RESUMO
BACKGROUND: Surgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date. OBJECTIVE: The aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence. PATIENTS AND METHODS: This was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000-2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan-Meier method and risk factor analysis was performed using the Cox regression model. RESULTS: Overall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p < 0.01). CONCLUSIONS: Approximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs.
Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Recidiva Local de Neoplasia/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
PURPOSE: Postoperative pancreatic fistula (POPF) is a complication discussed in the context of pancreatic surgery, but may also result from splenectomy; a relationship that has not been investigated extensively yet. METHODS: This retrospective single-center study aimed to analyze incidence of and risk factors for POPF after splenectomy. Patient characteristics included demographic data, surgical procedure, and intra- and postoperative complications. POPF was defined according to the International Study Group on Pancreatic Surgery as POPF of grade B and C or biochemical leak (BL). RESULTS: Over ten years, 247 patients were identified, of whom 163 underwent primary (spleen-associated pathologies) and 84 secondary (extrasplenic oncological or technical reasons) splenectomy. Thirty-six patients (14.6%) developed POPF of grade B/C or BL, of which 13 occurred after primary (7.9%) and 23 after secondary splenectomy (27.3%). Of these, 25 (69.4%) were BL, 7 (19.4%) POPF of grade B and 4 (11.1%) POPF of grade C. BL were treated conservatively while three patients with POPF of grade B required interventional procedures and 4 with POPF of grade C required surgery. POPF and BL was noted significantly more often after secondary splenectomy and longer procedures. Multivariate analysis confirmed secondary splenectomy and use of energy-based devices as independent risk factors for development of POPF/BL after splenectomy. CONCLUSION: With an incidence of 4.5%, POPF is a relevant complication after splenectomy. The main risk factor identified was secondary splenectomy. Although POPF and BL can usually be treated conservatively, it should be emphasized when obtaining patients' informed consent and treated at centers with experience in pancreatic surgery.
Assuntos
Fístula Pancreática , Esplenectomia , Humanos , Incidência , Fístula Pancreática/epidemiologia , Fístula Pancreática/etiologia , Fístula Pancreática/cirurgia , Pancreaticoduodenectomia/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Estudos Retrospectivos , Fatores de Risco , Esplenectomia/efeitos adversos , Esplenectomia/métodosRESUMO
Machine perfusion will become established as the standard of care for solid organ transplantation in the near future. Ongoing studies are investigating the appropriate perfusion algorithms for each specific organ. Although it is neither proven which perfusion principle nor type of device is superior, it has already been sufficiently shown that the increasing number of marginal organs that are currently transplanted in Germany would benefit from machine perfusion for conditioning before transplantation. The addition of hypothermic and normothermic perfusion sequences opens up the possibility of conditioning of previously damaged organs as well as viability testing. Overall, machine perfusion increases the safety for the recipient and can counteract the increasingly more difficult scenario of working hour restrictions because solid organ transplantations in the future will be plannable and carried out during the day.
Assuntos
Rim , Preservação de Órgãos , Alemanha , Fígado , PerfusãoRESUMO
BACKGROUND: The incidence of lymphatic complications after kidney transplantation varies considerably in the literature. This is partly because a universally accepted definition has not been established. This study aimed to propose an acceptable definition and severity grading system for lymphatic complications based on their management strategy. METHODS: Relevant literature published in MEDLINE and Web of Science was searched systematically. A consensus for definition and a severity grading was then sought between 20 high-volume transplant centres. RESULTS: Lymphorrhoea/lymphocele was defined in 32 of 87 included studies. Sixty-three articles explained how lymphatic complications were managed, but none graded their severity. The proposed definition of lymphorrhoea was leakage of more than 50 ml fluid (not urine, blood or pus) per day from the drain, or the drain site after removal of the drain, for more than 1 week after kidney transplantation. The proposed definition of lymphocele was a fluid collection of any size near to the transplanted kidney, after urinoma, haematoma and abscess have been excluded. Grade A lymphatic complications have a minor and/or non-invasive impact on the clinical management of the patient; grade B complications require non-surgical intervention; and grade C complications require invasive surgical intervention. CONCLUSION: A clear definition and severity grading for lymphatic complications after kidney transplantation was agreed. The proposed definitions should allow better comparisons between studies.
