RESUMO
An 88-year-old Inuit man from Northern Canada presented with an extensive skin rash associated with numerous violaceous skin nodules on his palms and lower extremities. Biopsy of a skin nodule revealed Kaposi's sarcoma (KS), a human herpesvirus 8 (HHV8)-associated malignancy, whereas biopsy of the erythematous skin showed an atypical infiltrate of CD4-positive T-cells that, together with TCR gene rearrangement and presence of clonal T-cells in peripheral blood by flow cytometry, was consistent with a T-cell lymphoma, mycosis fungoides (MF) subtype. Serology was negative for HIV and HTLV-I/II and no immunodeficiency syndrome was identified. The patient was successfully treated with an oral retinoid for KS, and with topical hydrocortisone and ultraviolet B (UVB) phototherapy for MF. This case highlights the existence of HHV8-related lesions in native persons of Northern Canada, and also that MF-induced immunosuppression combined with immunosenescence may play a role in the development of non-HIV-related KS.
Assuntos
Inuíte , Micose Fungoide/patologia , Neoplasias Primárias Múltiplas/patologia , Sarcoma de Kaposi/patologia , Neoplasias Cutâneas/patologia , Acitretina/uso terapêutico , Administração Cutânea , Idoso de 80 Anos ou mais , Anti-Inflamatórios/uso terapêutico , Herpesvirus Humano 8 , Humanos , Hidrocortisona/uso terapêutico , Hospedeiro Imunocomprometido , Imunossenescência , Masculino , Micose Fungoide/imunologia , Micose Fungoide/terapia , Neoplasias Primárias Múltiplas/imunologia , Neoplasias Primárias Múltiplas/terapia , Sarcoma de Kaposi/tratamento farmacológico , Sarcoma de Kaposi/etnologia , Sarcoma de Kaposi/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Terapia Ultravioleta/métodosRESUMO
BACKGROUND AND PURPOSE: Kaposi's sarcoma-associated herpes virus (KSHV) vIL-6 is sufficient to induce lymphatic reprogramming of vascular endothelial cells, which is a key event in Kaposi's sarcoma (KS) development. This study was aimed to investigate the effect of Chinese herb oroxylin A on lymphatic reprogramming and neovascularization by KSHV vIL-6 in vitro and in vivo. METHODS: The lymphatic-phenotype endothelial cell line was generated by lentiviral KSHV vIL-6 infection. Cell viability and apoptosis were determined by MTT assay or flow cytometry with annexin V/propidium iodide staining. Migration, invasion, and neovascularization of the vIL-6-expressing lymphatic-phenotype endothelial cells were determined by wound healing assay, transwell chamber assay, microtubule formation assay, and chick chorioallantoic membrane assay, respectively. Quantitative polymerase chain reaction and Western blot analysis were used to test the expression of Prox1, VEGFR3, podoplanin, LYVE-1, and PPARγ in cells. Co-localization of Prox1 and PPARγ was determined by immunofluorescence. Ubiquitination of Prox1 was detected by in vivo ubiquitination assay. RESULTS: The lymphatic-phenotype endothelial cell line expressing KSHV vIL-6 was successfully generated. Oroxylin A induced cellular invasion abrogation, apoptosis induction, and neovascularization inhibition of the vIL-6-expressing endothelial cells. Mechanically, oroxylin A elevated PPARγ expression, which in turn interacted with and facilitated Prox1 to undergo ubiquitinational degradation, and subsequently leads to VEGFR3, LYVE-1, and podoplanin reduction. CONCLUSION: Through modulating PPARγ/Prox1 axis, oroxylin A inhibits lymphatic reprogramming and neovascularization of KSHV vIL-6. Thus, oroxylin A may serve as a candidate for the treatment of KS as well as other aggressive angiomas.
Assuntos
Reprogramação Celular , Células Endoteliais/efeitos dos fármacos , Flavonoides/farmacologia , Herpesvirus Humano 8/efeitos dos fármacos , PPAR gama/imunologia , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/virologia , Animais , Diferenciação Celular , Linhagem Celular , Embrião de Galinha , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/imunologia , Humanos , Interleucina-6/imunologia , Neovascularização Patológica/imunologia , Transdução de Sinais , Fatores de TranscriçãoRESUMO
Abstract The association of mycosis fungoides and kaposi’s sarcoma in HIV-negative patients is a rare phenomenon. The presence of human herpesvirus 8 (HHV-8) – associated with all forms of Kaposi’s sarcoma – has also been recently identified in mycosis fungoides lesions. However, a causal association between HHV-8 and the onset of mycosis fungoides has not been established yet. The present case reports a patient who developed Kaposi’s sarcoma lesions after a two-year UVB phototherapy to treat a mycosis fungoides. Negative immunohistochemistry staining for Kaposi’s sarcoma-associated herpesvirus in the initial mycosis fungoides lesions strengthens the absence of a link between Kaposi’s sarcoma-associated herpesvirus and mycosis fungoides. Immunosuppression caused by the lymphoma and prolonged phototherapy were probably the contribut ing factors for the onset of Kaposi’s sarcoma.
