RESUMO
BACKGROUND: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. MATERIALS AND METHODS: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. RESULTS: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. CONCLUSIONS: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Pontuação de Propensão , Estudos Retrospectivos , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia , Prognóstico , Quinolinas , Estudos RetrospectivosAssuntos
Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Hemorragia Gastrointestinal/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Idoso de 80 Anos ou mais , Endoscopia por Cápsula , Feminino , Hemorragia Gastrointestinal/diagnóstico , Humanos , Intestino Delgado , Niacinamida/efeitos adversos , SorafenibeRESUMO
p59fyn, a member of the src-family protein tyrosine kinase, is expressed abundantly in thymus. We examined the possible involvement of p59fyn in thymic involution induced by a fasting stress in Fyn-/- mice. An acute 48 h fast resulted in severe atrophy of the thymus and a marked decrease of the total thymocyte number with depletion of the CD4+CD8+[double positive (DP)] population in Fyn+/+ (control) mice. A remarkable increase in terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling-positive signals was detected in the fasted group of control mice. However, these findings were not observed in Fyn-/- mice. Interestingly, MRL/MPJ-lpr/lpr, a Fas-deficient model animal, also showed no significant decrease of DP cell numbers in the fasted group. p59fyn is known to interact with Fas signalling, and these findings suggest that p59fyn is involved in fasting-induced thymic involution, raising the possibility that Fas/p59fyn-mediated signalling may, at least partially, be associated with the phenomenon.
Assuntos
Jejum/fisiologia , Proteínas Proto-Oncogênicas/imunologia , Timo/imunologia , Receptor fas/imunologia , Quinases da Família src/imunologia , Animais , Apoptose/imunologia , Relação CD4-CD8 , Corticosterona/sangue , Dexametasona/farmacologia , Feminino , Glucocorticoides/farmacologia , Histocitoquímica , Marcação In Situ das Extremidades Cortadas , Leptina/sangue , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Proteínas Proto-Oncogênicas c-fyn , Timo/citologiaRESUMO
A 28-year-old woman developed an acute exacerbation of chronic ulcerative colitis in the second trimester of pregnancy. She was treated by intensive medical treatment with intravenous prednisolone, betamethasone enema, oral salazosulfapyridine, intravenous ceftazitim, and total parenteral nutrition. The acute relapse subsided after 73 days of the treatment and a normal female newborn weighing 2,208 g was delivered vaginally after 40 weeks' gestation. Our experience showed that the intensive medical therapy did not impair either the course of the pregnancy or the fetal outcome.
Assuntos
Colite Ulcerativa/terapia , Complicações na Gravidez/terapia , Resultado da Gravidez , Adulto , Betametasona/administração & dosagem , Colite Ulcerativa/diagnóstico , Quimioterapia Combinada , Feminino , Humanos , Recém-Nascido , Nutrição Parenteral , Prednisolona/administração & dosagem , Gravidez , Complicações na Gravidez/diagnóstico , Terceiro Trimestre da Gravidez , Sigmoidoscopia , Sulfassalazina/administração & dosagem , Resultado do TratamentoRESUMO
Aseptic loosening of a prosthesis is a hazardous problem after total joint replacement. In revision surgery, fibrous granulation tissue is always seen between the prosthesis and the bone or between the bone cement and the bone. We refer to this granulation tissue as the "bone-implant-interface" and it invades into the bone, resulting in osteolysis around the prosthesis. In order to investigate the histology of this granulation tissue and the mechanism of bone resorption, we produced an experimental model of the loosening of implants (alumina ceramic, PMMA, HDP) in the distal femoral condyles of rabbit. Each implant was inserted into the distal femoral condyle and connected with a Kirschner wire which was wired down to the tibia and fixed tightly to the tibial cortex. The implants could then be mobilized when the rabbits moved their knees. We called this a "micro-motion model". Besides doing this, we also developed a similar model in rabbit with ferritin-induced arthritis to investigate whether or not arthritis exacerbated the loosening of a prosthesis. The histological examinations of the bone-implant-interface in the micro-motion model in normal rabbit revealed three layers: a surface layer containing small round cells such as synovial lining cells, a middle layer containing many fibroblasts, macrophages and giant cells which phagocytize wear debris, and a deep layer adjacent to the bone containing many osteoclasts. In the models with ferritin-induced arthritis, more synovial lining cells were seen in the surface layer and more osteoclasts were seen in the deep layer. Also more osteolysis occurred around the implant in the arthritis model. In summary, the results suggested that the mechanical stress of motion stimulated the growth of synovial lining cells and macrophages in the bone-implant-interface, resulting in increased numbers of osteoclasts and in subsequent osteolysis.
Assuntos
Reabsorção Óssea/patologia , Prótese Articular , Próteses e Implantes , Animais , Fenômenos Biomecânicos , Tecido de Granulação/patologia , Osteoclastos , Osteólise , Falha de Prótese , Coelhos , Estresse MecânicoRESUMO
The Kyoto total knee cementless prosthesis (KC-1) was used in 23 patients with rheumatoid arthritis. Its femoral component is made of alumina ceramics which articulated with a HDP plate supported by a ceramic plate. Although the followup period is short, the postoperative result is not satisfactory, because remarkable sinking of the tibial component was noticed in those patients who have bone atrophy. We had 6 cases of revision so far. Since 1986, we have been using bone cement in all cases of RA in doing TKA.
Assuntos
Artrite Reumatoide/patologia , Artrite Reumatoide/cirurgia , Prótese do Joelho/normas , Osseointegração , Adulto , Idoso , Óxido de Alumínio , Artrite Reumatoide/diagnóstico por imagem , Cimentos Ósseos , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Desenho de Prótese , Falha de Prótese , Radiografia , ReoperaçãoAssuntos
Penicilina G/análogos & derivados , Peritonite/tratamento farmacológico , Sulbenicilina/uso terapêutico , Adulto , Idoso , Avaliação de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peritonite/etiologia , Peritonite/microbiologia , Complicações Pós-Operatórias , Sulbenicilina/administração & dosagemRESUMO
TThe effect of prostaglandin F 2 alpha was studied clinically and electromyographically on the motility of the gastric antrum, duodenum, jejunum, ileum and transverse colon in 20 patients by giving 2 hours intravenous drip infusion at 0.3 approximately 0.5 microgram/kg/min for 2 hours after major abdominal surgery. Folling results were obtained. 1. The motility of stomach and colon was least active than any other site of alimentary tract during 48 hours after surgery. This seems to be one of the most important causes of so called postoperative ileus. 2. Recovery from reflex inhibition of motility of the alimentary tract after surgery was seen in duodenum at first, and then in jejunum and ileum in order. It was proved that intravenous drip infusion of PGF 2 alpha at 0.3 approximately 0.5 microgram/kg/min for 2 hours had produced the increase of electrical activity in any site of gastrointestinal tract and subsequently brought about increasing of propulsive movement. The effect of PGF 2 alpha is proportional to its concentration. 4. tit was concluded that PGF 2 alpha could be administered most effectively by intravvenous drip infusion at 0.5 microgram/kg/min 3 times daily for 3 days after surgery for the satisfactory recovery from the postoperative ileus, and no appreciable side effect was observed.