RESUMO
Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.
Assuntos
Tumor Carcinoide , Tumores Neuroendócrinos , Humanos , Antígeno B7-H1 , PulmãoRESUMO
Median arcuate ligament syndrome, which is characterized by postprandial pain, occurs as a result of the compression of the celiac trunk by the ligament. It is a rare pathology in pediatric patients. We present the case of a 14-year-old girl with recurrent abdominal pain. Ultrasound examination showed an increase in celiac trunk flow rate with flow reversal, while CT angiography demonstrated compression. It was surgically managed by dividing the arcuate ligament through videolaparoscopy. Symptoms disappeared right after surgery and did not reappear in the 24-month follow-up. The arcuate ligament is a fibrous band located at the level of the diaphragmatic crus. The fact that the celiac trunk originates at the supradiaphragmatic aorta makes the ligament exert compression during expiration, with transitory distal ischemia. Diagnosis is achieved through Doppler ultrasonography of the celiac trunk or CT angiography, among others. Surgical management involves dividing the arcuate ligament. This syndrome should be considered in the presence of recurrent abdominal pain. The laparoscopic route is the treatment approach suggested.
El síndrome de ligamento arcuato medio caracterizado por dolor posprandial se debe a la compresión del tronco celíaco por dicho ligamento. En pediatría su presentación es infrecuente. Niña de 14 años con dolor abdominal recurrente. Se diagnosticó por ecografía un aumento de la velocidad del flujo del tronco celíaco con inversión de flujo. La angiotomografía evidenció la compresión. Su resolución fue quirúrgica mediante la sección del ligamento arcuato por videolaparoscopia. Los síntomas desaparecieron inmediatamente luego de la cirugía y no recurrieron en 24 meses de seguimiento. El ligamento arcuato es una banda fibrosa en la crura diafragmática. El nacimiento del tronco celíaco en la aorta supradiafragmática conlleva que este ligamento comprima durante la espiración con isquemia distal transitoria. El diagnóstico se realiza con ecografía Doppler del tronco celíaco o angiotomografía, entre otros. La resolución quirúrgica consiste en la sección del ligamento arcuato. Este síndrome debe tenerse en cuenta ante un caso de dolor abdominal recurrente. La vía laparoscópica es sugerida para el tratamiento.
Assuntos
Laparoscopia , Síndrome do Ligamento Arqueado Mediano , Dor Abdominal/etiologia , Adolescente , Artéria Celíaca/diagnóstico por imagem , Artéria Celíaca/cirurgia , Criança , Feminino , Humanos , Ligamentos , Síndrome do Ligamento Arqueado Mediano/cirurgia , Cirurgia VídeoassistidaRESUMO
BACKGROUND AND OBJECTIVE: Enhanced recovery pathways or ERAS have been applied in gastric cancer surgery extrapolated from colorectal surgery. The objective of the study is to assess postoperative complications 30 days after gastric surgery for cancer, with any level of compliance with the ERAS protocol. The secondary objectives are to assess 30-day mortality, the relationship between adherence to the ERAS protocol and complications, the impact of each of the items of the protocol on postoperative complications and hospital stay, and to describe the impact of complications on length of hospital stay. MATERIALS AND METHODS: Multicenter, observational, prospective study including all consecutive patients undergoing scheduled gastric cancer surgery, over a period of 3 months, with a 30-day follow-up at participating centers, with any level of compliance with the protocol. RESULTS: The approval of the Comité Autonómico de Ética de la Investigación de Aragón has been obtained (C.P. - C.I. PI19 / 106, 27 th March 2019). POWER.4 was registered at www.clinicaltrials.gov on March 7, 2019 (NCT03865810). CONCLUSIONS: The data as a whole will be published in peer-reviewed journals. The data will not be made public by identifying each participating center. It is expected that the results of this study will identify potential areas for improvement in which more targeted research is needed.