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/virologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/virologia , Micose Fungoide/complicações , Micose Fungoide/patologia , Fototerapia , Sarcoma de Kaposi/imunologia , Pele/patologia , Pele/virologia , Neoplasias Cutâneas/imunologia , Biópsia , Imuno-Histoquímica , Terapia de Imunossupressão , Micose Fungoide/terapia , Herpesvirus Humano 8/isolamento & purificaçãoRESUMO
The association of mycosis fungoides and kaposi's sarcoma in HIV-negative patients is a rare phenomenon. The presence of human herpesvirus 8 (HHV-8) - associated with all forms of Kaposi's sarcoma - has also been recently identified in mycosis fungoides lesions. However, a causal association between HHV-8 and the onset of mycosis fungoides has not been established yet. The present case reports a patient who developed Kaposi's sarcoma lesions after a two-year UVB phototherapy to treat a mycosis fungoides. Negative immunohistochemistry staining for Kaposi's sarcoma-associated herpesvirus in the initial mycosis fungoides lesions strengthens the absence of a link between Kaposi's sarcoma-associated herpesvirus and mycosis fungoides. Immunosuppression caused by the lymphoma and prolonged phototherapy were probably the contribut ing factors for the onset of Kaposi's sarcoma.
Assuntos
Micose Fungoide/complicações , Micose Fungoide/patologia , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/virologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/virologia , Biópsia , Herpesvirus Humano 8/isolamento & purificação , Humanos , Imuno-Histoquímica , Terapia de Imunossupressão , Masculino , Pessoa de Meia-Idade , Micose Fungoide/terapia , Fototerapia , Sarcoma de Kaposi/imunologia , Pele/patologia , Pele/virologia , Neoplasias Cutâneas/imunologiaAssuntos
Síndrome da Imunodeficiência Adquirida/complicações , Hipopigmentação/radioterapia , Lasers de Estado Sólido/uso terapêutico , Terapia com Luz de Baixa Intensidade , Sarcoma de Kaposi/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , Antivirais/uso terapêutico , Contagem de Linfócito CD4 , Humanos , Hipopigmentação/imunologia , Hipopigmentação/patologia , Masculino , Pessoa de Meia-Idade , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Vincristina/uso terapêuticoRESUMO
OBJECTIVE: We aim to report a case of Kaposi sarcoma (KS) with Cushing's syndrome caused by endogenic glucocorticoid-induced immunosuppression. CLINICAL PRESENTATION: A 43-year-old woman presented with delirium, hirsutism, fatigue, and hypertension. At the time of presentation, physical findings showed a Cushingoid appearance, with moon-like facies, hirsutism, and hyperpigmentation. Laboratory findings showed the following: adrenocorticotropic hormone, 86.7 pg/mL (normal range, 0-46 pg/mL); baseline cortisol level, 50 microg/dL (normal range, 6.2-19 microg/dL); potassium, 2.2 mEq/L (normal range, 3.5-5 mEq/L); and midnight cortisol level, 33 microg/dL. Serum cortisol levels failed to suppress after low and high doses of dexamethasone; these findings confirmed the diagnosis of ectopic adrenocorticotropic hormone production. Magnetic resonance imaging revealed a 12 x 15-mm, round, hypothalamic mass lesion in the center of the median eminence. INTERVENTION: Endoscopic biopsy from the floor of the third ventricle was performed, and pathological examination of the lesion showed a diffuse adrenocorticotropic hormone-secreting adenoma. The patient developed diffuse skin lesions that were proven to be a KS by skin biopsy while she was prepared for transcranial surgery. After surgical removal of the adenoma, she became hypocortisolemic and required cortisol replacement. Within 1 month after surgery, all KS lesions disappeared spontaneously. CONCLUSION: Excessive cortisol may induce immunosuppression. KS is one of the most common malignant tumors of patients with immunosuppression. To the best of our knowledge, this is the first case of Cushing's syndrome with KS caused by endogenous glucocorticoid-induced immunosuppression.
