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1.
HPB (Oxford) ; 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30975599

RESUMO

BACKGROUND: The systemic inflammatory response seen after surgery seems to be related to postoperative complications. A reduction of the inflammatory response through minimally invasive surgery might therefore be the mechanism via which postoperative outcome could be improved. The aim of this study was to investigate if postoperative inflammatory markers differed between laparoscopic (LPD) and open pancreatoduodenectomy (OPD) and if there was a relationship between inflammatory markers and the occurrence of postoperative complications. METHODS: A side study of the multicenter randomized controlled LEOPARD-2 trial comparing LPD to OPD was performed. Area under the curve (AUC) for plasma inflammatory markers, including interleukin (IL-) 6, IL-8 and C reactive protein (CRP) levels, were determined during the first 96 postoperative hours and compared between LPD and OPD, Clavien-Dindo ≥ III complications, and postoperative pancreatic fistula (POPF) grade B/C. RESULTS: Overall, 38 patients were included (18 LPD and 20 OPD). The median AUC of IL-6 was 627 (195-1378) after LPD vs. 338 (175-694)pg/mL after OPD, (p = 0.114). The AUC of IL-8 and CRP were comparable. IL-6 levels were higher in patients with a Clavien-Dindo ≥ III complication (634[309-1489] vs. 297 [171-680], p = 0.034) and POPF grade B/C (994 [534-3265] vs. 334 [173-704], p = 0.003). In patients with a POPF grade B/C, IL-6 levels tended to be higher after LPD, as compared to OPD (3533[IQR 1133-3533] vs. 715[IQR 39-1658], p = 0.053). CONCLUSION: LPD, as compared to OPD, did not reduce the postoperative inflammatory response. IL-6 levels were associated with postoperative complications and pancreatic fistula.

2.
Sci Rep ; 9(1): 5132, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30914789

RESUMO

Induction of hypothermia and consequent hypometabolism by pharmacological downmodulation of the internal thermostat could be protective in various medical situations such as ischemia/reperfusion. Systemic hypoxia is a trigger of thermostat downregulation in some mammals, which is sensed though carotid chemoreceptors (carotid bodies, CBs). Using non-invasive thermographic imaging in mice, we demonstrated that surgical bilateral CB denervation does not hamper hypoxia-induced hypothermia. However, the recovery from a protective and reversible hypothermic state after restoration to normoxic conditions was impaired in CB-resected mice versus control animals. Therefore, the carotid chemoreceptors play an important role in the central regulation of hypoxia-driven hypothermia in mice, but only in the rewarming phase.

3.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1192-1200, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30658161

RESUMO

OBJECTIVE AND BACKGROUND: Activation of sterile inflammation after hepatic ischemia/reperfusion (I/R) culminates in liver injury. The route to liver damage starts with mitochondrial oxidative stress and cell death during early reperfusion. The link between mitochondrial oxidative stress, damage-associate molecular pattern (DAMP) release, and sterile immune signaling is incompletely understood and lacks clinical validation. The aim of the study was to validate this relation in a clinical liver I/R cohort and to limit DAMP release using a mitochondria-targeted antioxidant in I/R-subjected mice. METHODS: Plasma levels of the DAMPs high-mobility group box 1 (HMGB1), mitochondrial DNA, and nucleosomes were measured in 39 patients enrolled in an observational study who underwent a major liver resection with (N = 29) or without (N = 13) intraoperative liver ischemia. Circulating cytokine and neutrophil activation markers were also determined. In mice, the mitochondria-targeted antioxidant MitoQ was intravenously infused in an attempt to limit DAMP release, reduce sterile inflammation, and suppress I/R injury. RESULTS: In patients, HMGB1 was elevated following liver resection with I/R compared to liver resection without I/R. HMGB1 levels correlated positively with ischemia duration and peak post-operative transaminase (ALT) levels. There were no differences in mitochondrial DNA, nucleosome, or cytokine levels between the two groups. In mice, MitoQ neutralized hepatic oxidative stress and decreased HMGB1 release by ±50%. MitoQ suppressed transaminase release, hepatocellular necrosis, and cytokine production. Reconstituting disulfide HMGB1 during reperfusion reversed these protective effects. CONCLUSION: HMGB1 seems the most pertinent DAMP in clinical hepatic I/R injury. Neutralizing mitochondrial oxidative stress may limit DAMP release after hepatic I/R and reduce liver damage.

