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OBJECTIVE: To compare etanercept and adalimumab biosimilars (SB4 and ABP501) and respective bioriginators in terms of safety and efficacy in a real-life contest. METHODS: We consequently enrolled patients affected by rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, treated with SB4, and ABP501, or with corresponding originators, belonging to the main biological prescribing centers in the Lazio region (Italy), from 2017 to 2020. Data were collected at recruitment and after 4, 8, 12, and 24 months of therapy. RESULTS: The multicenter cohort was composed by 455 patients treated with biosimilars [SB4/ABP501 276/179; female/male 307/146; biologic disease-modifying anti-rheumatic drug (b-DMARD) naïve 56%, median age/ interquartile range 55/46-65 years] and 436 treated with originators (etanercept/adalimumab 186/259, female/ male 279/157, b-DMARD naïve 67,2%, median age/interquartile range 53/43-62 years). No differences were found about safety, but the biosimilar group presented more discontinuations due to inefficacy (p<0.001). Female gender, being a smoker, and being b-DMARD naïve were predictive factors of reduced drug survival (p=0.05, p=0.046, p=0.001 respectively). The retention rate at 24 months was 81.1% for bioriginators and 76.5% for biosimilars (median retention time of 20.7 and 18.9 months, respectively) (p=0.002). Patients with remission/low disease activity achievement at 4 months showed a cumulative survival of 90% to biosimilar therapy until 24 months (p=0.001); early adverse reactions instead represented a cause of subsequent drug discontinuation (p=0.001). CONCLUSIONS: Real-life data demonstrated a similar safety profile between biosimilars and originators, but a reduced biosimilar retention rate at 24 months. Biosimilars could be considered a valid, safe, and less expensive alternative to originators, allowing access to treatments for a wider patient population.
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Antirreumáticos , Artrite Reumatoide , Medicamentos Biossimilares , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adalimumab/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Medicamentos Biossimilares/efeitos adversos , Etanercepte/uso terapêutico , Etanercepte/efeitos adversos , Necrose/induzido quimicamente , Necrose/tratamento farmacológico , Resultado do Tratamento , AdultoRESUMO
Autoimmune thyroid disease has been described as a complication of HSCT for different indications and as a manifestation of inborn errors of immunity, like SCID. A 1-month female was diagnosed with RAG1-mutated SCID and received allogenic HSCT. She developed autoimmune hypothyroidism 5 months after transplantation and was treated with levo-thyroxine with a good response. Autoimmune thyroid disease can develop after HSCT during the immune reconstitution phase, leading to potentially severe neurological and growth impairment, particularly in SCID patients, often transplanted during the first year of life. Recommendations regarding early and frequent vigilance for thyroid function are needed in these patients.
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Doença de Hashimoto , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Feminino , Humanos , Encéfalo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia , Tireotropina , Recém-NascidoRESUMO
The gas-puff Z pinch has a long history with myriad applications as an efficient neutron or x-ray source. Its simplicity as a load configuration makes it suitable for studying fundamental plasma physics phenomena such as instabilities and energy transport. For example, the implosion of cylindrical shells onto a fusion fuel are inherently susceptible to instability growth on their external surfaces; if such instabilities are unmitigated, then the consequences in terms of degraded performance can be substantial. Similarly, mitigating heat transport from a hot fuel to its colder surrounding container can make fusion conditions more easily achievable. Here we have conducted a systematic study of triple-nozzle (outer liner, inner liner, fuel) gas puffs using two-dimensional (2D) magnetohydrodynamic simulations to investigate the effect of load material on the relevant dynamics. Analogous to past studies on spherical blast waves and converging shock waves, a trend emerges linking increased radiative cooling, lower adiabatic index, and increased magneto-Rayleigh-Taylor instability growth. Notably, our results suggest that, for the present configuration, Ar radiates less than both Ne and Kr during the early stages of the implosion while mass is being swept up and perturbations begin to seed instability growth. Consequently, pinches with Ar on the outer surface exhibit more stable 2D behavior. Here we also present a parameter scan of thermonuclear neutron yield, Y, as a function of peak current, I_{pk} and dopant concentration with Ne or Ar, depending on the inner liner material. Above 6 MA, our results suggest YâI_{pk}^{5} and even substantial mixing (10% by volume) of Ne into the fuel does not drastically reduce yield, suggesting an Ar/Ne/fuel configuration may reliably achieve DD thermonuclear yields of 10^{13}-10^{14}/cm in the 10-20 MA range.
