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Esofagectomía , Hernia Hiatal , Humanos , Esofagectomía/efectos adversos , Hernia Hiatal/etiologíaRESUMEN
Open esophagectomy is considered to be the main surgical procedure in the world for esophageal cancer treatment. Implementing a new surgical technique is associated with learning curve morbidity. The objective of this study is to determine the learning curve based on anastomotic leakage (AL) after implementing minimally invasive Ivor Lewis esophagectomy (MI-ILE) in January 2015. All 257 patients who underwent MI-ILE in a single high-volume center between January 2015 and December 2020 were retrospectively included in this study. The learning curve was evaluated using the standard CUSUM analysis with an expected AL rate of 11%. Secondary outcome parameters were postoperative complications, textbook outcome, and lymph node yield divided by the year of operation. Hierarchical binary logistic regression analysis was used to check for potential confounding variables. The CUSUM analysis showed a learning curve of 179 cases. The mean AL rate decreased from 33.3% in 2015 to 9.5% in 2020 (P = 0.007). There was an increase in the mean lymph node yield from 21 in 2018 to 28 in 2019 (P < 0.001) and textbook outcome from 37.3% in 2015 to 66.7% in 2020 (P = 0.005). A newly implemented MI-ILE has a learning curve of 179 patients based on a reference AL rate of 11% using the CUSUM method. Whether future generation surgeons will show similar learning curve numbers, implicating continuous development of different introduction programs of new techniques, will have to be the focus of future research.
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Esofagectomía , Curva de Aprendizaje , Humanos , Esofagectomía/efectos adversos , Estudios Retrospectivos , Complicaciones Posoperatorias/etiología , Fuga Anastomótica/etiologíaRESUMEN
BACKGROUND: After esophagectomy for esophageal carcinoma, 2-13% of patients develop brain metastases (BM) which are associated with a poor prognosis. Further investigation into treatment and prognosis is beneficial given the limited available literature and varying outcomes. METHODS: Case files of all 339 patients who underwent minimally invasive esophagectomy (MIE) in a single high-volume center between January 2015 and December 2020 were retrospectively reviewed. Patients with BM and isolated brain metastases (iBM) were identified and a survival analysis was performed. RESULTS: Fifteen out of 339 patients (4,4%) undergoing MIE developed BM of which 9 (60,0%) had iBM. Most patients were diagnosed with squamous cell carcinoma (55,6%), localized in the middle third of the esophagus (66,7%), and had a pathologic complete response (66,7%) after initial treatment. Treatment of iBM consisted of gamma knife (GK) radiosurgery (44,4%), surgical resection (22,2%), GK and surgical resection (11,1%), and best supportive care (22,2%). Median time to diagnose iBM was 8,4 months (range 0,2-37,5) and survival after detection of iBM was 14,3 months (95% CI 0,0-45.9). The 2-year survival rate after detection of iBM was 44,4%. CONCLUSIONS: iBM after esophagectomy for esophageal carcinoma is rare, but when encountered can and should be treated with a curative intent in selected cases in close collaboration with large neurosurgical centers. A large-scale study should be conducted to confirm our findings.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Humanos , Resultado del Tratamiento , Estudios Retrospectivos , Esofagectomía , Pronóstico , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas/patologíaRESUMEN
INTRODUCTION: Anastomotic leakage (AL) is one of the most feared complications after esophagectomy for esophageal cancer. We investigated the role of serum C-reactive protein (CRP) and drain amylase levels in the early detection of AL. METHODS: This is a retrospective study of 193 patients who underwent a minimally invasive Ivor-Lewis procedure between January 2017 and October 2021. Mean CRP and median drain amylase levels between patients with and without AL were compared during the first five postoperative days (POD). ROC curves on POD 3, 4 and 5 were plotted to calculate cut-off values for CRP. RESULTS: In 30 of the 193 patients (16%), AL was diagnosed with a median time to diagnosis of 9 days. Mean CRP was significantly higher in patients with AL on POD 3, 4 and 5. Cut-off values of 59, 110 and 106 mg/L had a high sensitivity of 93%, 90% and 90% on POD 3, 4 and 5. No difference in median drain amylase levels was observed. CONCLUSIONS: CRP levels with a cut-off point of 110 mg/L on POD 4 do not improve earlier detection of AL, but have a high sensitivity for excluding AL. The value of drain amylase in the first 5 days after surgery is limited.
