RESUMO
We report a rare case of confirmed early neurosyphilis with serofast state in HIV-negative patient, with uncontrolled type 2 diabetes mellitus. Syphilitic meningitis was diagnosed initially on serology and cerebrospinal fluid (CSF) analysis. The patient had persistently raised non-treponemal titres on serum with negative CSF venereal disease research laboratory result, following treatment during 3 years of follow-up.
Assuntos
Neurossífilis , Humanos , Neurossífilis/diagnóstico , Neurossífilis/tratamento farmacológico , Neurossífilis/complicações , Masculino , Treponema pallidum/isolamento & purificação , Treponema pallidum/imunologia , Diabetes Mellitus Tipo 2/complicações , Antibacterianos/uso terapêutico , Pessoa de Meia-Idade , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/líquido cefalorraquidianoRESUMO
FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.
Assuntos
Células Matadoras Naturais , Proteínas de Membrana , Animais , Feminino , Humanos , Masculino , Camundongos , Linfócitos B/metabolismo , Linfócitos B/citologia , Medula Óssea/metabolismo , Linhagem da Célula , Células Dendríticas/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/imunologia , Células de Langerhans/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Monócitos/metabolismo , Pele/metabolismo , Camundongos Endogâmicos C57BLAssuntos
Infecções por Papillomavirus , Lesões Intraepiteliais Escamosas , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Masculino , Humanos , Feminino , Estudos Retrospectivos , Displasia do Colo do Útero/patologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , PapillomaviridaeRESUMO
Sarcoidosis is a systemic disease that affects the skin in about 25% of patients. The treatment of cutaneous sarcoidosis is guided by the extent of lesions, associated symptoms and organ involvement. To evaluate rates of response to various potential first-line treatments for cutaneous sarcoidosis during the year following treatment initiation. This retrospective multicentre study included 120 patients with cutaneous sarcoidosis. Treatment response was assessed retrospectively from the patients' medical records. Univariate logistic regression analysis, with an estimation of unadjusted odds ratios (OR) and their 95% CI ,was performed to identify factors associated with complete cutaneous remission (CR), followed by multivariate logistic regression analysis. At one year, 43 of the 120 (36%) included patients had CR. The best response rates were obtained with oral corticosteroids (12/21, 57%), followed by a combination of hydroxychloroquine and topical steroids (6/13, 46%). In multivariate analysis, lupus pernio was the only predictor of a poor cutaneous response. We suggest the use of a combination of hydroxychloroquine and topical steroids as an optimal first-line treatment for cutaneous sarcoidosis, given the known adverse effects of systemic corticosteroids.
Assuntos
Sarcoidose , Dermatopatias , Humanos , Estudos Retrospectivos , Hidroxicloroquina/uso terapêutico , Dermatopatias/patologia , Sarcoidose/patologia , Corticosteroides/uso terapêutico , EsteroidesRESUMO
OBJECTIVES: Immunoglobulin A vasculitis (IgAV) is a small-vessel vasculitis most frequently benign in children while more severe in adults. We aimed to study the impact of age on presentation and outcome of adult IgAV. METHODS: We conducted a nationwide retrospective study including 260 IgAV patients. Patients were divided into four quartiles according to the age at IgAV diagnosis: <36, 36 ≤ age < 52; 52 ≤ age < 63 and ≥63 years. Comparison of presentation and outcome were performed according to age of disease onset. RESULTS: Mean age at diagnosis was 50.1 (18) years and 63% were male. IgAV diagnosed in the lowest quartile of age was associated with more frequent joint (P < 0.0001) and gastrointestinal involvement (P = 0.001). In contrast, the oldest patients had more severe purpura with necrotic lesions (P = 0.001) and more frequent renal involvement (P < 0.0001), with more frequent haematuria, renal failure, higher urine protein excretion and more frequent tubulointerstitial lesions. Patients were treated similarly in all groups of age, and clinical response and relapse rates were similar between groups. In the 127 treated patients with follow-up data for >6 months, clinical response and relapse rates were similar between the four groups. Median follow-up was of 17.2 months (9.1-38.3 months). Renal failure at the end of follow-up was significantly more frequent in the highest quartile of age (P = 0.02), but the occurrence of end-stage renal disease was similar in all groups. Last, overall and IgAV-related deaths were associated with increase in age. CONCLUSION: Aging negatively impacts the severity and outcome of IgAV in adults. Younger patients have more frequent joint and gastrointestinal involvement, while old patients display more frequent severe purpura and glomerulonephritis.