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The gas-puff Z-pinch is a well-known source of x-rays and/or neutrons, but it is highly susceptible to the magneto-Rayleigh-Taylor instability (MRTI). Approaches to MRTI mitigation include density profile tailoring, in which nozzles are added or modified to alter the acceleration trajectory, and axial pre-magnetization, in which perturbations are smoothed out via magnetic field line tension. Here, we present two-dimensional magnetohydrodynamic simulations of loads driven by an 850 kA, 160 ns driver that suggest these mitigation strategies can be additive. The initial axial magnetic field, B_{z0}, to stabilize a 2.5-cm-radius Ne gas liner imploding onto an on-axis deuterium target can be reduced from 0.7 T to 0.3 T by adding a second liner with a radius of 1.25 cm. Because MRTI mitigation tends to increasingly lower yield with higher B_{z0}, the use of a lower field is advantageous. Here, we predict a reduction in yield penalty from >100× with the single liner to <10× with a double liner. A premagnetized, triple nozzle gas puff could therefore be an attractive source for intense neutrons or other fusion applications.
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An experimental study of the magnetic field distribution in gas-puff Z pinches with and without a preembedded axial magnetic field (B_{z0}) is presented. Spatially resolved, time-gated spectroscopic measurements were made at the Weizmann Institute of Science on a 300 kA, 1.6 µs rise time pulsed-power driver. The radial distribution of the azimuthal magnetic field, B_{θ}, during the implosion, with and without a preembedded axial magnetic field of B_{z0}=0.26T, was measured using Zeeman polarization spectroscopy. The spectroscopic measurements of B_{θ} were consistent with the corresponding values of B_{θ} inferred from current measurements made with a B-dot probe. One-dimensional magnetohydrodynamic simulations, performed with the code trac-ii, showed agreement with the experimentally measured implosion trajectory, and qualitatively reproduced the experimentally measured radial B_{θ} profiles during the implosion when B_{z0}=0.26T was applied. Simulation results of the radial profile of B_{θ} without a preembedded axial magnetic field did not qualitatively match experimental results due to magneto-Rayleigh-Taylor (MRT) instabilities. Our analysis emphasizes the importance of MRT instability mitigation when studying the magnetic field and current distributions in Z pinches. Discrepancies of the simulation results with experiment are discussed.
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BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia , Prognóstico , QuinolinasAssuntos
Corticosteroides , Interações Medicamentosas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Múltiplas Afecções Crônicas , Preparações Farmacêuticas/classificação , Polifarmacologia , Risco Ajustado/métodos , Corticosteroides/classificação , Corticosteroides/farmacologia , Idoso , COVID-19/diagnóstico , COVID-19/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Itália/epidemiologia , Masculino , Múltiplas Afecções Crônicas/tratamento farmacológico , Múltiplas Afecções Crônicas/epidemiologia , Farmacocinética , Estudos Retrospectivos , Medição de Risco , SARS-CoV-2 , Resultado do Tratamento , Tratamento Farmacológico da COVID-19Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Inibidores de Checkpoint Imunológico/efeitos adversos , Nivolumabe/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Idoso , Anticorpos Antinucleares/análise , Quimiorradioterapia/métodos , Progressão da Doença , Humanos , Imunoterapia , Masculino , Reumatologistas , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologiaAssuntos
COVID-19 , Pérnio , Biópsia , Pérnio/diagnóstico , Criança , Família , Humanos , SARS-CoV-2RESUMO
Several studies have focused on the heart rate variability (HRV) of murine species, while studies discussing HRV in murine neonates and infants remain scarce, since recording hemodynamic signals through invasive methods in small animals has been found to be quite challenging. Thus, this study aimed at describing and validating a novel method to assess HRV in newborn rats. An electrocardiogram (ECG) system was used to determine RR intervals in awake newborns and evaluate HRV in normotensive (Wistar) and hypertensive (SHR) neonate rats. After birth, ECG was recorded in the awake newborns, and they were allowed to rest on a heated surface, restricted only by the weight of the adhesive ECG electrodes. The electrodes were cut and adapted to provide more comfort to the animal, and gently placed on the newborn's skin. RR intervals were recorded over a 30-min period using an ECG system together with LabChart software (4 KHz). Three sequences of 5 min each from the ECG recording period were analyzed in time and frequency domains, using CardioSeries software. ECG data resulted in a clearly interpretable signal that was used to generate an RR interval sequence through time for the analysis of HRV. SHR neonates presented increased cardiac sympathovagal balance compared to Wistar neonates (low frequency/high frequency: 3.85±0.71 vs 0.90±0.09). In conclusion, the ECG setup here described may be used to record RR intervals to assess HRV in neonate rats, thus detecting early impairment of HRV in hypertensive newborns.