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Amilasas , Anastomosis Quirúrgica , Fuga Anastomótica , Proteína C-Reactiva , Neoplasias Esofágicas , Esofagectomía , Humanos , Amilasas/análisis , Anastomosis Quirúrgica/efectos adversos , Fuga Anastomótica/diagnóstico , Fuga Anastomótica/etiología , Proteína C-Reactiva/análisis , Neoplasias Esofágicas/cirugía , Esofagectomía/efectos adversos , Esofagectomía/métodos , Estudios Retrospectivos , Procedimientos Quirúrgicos Mínimamente Invasivos/efectos adversos , Diagnóstico Precoz , Biomarcadores/análisisRESUMEN
BACKGROUND: Expansion of the organ donor pool can be obtained through novel interventions attenuating ischemic acute kidney injury, which will enable the use of kidneys that suffered prolonged ischemia. In basic science, new therapeutic targets are identified that should be tested in a relevant large animal model before use in human kidney transplantation. MATERIALS AND METHODS: The current paper provides a detailed description of the technique of autologous transplantation of ischemically injured kidneys in pigs with special emphasis on perioperative care. RESULTS: The animal model was validated by showing that renal function after transplantation was proportional to the duration of warm ischemia before organ recovery. The extent of renal dysfunction was reproducible following kidney transplantations with the same warm ischemia time. CONCLUSIONS: Our experience may reduce the learning curves of other research groups taking an interest in the model and improve preclinical testing of novel interventions that modulate renal ischemia and reperfusion injury in kidney transplantation.
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Supervivencia de Injerto/fisiología , Trasplante de Riñón , Riñón/fisiología , Recuperación de la Función/fisiología , Daño por Reperfusión/patología , Enfermedad Aguda , Animales , Modelos Animales de Enfermedad , Riñón/irrigación sanguínea , Riñón/cirugía , Masculino , Arteria Renal/cirugía , Sus scrofa , Temperatura , Factores de Tiempo , Trasplante AutólogoRESUMEN
BACKGROUND: This report describes a human in vivo ischemia reperfusion (IR) model of the small intestine. Animal models of intestinal IR are indispensable for our understanding of sequelae of IR induced organ damage. However, a functional experimental IR model of the human small intestine, allowing for translational research, can be considered critical for our pathophysiologic understanding of intestinal IR in man. MATERIALS AND METHODS: Patients with a healthy gut undergoing abdominal surgery with a Roux-Y or similar reconstruction were included, creating the opportunity to study IR of an isolated jejunal segment in a harmless model. RESULTS: Ischemia was induced by nontraumatic vascular clamping followed by reperfusion. This model can be adapted using variable ischemia and reperfusion times. Similarly, tissue and plasma can be collected at any given time point during ischemia until end of reperfusion, only determined by progress of the original, intended surgical procedure. CONCLUSION: A unique and harmless human IR model of the jejunum was created, which enables the study of acute damage to the epithelial lining and its subsequent repair mechanisms.