Assuntos
Recuperação Pós-Cirúrgica Melhorada/normas , Tempo de Internação , Complicações Pós-Operatórias/epidemiologia , Neoplasias Gástricas/cirurgia , Protocolos Clínicos , Coleta de Dados , Humanos , Incidência , Estudos Prospectivos , Tamanho da Amostra , Espanha/epidemiologia , Fatores de TempoRESUMO
Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , RNA Mensageiro/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , RNA Mensageiro/genética , Taxa de SobrevidaRESUMO
BACKGROUND AND AIMS: In the context of the shortage of donors, adult living donor liver transplantation (aLDLT) represents a feasible alternative for patients within as well as beyond the Milan criteria. METHODS: From 2001, we performed 42 aLDLTs for hepatocellular carcinoma (HCC). Sixteen of the recipients were within the Milan criteria, whereas 26 fulfilled the Barcelona-Clinic Liver Cancer Group (BCLC) expanded criteria (1 tumor ≤7 cm, 5 tumors ≤3 cm, or tumors 3 ≤5 cm without macrovascular invasion or down-staging to Milan after loco-regional therapies). The objective of the current study was to compare the post-transplantation results of these two groups. RESULTS: Six Milan-in and 16 beyond Milan patients received neo-adjuvant loco-regional therapies. One Milan-in and nine patients from the beyond Milan group presented an explant histological stage beyond Milan. After a median follow-up of 64 months, 5- and 10-year overall survival rates were 60.2% and 51.6% in the Milan-in group and 78% and 65% in the beyond Milan group. Five- and 10-year disease-free survival rates were 64.5% and 55.3% in the Milan-in patients and 67.9% and 56.6% in the beyond Milan patients. Being beyond up-to-seven criteria in the histology of the explant was a significant factor for HCC recurrence. CONCLUSION: The use of aLDLT in patients with HCC within and beyond Milan but within the BCLC expanded criteria offers acceptable survival and recurrence rates. Therefore, we believe that its use in this scenario is justified.
Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/métodos , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/patologia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/etiologia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: The aim of the study was to determine the clinical characteristics, frequency of opportunistic infections (OI), and the outcomes for liver transplant recipients with severe hepatitis C virus (HCV) recurrence. In addition, the objective was to evaluate HCV recurrence as a risk factor for developing an OI. METHODS: We conducted a retrospective observational study recording all liver transplant recipients from July 1, 2003, to December 31, 2012. Patients with liver disease due to HCV were selected. Active surveillance of infections was conducted periodically, and patients were classified according to presence of severe HCV recurrence. RESULTS: Three hundred seventy patients underwent liver transplantation because of chronic HCV. One hundred forty-seven patients presented severe recurrence (SR) (49%) and 50 (17%) of them had post-liver transplant cholestatic hepatitis C. Patients with SR presented OI, especially cytomegalovirus (CMV) infections and invasive fungal infections, more frequently than patients without SR (33% vs 13%; P < .001). From the diagnosis of SR to the presentation of OI, the median number of days was 169 (6-2083). Acute allograft rejection (OR 1.8 95% confidence interval [CI] 1.1-3.3) donor age ≥60 years (OR 2.9 95% CI 1.3-6.8), and SR (OR 2.8, 95% CI 1.6-5.1) were independently associated with the development of OI in liver transplant recipients. CONCLUSION: A high index of suspicion of opportunistic infections must be maintained when faced with severe HCV recurrence in liver transplant recipients. Moreover, active surveillance against CMV infection and other prophylactic strategies against opportunistic infections should be considered.
Assuntos
Hepatite C Crônica/epidemiologia , Transplante de Fígado , Infecções Oportunistas/epidemiologia , Adulto , Infecções por Citomegalovirus/epidemiologia , Feminino , Hepacivirus , Humanos , Infecções Fúngicas Invasivas/epidemiologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de RiscoRESUMO
Pyrogallol is a polyphenol that generates the superoxide anion. In this study, we investigated the influence of pyrogallol on human platelets. Our data showed that exposure of platelets to pyrogallol induced numerous manifestations of apoptosis including depolarization of mitochondrial inner membrane and release of cytochrome c from the mitochondria. Pyrogallol also induced downstream extra-mitochondrial apoptotic responses, including activation of caspase-3 and phosphatidylserine exposure on the outer leaflet of the plasma membrane. Addition of glutathione significantly rescued cells from pyrogallol- induced apoptosis, as evidenced by a decrease of all markers of apoptosis. Thus, pyrogallol appears to produce depletion of intracellular glutathione content in platelets, the main non-protein antioxidant in the cells. Furthermore, inhibition of γ-glutamyl transpeptidase, an enzyme that plays the main role in the cellular supply of glutathione, reverted the glutathione (GSH) protection over platelet apoptosis. Our results indicate that pyrogallol induces apoptosis by suppressing the natural anti-oxidation in human platelets.