5.
PLoS One ; 13(11): e0206692, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30395652

RESUMO

As an integral membrane protein, purification and characterization of phospho-N- acetylmuramyl- pentapeptide translocase MraY have proven difficult. Low yield and concerns of retaining stability and activity after detergent solubilization have hampered the structure-function analysis. The recently developed detergent-free styrene-maleic acid (SMA) co-polymer system offers an alternative approach that may overcome these disadvantages. In this study, we used the detergent free system to purify MraY from Bacillus subtilis. This allowed efficient extraction of MraY that was heterologously produced in Escherichia coli membranes into SMA-wrapped nanodiscs. The purified MraY embedded in these nanodiscs (SMA-MraY) was comparable to the micellar MraY extracted with a conventional detergent (DDM) with regard to the yield and the purity of the recombinant protein but required significantly less time. The predominantly alpha-helical secondary structure of the protein in SMA-wrapped nanodiscs was also more stable against heat denaturation compared to the micellar protein. Thus, this detergent-free system is amenable to extract MraY efficiently and effectively while maintaining the biophysical properties of the protein. However, the apparent activity of the SMA-MraY was reduced compared to that of the detergent-solubilized protein. The present data indicates that this is caused by a lower accessibility of the enzyme in SMA-wrapped nanodiscs towards its polyisoprenoid substrate.

6.
Sci Rep ; 8(1): 16529, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30409980

RESUMO

Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent sham surgery or reversible bile duct ligation (rBDL). PHx with concurrent internal biliary drainage was performed 7 days after rBDL. Animals were untreated or received OCA (10 mg/kg/day) per oral gavage from rBDL until sacrifice. After 7 days of OCA treatment, dry liver weight increased in the rBDL + OCA group, indicating OCA-mediated liver growth. Enhanced proliferation in the rBDL + OCA group prior to PHx concurred with a rise in Ki67-positive hepatocytes, elevated hepatic Ccnd1 and Cdc25b expression, and an induction of intestinal fibroblast growth factor 15 expression. Liver regrowth after PHx was initially stagnant in the rBDL + OCA group, possibly due to hepatomegaly prior to PHx. OCA increased hepatobiliary injury markers during BDL, which was accompanied by upregulation of the bile salt export pump. There were no differences in histological liver injury. In conclusion, OCA induces liver growth in cholestatic rats prior to PHx but exacerbates biliary injury during cholestasis, likely by forced pumping of bile acids into an obstructed biliary tree.

7.
Anesth Analg ; 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30451726

RESUMO

BACKGROUND: Glycocalyx shedding after traumatic hemorrhagic or septic shock, as well as different resuscitation fluids, has been causally linked to increased vascular barrier permeability (VBP) resulting in tissue edema. In nontraumatic hemorrhagic shock (NTHS), it remains questionable whether glycocalyx degradation in itself results in an alteration of VBP. The composition of fluids can also have a modulatory effect on glycocalyx shedding and VBP. We hypothesized that the shedding of the glycocalyx during NTHS has little effect on VBP and that the composition of fluids can modulate these effects. METHODS: Fully instrumented Wistar-albino rats were subjected to a pressure-controlled NTHS (mean arterial pressure of 30 mm Hg) for 60 minutes. Animals were fluid resuscitated with Ringer's acetate, balanced hydroxyethyl starch (HES) solution, or 0.9% normal saline to a mean arterial pressure of 80 mm Hg and compared with shams or nonresuscitated NTHS. Glycocalyx shed products were determined at baseline and 60 minutes after fluid resuscitation. Skeletal muscle microcirculation was visualized using handheld vital microscopy. VBP changes were assessed using plasma decay of 3 fluorescent dyes (40- and 500-kDa dextran and 70-kDa albumin), Evans blue dye exclusion, intravital fluorescence microscopy, and determination of tissue edema (wet/dry weight ratio). RESULTS: All glycocalyx shedding products were upgraded as a result of NTHS. Syndecan-1 significantly increased in NTHS (mean difference, -1668; 95% confidence interval [CI], -2336 to -1001; P < .0001), balanced crystalloid (mean difference, -964.2; 95% CI, -1492 to -436.4; P = .0001), and HES (mean difference, -1030; 95% CI, -1594 to -465.8; P = .0001) groups at the end of the experiment compared to baseline. Hyaluronan levels were higher at the end of the experiment in nonresuscitated NTHS (-923.1; 95% CI, -1216 to -630; P = .0001) and balanced crystalloid (-1039; 95% CI, -1332 to -745.5; P = .0001) or HES (-394.2; 95% CI, -670.1 to -118.3; P = .0027) groups compared to controls. Glycocalyx shedding resulted in microcirculation alterations as observed by handheld video microscopy. Total vessel density was altered in the normal saline (mean difference, 4.092; 95% CI, 0.6195-7.564; P = .016) and hemorrhagic shock (mean difference, 5.022; 95% CI, 1.55-8.495; P = .0024) groups compared to the control group, as well as the perfused vessel density and mean flow index. Despite degradation of endothelial glycocalyx, VBP as determined by 4 independent assays remained intact and continued to be so following fluid resuscitation. CONCLUSIONS: NTHS induced glycocalyx shedding and microcirculation alterations, without altering VBP. Fluid resuscitation partially restored the microcirculation without altering VBP. These results challenge the concept that the glycocalyx barrier is a significant contributor to VBP.

