RESUMEN
BACKGROUND: This study was part of a Phase 3 program treating crow's feet lines (CFL) with onabotulinumtoxinA. OBJECTIVE: To evaluate the efficacy and safety of onabotulinumtoxinA treatment of CFL. METHODS: This multicenter, double-blind, placebo-controlled, 5-month study randomized subjects with moderate-to-severe CFL (maximum smile) to onabotulinumtoxinA (24 U; n = 222) or placebo (n = 223). Investigators and subjects assessed CFL severity (maximum smile and rest) using the 4-grade Facial Wrinkle Scale (FWS). Co-primary end points were investigator- and subject-assessed proportion of subjects achieving a CFL FWS grade of 0 (none) or 1 (mild) at maximum smile (Day 30). Additional efficacy end points, patient-reported outcomes, and safety/adverse events (AEs) were evaluated. RESULTS: All primary and secondary end points were achieved; statistically significant differences favored onabotulinumtoxinA (p < .001, all comparisons vs placebo). Co-primary responder rates were 66.7% compared with 6.7% for investigator-assessed and 58.1% compared with 5.4% for subject-assessed response (onabotulinumtoxinA group and placebo, respectively; p < .001). A significantly greater proportion of the onabotulinumtoxinA group than placebo group achieved a 1 grade or greater improvement on the FWS (maximum smile and rest assessed by both the investigator and subject; all time points; p < .001). Most AEs were mild or moderate and did not result in discontinuations. CONCLUSION: Treatment of moderate-to-severe CFL with onabotulinumtoxinA was effective and well tolerated.
Asunto(s)
Toxinas Botulínicas Tipo A/uso terapéutico , Envejecimiento de la Piel/efectos de los fármacos , Adulto , Anciano , Toxinas Botulínicas Tipo A/administración & dosificación , Toxinas Botulínicas Tipo A/efectos adversos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Human donor skin allografts are suitable and much used temporary biological (burn) wound dressings. They prepare the excised wound bed for final autografting and form an excellent substrate for revascularisation and for the formation of granulation tissue. Two preservation methods, glycerol preservation and cryopreservation, are commonly used by tissue banks for the long-term storage of skin grafts. The burn surgeons of the Queen Astrid Military Hospital preferentially use partly viable cryopreserved skin allografts. After mandatory 14-day bacterial and mycological culture, however, approximately 15% of the cryopreserved skin allografts cannot be released from quarantine because of positive culture. To maximize the use of our scarce and precious donor skin, we developed a glycerolisation-based recovery method for these culture positive cryopreserved allografts. The inactivation and preservation method, described in this paper, allowed for an efficient inactivation of the colonising bacteria and fungi, with the exception of spore-formers, and did not influence the structural and functional aspects of the skin allografts.
Asunto(s)
Bacterias/efectos de los fármacos , Criopreservación/métodos , Hongos/efectos de los fármacos , Glicerol/farmacología , Trasplante de Piel , Piel/efectos de los fármacos , Piel/microbiología , Humanos , Donantes de Tejidos , Trasplante HomólogoRESUMEN
Since 1987, keratinocytes have been cultured at the Queen Astrid Military Hospital. These keratinocytes have been used routinely as auto and allografts on more than 1,000 patients, primarily to accelerate the healing of burns and chronic wounds. Initially the method of Rheinwald and Green was used to prepare cultured epithelial autografts, starting from skin samples from burn patients and using animal-derived feeder layers and media containing animal-derived products. More recently we systematically optimised our production system to accommodate scientific advances and legal changes. An important step was the removal of the mouse fibroblast feeder layer from the cell culture system. Thereafter we introduced neonatal foreskin keratinocytes (NFK) as source of cultured epithelial allografts, which significantly increased the consistency and the reliability of our cell production. NFK master and working cell banks were established, which were extensively screened and characterised. An ISO 9001 certified Quality Management System (QMS) governs all aspects of testing, validation and traceability. Finally, as far as possible, animal components were systematically removed from the cell culture environment. Today, quality controlled allograft production batches are routine and, due to efficient cryopreservation, stocks are created for off-the-shelf use. These optimisations have significantly increased the performance, usability, quality and safety of our allografts. This paper describes, in detail, our current cryopreserved allograft production process.