RESUMEN
In this study, we assessed the role of melanocortin 1 receptor (MC1R) variants and of two patched (PTCH) polymorphisms (c.3944C>T (P1315L), insertion 18 bp IVS1-83) as risk factors for basal cell carcinoma (BCC) in the French population. The population investigated comprised 126 BCC patients who were enrolled on the basis of specific criteria (multiple and/or familial BCC and/or onset before the age of 40 years and/or association with another tumor)--and 151 controls matched for ethnicity, age, and sex. MC1R variants appeared as a moderate risk factor for BCC (odds ratio (OR) for one and two variants, 2.17 [1.28-3.68] and 7.72 [3.42-17.38], respectively), independently of pigmentation characteristics (OR = 2.53 [1.34-4.8]). Interestingly, in addition to the predictable red hair color (RHC) alleles, two non-RHC alleles (V60L and V92M) were also closely associated with BCC risk (OR 3.21 [1.91-5.38] and 2.87 [1.5-5.48], respectively), which differs from the situation in the Celtic population. In addition, the PTCH c.3944C/C genotype was also associated with BCC risk (OR 1.94 [1.2-3.1]), especially in the subgroup of patients with multiple tumors (OR 2.16 [1.3-3.6]). Thus, our data show that MC1R and PTCH variants are associated with BCC risk in the French population. We further suggest that assessing MC1R and PTCH status could be useful, combined with the assessment of clinical risk factors, in identifying high-risk patients to be targeted for prevention or more rigorous surveillance.
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Carcinoma Basocelular/genética , Polimorfismo Genético , Receptor de Melanocortina Tipo 1/genética , Receptores de Superficie Celular/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Basocelular/etnología , Estudios de Casos y Controles , Femenino , Francia/etnología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Color del Cabello , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Receptores Patched , Receptor Patched-1 , Estudios Prospectivos , Receptor de Melanocortina Tipo 1/fisiología , Receptores de Superficie Celular/fisiología , Análisis de Regresión , Factores de Riesgo , Neoplasias Cutáneas/etnología , Población Blanca/genéticaRESUMEN
BACKGROUND: It has been demonstrated that, in patients treated by protease-inhibitor-based regimen, intermittent viraemia occurred frequently and was associated with higher concentrations of residual replication but not with virological failure. Risk factors associated with intermittent viraemia and its impact in patients treated by non-nucleoside-reverse-transcriptase-inhibitor-based (NNRTI) regimen need to be evaluated. METHODS: We analyzed the occurrence of blips (one HIV-1 RNA > 50 copies/ml with a subsequent value < 50 copies/ml), the level of these blips (between 3 and 50 copies/ml) and their effect on CD4 cell count and the occurrence of virological failure in 43 patients with stable suppression of HIV-1 plasma viraemia (< 50 copies/ml) under NNRTI-based therapy. RESULTS: Eight out of 43 patients had one episode of blips during the follow-up (median = 350 copies/ml). Comparing patients with and without blips, the median level of HIV-1 RNA at baseline was 7.5 versus 3 copies/ml (P = 0.008), respectively. Patients with blips had a significantly lower CD4 cell count after 12 and 18 months than the others. Plasma concentrations of NNRTI before, during, and after the blips were adequate. In addition, the occurrence of blips was not associated with virological failure. CONCLUSION: These results suggest that blips may reflect ongoing viraemia of below 50 copies/ml and can impair the CD4 cell count recovery under an NNRTI regimen. The impairment of CD4 cell count recovery seems to be affected more by the occurrence of blips than by the level of viraemia (< 50 copies/ml) itself. Nevertheless, despite a tight genetic barrier for resistance with NNRTI drugs, no virologic failure occurred during the follow-up.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Viremia/etiología , Adulto , Anciano , Alquinos , Benzoxazinas , Recuento de Linfocito CD4 , Ciclopropanos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nevirapina/uso terapéutico , Oxazinas/uso terapéutico , Estudios Retrospectivos , Carga ViralRESUMEN