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Investigación Biomédica/métodos , Mucosa Intestinal/irrigación sanguínea , Yeyuno/irrigación sanguínea , Daño por Reperfusión/metabolismo , Daño por Reperfusión/fisiopatología , Enfermedad Aguda , Anastomosis en-Y de Roux , Experimentación Humana , Humanos , Mucosa Intestinal/cirugía , Periodo Intraoperatorio , Yeyuno/cirugía , Pancreaticoduodenectomía , Pancreatoyeyunostomía , Instrumentos QuirúrgicosRESUMEN
Human intestinal ischemia-reperfusion (IR) is a frequent phenomenon carrying high morbidity and mortality. Although intestinal IR-induced inflammation has been studied extensively in animal models, human intestinal IR induced inflammatory responses remain to be characterized. Using a newly developed human intestinal IR model, we show that human small intestinal ischemia results in massive leakage of intracellular components from ischemically damaged cells, as indicated by increased arteriovenous concentration differences of intestinal fatty acid binding protein and soluble cytokeratin 18. IR-induced intestinal barrier integrity loss resulted in free exposure of the gut basal membrane (collagen IV staining) to intraluminal contents, which was accompanied by increased arteriovenous concentration differences of endotoxin. Western blot for complement activation product C3c and immunohistochemistry for activated C3 revealed complement activation after IR. In addition, intestinal IR resulted in enhanced tissue mRNA expression of IL-6, IL-8, and TNF-alpha, which was accompanied by IL-6 and IL-8 release into the circulation. Expression of intercellular adhesion molecule-1 was markedly increased during reperfusion, facilitating influx of neutrophils into IR-damaged villus tips. In conclusion, this study for the first time shows the sequelae of human intestinal IR-induced inflammation, which is characterized by complement activation, production and release of cytokines into the circulation, endothelial activation, and neutrophil influx into IR-damaged tissue.
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Intestino Delgado/patología , Daño por Reperfusión/patología , Anciano , Anciano de 80 o más Años , Complemento C3c/biosíntesis , Femenino , Humanos , Inmunohistoquímica/métodos , Inflamación , Interleucina-6/biosíntesis , Interleucina-8/biosíntesis , Masculino , Persona de Mediana Edad , Técnicas de Cultivo de Tejidos/métodos , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
BACKGROUND: Recently, we observed that small-intestinal ischemia and reperfusion was found to entail a rapid loss of apoptotic and necrotic cells. This study was conducted to investigate whether the observed shedding of ischemically damaged epithelial cells affects IR induced inflammation in the human small gut. METHODS AND FINDINGS: Using a newly developed IR model of the human small intestine, the inflammatory response was studied on cellular, protein and mRNA level. Thirty patients were consecutively included. Part of the jejunum was subjected to 30 minutes of ischemia and variable reperfusion periods (mean reperfusion time 120 (+/-11) minutes). Ethical approval and informed consent were obtained. Increased plasma intestinal fatty acid binding protein (I-FABP) levels indicated loss in epithelial cell integrity in response to ischemia and reperfusion (p<0.001 vs healthy). HIF-1alpha gene expression doubled (p = 0.02) and C3 gene expression increased 4-fold (p = 0.01) over the course of IR. Gut barrier failure, assessed as LPS concentration in small bowel venous effluent blood, was not observed (p = 0.18). Additionally, mRNA expression of HO-1, IL-6, IL-8 did not alter. No increased expression of endothelial adhesion molecules, TNFalpha release, increased numbers of inflammatory cells (p = 0.71) or complement activation, assessed as activated C3 (p = 0.14), were detected in the reperfused tissue. CONCLUSIONS: In the human small intestine, thirty minutes of ischemia followed by up to 4 hours of reperfusion, does not seem to lead to an explicit inflammatory response. This may be explained by a unique mechanism of shedding of damaged enterocytes, reported for the first time by our group.