Assuntos
Envelhecimento/imunologia , Imunoglobulina A , Falência Renal Crônica/etiologia , Vasculite/diagnóstico , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Falência Renal Crônica/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Retrospectivos , Vasculite/imunologiaAssuntos
Neoplasias do Ânus/virologia , Neoplasias Primárias Múltiplas/virologia , Infecções por Papillomavirus/complicações , Lesões Intraepiteliais Escamosas/virologia , Neoplasias do Colo do Útero/virologia , Neoplasias Vaginais/virologia , Neoplasias Vulvares/virologia , Adolescente , Adulto , Idoso , Neoplasias do Ânus/patologia , Feminino , Humanos , Hospedeiro Imunocomprometido , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/patologia , Estudos Retrospectivos , Fumar , Lesões Intraepiteliais Escamosas/patologia , Neoplasias do Colo do Útero/patologia , Neoplasias Vaginais/patologia , Neoplasias Vulvares/patologia , Adulto JovemRESUMO
OBJECTIVE: IgA vasculitis (IgAV) frequently occurs during or after a mucosal infection; it also rarely occurs in patients with cancer. We hypothesized that cancer could impact the baseline characteristics and/or outcome of vasculitis. We aimed to describe the presentation of IgAV in patients with cancer (IgAV ca+) compared to patients without cancer. METHODS: We conducted a nationwide retrospective study of adult patients in France who presented with both IgAV and cancer. Baseline characteristics were described and compared with those of the 260 patients included in a nationwide French IgAV study. RESULTS: Thirty patients were included. The mean age was 69 ± 12 years; 80% were men. Compared to patients without underlying cancer, IgAV ca+ patients were older (69 ± 12 vs. 50 ± 18 years; p < 0.0001) and they presented more frequently with necrotic purpura (53 vs. 26%; p < 0.002) and intra-alveolar hemorrhage (10 vs. 0.5%; p < 0.0001). IgAV ca+ patients frequently had elevated serum IgA levels (79 vs. 53%; p < 0.034); most (n = 22, 73%) had adenocarcinoma or urothelial carcinoma involving the large intestines (n = 6), bladder (n = 5), and lung (n = 5). Most IgAV ca+ patients had progressive cancer (n = 21); a minority had metastatic disease (n = 2) at IgAV diagnosis. After a median follow-up of 3 months, 8 deaths were observed but none was related to IgAV. CONCLUSION: Compared to their noncancer counterpart, patients with IgAV related to cancer were older and more frequently presented with necrotizing purpura, intra-alveolar hemorrhage, and elevated serum IgA levels. Adult patients with IgAV and these latter characteristics should be carefully screened for cancer. Key Points ⢠Clinical and biological characteristics of patients presenting with IgAV are distinct depending on the underlying cause of vasculitis related to cancer. ⢠Patients with IgAV related to cancer are older, and compared to their counterparts without IgAV, they present more frequently with necrotic purpura, alveolar hemorrhage, and elevated serum IgA levels. ⢠All adult patients with IgAV should be screened for cancer, and there should be a focus on elderly male patients presenting with necrotic purpura and/or alveolar hemorrhage.
Assuntos
Vasculite por IgA , Neoplasias , Vasculite , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , França/epidemiologia , Humanos , Imunoglobulina A , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/epidemiologia , Estudos Retrospectivos , Vasculite/complicações , Vasculite/epidemiologiaRESUMO
Benzathine penicillin G (BPG) is the reference treatment for early syphilis, but shortages have recently been reported, highlighting a need for the validation of alternative treatments. The aim of this study was to evaluate the genomic resistance of Treponema pallidum subspecies pallidum (TPA) to macrolides and doxycycline in France. Swabs from genital, anal, oral and cutaneous lesions were obtained from 146 patients with early syphilis in France. They were screened for mutations conferring resistance to macrolides and doxycycline by nested PCR and sequencing. Resistance to macrolides was detected in 85% of the isolates, but no point mutations conferring doxycycline resistance were detected. These findings confirm that, in France, resistance to macrolides is widespread. Moreover, we confirmed the absence of genomic resistance to doxycycline in the TPA strains. Therefore, doxycycline could be safely recommended as an alternative to BPG for the treatment of early syphilis.