BACKGROUND: NRTI-induced host toxicity is proposed to involve cellular mitochondrial DNA (mtDNA) depletion. Determinants of cellular mtDNA copy number from HIV-infected patients receiving HAART and HIV-seronegative controls were investigated from subcutaneous fat samples, and relation with antiretroviral regimen was studied. STUDY DESIGN: HIV-infected patients receiving HAART (n = 50), HIV-infected patients not currently under HAART regimen (n = 2) and HIV-seronegative controls (n = 9) of similar age and BMI were enrolled prospectively when undergoing Coleman's lipostructure for correction of facial lipoatrophy or plastic surgery, respectively. After centrifugation, abdominal fat tissue was collected and stored at -80 degrees C. MtDNA analysis was blindly performed after a total DNA extraction from adipose tissue, followed by a real-time PCR quantification. The log of mtDNA copies/cell in adipose tissue [log(DNA)] was compared between groups by means of analysis of variance. RESULTS: The log(DNA) in adipose tissue of HIV-infected patients was significantly lower than in the HIV-seronegative control group (P < 0.0001). In HIV-infected patients, log(DNA) was significantly reduced in the 50 NRTI-treated patients (P < 0.01), but not when considering mtDNA level according to the use of PI or NNRTI in current HAART regimen. In NRTI-treated patients, only stavudine (n = 20) and didanosine (n=14) were significantly and independently associated with reduced mtDNA level (P < 0.0001 and <0.05, respectively). Currently stavudine or didanosine-treated patients had a significant reduced mtDNA level compared to past users (P < 0.0001 and <0.05, respectively). Other clinical, biological, and immuno-virological variables than NRTI did not correlate significantly to adipocyte mtDNA level. CONCLUSION: This study supports that current treatment by NRTI is a main determinant of mtDNA depletion in adipose tissue of HIV-seropositive patients with peripheral fat wasting. Stavudine or didanosine current intake is significantly associated with mtDNA depletion in vivo, that could be reversible after the discontinuation of these molecules, when considering mtDNA level according to current use versus past use of these molecules.
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Tejido Adiposo/patología , Fármacos Anti-VIH/efectos adversos , ADN Mitocondrial/metabolismo , Infecciones por VIH/tratamiento farmacológico , Síndrome de Lipodistrofia Asociada a VIH/inducido químicamente , Inhibidores de la Transcriptasa Inversa/efectos adversos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Adolescente , Adulto , Anciano , ADN Mitocondrial/efectos de los fármacos , Didanosina/efectos adversos , Femenino , Infecciones por VIH/virología , VIH-1 , Humanos , Masculino , Persona de Mediana Edad , Estavudina/efectos adversosRESUMEN
BACKGROUND: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL). Patients with limited patch and/or plaque disease have a normal life expectancy. Neutrophilic dermatosis (ND) may be associated with various hematologic disorders. However, its association with CTCL is exceptional and has been reported only twice with leukemic forms of CTCL. OBSERVATIONS: Three patients with MF developed ND resistant to conventional therapies and responsible for an impaired quality of life due to constitutional symptoms and painful cutaneous lesions. All patients underwent an aggressive treatment course despite their varying initial clinical stages of MF, and all experienced a fatal outcome less than 18 months after the onset of ND. CONCLUSIONS: The association of MF with ND is exceptional and carries a poor prognosis, but the pathophysiologic nature of this association remains unclear. It may involve neutrophil chemoattractant cytokine production by tumor cells. A triggering role of interferon alfa is also possible.