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Enterocitos/metabolismo , Epitelio/patología , Inflamación , Intestino Delgado/patología , Isquemia/patología , Anciano , Apoptosis , Femenino , Humanos , Lipopolisacáridos/metabolismo , Masculino , Persona de Mediana Edad , Necrosis , Daño por Reperfusión , Cicatrización de HeridasRESUMEN
BACKGROUND: With consideration of the central role of the innate immune system in atherogenesis and mannose-binding lectin (MBL) as an innate regulator of immunity, the role of MBL in experimental and human atherosclerosis was assessed. METHODS AND RESULTS: With the use of immunohistochemistry and polymerase chain reaction, deposition and gene expression of MBL-A and -C were assessed in murine atherosclerosis from mice deficient for the low-density lipoprotein receptor (LDLR(-/-)) after 10 or 18 weeks of high-fat feeding. MBL was present and was produced in 10-week-old lesions, whereas deposition and gene expression were minimal after 18 weeks of high-fat feeding and absent in healthy vasculature. Interestingly, deposition of MBL-A and -C differed: MBL-A predominantly localized in upper medial layers, whereas MBL-C was found in and around intimal macrophages. To further study the role of local MBL production by monocytic cells in atherosclerosis, LDLR(-/-) mice with MBL-A and -C(-/-) monocytic cells were construed by bone marrow transplantation. Mice carrying MBL-A and -C double deficient macrophages had increased (30%) atherosclerotic lesions compared with wild-type controls (P=0.015) after 10 weeks of high-fat diet. Subsequently, analysis of MBL deposition and gene expression in advanced human atherosclerotic lesions revealed the presence of MBL protein in ruptured but not stable atherosclerotic lesions. Putatively in agreement with murine data, no MBL gene expression could be detected in advanced human atherosclerotic lesions. CONCLUSIONS: These results are the first to show that MBL is abundantly present and locally produced during early atherogenesis. Local MBL expression, by myeloid cells, is shown to critically control development of atherosclerotic lesions.
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Aterosclerosis/fisiopatología , Macrófagos/fisiología , Lectina de Unión a Manosa/genética , Receptores de LDL/genética , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Trasplante de Médula Ósea , Colesterol/sangre , Femenino , Expresión Génica/inmunología , Humanos , Lipasa/sangre , Macrófagos/patología , Lectina de Unión a Manosa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones MutantesRESUMEN
BACKGROUND: Intestinal ischemia-reperfusion (IR) is a phenomenon related to physiological conditions (e.g. exercise, stress) and to pathophysiological events (e.g. acute mesenteric ischemia, aortic surgery). Although intestinal IR has been studied extensively in animals, results remain inconclusive and data on human intestinal IR are scarce. Therefore, an experimental harmless model for human intestinal IR was developed, enabling us to clarify the sequelae of human intestinal IR for the first time. METHODS AND FINDINGS: In 30 patients undergoing pancreatico-duodenectomy we took advantage of the fact that in this procedure a variable length of jejunum is removed. Isolated jejunum (5 cm) was subjected to 30 minutes ischemia followed by reperfusion. Intestinal Fatty Acid Binding Protein (I-FABP) arteriovenous concentration differences across the bowel segment were measured before and after ischemia to assess epithelial cell damage. Tissue sections were collected after ischemia and at 25, 60 and 120 minutes reperfusion and stained with H&E, and for I-FABP and the apoptosis marker M30. Bonferroni's test was used to compare I-FABP differences. Mean (SEM) arteriovenous concentration gradients of I-FABP across the jejunum revealed rapidly developing epithelial cell damage. I-FABP release significantly increased from 290 (46) pg/ml before ischemia towards 3,997 (554) pg/ml immediately after ischemia (p<0.001) and declined gradually to 1,143 (237) pg/ml within 1 hour reperfusion (p<0.001). Directly after ischemia the intestinal epithelial lining was microscopically normal, while subepithelial spaces appeared at the villus tip. However, after 25 minutes reperfusion, enterocyte M30 immunostaining was observed at the villus tip accompanied by shedding of mature enterocytes into the lumen and loss of I-FABP staining. Interestingly, within 60 minutes reperfusion the epithelial barrier resealed, while debris of apoptotic, shedded epithelial cells was observed in the lumen. At the same time, M30 immunoreactivity was absent in intact epithelial lining. CONCLUSIONS: This is the first human study to clarify intestinal IR induced cell damage and repair and its direct consequences. It reveals a unique, endogenous clearing mechanism for injured enterocytes: rapid detachment of damaged apoptotic enterocytes into the lumen. This process is followed by repair of the epithelial continuity within an hour, resulting in a normal epithelial lining.