Assuntos
Sífilis , Treponema pallidum , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana/genética , França/epidemiologia , Globo Pálido , Humanos , Sífilis/diagnóstico , Sífilis/tratamento farmacológico , Sífilis/epidemiologia , Treponema pallidum/genéticaRESUMO
Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)-producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Neuropatias Diabéticas/metabolismo , Receptores X do Fígado/metabolismo , NADPH Oxidase 4/metabolismo , Células de Schwann/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatias Diabéticas/etiologia , Feminino , Humanos , Hidrocarbonetos Fluorados/farmacologia , Receptores X do Fígado/agonistas , Masculino , Camundongos , Proteínas da Mielina/genética , NADPH Oxidase 4/antagonistas & inibidores , Pirazóis/farmacologia , Pirazolonas , Piridinas/farmacologia , Piridonas , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Sulfonamidas/farmacologiaRESUMO
BACKGROUND: Programmed cell death protein-1 (PD-1) inhibitors (pembrolizumab and nivolumab) have been approved for the treatment of advanced melanoma. Over the past decades, patients older than 85 years represent an expanding group of patients in developed countries. In France, 25% of melanomas are diagnosed in patients older than 75 years. OBJECTIVE: To perform a monocentric retrospective study of patients older than 85 years and treated with pembrolizu-mab for unresectable or metastatic melanoma in order to evaluate tolerance and potential benefits of this immunotherapy. METHODS: Medical records of patients treated with the PD-1 inhibitor pembrolizumab between January 2015 and January 2018 were reviewed. RESULTS: Nine patients (6 women and 3 men) older than 85 years were included in the study. The mean age was 89.6 (85-97) years at inclusion. All patients were PS 0 or 1. The mean number of infusions was 4 (1-12). However, most patients were not able to tolerate the 4-infusion schedule. One patient refused the second infusion for personal reasons. Seven patients had grade 3 or 4 treatment-related adverse events. CONCLUSION: These results indicate that pembrolizumab treatment in patients older than 85 years may induce responses but is associated with a high risk of toxicity and impaired autonomy.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Melanoma/tratamento farmacológico , Segurança do Paciente , Neoplasias Cutâneas/tratamento farmacológico , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Tolerância a Medicamentos , Feminino , Seguimentos , Avaliação Geriátrica , Humanos , Infusões Intravenosas , Masculino , Melanoma/diagnóstico , Melanoma/mortalidade , Estudos Retrospectivos , Medição de Risco , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: Data on adult IgA vasculitis (Henoch-Schönlein) (IgAV) are scarce. This survey was designed to better define the clinical spectrum of IgAV and efficacy of treatments in a French patient population. METHODS: Data on clinical characteristics, histologic features, and treatment response from 260 patients with IgAV included in a French multicenter retrospective survey were analyzed. Efficacy data were compared using different statistical models. RESULTS: The mean ± SD age of the patients with IgAV at diagnosis was 50.1 ± 18 years, and 63% of patients were male. Baseline manifestations included purpura (100%), arthralgias/arthritis/myalgia (61%), glomerulonephritis (70%), and/or gastrointestinal involvement (53%). Thirty percent of patients showed renal failure at baseline. In univariate analysis, the response to therapy was 80% (64 of 80) in patients treated with corticosteroids (CS) alone, compared to 77% (23 of 30) in patients treated with CS plus cyclophosphamide (CYC) and 59% (10 of 17) in patients treated with colchicine (P = 0.17). Multivariable analysis showed that treatment with CS or CS plus CYC was more effective than colchicine in achieving a response. Efficacy differences were demonstrated using different statistical models: in the multivariable logistic regression model, odds ratio (OR) 3.68, 95% confidence interval (95% CI) 1.10-12.33 (P = 0.03); in the inverse probability weighting on propensity score model, OR 3.75, 95% CI 1.28-10.99 (P = 0.02). The efficacy of CS plus CYC as compared to CS alone was discordant according to the analytic method used. Analysis with the multivariable logistic regression model did not demonstrate a difference between CS plus CYC and CS alone (OR 0.88, 95% CI 0.29-2.67; P = 0.82). In contrast, inverse probability weighting on propensity score showed that CS plus CYC was more effective than CS alone (OR 1.79, 95% CI 1.00-3.20; P = 0.049). CONCLUSION: This series constitutes the largest series of adults with IgAV reported in the literature so far. It provides data on clinical and histologic presentation and therapeutic efficacy, suggesting that CS alone appears to be a reasonable first-line therapy in patients with IgAV, while the benefit of adding CYC to CS remains uncertain.