Asunto(s)
Micosis Fungoide/patología , Neoplasias Cutáneas/patología , Síndrome de Sweet/diagnóstico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Biopsia con Aguja , Progresión de la Enfermedad , Resultado Fatal , Humanos , Inmunohistoquímica , Inmunosupresores/uso terapéutico , Linfoma Cutáneo de Células T , Masculino , Persona de Mediana Edad , Micosis Fungoide/complicaciones , Micosis Fungoide/tratamiento farmacológico , Estadificación de Neoplasias , Medición de Riesgo , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/tratamiento farmacológico , Síndrome de Sweet/complicaciones , Síndrome de Sweet/tratamiento farmacológicoRESUMEN
OBJECTIVE: To evaluate the efficiency of Coleman lipostructure in patients infected with human immunodeficiency virus (HIV). DESIGN: Open-label study and survey. SETTING: Ambulatory dermatosurgery department of a university hospital. PATIENTS: Thirty-three consecutive HIV-infected patients undergoing Coleman lipostructure between 2000 and 2001. INTERVENTIONS: Clinical examination, blood tests, and standardized photographs at baseline and 1 year after the lipostructure. MEAN OUTCOME MEASURES: Efficiency was assessed by the agreement of 3 independent medical specialists on facial lipodystrophy improvement after surgery and by patient satisfaction. RESULTS: Facial lipoatrophy was improved in 12 patients (36%; 95% confidence interval, 20%-52%) as judged by all 3 evaluators. Quantity of fat injected (P = .01) and a low serum triglyceride level before surgery (P = .03) were significantly associated with improvement of facial lipoatrophy. Of the 33 patients, 14 (43%) were very satisfied, 17 (50%) were partly satisfied, and 27 (81%) had a better quality of life. The most common comment was that the patient looked better and appeared less ill. CONCLUSION: Our 1-year evaluation of Coleman lipostructure for correction of facial lipoatrophy in HIV-infected patients proved the efficiency of this treatment when measured conservatively by agreement on improvement by 3 independent specialists and demonstrated a patient satisfaction rate of 93%.
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Tejido Adiposo/trasplante , Terapia Antirretroviral Altamente Activa/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Lipodistrofia/inducido químicamente , Lipodistrofia/cirugía , Adulto , Femenino , Humanos , Inyecciones Subcutáneas , Lipodistrofia/patología , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Trasplante Autólogo/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVE: To identify the prognostic factors of bullous pemphigoid (BP). DESIGN: Prospective study of patients with BP included in a randomized, controlled trial. SETTING: Twenty dermatology departments in France. Patients One hundred seventy patients with BP initially treated with a 40-g/d dosage of clobetasol propionate cream (testing sample) and 171 patients initially treated with oral corticosteroids at a dosage of 0.5 or of 1.0 mg/kg per day, depending on the extent of BP (validation samples). MAIN OUTCOME MEASURES: The end point was overall survival during the first year after BP diagnosis. From the testing sample, associations of clinical and biological variables with overall survival were assessed using univariate and multivariate analyses. Selected predictors were included in a prognostic model. To verify that these predictors were not dependent on the treatment used, the model was then validated independently on the 2 series of BP patients treated with oral corticosteroids. RESULTS: Median age of the BP patients included in the testing sample was 83 years. The 1-year Kaplan-Meier survival rate was 74%. From univariate analysis, the main deleterious predictors were demographic factors (ie, older age and female sex), associated medical conditions (ie, cardiac insufficiency, history of stroke, and dementia), and low Karnofsky score, which is a measure of the patient's general condition. No factors directly related to BP, in particular extent of cutaneous lesions, were shown to be related to the patients' prognosis. From multivariate analysis, only older age (P = .02) and low Karnofsky score (P<.001) appeared independently predictive of death. From the Cox model including these 2 predictors, the predicted 1-year survival rates were 90% (95% confidence interval [CI], 85%-96%) for patients 83 years or younger with Karnofsky score greater than 40, 79% (95% CI, 69%-90%) for patients older than 83 years with Karnofsky score greater than 40, 65% (95% CI, 50%-86%) for patients 83 years or younger with Karnofsky score of 40 or less, and 38% (95% CI, 26%-57%) for patients older than 83 years with Karnofsky score of 40 or less. Kaplan-Meier survival distributions of patients from the validation samples appeared clearly separated according to these 4 categories and were in close agreement with corresponding predicted 1-year survival rates obtained from the testing sample. CONCLUSIONS: The prognosis of patients with BP is influenced by age and Karnofsky score. These predictors are easy to use and should facilitate the management of BP.