Assuntos
Síndrome de ACTH Ectópico/imunologia , Adenoma/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Neoplasias Hipotalâmicas/metabolismo , Neoplasias Hipofisárias/metabolismo , Sarcoma de Kaposi/imunologia , Síndrome de ACTH Ectópico/patologia , Síndrome de ACTH Ectópico/fisiopatologia , Adenoma/patologia , Adenoma/cirurgia , Hormônio Adrenocorticotrópico/sangue , Adulto , Coristoma/patologia , Coristoma/fisiopatologia , Coristoma/cirurgia , Síndrome de Cushing/complicações , Síndrome de Cushing/imunologia , Síndrome de Cushing/fisiopatologia , Feminino , Humanos , Hidrocortisona/sangue , Neoplasias Hipotalâmicas/patologia , Neoplasias Hipotalâmicas/cirurgia , Hipotálamo/metabolismo , Hipotálamo/patologia , Hipotálamo/cirurgia , Tolerância Imunológica/imunologia , Hospedeiro Imunocomprometido/imunologia , Imageamento por Ressonância Magnética , Eminência Mediana/metabolismo , Eminência Mediana/patologia , Eminência Mediana/cirurgia , Procedimentos Neurocirúrgicos , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/fisiopatologia , Resultado do TratamentoRESUMO
OBJECTIVES: (1) To determine the safety and feasibility of repetitive reinfusions of activated autologous CD8 cells followed by low-dose continuous interleukin (IL)-2 infusion in patients with AIDS. (2) To study the relationships between clinical responses, surface marker phenotypic distributions and cytokine expression patterns of both cultured CD8 cells and lymphocytes in the peripheral blood compartment. DESIGN: Six adult patients with Centers for Disease Control and Prevention group IV HIV-1 disease ranging from mild to severe, were studied. All patients were receiving zidovudine prior to and during the study period, and had initial CD4 and CD8 cell counts > 50 and 200 x 10(6)/l, respectively. METHODS: Autologous CD8 T cells (10(8)-10(10)) were reinfused five times after ex vivo culture and stimulation with phytohemagglutinin and recombinant (r) IL-2. The fifth such infusion was followed by 5 days of rIL-2 infusion. Phenotypes and cytokine expression patterns of the expanded cells were determined as well as serum levels of immune mediators throughout the study. RESULTS: Patients showed stable CD4 and CD8 cell counts, p24 antigenemia, and minimal toxicity over the 24-week protocol study. Clinical improvement was observed in lymphadenopathy (six out of six), oral hairy leukoplakia (three out of four), and Kaposi's sarcoma (KS; two out of two) in the patients studied. In vivo induction of detectable levels of bioactive acid-stable interferon (IFN)-alpha, but not of other cytokines studied, upon activated CD8 cell reinfusion was associated consistently with improvement of oral hairy leukoplakia. However, partial regression of KS was observed after the CD8 cell infusion cycles and without IFN-alpha induction. In one of the two patients studied, KS regression was associated with decreased IL-1 alpha serum levels. In the other patient, who had failed previous IFN-alpha therapy, KS regression was observed after a decline in reinfused CD8 cell-associated gene expression of tumor necrosis factor (TNF)-beta. Both IL-1 alpha and TNF-beta are growth factors for KS cells. CONCLUSIONS: These observations demonstrate the feasibility and safety of ex vivo CD8 cell activation, expansion, and reinfusion, and rIL-2 infusion in AIDS patients. The findings in this Phase I trial suggest potential clinical efficacy and encourage Phase II trials. The correlations obtained between clinical and immunological states could contribute to an understanding of the relationship between CD8 T-cell function and HIV-1-associated disease progression.
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva , Interleucina-2/uso terapêutico , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/terapia , Antígenos CD/análise , Transfusão de Sangue Autóloga , Citotoxicidade Imunológica , Feminino , Antígenos HLA-DR/análise , Humanos , Infusões Intravenosas , Interleucina-2/administração & dosagem , Transfusão de Linfócitos , Linfotoxina-alfa/biossíntese , Masculino , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/terapiaRESUMO
Ten Caucasian males with HIV-related Kaposi's sarcoma, a disseminated disease which is refractory to usual therapies, underwent a single session of systemic hyperthermia with maintenance of core temperatures at 42 degrees C for 1 h. One complete remission and 7 partial remissions were identified when assessed 30 days post-treatment. Two mixed responses were noted in patients whose tumors showed autocrine growth. At 60 days 2 of the 7 partial responders began to show tumor progression. The complete remission persisted at 120 days. Surrogate markers of HIV activity fell in all responding patients. In no patient was there evidence of HIV activation. No adverse effects of heating were noted on CMV retinitis. Hairy leukoplakia resolved with heating in all patients. CD4 counts showed no appreciable change in any of the 8 patients with a presenting CD4 count below 60. In the 2 patients who presented with a CD4 count above 400, CD4 counts rose dramatically following treatment. No deaths were noted in this phase I study. The use of systemic hyperthermia in treatment of HIV-related illness warrants further study.