8.
Int J Pharm ; 550(1-2): 190-199, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30130606

RESUMO

Thermosensitive liposomes grafted with cholesterol-conjugated poly(N-(2-hydroxypropyl) methacrylamide mono/dilactate) (chol-pHPMAlac) have been developed for heat-induced release of doxorubicin (DOX). These liposomes release DOX completely during mild hyperthermia, but their interaction with blood cells and cancer cells has not been studied. Following intravenous administration, liposomes may interact with plasma proteins and various types of cells (e.g., endothelial cells, platelets, and macrophages), which would reduce their disposition in the tumor stroma. Interaction between liposomes and platelets may further cause platelet activation and thrombosis, which could lead to vascular occlusion and thromboembolic complications. The aim was to investigate DOX release kinetics in the presence of serum, stability, in vitro uptake by and toxicity to cancer cells and somatic cells, and platelet activating potential of the chol-pHPMAlac liposomes. DOX release was determined spectrofluorometrically. Liposome stability was determined in buffer and serum by dynamic light scattering and nanoparticle tracking analysis. Association with/uptake by and toxicity of empty liposomes to AML-12, HepG2 (both hepatocyte-derived cancer cells), RAW 264.7 (macrophages), and HUVEC (endothelial) cells was assayed in vitro. Platelet activation was determined by analysis of P-selectin expression and fibrinogen binding. DOPE:EPC liposomes (diameter = 135 nm) grafted with 5% chol-pHPMAlac (cloud point (CP) = 16 °C; Mn = 8.5 kDa) released less than 10% DOX at 37 °C in 30 min, whereas complete release took place at 47 °C or higher within 10 min. The size of these liposomes remained stable in buffer and serum during 24 h at 37 °C. Fluorescently labeled but DOX-lacking chol-pHPMAlac-liposomes exhibited poor association with/uptake by all cells under investigation, were not cytotoxic, and did not activate platelets in both buffered solution and whole blood. In conclusion, thermosensitive chol-pHPMAlac-grafted liposomes rapidly release DOX during mild hyperthermia. The liposomes are stable in a physiological milieu, are not taken up by cells that are encountered in an in vivo setting, and are non-antagonistic towards platelets. Chol-pHPMAlac-grafted liposomes are therefore good candidates for DOX delivery to tumors and temperature-triggered release in tumor stroma.

9.
Sci Rep ; 8(1): 3855, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29497053

RESUMO

Hydrogen sulfide (H2S, 80 ppm) gas in an atmosphere of 17.5% oxygen reportedly induces suspended animation in mice; a state analogous to hibernation that entails hypothermia and hypometabolism. However, exogenous H2S in combination with 17.5% oxygen is able to induce hypoxia, which in itself is a trigger of hypometabolism/hypothermia. Using non-invasive thermographic imaging, we demonstrated that mice exposed to hypoxia (5% oxygen) reduce their body temperature to ambient temperature. In contrast, animals exposed to 80 ppm H2S under normoxic conditions did not exhibit a reduction in body temperature compared to normoxic controls. In conclusion, mice induce hypothermia in response to hypoxia but not H2S gas, which contradicts the reported findings and putative contentions.