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Corticoesteroides/uso terapéutico , Causas de Muerte , Clobetasol/uso terapéutico , Penfigoide Ampolloso/diagnóstico , Penfigoide Ampolloso/tratamiento farmacológico , Penfigoide Ampolloso/mortalidad , Administración Oral , Administración Tópica , Análisis de Varianza , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Análisis Multivariante , Valor Predictivo de las Pruebas , Probabilidad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Specific skin lesions are rare in Waldenstrom's macroglobulinemia (WM). We report a case of a 58-year-old man who presented macules, papules, and an erythema of the trunk with the "deck-chair" sign revealing the relapse of WM. Histologic and immunohistochemical examinations confirmed that cutaneous lesions were related to specific infiltration with neoplastic cells. Remission of both skin lesions and immunological abnormalities was obtained with oral cyclophosphamide.
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Antineoplásicos Alquilantes/uso terapéutico , Ciclofosfamida/uso terapéutico , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/patología , Macroglobulinemia de Waldenström/tratamiento farmacológico , Macroglobulinemia de Waldenström/patología , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de la Piel/inmunología , Macroglobulinemia de Waldenström/inmunologíaAsunto(s)
Síndrome Antifosfolípido/inmunología , Inmunoterapia/efectos adversos , Melanoma/terapia , Piel/inmunología , Anticoagulantes/uso terapéutico , Antineoplásicos/efectos adversos , Síndrome Antifosfolípido/tratamiento farmacológico , Síndrome Antifosfolípido/patología , Biopsia , Bloqueadores de los Canales de Calcio/uso terapéutico , Células Dendríticas/inmunología , Células Dendríticas/trasplante , Quimioterapia Combinada , Mano , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Metástasis Linfática , Masculino , Melanoma/inmunología , Melanoma/secundario , Persona de Mediana Edad , Necrosis , Polietilenglicoles/efectos adversos , Proteínas Recombinantes , Piel/patología , Dedos del Pie , Resultado del TratamientoRESUMEN
OBJECTIVE: To determine HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy. METHODS: Twenty-three consecutive HIV-infected patients (median age, 43 years; male:female ratio, 18:5; median CD4 cell count, 419 x 10(6)/l) undergoing Coleman's lipostructure were enrolled prospectively in this study. HIV-1 RNA and plasma concentration of antiretroviral drugs were determined blindly in plasma and adipocyte lysate samples. HIV-1 proviral DNA was detected by nested PCR in fresh frozen adipocytes. RESULTS: Mean plasma HIV-1 RNA was significantly higher than that in adipocyte lysate samples (this was below the limit of detection in all patients tested). HIV-1 proviral DNA was positive in two out of 18 adipocyte samples with a level between 2 and 5 copies; the distribution seemed to be specific and comparable within each therapeutic class--protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). NNRTI concentrations in adipocyte lysates were approximately 100-fold higher than those of PI. Efavirenz may accumulate in fat tissue as a function of treatment duration. CONCLUSION: Our results suggest that HIV does not replicate and does not integrate its genome in fat tissue in patients with fat redistribution abnormalities. In patients with effective nadir plasma concentrations of PI and NNRTI, determination of concentration in adipocyte lysates suggests that PI may diffuse in fat tissue with the same pattern of distribution for all structurally related components tested. NNRTI present a high affinity for fat tissue and may accumulate in this compartment.
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Tejido Adiposo/virología , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Síndrome de Lipodistrofia Asociada a VIH/sangre , Adipocitos/virología , Tejido Adiposo/química , Fármacos Anti-VIH/análisis , Fármacos Anti-VIH/sangre , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Femenino , Infecciones por VIH/sangre , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inhibidores de Proteasas/análisis , ARN Viral/análisisRESUMEN
The aims of this study were to measure Kaposi's sarcoma-associated herpesvirus (KSHV) load in oral mucosa and blood and to determine their relationship with clinical activity of KS in both AIDS-Kaposi's sarcoma (KS) and HIV-unrelated KS patients. Among AIDS patients, KSHV viral load in peripheral blood mononuclear cells (PBMCs) was higher in patients with active KS than in patients with KS in complete remission. In HIV-unrelated KS patients, KSHV viral load in PBMCs was not correlated with clinical stage. Thus, monitoring KSHV viral load in PBMCs could be useful, particularly in the context of HIV infection. In patients with HIV-unrelated KS, KSHV viral load in oral compartments can be very high even in patients with nonactive KS, implying that patients with nonactive KS are still a potential source of transmission of KSHV through oral contact.