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Enterocitos/patología , Intestinos/irrigación sanguínea , Daño por Reperfusión/patología , Adulto , Anciano , Proteínas de Unión a Ácidos Grasos/sangre , Humanos , Intestinos/patología , Persona de Mediana EdadRESUMEN
BACKGROUND: Although activation of the complement system has been implicated in the progression of human atherosclerosis, its function during arterial remodeling after injury has not been investigated. Here, we examined the contribution of the complement cascade to neointima formation in apolipoprotein E-deficient mice using a C1-esterase inhibitor (C1-inhibitor). METHODS AND RESULTS: Apolipoprotein E-deficient mice fed an atherogenic diet were subjected to wire-induced endothelial denudation of the carotid artery and treated with C1-inhibitor (Berinert; 15 IU i.v.) or vehicle perioperatively and subsequently every 2 days. The effectiveness of C1-inhibitor treatment was confirmed by measurement of plasma C1-inhibitor activity. A significant reduction in serum triglyceride levels was observed in C1-inhibitor-treated mice, whereas cholesterol levels did not differ. After 3 weeks, neointimal area was significantly reduced in C1-inhibitor-treated mice versus controls, whereas medial area was unaltered. This was associated with a significant decrease in neointimal and medial macrophage and CD3+ T-cell content. Expression of C3 mRNA was significantly reduced in plaques of C1-inhibitor-treated mice 10 days after injury, as assessed by reverse-transcription polymerase chain reaction. The peak in serum C3 levels after injury was markedly downregulated by C1-inhibitor, as evidenced by ELISA. Immunohistochemistry revealed strong expression of C3 and C3c, which colocalized to plaque macrophages and was reduced in C1-inhibitor-treated mice. C1-inhibitor impaired monocyte arrest on activated endothelium and platelets under flow conditions in vitro and leukocyte recruitment to carotid arteries 1 day after injury in vivo. CONCLUSIONS: C1-inhibitor limits neointimal plaque formation and inflammation. This may involve blockade of complement activation, inhibition of leukocyte recruitment, and reduced triglyceride levels, thus providing a multimodal approach to treat arterial disease.
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Arterias/lesiones , Aterosclerosis/prevención & control , Proteína Inhibidora del Complemento C1/farmacología , Regeneración/efectos de los fármacos , Túnica Íntima/patología , Animales , Apolipoproteínas E/deficiencia , Arterias/patología , Aterosclerosis/etiología , Quimiotaxis de Leucocito/efectos de los fármacos , Activación de Complemento/efectos de los fármacos , Modelos Animales de Enfermedad , Endotelio Vascular/lesiones , Endotelio Vascular/patología , Inflamación/prevención & control , Ratones , Triglicéridos/sangreRESUMEN
In this study the role of myeloperoxidase (MPO) in a murine (C57BL/6) model of ischemia and reperfusion (I/R)-induced renal failure was investigated. The renal function after I/R was analyzed in MPO-deficient (Mpo(-/-)) mice and compared with wild-type (WT) controls. A significant reduction in renal function loss (blood urea nitrogen) was observed after 24 hours of reperfusion of ischemically damaged kidneys in Mpo(-/-) mice compared with I/R WT controls (I/R Mpo(-/-) = 31.3 +/- 1.7 mmol/L versus I/R WT = 42.8 +/- 2.1 mmol/L, sham = 7.0 +/- 0.5 mmol/L; P = 0.003). The early reperfusion phase (2 hours of reperfusion) was characterized by a substantial increase in apoptosis and early complement activation, surprisingly similar in Mpo(-/-) and WT mice. Improved renal function in Mpo(-/-) mice after extended reperfusion was accompanied by a reduced neutrophil influx (P = 0.017) compared with WT controls. Activation and deposition of complement was not significantly reduced in Mpo(-/-) mice compared with WT controls after 24 hours of reperfusion, indicating no specific in vivo role for MPO in activating complement after renal I/R. Taken together, these results demonstrated an important contribution of MPO in the induction of organ damage after renal I/R by influencing critical factors such as neutrophil extravasation but not complement activation.