10.
J Cosmet Laser Ther ; 20(2): 77-84, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29384394

RESUMO

BACKGROUND: Pulsed dye laser is the gold standard for port-wine stain (PWS) treatment. However, pulsed dye lasers achieve suboptimal clinical results in a majority of patients. Patient demand for novel therapies and willingness to participate in clinical studies is currently unknown, yet, imperative for steering R&D activity. The objective of this study was to evaluate these two factors in relation to PWS patient demographics. METHODS: A questionnaire was used to assess patient and PWS characteristics, treatment history, efficacy, and satisfaction, stress level, willingness to travel and pay for an effective treatment, participation in clinical studies, and amenability to intravenous drug administration. Descriptive statistics and correlation analysis were performed. RESULTS: Of the respondents (N = 108), 65% would participate in clinical studies and 49% would accept intravenous drugs. For an effective treatment, 58% was prepared to pay over €2,000 and 48% would travel more than 6 h. Travel time was inversely correlated with age, clearance rate, and satisfaction. Facial PWS patients had undergone more treatments, were less satisfied, and less willing to participate in studies or accept intravenous drugs. Stress levels were higher in females. CONCLUSION: There is considerable demand for new PWS therapies, and a substantial proportion of patients are willing to participate in clinical studies.


Assuntos
Lasers de Corante/uso terapêutico , Preferência do Paciente , Satisfação do Paciente , Mancha Vinho do Porto/radioterapia , Sujeitos da Pesquisa/psicologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Países Baixos , Mancha Vinho do Porto/terapia , Estudos Prospectivos , Fatores Socioeconômicos , Estresse Psicológico , Adulto Jovem
11.
Biochim Biophys Acta Mol Basis Dis ; 1864(3): 942-951, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29196240

RESUMO

Obstructive cholestasis causes liver injury via accumulation of toxic bile acids (BAs). Therapeutic options for cholestatic liver disease are limited, partially because the available murine disease models lack translational value. Profiling of time-related changes following bile duct ligation (BDL) in Gold Syrian hamsters revealed a biochemical response similar to cholestatic patients in terms of BA pool composition, alterations in hepatocyte BA transport and signaling, suppression of BA production, and adapted BA metabolism. Hamsters tolerated cholestasis well for up to 28days and progressed relatively slowly to fibrotic liver injury. Hepatocellular necrosis was absent, which coincided with preserved intrahepatic energy levels and only mild oxidative stress. The histological response to cholestasis in hamsters was similar to the changes seen in 17 patients with prolonged obstructive cholestasis caused by cholangiocarcinoma. Hamsters moreover upregulated hepatic fibroblast growth factor 15 (Fgf15) expression in response to BDL, which is a cytoprotective adaptation to cholestasis that hitherto had only been documented in cholestatic human livers. Hamster models should therefore be added to the repertoire of animal models used to study the pathophysiology of cholestatic liver disease.


Assuntos
Colestase/etiologia , Colestase/patologia , Modelos Animais de Doenças , Animais , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/patologia , Cricetinae , Humanos , Fígado/patologia , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Masculino , Mesocricetus
12.
BMJ Open ; 7(9): e015810, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28864693