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Síndrome de Inmunodeficiencia Adquirida/complicaciones , Herpesvirus Humano 8/aislamiento & purificación , Sarcoma de Kaposi/virología , Síndrome de Inmunodeficiencia Adquirida/sangre , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/virología , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Humanos , Mucosa Bucal/virología , Saliva/virología , Sarcoma de Kaposi/sangreRESUMEN
BACKGROUND: Skin eruptions resembling epidermodysplasia verruciformis (EV) are rarely observed in immunocompromised patients. We focused on the epidemiologic, clinical, virologic, and immunologic features of EV in human immunodeficiency virus (HIV)-positive patients. OBSERVATIONS: We studied 11 HIV-positive patients (6 men and 5 women) with clinical and histological features of EV observed at our department. The median age at HIV diagnosis was 27 years. At the onset of eruption, the median age was 40 years and the median CD4 T-cell count was 170/µL. Clinical presentation included flat warts (n = 11), pityriasis versicolor-like macules (n = 5), and lichenoid papules (n = 3) on sun-exposed skin. Detection and typing of cutaneous human papillomavirus (HPV) were carried out in 8 cases and always revealed ß-HPV infection, including oncogenic HPV-5 or 8 (n = 6). Mucosal HPV-related diseases were present in 7 cases. Histories of skin cancer and lymphoproliferative disorder were recorded in 3 and 4 patients, respectively, including 2 fatal cases. Skin eruption was never improved by highly active antiretroviral therapy (HAART). In 2 cases, EV was associated with an immune reconstitution syndrome. The present series is the largest with a complete characterization. A review of similar cases was carried out. CONCLUSION: Despite effective HAART, HIV-infected patients with EV require a prolonged and careful follow-up to detect mucosal HPV-related diseases, lymphoproliferative disorders, and skin cancers.
Asunto(s)
Terapia Antirretroviral Altamente Activa , Epidermodisplasia Verruciforme/complicaciones , Epidermodisplasia Verruciforme/virología , Infecciones por VIH/complicaciones , Infecciones por Papillomavirus/complicaciones , Adulto , Epidermodisplasia Verruciforme/patología , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Papillomaviridae/genética , Infecciones por Papillomavirus/patología , Piel/patología , Adulto JovenRESUMEN
Superpotent topical corticosteroids (CS) have been demonstrated to improve bullous pemphigoid (BP) patients' survival. We assessed whether a mild regimen using lower doses of topical CS and a shorter duration could improve the outcome of BP patients even more. Three-hundred and twelve BP patients were included in a multicenter randomized controlled trial and stratified depending on the extent of BP as moderate (n=134) or extensive (n=178). Patients were randomly assigned to the standard regimen (clobetasol propionate cream, 40 g per day initially, with CS tapering over 12 months) or the mild regimen (10-30 g per day), with CS tapering over 4 months. A noninferior rate of BP control was obtained with the mild regimen 156/159 (98%) as compared with the standard regimen 150/150 (100%; P=0.005). Event-free survival, that is, the combined outcome of deaths and life-threatening adverse events did not differ between the two treatment groups (P=0.77). However, upon adjusting through the Cox model for age and Karnofsky score, a strong beneficial effect of the mild regimen was observed in patients with moderate BP, with an almost twofold decrease in the risk of death or life-threatening adverse events relative to the standard regimen (hazard ratio=0.54; 95% confidence interval, 0.30-0.97; P=0.039). This mild regimen allows a 70% reduction of the cumulative doses of CS and improves BP patients' outcome.
