Oncoimmunology ; 11(1): 2015113, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36524210

RESUMEN

We evaluated the immunological responses of lymph-node involved (stage III) melanoma patients to adjuvant dendritic cell vaccination with subsets of naturally occurring dendritic cells (nDCs). Fifteen patients with completely resected stage III melanoma were randomized to receive adjuvant dendritic cell vaccination with CD1c+ myeloid dendritic cells (cDC2s), plasmacytoid dendritic cells (pDCs) or the combination. Immunological response was the primary endpoint and secondary endpoints included safety and survival. In 80% of the patients, antigen-specific CD8+ T cells were detected in skin test-derived T cells and in 55% of patients, antigen-specific CD8+ T cells were detectable in peripheral blood. Functional interferon-γ-producing T cells were found in the skin test of 64% of the patients. Production of nDC vaccines meeting release criteria was feasible for all patients. Vaccination only induced grade 1-2 adverse events, mainly consisting of fatigue. In conclusion, adjuvant dendritic cell vaccination with cDC2s and/or pDCs is feasible, safe and induced immunological responses in the majority of stage III melanoma patients.


Asunto(s)
Vacunas contra el Cáncer , Melanoma , Humanos , Linfocitos T CD8-positivos , Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas , Melanoma/terapia , Adyuvantes Inmunológicos , Vacunación , Glicoproteínas , Antígenos CD1 , Melanoma Cutáneo Maligno
14.
Acta Derm Venereol ; 91(1): 5-11, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20927490

RESUMEN

It is well known that the genital skin may be affected by psoriasis. However, little is known about the prevalence and clinical appearance of genital psoriasis, and genital skin is often neglected in the treatment of psoriatic patients. We performed an extensive systematic literature search for evidence-based data on genital psoriasis with respect to epidemiology, aetiology, clinical and histopathological presentation, diagnosis and treatment. Three bibliographical databases (PubMed, EMBASE and the Cochrane Library) were used as data sources. Fifty-nine articles on genital psoriasis were included. The results show that psoriasis frequently affects the genital skin, but that evidence-based data with respect to the efficacy and safety of treatments for genital psoriasis are extremely limited. An advised treatment paradigm for genital psoriasis, based on the levels of evidence, is: first-line: (weak) topical corticosteroids; second-line: vitamin D preparations or tar-based treatments.


Asunto(s)
Enfermedades de los Genitales Femeninos , Enfermedades de los Genitales Masculinos , Psoriasis , Femenino , Enfermedades de los Genitales Femeninos/diagnóstico , Enfermedades de los Genitales Femeninos/patología , Enfermedades de los Genitales Femeninos/terapia , Enfermedades de los Genitales Masculinos/diagnóstico , Enfermedades de los Genitales Masculinos/terapia , Humanos , Masculino , Psoriasis/diagnóstico , Psoriasis/patología , Psoriasis/terapia , Piel/patología
15.
Transpl Int ; 23(2): 191-9, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19793075

RESUMEN

SUMMARY: Immunosuppressive therapy in renal transplant recipients (RTRs) is associated with an increased risk for the development of (pre)malignancies involving the skin and the female lower genital tract. We assessed whether yearly cervical screening was performed and evaluated the development of skin cancer and gynaecological (pre)malignancies in RTRs. Female RTRs (n = 224), transplanted between 1991 and 1995, were analysed retrospectively. Sociodemographic patient characteristics, frequency and results of cervical smears and prevalence of cutaneous, cervical, vaginal or vulvar (pre)malignancies were investigated and compared with that in the general population. A mean of 0.2 cervical smears per patient per year was found to have been performed in RTRs, which is significantly less than the recommended screening ratio of 1.0 for female RTRs (P < 0.001). The risk for RTRs to develop malignancies of the female lower genital tract was increased: twofold to sixfold for cervical intraepithelial neoplasia, threefold for cervical carcinoma and 50-fold for vulvar carcinoma. Cervical screening is not performed in accordance with the advised yearly intervals, and the risk for RTRs to develop vulvar and cervical (pre)malignancies is increased. More attention should be paid to the vulvar and cervical surveillance of RTRs by both medical specialists and general physicians.


Asunto(s)
Neoplasias de los Genitales Femeninos/etiología , Inmunosupresores/efectos adversos , Trasplante de Riñón/efectos adversos , Neoplasias Cutáneas/etiología , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Trasplante de Riñón/inmunología , Tamizaje Masivo , Persona de Mediana Edad , Países Bajos , Estudios Retrospectivos , Factores de Riesgo , Neoplasias del Cuello Uterino/etiología , Neoplasias Vaginales/etiología , Neoplasias de la Vulva/etiología , Adulto Joven , Displasia del Cuello del Útero/etiología
16.
Clin Cancer Res ; 15(7): 2531-40, 2009 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-19318472

RESUMEN

PURPOSE: The success of immunotherapy with dendritic cells (DC) to treat cancer is dependent on effective migration to the lymph nodes and subsequent activation of antigen-specific T cells. In this study, we investigated the fate of DC after intradermal (i.d.) or intranodal (i.n.) administration and the consequences for the immune activating potential of DC vaccines in melanoma patients. EXPERIMENTAL DESIGN: DC were i.d. or i.n. administered to 25 patients with metastatic melanoma scheduled for regional lymph node resection. To track DC in vivo with scintigraphic imaging and in lymph nodes by immunohistochemistry, cells were labeled with both [(111)In]-indium and superparamagnetic iron oxide. RESULTS: After i.d. injection, maximally 4% of the DC reached the draining lymph nodes. When correctly delivered, all DC were delivered to one or more lymph nodes after i.n. injection. Independent of the route of administration, large numbers of DC remained at the injection site, lost viability, and were cleared by infiltrating CD163+ macrophages within 48 hours. Interestingly, 87 +/- 10% of the surviving DC preferentially migrated into the T-cell areas, where they induced antigen-specific T-cell responses. Even though more DC reached the T-cell areas, i.n. injection of DC induced similar antigen-specific immune responses as i.d. injection. Immune responses were already induced with <5 x 10(5) DC migrating into the T-cell areas. CONCLUSIONS: Monocyte-derived DC have high immune activating potential irrespective of the route of vaccination. Limited numbers of DC in the draining lymph nodes are sufficient to induce antigen-specific immunologic responses.