ANTECEDENTES: La incidencia de complicaciones linfáticas tras el trasplante renal (post-kidney-transplantation lymphatic, PKTL) varía considerablemente en la literatura. Esto se debe en parte a que no se ha establecido una definición universalmente aceptada. Este estudio tuvo como objetivo proponer una definición aceptable para las complicaciones PKTL y un sistema de clasificación de la gravedad basado en la estrategia de tratamiento. MÉTODOS: Se realizó una búsqueda sistemática de la literatura relevante en MEDLINE y Web of Science. Se logró un consenso para la definición y la clasificación de gravedad de las PKTL entre veinte centros de trasplante de alto volumen. RESULTADOS: En 32 de los 87 estudios incluidos se definía la linforrea/linfocele. Sesenta y tres artículos describían como se trataban las PKTL, pero ninguno calificó la gravedad de las mismas. La definición propuesta para la linforrea fue la de un débito diario superior a 50 ml de líquido (no orina, sangre o pus) a través del drenaje o del orificio cutáneo tras su retirada, más allá del 7º día postoperatorio del trasplante renal. La definición propuesta para linfocele fue la de una colección de líquido de tamaño variable adyacente al riñón trasplantado, tras haber descartado un urinoma, hematoma o absceso. Las PKTL de grado A fueron aquellas con escaso impacto o que no requirieron tratamiento invasivo; las PKTL de grado B fueron aquellas que precisaron intervención no quirúrgica y las PKTL de grado C aquellas en que fue necesaria la reintervención quirúrgica. CONCLUSIÓN: Se propone una definición clara y una clasificación de gravedad basada en la estrategia de tratamiento de las PKTLs. La definición propuesta y el sistema de calificación en 3 grados son razonables, sencillos y fáciles de comprender, y servirán para estandarizar los resultados de las PKTL y facilitar las comparaciones entre los diferentes estudios.
Assuntos
Transplante de Rim/efeitos adversos , Doenças Linfáticas/etiologia , Humanos , Doenças Linfáticas/diagnóstico , Doenças Linfáticas/patologia , Índice de Gravidade de Doença , Terminologia como AssuntoRESUMO
Although gastric neuroendocrine neoplasias (gNEN) are an orphan disease, their incidence is rising. The heterogeneous clinical course powers the ongoing discussion of the most appropriate classification system and management. Prognostic relevance of proposed classifications was retrospectively analysed in 142 patients from a single tertiary referral centre. Baseline, management and survival data were acquired for statistical analyses. The distribution according to the clinicopathological typification was gNEN-1 (n = 86/60.6%), gNEN-2 (n = 7/4.9%), gNEN-3 (n = 24/16.9%) and gNEN-4 (n = 25/17.6%), while hypergastrinemia-associated gNEN-1 and -2 were all low-grade tumours (NET-G1/2), formerly termed sporadic gNEN-3 could be subdivided into gNEN-3 with grade 1 or 2 and gNEN-4 with grade 3 (NEC-G3). During follow-up 36 patients died (25%). The mean overall survival (OS) of all gNEN was 14.2 years. The OS differed statistically significant across all subgroups with either classification system. According to UICC 2017 TNM classification, OS differed for early and advanced stages, while WHO grading indicated poorer prognosis for NEC-G3. Cox regression analysis confirmed the independent prognostic validity of either classification system for survival. Particularly careful analysis of the clinical course of gNEN-1 (ECLomas, gastric carcinoids) confirmed their mostly benign, but recurrent and extremely slowly progressive behaviour with low risk of metastasis (7%) and an efficient long-term control by repetitive endoscopic procedures. Our study provides evidence for the validity of current classifications focusing on typing, grading and staging. These are crucial tools for risk stratification, especially to differentiate gNEN-1 as well as sporadic gNET and gNEC (gNEN-3 vs -4).
Assuntos
Neoplasias Intestinais/patologia , Antígeno Ki-67/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/patologia , Adulto , Estudos de Coortes , Feminino , Humanos , Neoplasias Intestinais/classificação , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/classificação , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/terapia , Taxa de SobrevidaRESUMO
BACKGROUND: Gastrointestinal surgery is still associated with a relevant morbidity with the intestinal microbiome being of high importance in the pathogenesis of infectious complications. Various approaches, such as mechanical bowel preparation (MBP) with or without administration of oral antibiotics, fasting or dietary supplements aim at modulating the intestinal flora. OBJECTIVE: This review summarizes the current literature pertinent to the influence of preoperative bowel conditioning on postoperative morbidity. MATERIAL AND METHODS: A literature search was performed using the mentioned keywords with a focus on recent meta-analyses. RESULTS AND CONCLUSION: Bowel conditioning reduces postoperative infectious complications. Promising approaches are MBP plus administration of oral antibiotics, dietary supplements aiming at stabilization of the intestinal flora as well as the screening for and equilibration of malnutrition. The use of MBP as monotherapy without antibiotics should no longer be considered part of the clinical routine.