RESUMO

INTRODUCTION: The majority of patients with perihilar cholangiocarcinoma (PHC) has locally advanced disease or distant lymph node metastases on presentation or exploratory laparotomy, which makes them not eligible for resection. As the prognosis of patients with locally advanced PHC or lymph node metastases in the palliative setting is significantly better compared with patients with organ metastases, ablative therapies may be beneficial. Unfortunately, current ablative options are limited. Photodynamic therapy causes skin phototoxicity and thermal ablative methods, such as stereotactic body radiation therapy and radiofrequency ablation, which are affected by a heat/cold-sink effect when tumours are located close to vascular structures, such as the liver hilum. These limitations may be overcome by irreversible electroporation (IRE), a relatively new ablative method that is currently being studied in several other soft tissue tumours, such as hepatic and pancreatic tumours. METHODS AND ANALYSIS: In this multicentre phase I/II safety and feasibility study, 20 patients with unresectable PHC due to vascular or distant lymph node involvement will undergo IRE. Ten patients who present with unresectable PHC will undergo CT-guided percutaneous IRE, whereas ultrasound-guided IRE will be performed in 10 patients with unresectable tumours detected at exploratory laparotomy. The primary outcome is the total number of clinically relevant complications (Common Terminology Criteria for Adverse Events, score of≥3) within 90 days. Secondary outcomes include quality of life, tumour response, metal stent patency and survival. Follow-up will be 2 years. ETHICS AND DISSEMINATION: The protocol has been approved by the local ethics committees. Data and results will be submitted to a peer-reviewed journal. CONCLUSION: The Ablation with irreversible eLectroportation in Patients with Advanced perihilar CholangiocarcinomA (ALPACA) study is designed to assess the feasibility of IRE for advanced PHC. The main purpose is to inform whether a follow-up trial to evaluate safety and effectiveness in a larger cohort would be feasible.


Assuntos
Neoplasias dos Ductos Biliares/terapia , Ductos Biliares , Ablação por Cateter/métodos , Eletroporação/métodos , Tumor de Klatskin/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ductos Biliares/patologia , Ductos Biliares/cirurgia , Estudos de Coortes , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Projetos de Pesquisa , Adulto Jovem
13.
Cancer Cell ; 32(2): 238-252.e9, 2017 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-28810146

RESUMO

Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83-0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.


Assuntos
Algoritmos , Inteligência Artificial , Plaquetas/fisiologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Diagnóstico por Computador/métodos , Neoplasias Pulmonares/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/genética , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Máquina de Vetores de Suporte
14.
HPB (Oxford) ; 19(10): 850-858, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28687148

RESUMO

BACKGROUND: Posthepatectomy liver failure (PHLF) is a threatening complication after liver surgery, especially in perihilar cholangiocarcinoma (PHC). This study aimed to assess the value of preoperative assessment of liver function using 99mTc-mebrofenin hepatobiliary scintigraphy (HBS) to predict PHLF in comparison with liver volume in PHC patients. METHODS: All patients who underwent resection of suspected PHC in a single center between 2000 and 2015 were included in the analysis. PHLF was graded according to the ISGLS criteria with grade B/C considered clinically relevant. A cut-off value for the prediction of PHLF was calculated using the receiver operating characteristic curve (ROC) analysis. RESULTS: A total of 116 patients were included of which 27 (23%) suffered of PHLF. ROC values for the prediction of PHLF were 0.74 (0.63-0.86) for future liver remnant function and 0.63 (0.47-0.80) for volume. A cut-off for liver function was set at 8.5%/min, which resulted in a negative predictive value of 94% and positive predictive value of 41%. CONCLUSIONS: Assessment of liver function with HBS had better predictive value for PHLF than liver volume in patients undergoing major liver resection for suspected PHC. The cut-off of 8.5%/min can help to select patients for portal vein embolization and might help to reduce postoperative liver failure.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/cirurgia , Hepatectomia/efeitos adversos , Iminoácidos/administração & dosagem , Tumor de Klatskin/diagnóstico por imagem , Tumor de Klatskin/cirurgia , Falência Hepática/etiologia , Testes de Função Hepática , Compostos de Organotecnécio/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Idoso , Área Sob a Curva , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Feminino , Hepatectomia/mortalidade , Humanos , Tumor de Klatskin/mortalidade , Tumor de Klatskin/patologia , Falência Hepática/diagnóstico , Falência Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Países Baixos , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
16.
BMC Surg ; 17(1): 35, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28399849