Assuntos
Apoptose/efeitos dos fármacos , Plaquetas/citologia , Pirogalol/farmacologia , Biomarcadores/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Boratos/farmacologia , Citocromos c/metabolismo , Glutationa/farmacologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Serina/farmacologiaRESUMO
Mannose-binding lectin (MBL) is synthesized by the liver and binds to microbes. MBL2 gene polymorphisms produce intermediate/low/null or normal MBL serum levels (MBL-deficient or MBL-sufficient phenotypes, respectively). We aimed to evaluate the incidence and severity of infection, rejection, and survival within 1 year after liver transplantation (LT) according to donor and recipient MBL2 gene polymorphisms. A repeated-event analysis for infection episodes (negative binomial regression, Andersen-Gill model) was performed in 240 LTs. Four hundred twenty-eight infectious episodes (310 bacterial, 15 fungal, 65 cytomegalovirus [CMV]-related, and 38 viral non-CMV-related episodes) and 48 rejection episodes were recorded. The main bacterial infections were urinary (n = 82, 26%) and pneumonia (n = 69, 22%). LT recipients of MBL-deficient livers had a higher risk of bacterial infection (incidence rate ratio [IRR] 1.48 [95% confidence interval 1.04-2.09], p = 0.028), pneumonia (IRR 2.4 [95% confidence interval 1.33-4.33], p = 0.013), and septic shock (IRR 5.62 [95% confidence interval 1.92-16.4], p = 0.002) compared with recipients of MBL-deficient livers. The 1-year bacterial infection-related mortality was higher in recipients of MBL-deficient versus MBL-sufficient livers (65.8% vs. 56.1%, respectively; p = 0.0097). The incidence of rejection, viral, or fungal infection was similar in both groups. Recipient MBL2 genotype did not significantly increase the risk of bacterial infection. LT recipients of MBL-deficient livers have a higher risk of bacterial infection, pneumonia, septic shock, and 1-year bacterial infection-related mortality after LT.
Assuntos
Infecções Bacterianas/mortalidade , Rejeição de Enxerto/mortalidade , Transplante de Fígado/mortalidade , Lectina de Ligação a Manose/genética , Polimorfismo Genético , Complicações Pós-Operatórias , Doadores de Tecidos , Adulto , Idoso , Infecções Bacterianas/etiologia , Infecções Bacterianas/patologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Lectina de Ligação a Manose/deficiência , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
The use of hydroxychloroquine (HCQ) in Primary Sjögren's Syndrome (pSS) has been assessed in different studies over the last years, with conflicting results regarding its efficacy in sicca syndrome and extraglandular manifestations (EGM). The goal of this study was to compare the incidence rate of EGM in pSS patients with and without HCQ therapy.We performed a multicenter retrospective study, including patients with pSS (European classification criteria) with at least 1 year of follow-up. Subjects with concomitant fibromyalgia, autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis were excluded. Demographics and pSS characteristics were recorded. The EGM were defined by EULAR-SS disease activity index (ESSDAI). Patients were divided into two groups according to their use or not of HCQ therapy. We evaluated the use of HCQ and its relationship to EGM. HCQ therapy was defined as the continuous use of the drug for at least 3 months. A descriptive analysis of demographics and pSS characteristics was performed. We compared the incidence of EGM between groups defined by HCQ therapy using chi2 test or Fisher's exact test. A total of 221 patients were included (97.3% women), mean age, 55.7 years (SD 14). Mean age at diagnosis, 48.8 years (SD 15); median disease duration, 60 months (IQR 35-84). One hundred and seventy patients (77%) received HCQ. About half of the patients had at least one EGM during the course of the disease, 20% of them developed an EGM before the onset of the sicca syndrome and 26% simultaneously with dryness symptom. Overall, EGM were less frequent in those on HCQ therapy (36.5% vs 63.5%, p < 0.001). Considering each EGM individually, the following manifestations were more frequent in the non-treated group: arthritis (p < 0.001), fatigue (p < 0.001), purpura (p = 0.01), Raynaud phenomenon (p = 0.003), and hypergammaglobulinemia (p = 0.006). Immunosuppressive treatment was indicated on 28 patients (12.7%), 13 of which were receiving also HCQ. The first reason for those treatments was the presence of arthritis in 12/28 patients (42.8%), and the drug used in all the cases was methotrexate. Only three patients required immunosuppressive therapy with cyclophosphamide, due to the presence of glomerulonephritis, vasculitis, and interstitial lung disease. None of the patients received biologic therapy. The lower incidence of EGM was observed in patients on HCQ therapy supports its efficacy in pSS. However, further large scale prospective studies are needed to confirm these findings.