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Técnicas de Cultivo de Célula/normas , Células Nutrientes/citología , Prepucio/citología , Queratinocitos/citología , Seguridad , Animales , Biopsia , Proliferación Celular , Separación Celular , Células Cultivadas , Prepucio/trasplante , Humanos , Recién Nacido , Queratinocitos/trasplante , Masculino , Ratones , Bancos de Tejidos , Donantes de Tejidos , Trasplante HomólogoRESUMEN
The immunostimulatory capacity of dendritic cells is improved by co-electroporation with mRNA encoding CD40 ligand, constitutively active toll-like receptor 4, and CD70 (TriMix-DC). This pilot clinical trial evaluated the feasibility, safety, and immunogenicity of a therapeutic vaccination containing autologous TriMix-DC co-electroporated with mRNA encoding a human leukocyte antigen class II-targeting signal linked to 1 of 4 melanoma-associated antigens (MAGE-A3, MAGE-C2, tyrosinase, and gp100) in patients with advanced melanoma. Thirty-five American Joint Committee on Cancer stage III/IV melanoma patients received autologous TriMix-DC (4 administrations 2 weeks apart). Immune monitoring was performed by evaluating skin biopsies of delayed type IV hypersensitivity (DTH) reactions for presence of vaccinal antigen-specific DTH-infiltrating lymphocytes (DIL). Thereafter, patients could receive interferon-alpha-2b (IFN-α-2b) 5 MU subcutaneously 3 times weekly and additional TriMix-DC every 8 weeks. TriMix-DC-related adverse events comprised grade 2 local injection site reactions (all patients), and grade 2 fever and lethargy (2 patients). Vaccinal antigen-specific DIL were found in 0/6 patients tested at vaccine initiation and in 12/21 (57.1%) assessed after the fourth vaccine. A positive postvaccination DTH test correlated with IL-12p70 secretion capacity of TriMix-DC. No objective responses to TriMix-DC alone were seen according to RECIST. Twenty-nine patients received IFN-α-2b after the fourth vaccine without unexpected adverse events. During TriMix-DC/IFN-α-2b combination therapy, 1 partial response and 5 stable disease (disease control of >6 months with regression of metastases) were observed in 17 patients with evaluable disease at baseline. In conclusion, this study demonstrated that therapeutic vaccination with autologous TriMix-DC is feasible, safe, and immunogenic and can be combined with sequential IFN-α-2b.
Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Células Dendríticas/inmunología , Quimioterapia Combinada/métodos , Interferón-alfa/administración & dosificación , Melanoma , ARN Mensajero/inmunología , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Ligando CD27/inmunología , Ligando CD27/metabolismo , Antígenos CD40/inmunología , Antígenos CD40/metabolismo , Vacunas contra el Cáncer/administración & dosificación , Células Dendríticas/citología , Células Dendríticas/metabolismo , Electroporación , Femenino , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Hipersensibilidad Tardía/inmunología , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , ARN Mensajero/metabolismo , Proteínas Recombinantes , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismo , VacunaciónRESUMEN
Metastatic melanoma runs a predictable detrimental course in the vast majority of patients. New modalities of immunotherapy, such as melanoma antigen-specific therapeutic vaccination and cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor blockade by monoclonal antibodies (mAbs), have been associated with atypical kinetics of tumor response that differ from those observed during cytotoxic treatment. Recently, new tumor response criteria have been proposed based on the tumor response characteristics observed in clinical studies with ipilimumab (the so-called 'immune-related response criteria'). We report three illustrative cases of the American Joint Committee on Cancer stage IV-M1c melanoma patients who experienced atypical kinetics of tumor response to the treatment with the CTLA-4-blocking mAb, ipilimumab (case 1), or an autologous dendritic cell vaccine in combination with interferon α-2b (cases 2 and 3). These cases show that atypical response patterns not only relate to the outcome of CTLA-4-blocking mAb therapy but also to the treatment with therapeutic vaccines and interferon α-2b.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia/métodos , Melanoma/inmunología , Melanoma/terapia , Adulto , Anciano , Femenino , Humanos , Ipilimumab , Masculino , Melanoma/patología , Melanoma/secundario , Persona de Mediana Edad , Metástasis de la NeoplasiaRESUMEN