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Clobetasol/administración & dosificación , Glucocorticoides/administración & dosificación , Penfigoide Ampolloso/tratamiento farmacológico , Administración Tópica , Glándulas Suprarrenales/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Clobetasol/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Glucocorticoides/efectos adversos , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Modelos de Riesgos Proporcionales , Recurrencia , Resultado del TratamientoRESUMEN
BACKGROUND: Four epidemiologic forms of Kaposi's sarcoma have been described, all of which are associated with the human herpesvirus-8. In western countries, human herpesvirus-8 is more prevalent in homosexual men than in the general population, and anecdotal cases of Kaposi's sarcoma in HIV-negative homosexual men have been reported. PATIENTS AND METHODS: We included HIV-negative homosexual and bisexual male patients with histologically proven Kaposi's sarcoma in a retrospective study. Clinical data were collected using a standardized form. Risk factors for human herpesvirus-8 infection and for the development of Kaposi's sarcoma were systematically recorded. RESULTS: Between 1995 and 2007, 28 men met the defined inclusion criteria. Mean age at first symptoms of Kaposi's sarcoma was 53 years. Clinical presentation resembled classical Kaposi's sarcoma, with limited disease in most patients. No cellular or humoral immunodeficiency was observed. Serologic tests for human herpesvirus-8 (latent immunofluorescence assay) were positive in 88% of patients, and only two patients displayed human herpesvirus-8 viremia at the time of Kaposi's sarcoma diagnosis. Three patients developed lymphoproliferative disorders (Castleman disease, follicular lymphoma and Burkitt lymphoma). In this population, alpha-interferon was well tolerated and gave a complete response, but most patients require only local treatment, if any. CONCLUSION: Kaposi's sarcoma may develop in homosexual or bisexual men without HIV infection. This type of Kaposi's sarcoma has clinical features in common with classical Kaposi's sarcoma but occurs in younger patients. Its prognosis is good, as Kaposi's sarcoma is generally limited, but clinicians should be aware of the association with lymphoproliferative diseases, which may affect prognosis.
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Bisexualidad/estadística & datos numéricos , Seronegatividad para VIH , Homosexualidad Masculina/estadística & datos numéricos , Sarcoma de Kaposi/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sarcoma de Kaposi/patologíaRESUMEN
The primary goal of cancer vaccines is to induce CD8+ T cells specific for tumor-associated antigens (TAA) but the characterization of these cells has been difficult because of the low sensitivity of ex vivo assays. Here, we focused on TAA-specific CD8+ T-cell responses in melanoma patients after vaccination with autologous dendritic cells loaded with lysates derived from allogeneic tumor-cell lines (Lysate-DC). Out of 40 patients treated, 16 patients developed immune response to tumor-cell lysate and/or CD8+ T cells specific for differentiation and cancer-testis antigens. TAA-specific CD8+ T-cell responses were detected by interferon (IFN)-gamma enzyme-linked immunospot after in vitro sensitization and were, either transient during the treatment period or delayed, that is, observed after completion of all vaccinations. We could not correlate these immune responses to clinical data as none of the patients achieved an overall objective response according to Response Evaluation Criteria in Solid Tumors criteria. Three patients were reported as stable disease and 10 patients presented evidence of antitumor activity. We found that TAA-specific T cells characterized in 4 patients produced perforin ex vivo, but no IFN-gamma in enzyme-linked immunospot. Differential expression of IFN-gamma and perforin was also observed for viral-specific T cells. Altogether, our results show that Lysate-DC therapy elicited tumor-specific CD8+ T cells nonlimited to human leukocyte antigen-A2+ patients, with some T cells secreting perforin ex vivo and IFN-gamma only after restimulation. The differential expression of perforin and IFN-gamma by antitumor and antiviral CD8+ T cells supports that the sole use of IFN-gamma production to monitor T cells overlooks functional T-cell subpopulations triggered by vaccines.