Assuntos
Antirreumáticos/uso terapêutico , Hidroxicloroquina/uso terapêutico , Síndrome de Sjogren/complicações , Síndrome de Sjogren/tratamento farmacológico , Adulto , Fadiga/epidemiologia , Fadiga/etiologia , Feminino , Humanos , Hipergamaglobulinemia/epidemiologia , Hipergamaglobulinemia/etiologia , Incidência , Masculino , Pessoa de Meia-Idade , Púrpura/epidemiologia , Púrpura/etiologia , Doença de Raynaud/epidemiologia , Doença de Raynaud/etiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Inguinal orchiectomy is curative in 70-80% of clinical stage I testicular germ cell tumours (CS I TGCT). The identification of patients who are at low risk of relapse is critical to avoid unnecessary treatment. The aim of this study is to explore EGFR, hMLH-1/hMSH-2 and microsatellite instability (MSI) as potential prognostic factors of recurrence in CS I TGCT. METHODS: Fifty-six CS I TGCT patients who underwent inguinal orchiectomy were included in this study. We analysed the relationship between clinicopathological and molecular factors with survival. Analysis of hMLH1, hMSH2 and EGFR expression was carried out by immunohistochemistry. Methylation status of the hMLH1 promoter was determined by pyrosequencing analysis in selected cases. EGFR exons 19, 20, 21 were analysed by PCR labeled-fragments and MSI status was determined using standard Multiplex MSI assays. RESULTS: Classical pathological factors such as lymphovascular invasion, high percentage of embryonal carcinoma, rete testis invasion or tumour size ≥4 cm showed a significant relationship with a higher risk of relapse. Additionally, it was found that an epididymis invasion proved to be a significant independent poor prognostic factor of recurrence (p = 0.001). hMLH1 or hMSH2 expression showed no significant association with risk of relapse and no MSI was found. EGFR expression was observed in 30.4% of samples and its expression was associated with higher risk of relapse (HR 3.5; 95% CI 1.3-9.8; p = 0.016). None of the cases presented EGFR kinase domain mutations. CONCLUSIONS: Epididymis invasion and EGFR expression, but not hMLH-1/hMSH-2 or MSI, could be potentially useful as new prognostic factors of recurrence for CS I TGCT.
Assuntos
Biomarcadores Tumorais/metabolismo , Epididimo/patologia , Receptores ErbB/metabolismo , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Adulto , Metilação de DNA/genética , Demografia , Intervalo Livre de Doença , Éxons/genética , Genoma Humano , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/metabolismo , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/genética , Prognóstico , Regiões Promotoras Genéticas , Fatores de Risco , Neoplasias Testiculares/genéticaRESUMO
BACKGROUND: The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. METHODS: Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. RESULTS: Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. CONCLUSION: Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Terapia de Salvação/métodos , Espanha , Resultado do TratamentoRESUMO
BACKGROUND: The early identification of patients at high risk of severe post liver transplant hepatitis C recurrence is relevant, as these patients may be treated using interferon (IFN)-free regimens. METHODS: In a retrospective study with prospectively collected data, we investigated whether the use of several non-invasive methods (fibrosis 4 index [FIB-4], AST-to-platelets ratio index [APRI], enhanced liver fibrosis test [ELF], IFN-γ-inducible protein 10 [IP-10], and transient elastography by Fibroscan) and their combinations 6 months after transplantation could identify those recipients at higher risk of severe recurrence, defined by the presence of significant fibrosis (F ≥2) and/or portal hypertension (hepatic venous pressure gradient ≥6 mmHg) 12 months after transplant. Seventy-two hepatitis C virus (HCV)-infected liver transplant patients and 10 recipients in whom HCV was eradicated before transplantation were included in the study. RESULTS: The levels of all biomarkers were significantly higher in HCV-infected recipients than in controls. Among HCV recipients, levels of biomarkers were significantly higher in patients with severe recurrence. Although there were no statistically significant differences between biomarkers, APRI, ELF, and FIB-4 obtained the highest area under the ROC curve values. The combination of serum biomarkers with Fibroscan increased the negative and positive predictive values, although diagnostic accuracy of individual tests was not significantly improved. CONCLUSIONS: Patients at higher risk of severe HCV recurrence can be identified early, 6 months after transplantation, using readily available non-invasive methods.