Assuntos
Antibioticoprofilaxia , Procedimentos Cirúrgicos do Sistema Digestório , Infecção da Ferida Cirúrgica , Administração Oral , Catárticos , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Humanos , Cuidados Pré-Operatórios , Infecção da Ferida Cirúrgica/prevenção & controleRESUMO
Neuroendocrine neoplasms (NEN) represent a group of potentially malignant tumors, which can be located in every section of the gastrointestinal tract, the pancreas and the bronchopulmonary system. Gastroduodenal NENs have a relatively good prognosis in comparison to other subentities, e.g. pancreatic or ileojejunal NENs. In the stomach there are four different types of NENs, while in the duodenum there are five types and all vary in the malignant potential and the therapeutic approach. Due to the simple access endoscopic methods not only have diagnostic but also important therapeutic relevance in this subgroup. Lesions smaller than 1 cm can easily be resected with forceps or snare resection and for larger lesions up to 2 cm more invasive strategies, such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) are available. Important criteria in gastric NEN for the risk evaluation of endoscopic treatment alone are the size of the lesion, depth of invasion and the tumor biology, e.g. neuroendocrine tumor (NET) G1/G2 versus neuroendocrine carcinoma (NEC) G3. In duodenal NEN the aforementioned risk factors also apply and in addition only lesions outside the ampulla of Vater should be endoscopically resected whereas periampullary lesions need to be addressed surgically. As an individualized therapeutic approach the possibility of a combined endoscopic and laparoscopic resection technique exists. Follow-up endoscopic investigations are necessary, especially in gastric type 1 NENs, which have a tendency to relapse.
Assuntos
Neoplasias Duodenais/patologia , Neoplasias Duodenais/cirurgia , Duodenoscopia/métodos , Gastroscopia/métodos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Humanos , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Síndrome de Zollinger-Ellison/patologia , Síndrome de Zollinger-Ellison/cirurgiaRESUMO
Intestinal failure (IF) is a debilitating condition of inadequate nutrition due to an anatomical and/or physiological deficit of the intestine. Surgical management of patients with acute and chronic IF requires expertise to deal with technical challenges and make correct decisions. Dedicated IF units have expertise in patient selection, operative risk assessment and multidisciplinary support such as nutritional input and interventional radiology, which dramatically improve the morbidity and mortality of this complex condition and can beneficially affect the continuing dependence on parenteral nutritional support. Currently there is little guidance to bridge the gap between general surgeons and specialist IF surgeons. Fifteen European experts took part in a consensus process to develop guidance to support surgeons in the management of patients with IF. Based on a systematic literature review, statements were prepared for a modified Delphi process. The evidence for each statement was graded using Oxford Centre for Evidence-Based Medicine Levels of Evidence. The current paper contains the statements reflecting the position and practice of leading European experts in IF encompassing the general definition of IF surgery and organization of an IF unit, strategies to prevent IF, management of acute IF, management of wound, fistula and stoma, rehabilitation, intestinal and abdominal reconstruction, criteria for referral to a specialist unit and intestinal transplantation.