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Animais , Coelhos , Ratos , Software , Eletrocardiografia , Ratos Endogâmicos SHR , Ratos Wistar , Frequência Cardíaca , HipertensãoRESUMO
Autoimmune diseases (AIDs) are complex diseases characterized by persistent or recurrent inflammation, alteration of immune response, and production of specific autoantibodies. It is known that different AIDs share several susceptibility genetic loci. Tumor necrosis factor alpha inducible protein 3 (TNFAIP3) encodes the ubiquitin-modifying enzyme A20, which downregulates inflammation by restricting NF-κB, a transcription factor that regulates expression of various proinflammatory genes. Variants in TNFAIP3 gene have been described as associated with susceptibility to several AIDs. Here, we analyzed two TNFAIP3 polymorphisms in Italian patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjogren's syndrome (pSS), to verify if the genetic variability of TNFAIP3 gene is involved in genetic predisposition to AIDs also in the Italian population. We recruited 313 SLE patients, 256 RA patients, 195 pSS patients, and 236 healthy controls. Genotyping of rs2230926 and rs6920220 in TNFAIP3 gene was performed by an allelic discrimination assay. We carried out a case/control association study and a genotype/phenotype correlation analysis. A higher risk to develop SLE was observed for rs2230926 (P = 0.02, OR = 1.92). No association was observed between this SNP and the susceptibility to pSS or RA. However, the rs2230926 variant allele seems to confer a higher risk to develop lymphoma in pSS patients, while in RA patients, the presence of RF resulted significantly associated with the variant allele. Regarding the rs6920220 SNP, we observed a significant association of the variant allele with SLE (P = 0.03, OR = 1.53), pSS (P = 0.016, OR = 1.69), and RA (P = 0.0001, OR = 2.35) susceptibility. Furthermore, SLE patients carrying the variant allele showed a higher risk to develop pericarditis, pleurisy, and kidney complications. Our results support the importance of the TNFAIP3 gene variant role in the development of different autoimmune diseases in the Italian population and furtherly confirm a sharing of genetic predisposing factors among these three pathologies.
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Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Alelos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Estudos de Casos e Controles , Frequência do Gene , Genótipo , Humanos , Itália , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Fenótipo , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/genéticaRESUMO
Detection of secondary D(t, n)4He neutrons produced when thin argon or krypton gas shells implode on a deuterium gas target is a very challenging task because the secondary neutron yield is a small fraction of the primary neutron yield and because the implosion is often accompanied by an intense hard X-ray burst. We built a large volume neutron time of flight (nTOF) detector using liquid scintillator (xylene solvent with small quantities of wavelength shifting PPO + bis-MSB fluors) in an attempt to increase the detection probability for secondary neutrons in our staged Z-pinch experiments at the 1 MA Zebra pulsed-power generator. Two fast, gated microchannel plate photomultiplier tubes detect the light created in 21 liters of liquid. The hard X-rays were successfully suppressed in the recorded nTOF traces, but we found no evidence of secondary neutrons. The signal quality from the primary D(d, n)3He neutrons was higher compared to the signal quality from a plastic scintillator nTOF, thus providing a more reliable estimate of the deuterium ion temperature at the pinch stagnation time. Cross-calibration with a silver activation detector enables standalone neutron yield measurement.
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BACKGROUND: Immune response failure against hepatitis C virus (HCV) has been associated with an increased regulatory T cell (Treg) activity. After liver transplantation (LT), 80% of patients experience an accelerated progression of hepatitis C recurrence. The aim of this work was to assess the involvement of Tregs, T helper (Th) 1, 2 and 17 cells in recurrent hepatitis C. METHODS: Peripheral blood cells obtained before and one month after LT from 22 recipients were analysed. Forty-four key molecules related to Treg, Th1, 2 and 17 responses, were evaluated using qRT-PCR. Liver recipients were classified in two groups according to graft fibrosis evaluated by the METAVIR score on the biopsy performed one year after LT (mild: F ≤ 1, n = 13; severe: F > 1, n = 9). Patients developing a severe recurrence were compared with patients with a mild recurrence. RESULTS: mRNA levels of Treg markers obtained one month after LT were significantly increased in patients with a severe disease course when compared to patients with a mild recurrence. Markers of the Th1 response were elevated in the same group. No differences in the markers determined before LT were observed. CONCLUSION: These findings suggest that Treg, induced by a multifactorial process, which could include a strong Th1 response itself, may play a role in suppressing the early antiviral response, leading to a severe recurrence of hepatitis C.