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Enfermedades Renales/patología , Peroxidasa/fisiología , Daño por Reperfusión/patología , Animales , Apoptosis/genética , Activación de Complemento/genética , Enfermedades Renales/enzimología , Enfermedades Renales/inmunología , Ratones , Ratones Mutantes , Neutrófilos/inmunología , Peroxidasa/genética , Daño por Reperfusión/enzimología , Daño por Reperfusión/inmunologíaRESUMEN
Renal ischemia-reperfusion (I/R) injury is an important cause of acute renal failure as observed after renal transplantation, major surgery, trauma, and septic as well as hemorrhagic shock. We previously showed that the inhibition of apoptosis is protective against renal I/R injury, indicating that apoptotic cell-death is an important feature of I/R injury. Lysophosphatidic acid (LPA) is an endogenous phospholipid growth factor with anti-apoptotic properties. This tempted us to investigate the effects of exogenous LPA in a murine model of renal I/R injury. LPA administered at the time of reperfusion dose dependently inhibited renal apoptosis as evaluated by the presence of internucleosomal DNA cleavage. I/R-induced renal apoptosis was only present in tubular epithelial cells with evident disruption of brush border as assessed by immunohistochemistry for active caspase-7 and filamentous actin, respectively. LPA treatment specifically prevented tubular epithelial cell apoptosis but also reduced the I/R-induced loss of brush-border integrity. Besides, LPA showed strong anti-inflammatory effects, inhibiting the renal expression of tumor necrosis factor-alpha and abrogating the influx of neutrophils. Next, LPA dose dependently inhibited activation of the complement system. Moreover, treatment with LPA abrogated the loss of renal function in the course of renal I/R. This study is the first to show that administration of the phospholipid LPA prevents I/R injury, abrogating apoptosis and inflammation. Moreover, exogenous LPA is capable of preventing organ failure because of an ischemic insult and thus may provide new means to treat clinical conditions associated with I/R injury in the kidney and potentially also in other organs.
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Apoptosis/fisiología , Activación de Complemento , Riñón/metabolismo , Lisofosfolípidos/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Animales , Caspasa 7 , Caspasas/metabolismo , Complemento C3/metabolismo , Complemento C6/metabolismo , Modelos Animales de Enfermedad , Activación Enzimática , Humanos , Riñón/patología , Masculino , Ratones , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Complement has been implicated in the pathophysiology of renal ischemia-reperfusion (I/R) injury. However, the mechanism underlying complement-mediated renal I/R injury is thus far unknown. To investigate the involvement of complement in I/R injury, we studied the activation and deposition of complement in a murine model of renal I/R injury. Furthermore, we examined the effect of inhibition of complement-factor C5 on renal I/R injury. METHODS: Mice were subjected to 45 min of unilateral ischemia and subsequent contralateral nephrectomy and reperfusion for 2, 12, or 24 hr. Mice were control treated or treated with BB5.1, a monoclonal antibody that prevents cleavage of complement factor C5, thereby preventing C5a generation and formation of the membrane attack complex (MAC). RESULTS: Renal I/R induced extensive deposition of C3 early after reperfusion, whereas C6 and C9 deposition (MAC formation) occurred relatively late. I/R-induced complement deposition was mainly localized to tubular epithelium. Treatment with BB5.1 totally prevented MAC formation but also reduced C3 deposition. Inhibition of C5 strongly inhibited late inflammation, as measured by neutrophil influx and induction of the murine CXC chemokines macrophage inflammatory protein-2, KC, and lipopolysaccharide-induced CXC chemokine. Anti-C5 treatment furthermore abrogated late I/R-induced apoptosis, whereas early apoptosis was not affected. Moreover, BB5.1 treatment significantly protected against I/R-induced renal dysfunction. CONCLUSIONS: Renal I/R is followed by activation of the complement system and intrarenal deposition of C3 and MAC. Complement activation plays a crucial role in the regulation of inflammation and late apoptosis. Complement inhibition, by preventing C5 activation, abrogates late apoptosis and inflammation, being strongly protective against renal function loss.