Assuntos
Antivirais/uso terapêutico , Hepacivirus/isolamento & purificação , Hepatite C Crônica/diagnóstico , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias , Idoso , Algoritmos , Biomarcadores/sangue , Feminino , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/patologia , Hipertensão Portal/virologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos RetrospectivosRESUMO
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms capable of producing hormones. The development of new treatments has improved progression-free survival, albeit with increased toxicity. Health-related quality of life (HRQoL) has become an important endpoint in clinical research to evaluate patients' well-being in such a contradictory scenario. In this review, we examine key reported outcomes across clinical studies exploring HRQoL in patients with GEP-NETs. We have conducted a review of the literature using PubMed, The Cochrane Library, EMBASE, and Google Scholar. Selection criteria for articles were (1) publication in English between 1995 and 2014, (2) patients with GEP-NET, and (3) analysis of HRQoL, including mental health and psychological symptoms. Forty-nine studies met the inclusion criteria (31 clinical trials, 14 observational studies, and 4 developments of NET-specific HRQoL instruments). The scope and nature of the literature was diverse with 27 instruments used to measure aspects of HRQoL. EORTC QLQ-C30 was the most frequently used, in 38 of the 49 studies. Standardized measures revealed that in spite of generally good HRQoL, GEP-NET patients have specific psychological and physical complaints. The clinical benefit of somatostatin analogs and sunitinib has been clearly supported by HRQoL assessment. Improvement in HRQoL scores or symptom relief over time was also reported in 14 trials of peptide receptor radionuclide therapy, however the absence of randomized studies obviate definitive conclusions. We have also identified several unanswered questions that should be addressed in further research concerning chemotherapy, everolimus, surgery, local ablative therapies, and chemoembolization. Future research should incorporate GEP-NET-specific HRQoL instruments into phase III trials. This review may help both clinicians and researchers to select the most appropriate tools to assess changes in HRQoL in this population.
Assuntos
Neoplasias Intestinais/complicações , Neoplasias Intestinais/psicologia , Neoplasias Intestinais/terapia , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/psicologia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/psicologia , Neoplasias Pancreáticas/terapia , Qualidade de Vida , Neoplasias Gástricas/complicações , Neoplasias Gástricas/psicologia , Neoplasias Gástricas/terapia , HumanosRESUMO
Data on gastroenteropancreatic neuroendocrine neoplasms (NEN) G3 (well-differentiated neuroendocrine tumors (NET G3) and neuroendocrine carcinoma (NEC)) are limited. We retrospectively study patients with NET G3 and NEC from eight European centers. Data examined included clinical and pathological characteristics at diagnosis, therapies and outcomes. Two hundred and four patients were analyzed (37 NET G3 and 167 NEC). Median age was 64 (21-89) years. Tumor origin included pancreas (32%) and colon-rectum (27%). The primary tumor was resected in 82 (40%) patients. Metastatic disease was evident at diagnosis in 88% (liver metastases: 67%). Median Ki-67 index was 70% (30% in NET G3 and 80% in NEC; P<0.001). Median overall survival (OS) for all patients was 23 (95% CI: 18-28) months and significantly higher in NET G3 (99 vs 17 months in NEC; HR=8.3; P<0.001). Platinum-etoposide first line chemotherapy was administered in 113 (68%) NEC and 12 (32%) NET G3 patients. Disease control rate and progression free survival (PFS) were significantly higher in NEC compared to NET G3 (P<0.05), whereas OS was significantly longer in NET G3 (P=0.003). Second- and third-line therapies (mainly FOLFIRI and FOLFOX) were given in 79 and 39 of NEC patients; median PFS and OS were 3.0 and 7.6 months respectively after second-line and 2.5 and 6.2 months after third-line chemotherapy. In conclusion, NET G3 and NEC are characterized by significant differences in Ki-67 index and outcomes. While platinum-based chemotherapy is effective in NEC, it seems to have limited value in NET G3.
Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Antígeno Ki-67/metabolismo , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/metabolismo , Compostos Organoplatínicos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Prognóstico , Análise de Sobrevida , Adulto JovemRESUMO
OBJECTIVE AND DESIGN: Carrageenan-induced paw edema has been described as a local and acute inflammatory process. In fact, little is known about the time course and systemic changes following a carrageenan injection. In this study, we examine the systemic changes that follow carrageenan injection in the paw. METHODS: Acute inflammation was produced by subplantar injection of carrageenan in a hind paw of Sprague-Dawley rats. Saline was used in control rats. Paw volume was measured with a plethysmometer. The hot plate latency test was used to quantify antinociception. C-reactive protein (CRP) levels were measured with a sandwich enzyme immunoassay. Fibrinogen concentration was measured using the gravimetric method. Lung morphometric analysis was performed using an image processing package. Lungs and paws were also examined for tissue factor (TF) and proinflammatory cytokines expression by immunohistochemistry. RESULTS: We found diverse systemic changes including increased levels of acute phase proteins, such as CRP and fibrinogen, and a lung inflammatory process characterized by lung edema, fibrin deposition, and leukocyte infiltration. An elevated expression of TF, IL-6, IL-1ß, and TNFα, was observed in paw and lung tissue sections by immunohistochemical methods. CONCLUSION: This study provides new evidence that a local carrageenan injection induces a systemic response.
Assuntos
Carragenina , Inflamação/patologia , Animais , Proteína C-Reativa/metabolismo , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/patologia , Fibrinogênio/metabolismo , Pé/patologia , Inflamação/induzido quimicamente , Pulmão/patologia , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tromboplastina/metabolismoRESUMO
The value of transient elastography (TE) to assess clinical outcomes in hepatitis C recurrence after liver transplantation (LT) has not been explored so far. We studied 144 hepatitis C-infected and 48 non-hepatitis C virus (HCV)-infected LT recipients and evaluated the prognostic value of TE 1 year after transplantation to predict clinical decompensations and graft and patient survival. In HCV patients, cumulative probabilities of liver decompensation 5 years after LT were 8% for patients with liver stiffness measurement (LSM) <8.7 kilopascals (kPa) versus 47% for patients with LSM ≥ 8.7 kPa (p<0.001). Five-year graft and patient cumulative survival were 90% and 92% in patients with LSM<8.7 kPa (p<0.001) and 63% and 64% in patients with LSM ≥ 8.7 kPa, respectively (p<0.001). Patients with low LSM 1 year after LT had excellent outcomes independently from receiving antiviral treatment or achieving sustained virological response (SVR). In contrast, graft survival significantly improved in patients with LSM ≥ 8.7 kPa who achieved SVR. No association between outcomes and LSM at 12 months was observed in non-HCV patients. In conclusion, LSM 1 year after LT is a valuable tool to predict hepatitis C-related outcomes in recurrent hepatitis C and can be used in clinical practice to identify the best candidates for antiviral therapy.
Assuntos
Antivirais/uso terapêutico , Sobrevivência de Enxerto , Hepatite C/tratamento farmacológico , Hepatite C/cirurgia , Transplante de Fígado/efeitos adversos , Fígado/patologia , Complicações Pós-Operatórias , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Técnicas de Imagem por Elasticidade , Feminino , Seguimentos , Hepacivirus/patogenicidade , Hepatite C/virologia , Humanos , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Adulto JovemRESUMO
IL28B gene polymorphisms are associated with the response to antiviral therapy in hepatitis C patients. We investigated the influence of IL28B polymorphisms on the response to therapy before and after liver transplantation (LT). Genotyping of SNPs rs8099917 and rs12979860 was performed in 128 HCV-infected liver transplant recipients and in their donors; all patients underwent antiviral treatment after LT. The prevalence of genotypes rs12979860CC and rs8099917TT was higher in donors than in recipients (50% vs.19%, p < 0.001 and 67% vs. 38%, p < 0.001, respectively). Response to antiviral therapy was significantly higher for recipient genotype rs12979860CC as compared to rs12979860CT/TT both before (100% vs. 48% p = 0.013) and after LT (59% vs. 25% p = 0.002). The figures were almost identical for SNP rs8099917. Sustained virological response after LT was particularly high in patients with favorable recipient and donor genotypes (p < 0.01 for both SNPs). In a subgroup of 34 patients treated while awaiting LT, a favorable donor IL28B genotype was associated with an improved virological response after LT. Our results support a major role of recipient IL28B genotype in the response to antiviral treatment for hepatitis C recurrence. Interestingly, donor genotype also seems to influence the response pattern, especially in recipients who have a favorable IL28B genotype.