Asunto(s)
Movimiento Celular , Células Dendríticas/inmunología , Activación de Linfocitos , Melanoma/inmunología , Neoplasias Cutáneas/inmunología , Linfocitos T/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/farmacocinética , Células Dendríticas/trasplante , Humanos , Inyecciones , Ganglios Linfáticos/inmunología , Melanoma/metabolismo , Fagocitosis , Neoplasias Cutáneas/metabolismo
17.
J Low Genit Tract Dis ; 14(2): 118-23, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20354420

RESUMEN

OBJECTIVE: To compare the treatment and follow-up of patients with lichen sclerosus (LS) at the departments of Gynaecology and Dermatology at the Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands, to evaluate the need for a multidisciplinary vulvar clinic. MATERIALS AND METHODS: Treatment and follow-up data of all women with histologically proven (between January 1995 and January 2001) anogenital LS visiting the outpatient clinics of the departments of Obstetrics & Gynaecology and Dermatology were collected (last date of follow-up: January 2008). RESULTS: Eighty-four patients with LS were included in this study, 10 patients (12%) of which were treated by both specialties. At the Gynaecology department, LS patients more often received surgical treatment, topical estrogens, and lidocaine ointment, whereas at the Dermatology department, local class 2/3 corticosteroids were more often prescribed. Follow-up frequencies were similar in both specialties and took place at 3 to 4 visits in the first year and at least once a year afterward. One patient developed vulvar squamous cell carcinoma. This patient had withdrawn from follow-up and had her condition diagnosed with carcinoma 74 months after the LS had been diagnosed. CONCLUSIONS: Although no hospital guidelines existed, management of patients with LS agreed with current recommendations in the literature, although differences in secondary and supportive therapy existed owing to differences in expertise. The relatively high percentage of patients treated by both specialties with a high frequency of visits emphasizes the need for a multidisciplinary clinic for vulvar disease.


Asunto(s)
Liquen Escleroso y Atrófico/tratamiento farmacológico , Liquen Escleroso y Atrófico/cirugía , Centros Médicos Académicos , Administración Tópica , Corticoesteroides/administración & dosificación , Anestésicos Locales/administración & dosificación , Antiinflamatorios/administración & dosificación , Estrógenos/administración & dosificación , Femenino , Humanos , Lidocaína/administración & dosificación , Persona de Mediana Edad , Países Bajos , Servicio Ambulatorio en Hospital , Resultado del Tratamiento
18.
Dermatol Online J ; 16(6): 7, 2010 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-20579462

RESUMEN

Eight cases of the acanthosis nigricans form of epidermal nevus have been described in literature. The present case is impressive and has an extensive segmental distribution. Although etiological factors, such as mutations in the FGFR3 gene, are becoming recognized, treatment options remain limited. We present a case of a 14-year-old male with multiple hyperpigmented, hyperkeratotic plaques on the upper body, axillae, and groin with a segmental distribution following Blaschko lines. Histopathological investigation showed aspects of both acanthosis nigricans and epidermal nevus. So far, screening has not revealed any internal abnormalities. As previous cases show a clear association with internal diseases, repetitive screening for internal diseases and syndromes is suggested in the case of the acanthosis nigricans form of epidermal nevus. Treatment of the condition remains a challenge.


Asunto(s)
Acantosis Nigricans/patología , Nevo/patología , Neoplasias Cutáneas/patología , Acantosis Nigricans/diagnóstico , Acantosis Nigricans/terapia , Adolescente , Antineoplásicos/uso terapéutico , Humanos , Masculino , Nevo/diagnóstico , Nevo/terapia , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapia , Tretinoina/uso terapéutico
19.
J Immunother Cancer ; 7(1): 302, 2019 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-31727154

RESUMEN

BACKGROUND: Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived CD1c+ myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs). METHODS: In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and overall survival. Radiological responses were assessed by MRIs and contrast-enhanced 68Ga-prostate-specific membrane antigen PET/CT, according to RECIST 1.1, PCWG2 criteria and immune-related response criteria. RESULTS: Both tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) antigen specific T cells were detected more frequently in skin biopsies of patients with radiological non-progressive disease (5/13 patients; 38%) compared to patients with progressive disease (0/8 patients; 0%). In these patients with vaccination enhanced dm+ and IFN-γ+ antigen-specific T cells median rPFS was 18.8 months (n = 5) vs. 5.1 months (n = 16) in patients without IFN-γ-producing antigen-specific T cells (p = 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1-2 toxicity. CONCLUSIONS: Immunotherapy with blood-derived DC subsets was feasible and safe and induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with an improved clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02692976, registered 26 February 2016, retrospectively registered.


Asunto(s)
Vacunas contra el Cáncer , Células Dendríticas/inmunología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Anciano , Antígenos de Neoplasias/inmunología , Humanos , Estimación de Kaplan-Meier , Masculino , Proteínas de la Membrana/inmunología , Persona de Mediana Edad , Mucina-1/inmunología , Proteínas de Neoplasias/inmunología , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Piel/inmunología , Linfocitos T/inmunología , Resultado del Tratamiento , Vacunación/efectos adversos
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