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Hepatite C Crônica/diagnóstico , Transplante de Fígado , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/metabolismo , Idoso , Biomarcadores/metabolismo , Antígenos CD28/genética , Antígenos CD28/metabolismo , Ligante de CD40/genética , Ligante de CD40/metabolismo , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Progressão da Doença , Feminino , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Subunidade alfa de Receptor de Interleucina-10/genética , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Subunidade beta de Receptor de Interleucina-10/genética , Subunidade beta de Receptor de Interleucina-10/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-23/genética , Interleucina-23/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
BACKGROUND: Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate. METHODS: Peripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry. The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA. RESULTS: PBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs. Additionally, the expression of LC3-II correlated with DAS28. TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS. Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins. CONCLUSIONS: Our results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression. This suggests that inhibition of autophagy represents a possible therapeutic target in RA.
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Apoptose/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Autofagia/efeitos dos fármacos , Etanercepte/uso terapêutico , Metotrexato/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Células Cultivadas , Etanercepte/metabolismo , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Microparticles (MPs) are small membrane vesicles released by many cell types under physiological and pathological conditions. In the last years, these particles were considered as inert cell debris, but recently many studies have demonstrated they could have a role in intercellular communication. Increased levels of MPs have been reported in various pathological conditions including infections, malignancies, and autoimmune diseases, such as rheumatoid arthritis (RA). RA is an autoimmune systemic inflammatory disease characterized by chronic synovial inflammation, resulting in cartilage and bone damage with accelerated atherosclerosis increasing mortality. According to the literature data, also MPs could have a role in endothelial dysfunction, contributing to atherosclerosis in RA patients. Moreover many researchers have shown that a dysregulated autophagy seems to be involved in endothelial dysfunction. Autophagy is a reparative process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. It has been shown in many works that basal autophagy is essential to proper vascular function. Taking into account these considerations, we hypothesized that in RA patients MPs could contribute to atherosclerosis process by dysregulation of endothelial autophagy process.
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Artrite Reumatoide/imunologia , Aterosclerose/imunologia , Autofagia/imunologia , Micropartículas Derivadas de Células/imunologia , Animais , Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Humanos , Inflamação/imunologiaRESUMO
Several studies have suggested a link between human microbiome and rheumatoid arthritis (RA) development. Porphyromonas gingivalis seems involved in RA initiation and progression, as supported by the high occurrence of periodontitis. In this case-control study, we analysed tongue P. gingivalis presence and quantification in a large healthy and RA cohort. We enrolled 143 RA patients [male/female (M/F) 32/111, mean ± standard deviation (s.d.), age 57·5 ± 19·8 years, mean ± s.d. disease duration 155·9 ± 114·7 months); 36 periodontitis patients (M/F 11/25, mean ± s.d., age 56 ± 9·9 years, mean ± s.d. disease duration 25·5 ± 20·9 months); and 57 patients (M/F 12/45, mean ± s.d., age 61·4 ± 10·9 years, mean ± s.d. disease duration 62·3 ± 66·9 months) with knee osteoarthritis or fibromyalgia. All subjects underwent a standard cytological swab to identify the rate of P. gingivalis/total bacteria by using quantitative real-time polymerase chain reaction. The prevalence of P. gingivalis resulted similarly in RA and periodontitis patients (48·9 versus 52·7%, P = not significant). Moreover, the prevalence of this pathogen was significantly higher in RA and periodontitis patients in comparison with control subjects (P = 0·01 and P = 0·003, respectively). We found a significant correlation between P. gingivalis rate in total bacteria genomes and disease activity score in 28 joints (DAS28) (erythrocyte sedimentation rate) (r = 0·4, P = 0·01). RA patients in remission showed a significantly lower prevalence of P. gingivalis in comparison with non-remission (P = 0·02). We demonstrated a significant association between the percentage of P. gingivalis on the total tongue biofilm and RA disease activity (DAS28), suggesting that the oral cavity microbiological status could play a role in the pathogenic mechanisms of inflammation, leading to more active disease.