RESUMO

BACKGROUND: Extrahepatic cholestasis sensitizes the liver to ischemia/reperfusion (I/R) injury during surgery for perihilar cholangiocarcinoma. It is associated with pre-existent sterile inflammation, microvascular perfusion defects, and impaired energy status. Statins have been shown to protect against I/R injury in normal and steatotic mouse livers. Therefore, the hepatoprotective properties of atorvastatin were evaluated in a rat model of cholestatic I/R injury. METHODS: Male Wistar rats were subjected to 70% hepatic ischemia (during 30 min) at 7 days after bile duct ligation. Rats were randomized to atorvastatin treatment or vehicle-control in three test arms: (1) oral treatment with 5 mg/kg during 7 days after bile duct ligation; (2) intravenous treatment with 2.5, 5, or 7.5 mg/kg at 24 h before ischemia; and (3) intravenous treatment with 5 mg/kg at 30 min before ischemia. Hepatocellular damage was assessed by plasma alanine aminotransferase (ALT) and histological necrosis. RESULTS: I/R induced severe hepatocellular injury in the cholestatic rat livers (~10-fold increase in ALT at 6 h after I/R and ~30% necrotic areas at 24 h after I/R). Both oral and intravenous atorvastatin treatment decreased ALT levels before ischemia. Intravenous atorvastatin treatment at 5 mg/kg at 24 h before ischemia was the only regimen that reduced ALT levels at 6 h after reperfusion, but not at 24 h after reperfusion. None of the tested regimens were able to reduce histological necrosis at 24 h after reperfusion. CONCLUSION: Pre-treatment with atorvastatin did not protect cholestatic livers from hepatocellular damage after I/R. Clinical studies investigating the role of statins in the protection against hepatic I/R injury should not include cholestatic patients with perihilar cholangiocarcinoma. These patients require (pharmacological) interventions that specifically target the cholestasis-associated hepatopathology.


Assuntos
Atorvastatina/uso terapêutico , Colestase Extra-Hepática/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fígado/patologia , Complicações Pós-Operatórias/prevenção & controle , Substâncias Protetoras/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Administração Oral , Animais , Ductos Biliares/cirurgia , Esquema de Medicação , Injeções Intravenosas , Ligadura , Masculino , Necrose/etiologia , Necrose/prevenção & controle , Complicações Pós-Operatórias/etiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Resultado do Tratamento
17.
Int J Oncol ; 2017 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-28350107

RESUMO

A method for the enumeration and quantification of osteosarcoma (OS) circulating tumor cells (CTCs) is currently not available. A correlation between the number of CTCs and progression-free survival (PFS) has been established for other cancers, but not for OS CTCs. A method was therefore developed for CTC quantification in OS and validated in a prospective cohort of surgical patients with primary and recurrent/metastatic OS (N=23). Human OS cells, acting as CTCs, were enumerated from spiked human peripheral blood (PB) following erythrocyte and leukocyte depletion. The OS cells were quantified microscopically based on aneuploidy and a CK18-/CD45- phenotype. Aneuploidy was assayed by fluorescence in situ hybridization (FISH) using fluorescence-labeled alpha-satellite probes for the centromeres of chromosome (CEP 8). CK18 and CD45 phenotyping was performed with immunocytochemistry. HOS cells in spiked PB could be effectively retrieved with the FISH-based enumeration method, which was subsequently employed in an OS patient cohort. PB of recurrent/metastatic OS patients contained more CTCs than the PB of primary OS patients. OS patients with ≥2 CTCs per 7.5 ml of PB had worse PFS than patients whose PB contained <2 CTCs. In 2 cases, CTCs were present in PB of OS patients with negative X-ray and chest CT scans. In conclusion, our method was able to quantitate CTCs in liquid biopsies of OS patients. The number of CTCs has diagnostic and prognostic value.