Since 1991, the skin bank of the Queen Astrid Military Hospital uses food-grade aluminum foil as a primary support for storing cryo preserved human donor skin (511 donors). The possible release of heavy metals into the cryo preservation media (30% (v/v) glycerol in physiological water) and the possible impact this release could have on the quality of the cryo preserved donor skin was evaluated. Aluminum was the principal detection target. Possible contaminants of the aluminum foil as such (arsenic, cadmium, chromium and lead) were also investigated. The evaluation was set up after a Belgian Competent Authority inspection remark. Aluminum was detected at a concentration of 1.4 mg/l, arsenic and lead were not detected, while cadmium and chromium were detected in trace element quantities. An histological analysis revealed no differences between cryo preserved and fresh donor skin. No adverse reactions in patients, related to the presence of aluminum or heavy metal traces, were reported since the introduction of the cryo preserved donor skin in our burn wound centre.
Asunto(s)
Aluminio/aislamiento & purificación , Criopreservación/métodos , Metales Pesados/aislamiento & purificación , Piel/química , Bancos de Tejidos , Humanos , Piel/ultraestructura , Trasplante de Piel/efectos adversos , Trasplante HomólogoRESUMEN
Melanoma metastases are characterized by pronounced neo-angiogenesis and spontaneous bleeding frequently occurring within central nervous system metastases. Clinically apparent spontaneous hemorrhage within subcutaneous melanoma metastases, however, is a rare event that coincides with progression of such metastases. We report, to our knowledge the first observation, on regression of subcutaneous metastases with hemorrhage of the overlying skin in three patients with stage IV melanoma who participated in clinical trials on therapeutic vaccination. In two patients, loss of arterial flow on Doppler ultrasound imaging was documented in the metastasis at the time of hematoma formation. One patient suffered from an intracranial hemorrhage in a subcentimetric brain metastasis coincident with the hemorrhagic regression of some of his skin metastases.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Neoplasias del Sistema Nervioso Central/secundario , Hemorragia/complicaciones , Melanoma/secundario , Adulto , Neoplasias del Sistema Nervioso Central/irrigación sanguínea , Neoplasias del Sistema Nervioso Central/patología , Progresión de la Enfermedad , Femenino , Humanos , Hemorragias Intracraneales/etiología , Masculino , Melanoma/irrigación sanguínea , Melanoma/terapia , Persona de Mediana Edad , Neovascularización Patológica , Neoplasias Cutáneas/irrigación sanguínea , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , VacunaciónRESUMEN
We describe a case of an HIV-seropositive patient presenting with a severe stomatitis that initially improved with anti-infective agents. Only 13 days after the onset of the stomatitis, the patient developed rapidly progressive constitutional symptoms and a cutaneous eruption. He was diagnosed with a Stevens-Johnson syndrome (SJS) caused by the antiretroviral drug nevirapine (NVP). Despite meticulous supportive care and withdrawal of all drugs, his situation worsened and developed into a toxic epidermal necrolysis (TEN), or Lyell's syndrome, complicated by a toxic hepatitis. Treatment with a novel combination of intravenous immunoglobulins (IVIG) and N-acetylcysteine (NAC) resulted in an exceptionally fast recovery. A literature research revealed no other cases of patients treated with both NAC and IVIG for the combination of TEN and toxic hepatitis. Because of the rapid clinical recovery, this approach merits further investigation. This case report also illustrates the importance of early suspicion of SJS when an HIV-infected patient treated with nevirapine presents with stomatitis.