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Artrite Reumatoide/imunologia , Infecções por Bacteroidaceae/imunologia , Microbiota/imunologia , Periodontite/imunologia , Porphyromonas gingivalis/fisiologia , Língua/patologia , Adulto , Idoso , Artrite Reumatoide/epidemiologia , Infecções por Bacteroidaceae/epidemiologia , Biofilmes , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Língua/microbiologiaRESUMO
BACKGROUND: The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown. AIM: We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients. METHODS: From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen. RESULTS: The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class. CONCLUSION: This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.
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Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Idoso , Benzimidazóis/administração & dosagem , Carbamatos , Carcinoma Hepatocelular/etiologia , Estudos de Coortes , Quimioterapia Combinada , Feminino , Fluorenos/administração & dosagem , Genótipo , Hepacivirus/genética , Encefalopatia Hepática/epidemiologia , Humanos , Imidazóis/administração & dosagem , Interferons/uso terapêutico , Itália , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirrolidinas , Ribavirina/uso terapêutico , Simeprevir/administração & dosagem , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/análogos & derivados , Valina/análogos & derivadosRESUMO
Angiosarcoma is a rare type of soft tissue sarcoma that accounts for less than 1% of all sarcomas and only 2% of all primary hepatic tumours. Thorotrast, arsenic, and vinyl chloride monomer are frequently listed as occupational exposure risks. The estimated latency is long (10-40 years) in occupational cases and very long (60 years or more) in non-occupational cases. The symptoms and CT-scan appearance of hepatic angiosarcoma (HAS) are non-specific. We present a case of a 65-year-old Caucasian male with history of cryptogenic cirrhosis, low alpha-foetoprotein levels and a single, 4-cm nodule of potential atypical hepatocellular carcinoma (no washout at MRI and CT-scan) in segment VIII. Laparoscopic radiofrequency ablation (a biopsy of the neoplastic lesion was technically impossible) was performed, followed by liver transplantation (LT) 6 months later. High-grade multifocal HAS was found in the explanted liver, with extensive involvement of the venous portal structures. No complications were observed during the postoperative course, and initial immunosuppression included tacrolimus, mycophenolate mofetil and corticosteroids. Because of the histological findings, tacrolimus was switched to everolimus as the main immunosuppressive drug one month after LT. Despite this conversion, the patient developed bone metastases 3 months after LT and peritoneal carcinosis one month later. This case report suggests that everolimus conversion does not inhibit the development of tumour metastases. Consequently, HAS remains an absolute contraindication to LT because of the poor outcome. If LT has been performed for incidental HAS, new molecular therapies (e.g. vascular endothelial growth factor antagonists) should be considered immediately after LT to improve the outcome.
Assuntos
Hemangiossarcoma , Neoplasias Hepáticas , Transplante de Fígado , Idoso , Evolução Fatal , Hemangiossarcoma/diagnóstico por imagem , Hemangiossarcoma/patologia , Hemangiossarcoma/cirurgia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Resultado do TratamentoRESUMO
The effectiveness of a 12-week course of sofosbuvir-ledipasvir in treatment-experienced HCV genotype 1b-infected patients with cirrhosis is still under debate. Our primary endpoint was to compare the sustained virological response at post-treatment week 12 (SVR12) of sofosbuvir-ledipasvir in combination with ribavirin for 12 weeks, and sofosbuvir-ledipasvir alone for 24 weeks. This was a prospective observational study that enrolled 424 (195 naive, 229 experienced; 164 treated for 12 weeks with Ribavirin and 260 with sofosbuvir-ledipasvir alone for 24 weeks) consecutive HCV genotype 1b-infected patients with cirrhosis. The SVR12 rates were 93.9% and 99.2% in patients treated for 12 and 24 weeks, respectively (P = .002). The baseline characteristics of patients treated for 12 weeks were significantly different from those treated for 24 weeks as regards their younger age (P = .002), prevalence of Child-Pugh class A (P = .002), lower MELD scores (P = .001) and smaller number of nonresponders (P = .04). The shorter treatment was significantly associated with a lower SVR12 in univariate and multivariate analyses (P = .007 and P = .008, respectively). The SVR rate was unaffected by age, gender, BMI, Child-Pugh class, MELD score or previous antiviral treatment. Patients receiving ribavirin experienced more episodes of ascites and headache but less recurrence of hepatocellular carcinoma (HCC), and were prescribed more diuretics and cardiopulmonary drugs. No patient discontinued treatment. The therapeutic regimen of sofosbuvir-ledipasvir plus ribavirin administered for 12 weeks was less effective than sofosbuvir-ledipasvir alone given for 24 weeks. At odds with European guidelines, the recommended 12-week treatment with sofosbuvir-ledipasvir alone might be suboptimal for this setting of patients.