Assuntos
Síndromes de Malabsorção/terapia , Desnutrição/terapia , Desequilíbrio Hidroeletrolítico/terapia , Consenso , Humanos , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/etiologia , Desnutrição/etiologia , Nutrição Parenteral , Desequilíbrio Hidroeletrolítico/etiologiaAssuntos
Neoplasias Duodenais/terapia , Tumores Neuroendócrinos/terapia , Neoplasias Gástricas/terapia , Neoplasias Duodenais/diagnóstico , Neoplasias Duodenais/epidemiologia , Neoplasias Duodenais/patologia , Europa (Continente) , Humanos , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologiaRESUMO
Efficacy and safety of protein kinase C inhibitor sotrastaurin (STN) with tacrolimus (TAC) was assessed in a 24-month, multicenter, phase II study in de novo liver transplant recipients. A total of 204 patients were randomized (1:1:1:1) to STN 200 mg b.i.d. + standard-exposure TAC (n = 50) or reduced-exposure TAC (n = 52), STN 300 mg b.i.d. + reduced-exposure TAC (n = 50), or mycophenolate mofetil (MMF) 1 g b.i.d. + standard-exposure TAC (control, n = 52); all with steroids. Owing to premature study termination, treatment comparisons were only conducted for Month 6. At Month 6, composite efficacy failure rates (treated biopsy-proven acute rejection episodes of Banff grade ≥1, graft loss, or death) were 25.0%, 16.5%, 20.9% and 15.9% for STN 200 mg + standard TAC, STN 200 mg + reduced TAC, STN 300 mg + reduced TAC and control groups, respectively. Median estimated glomerular filtration rates were 84.0, 83.3, 81.1 and 75.3 mL/min/1.73 m(2), respectively. Gastrointestinal events (constipation, diarrhea, and nausea), infection, and tachycardia were more frequent in STN groups. More patients in STN groups experienced serious adverse events compared with the control group (62.3-70.8% vs. 51.9%). STN-based regimens were associated with a higher efficacy failure rate and higher incidence of adverse events with no significant difference in renal function between the groups.
Assuntos
Inibidores Enzimáticos/administração & dosagem , Falência Hepática/cirurgia , Transplante de Fígado/métodos , Proteína Quinase C/antagonistas & inibidores , Pirróis/administração & dosagem , Quinazolinas/administração & dosagem , Adulto , Idoso , Biópsia , Feminino , Taxa de Filtração Glomerular , Rejeição de Enxerto , Humanos , Imunossupressores/administração & dosagem , Incidência , Estimativa de Kaplan-Meier , Transplante de Rim , Falência Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Tacrolimo/administração & dosagem , Fatores de Tempo , Resultado do TratamentoRESUMO
The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.
Assuntos
Inibidores de Calcineurina , Ciclosporina/administração & dosagem , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/administração & dosagem , Hepatopatias/cirurgia , Transplante de Fígado , Sirolimo/análogos & derivados , Adolescente , Adulto , Idoso , Ciclosporina/efeitos adversos , Everolimo , Estudos de Viabilidade , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Sirolimo/administração & dosagem , Fatores de Tempo , Suspensão de Tratamento , Adulto JovemRESUMO
Liver and kidney transplantations have been performed for almost 50 years and is nowadays a routine procedure for the treatment of terminal liver failure and terminal-stage renal failure. Under given optimal conditions and increasing experience good results can be achieved. Improvements in surgical techniques have led to a decrease in the incidence of surgical complications after transplantation. Nevertheless after liver and kidney transplantation complications can occur and increase the morbidity and mortality. There are a number of possible complications which range from harmless wound healing disorders to severe vascular, biliary or urinary complications that can be associated with graft dysfunction and lead to graft loss. In order to identify risk factors preoperatively and achieve good outcome after transplantation a good preparation of the recipients is necessary. Furthermore, a good interdisciplinary cooperation is necessary both to recognize complications early and to treat these adequately.
Assuntos
Imunossupressores/efeitos adversos , Transplante de Rim , Falência Hepática/cirurgia , Transplante de Fígado , Complicações Pós-Operatórias/cirurgia , Insuficiência Renal/cirurgia , Comportamento Cooperativo , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/cirurgia , Hepatectomia , Humanos , Imunossupressores/uso terapêutico , Comunicação Interdisciplinar , Nefrectomia , Prognóstico , Reoperação , Fatores de Risco , Taxa de Sobrevida , Cicatrização/efeitos dos fármacosRESUMO
Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal-sparing alternative. In this randomized 1-year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post-LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft-Gault formula (-2.9 mL/min in favor of EVR, 95%-CI: [-10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (-7.8 mL/min, 95%-CI: [-14.366; -1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy-proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI-based to EVR-based immunosuppression proved to be a safe alternative post-LTx that deserves further investigation in terms of nephroprotection.
Assuntos
Inibidores de Calcineurina , Imunossupressores/administração & dosagem , Transplante de Fígado , Sirolimo/análogos & derivados , Adulto , Everolimo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sirolimo/administração & dosagemRESUMO
A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression.