Assuntos
Antirreumáticos/uso terapêutico , Vasculite por IgA/tratamento farmacológico , Vasculite por IgA/patologia , Corticosteroides/uso terapêutico , Adulto , Idoso , Artralgia/epidemiologia , Artralgia/etiologia , Colchicina/uso terapêutico , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Feminino , França/epidemiologia , Gastroenteropatias/epidemiologia , Gastroenteropatias/etiologia , Glomerulonefrite por IGA/epidemiologia , Glomerulonefrite por IGA/etiologia , Humanos , Vasculite por IgA/complicações , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pontuação de Propensão , Estudos Retrospectivos , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors. Sarcopenic obesity is associated with increased acute toxicity of cytotoxic agents and targeted therapies. We explored whether body composition also influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in melanoma patients. This is a monocentric, retrospective study analyzing toxicity outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab. Various parameters linked to the patient or the disease status have been analysed. Body mass index (BMI; kg/m2) and muscle mass using CT were measured prior to treatment initiation. Chi-squared test and Mann-Whitney's tests were used for the comparison of categorical and continuous variables respectively. Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21 nivolumab), 38 (56%) patients had a BMI ≥ 25 kg/m2 and 11 (16%) a BMI ≥ 30, while 13 (19%) had both sarcopenia and a BMI ≥ 25 kg/m2. For the 11 (16%) patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7 kg/m2; p = 0.04). Among the 32 female patients, sarcopenic overweight patients had a 6.5-fold increased risk of ALT (50 versus 7.7%; p = 0.01). Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Melanoma/tratamento farmacológico , Sobrepeso , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sarcopenia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe , Sobrepeso/tratamento farmacológico , Estudos Retrospectivos , Sarcopenia/tratamento farmacológico , Adulto JovemRESUMO
Cutaneous squamous cell carcinoma (cSCC) is a frequent side-effect of vemurafenib treatment. The main aim of this study was to identify the clinical risk factors associated with the development of cSCC in melanoma patients treated with vemurafenib. We carried out a retrospective study, including 63 consecutive melanoma patients treated with vemurafenib for BRAF-mutant metastatic melanoma in an oncodermatological department. Clinical and follow-up data were collected and analysed, and a comparison of the subgroups who did and did not develop cSCC was performed. A total of 42.9% of patients (n=27) treated with vemurafenib developed one or more cSCC. Patients with cSCC were significantly older (P=0.01). Clear eyes were also associated with a higher risk of developing cSCC (odds ratio=3.50; 95% confidence interval: 1.08-12.43). Three patients developed cSCC more than 1 year after the initiation of treatment (12, 16 and 18 months, respectively). Clinicians should be vigilant in older patients undergoing vemurafenib therapy as well as patients with clear eyes as they seem to be at increased risk of developing cSCC, even late after the initiation of treatment.
Assuntos
Agonistas alfa-Adrenérgicos/efeitos adversos , Carcinoma de Células Escamosas/etiologia , Indóis/efeitos adversos , Melanoma/complicações , Nafazolina/efeitos adversos , Neoplasias Cutâneas/etiologia , Sulfonamidas/efeitos adversos , Fatores Etários , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Indóis/farmacologia , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Neoplasias Cutâneas/patologia , Sulfonamidas/farmacologia , VemurafenibAssuntos
Antineoplásicos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Imunoterapia/métodos , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Vaginais/terapia , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Humanos , Mesilato de Imatinib/administração & dosagem , Infusões Intravenosas , Ipilimumab , Melanoma/diagnóstico , Melanoma/patologia , Resultado do Tratamento , Neoplasias Vaginais/diagnóstico , Neoplasias Vaginais/patologiaRESUMO
Given the NK cell-based immunosurveillance of melanoma, we investigated the prognostic value of NKp46 transcript and NKp30 isoform (NKp30A, NKp30B and NKp30C) profiling in blood of 187 melanoma patients including 13 long survivors (LS), metastatic patients that have controlled the disease. Compared to healthy volunteers (HV), patients had reduced amounts of transcripts of the three NKp30 isoforms (NKp30 A, B and C) but similar ratios between NKp30 isoforms (ΔAB, ΔAC, ΔBC). Stratification of patients according to disease stage showed higher NKp30C and lower NKp46 transcripts in stage IV patients. Furthermore, patients with previous history of conventional chemotherapy displayed reduced NKp30A transcripts. The expression levels of NKp30 isoforms failed to predict survival from sampling of patients, while NKp46 expression predicted melanoma outcome. LS patients displayed elevated NKp30A levels, accordingly high ΔAB and ΔBC ratios, and a unique pattern of rare allelic variants of NKp30 SNPs. Moreover, NK cells from LS displayed correlated NKp30/NKp46 membrane expression, high spontaneous and NKp30- or NKp46-triggered degranulation. These data outline the impact of NKp30 and NKp46 transcripts on melanoma evolution and identify unique genetic features of NKp30 associated with higher NK activation in rare LS melanoma patients that control a metastatic disease.