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Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/trasplante , Melanoma/terapia , Linfocitos T/inmunología , Antígenos Virales/inmunología , Vacunas contra el Cáncer/inmunología , Células Dendríticas/inmunología , Epítopos de Linfocito T/inmunología , Humanos , Interferón gamma/metabolismo , Cinética , Leucocitos Mononucleares/inmunología , Activación de Linfocitos/inmunología , Melanoma/inmunología , Melanoma/patología , Metástasis de la Neoplasia , Perforina/metabolismo , Linfocitos T/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Kaposi sarcoma (KS) occurs mainly in immunocompromised patients and is strongly associated with infection with human herpesvirus 8 (HHV-8; also known as "KS-associated herpesvirus"). We hypothesized that KS is linked to deficiencies in specific anti-HHV-8 T cell immunity. METHODS: We studied asymptomatic HHV-8 carriers coinfected with human immunodeficiency virus (HIV; n = 23) and patients with HIV-related or classic KS (n = 29). We used an interferon- gamma enzyme-linked immunospot assay with 56 specific peptides distributed on 6 HHV-8 proteins (glycoprotein [gp] B, gpH, gp35/37, latent nuclear antigen 1 [LANA-1], K12, and K15) to detect HHV-8-specific T cell responses. RESULTS: We found that patients with KS responded to these peptides less often and had much lower HHV-8-specific T cells counts than did asymptomatic HHV-8 carriers (P = .001 and P = .0004, respectively), regardless of CD4 T cell count or HHV-8 load. The frequency of Epstein-Barr virus-specific T cells was similar in both groups. CONCLUSIONS: Our results suggest that HIV-related and classic KS are associated with a lack of HHV-8-specific T cells. Also, we have described 8 new HHV-8 T cell epitopes in LANA-1, K12, and K15, including 2 CD4 T cell epitopes. These data provide new insight into HHV-8 cellular immunity.
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Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Herpesvirus Humano 8/inmunología , Sarcoma de Kaposi/inmunología , Linfocitos T/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/virología , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Linfocito CD4 , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sarcoma de Kaposi/virología , Carga ViralRESUMEN
To assess the clinical benefit of rituximab for HIV-associated Castleman disease, 5 patients infected with HIV with histologic-proven Castleman disease were prospectively enrolled to receive 4 infusions of rituximab. Clinical and biologic parameters (C-reactive protein, CD19 cell count, Kaposi sarcoma-associated herpesvirus [KSHV] viral load in peripheral blood mononuclear cells) were assessed before and at different time points following rituximab infusions. Two patients died very quickly after the beginning of rituximab therapy with no effect on both KSHV viral load and CD19 cell count. Three of 5 patients were considered in complete remission with no more clinical symptoms related to Castleman disease with a follow-up of 4 to 14 months. In 2 cases, clinical remission correlated with a dramatic decrease of KSHV viral load and C-reactive protein levels and a transitory but sharp decrease of CD19 cell count. In 2 responders, we observed an aggravation of Kaposi sarcoma. Our preliminary results suggest that rituximab may be effective in controlling Castleman disease in a subset of patients, although it may exacerbate concomitant Kaposi sarcoma.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Enfermedad de Castleman/tratamiento farmacológico , Infecciones por VIH/complicaciones , Adulto , Anticuerpos Monoclonales de Origen Murino , Antígenos CD19/sangre , Proteína C-Reactiva/biosíntesis , Antígenos CD4/sangre , ADN Viral/sangre , Femenino , Herpesvirus Humano 8/metabolismo , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Inducción de Remisión , Rituximab , Factores de Tiempo , Resultado del TratamientoRESUMEN
To assess the relationship between antiretroviral drug exposure and lipodystrophy, 69 human immunodeficiency virus type 1-infected patients receiving nelfinavir were investigated cross-sectionally. Lipodystrophy was defined by patients' self-report. Nelfinavir trough concentrations in plasma were significantly related to overall lipodystrophy and peripheral fat wasting scores and appeared to be an independent risk factor for lipodystrophy