Assuntos
Inibidores de Calcineurina , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/administração & dosagem , Transplante de Fígado , Sirolimo/administração & dosagem , Adolescente , Adulto , Idoso , Ciclosporina/administração & dosagem , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tacrolimo/administração & dosagem , Resultado do TratamentoAssuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/cirurgia , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/cirurgia , Quimioterapia Adjuvante , Terapia Combinada , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/radioterapia , Humanos , Terapia de Alvo Molecular/métodos , Estadiamento de Neoplasias , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/radioterapia , Medicina de Precisão , Prognóstico , Radioterapia/métodos , Radioterapia Adjuvante , Somatostatina/análogos & derivadosRESUMO
Dendritic cell (DC) function is believed to be of critical importance for the pathogenesis of inflammatory bowel disease (IBD). To date, most research in animal models and the few human data available is restricted to myeloid DC, while plasmacytoid DC (pDC) capable of controlling both innate and adaptive immune responses have not yet been investigated systematically in human Crohn's disease (CD) or ulcerative colitis (UC). CD11c(-) , CD303(+) /CD304(+) and CD123(+) pDC from peripheral blood (n = 90), mucosal tissue (n = 28) or mesenteric lymph nodes (n = 40) (MLNs) of patients with UC and CD or controls were purified and cultured. Thereafter, pDC were enumerated, phenotyped and cytokine secretion measured by flow cytometry (FACS), immunohistochemistry and/or cytometric bead array, respectively. Interferon (IFN)-α secretion following cytosine phosphatidyl guanine (CpG) A oligodeoxynucleotide (ODN) 2216 (5'-GGGGGACGATCGTCGGGGGG-3') stimulation was assessed by enzyme-linked immunosorbent assay (ELISA). We found a significantly higher frequency of pDC in the inflamed colonic mucosa and MLN of IBD patients. Moreover, the fraction of CD40 and CD86 expressing cultured peripheral blood pDC was significantly higher in flaring UC and CD patients and their secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 were increased significantly compared with controls. In contrast, the IFN-α secretion of peripheral blood pDC isolated from flaring IBD, particularly in UC patients, was reduced significantly compared with controls. Our data suggest an aberrant distribution and function of pDC in IBD, contrary to their generally implicated role as inducers of tolerance. We speculate that the impaired IFN-α secretion may relate to the hypothesized defect in innate immunity in IBD and could also impact upon the generation of regulatory T cells (T(reg) ).
Assuntos
Colite Ulcerativa , Doença de Crohn , Células Dendríticas , Mucosa Intestinal/imunologia , Linfonodos/imunologia , Adulto , Idoso , Antígenos CD/análise , Antígenos CD/biossíntese , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Doença de Crohn/imunologia , Doença de Crohn/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Interferon-alfa/análise , Interferon-alfa/biossíntese , Interleucina-6/análise , Interleucina-6/biossíntese , Interleucina-8/análise , Interleucina-8/biossíntese , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Oligodesoxirribonucleotídeos/farmacologia , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/biossínteseRESUMO
We reported the successful administration of infliximab for late-onset OKT3-resistant rejection in two patients, who presented persistent ulcerative inflammation of the ileal graft after intestinal transplantation (ITX). Based on this experience, the present study demonstrated our long-term experience with infliximab for different types of rejection-related and inflammatory allograft alterations. Infliximab administration (5 mg/kg body weight (BW)) was initiated at a mean of 18.2 ± 14.1 months after transplantation. The number of administrations per patient averaged 8.4 ± 6.7. Repeat dosing was timed according to clinical signs and graft histology in addition to serum-levels of tumor necrosis factor alpha (TNFα), lipopolysaccharide binding protein (LBP) and C-reactive protein (CRP). Infliximab was successful in the following patients: patients with late-onset OKT3- and steroid-refractory rejection who presented persistent ulcerative alterations of the ileal graft (n = 5), patients with ulcerative ileitis/anastomositis, who did not show typical histological rejection signs (n = 2), and one patient with early-onset OKT3-resistant rejection. Infliximab was not successful in one patient with early-onset OKT3-resistant rejection that was accompanied by treatment-refractory humoral rejection. In conclusion, infliximab can expand therapeutic options for late-onset OKT3- and steroid-refractory rejection and chronic inflammatory graft alterations in intestinal allograft recipients.