18.
Surgery ; 162(1): 48-58, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28343696

RESUMO

BACKGROUND: In situ hypothermic perfusion during liver resection performed under vascular inflow occlusion decreases hepatic ischemia-reperfusion injury, but technical limitations have restricted its widespread use. In situ hypothermic perfusion with retrograde outflow circumvents these impediments and thus could extend the applicability of in situ hypothermic perfusion. The safety and feasibility of in situ hypothermic perfusion with retrograde outflow were analyzed in selected patients undergoing right (extended) hepatectomy and compared to intermittent vascular inflow occlusion, the gold standard method, in this randomized pilot study. METHODS: Patients were first screened for parenchymal liver disease (exclusion criteria: steatosis ≥30%, cirrhosis, or cholestasis). Study participants were randomized intraoperatively to undergo in situ hypothermic perfusion with retrograde outflow (n = 9) or intermittent vascular inflow occlusion (n = 9). The target liver core temperature during in situ hypothermic perfusion with retrograde outflow was 28°C. The primary end point was ischemia-reperfusion injury (expressed by peak postoperative transaminase levels). Secondary outcomes included functional liver regeneration (assessed by hepatobiliary scintigraphy) and clinical outcomes. RESULTS: Peak transaminase levels, total bilirubin, and the international normalized ratio were similar between both groups, although a trend toward more rapid normalization of bilirubin levels was noted for the in situ hypothermic perfusion with retrograde outflow group. Functional liver regeneration as evaluated by hepatobiliary scintigraphy was improved on postoperative day 3 fafter in situ hypothermic perfusion with retrograde outflow but not after intermittent vascular inflow occlusion. Furthermore, in situ hypothermic perfusion with retrograde outflow (requiring continuous ischemia) was comparable to intermittent vascular inflow occlusion for all clinical outcomes, including postoperative complications and hospital stay. CONCLUSION: The use of in situ hypothermic perfusion with retrograde outflow appears to be safe and feasible in selected patients with healthy liver parenchyma and may benefit early functional liver regeneration. Future applications of in situ hypothermic perfusion with retrograde outflow include patients with damaged liver parenchyma who would require major hepatic resection with a prolonged vascular inflow occlusion duration.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Hepatectomia/métodos , Hipotermia Induzida/métodos , Hepatopatias/cirurgia , Perfusão/métodos , Traumatismo por Reperfusão/prevenção & controle , Idoso , Estudos de Viabilidade , Feminino , Hepatectomia/efeitos adversos , Humanos , Regeneração Hepática , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Transaminases/metabolismo , Resultado do Tratamento
19.
Nature ; 543(7643): 40, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28252078
20.
Surgery ; 162(4): 732-741, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28173999

RESUMO

BACKGROUND: Associating liver partition with portal vein ligation for staged hepatectomy induces more extensive liver hypertrophy than ligation alone; however, the mechanisms underlying the accelerated liver regrowth and the functional quality of the hypertrophic liver are presently elusive. This study, therefore, investigated the effect of parenchymal transection on liver volume and function after portal vein embolization in a standardized rabbit model. METHODS: Twelve rabbits were subjected to portal vein embolization of the cranial liver lobes and randomized between parenchymal transection of the left lateral liver lobe versus no transection (portal vein embolization only). Liver volume of the nonembolized liver lobe was assessed using computed tomography-volumetry, and liver uptake function was determined by 99mTc-mebrofenin hepatobiliary scintigraphy before and 3 and 7 days after portal vein embolization. RESULTS: The increase in nonembolized liver volume 3 days after portal vein embolization was 2.7-fold greater in the transected group compared with the portal vein embolization only group (56 ± 16% vs 21 ± 12%, respectively, P < .01) and 1.7-fold greater 7 days after portal vein embolization (113 ± 34% vs 68 ± 24%, P < .01). Liver uptake function did not differ between groups before portal vein embolization (8.4 ± 3.7%/min in the transection group vs 8.9 ± 1.6%/min) on day 3 (33.2 ± 4.7% after transection vs 30.3 ± 4.6%/min, respectively) and day 7 after portal vein embolization (42.6 ± 8.4% vs 39.1 ± 5.3%/min, respectively). CONCLUSION: Parenchymal transection after portal vein embolization increases liver growth in terms of volume but not function. These results indicate that the rapid volume increase observed after associating liver partition with portal vein ligation for staged hepatectomy does not coincide with the clinically more relevant functional increase. Quantitative liver function tests might be essential in associating liver partition with portal vein ligation for staged hepatectomy to better assess the hypertrophy response and improve clinical decision-making.


Assuntos
Embolização Terapêutica , Hepatectomia/métodos , Regeneração Hepática , Fígado/patologia , Veia Porta/cirurgia , Animais , Feminino , Modelos Animais , Tamanho do Órgão , Coelhos , Distribuição Aleatória
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