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BACKGROUND: Resectability of colorectal liver metastasis (CRLM) depends on major vascular involvement and is affected by chemotherapy-induced liver injury. Parenchyma-sparing with combined resection and reconstruction of involved vessels may expand the indications and safety of hepatectomy. METHODS: Of 92 patients who underwent hepatectomy for CRLM, 15 underwent major vascular resection and reconstruction. The reconstructed vessels were the portal vein (PV) in five cases, the major hepatic vein (HV) in nine cases, and the inferior vena cava in six cases. RESULTS: All PV reconstructions were direct anastomoses. The HV was reconstructed with an autologous inferior mesenteric venous patch or an external iliac vein interposition graft. Total hepatic vascular exclusion was performed for six patients. Of nine patients with HV reconstruction, three had tumors involving all three major HVs, in whom the left HV was reconstructed as an only vein after extended right hepatectomy. In another six patients, multiple bilobar tumors or tumors in the liver that had chemotherapy-induced injury involved one or two HVs. Parenchyma-sparing by reconstruction of the HV was performed to secure the residual liver function. The patients with vascular reconstruction had an operative time of 462 ± 111 min and a blood loss of 1278 ± 528 mL. No complication classified as Clavien-Dindo 3 or more developed. The median hospital stay was 17 days (range 8-26 days). The cumulative 5-year survival rate for all the patients was 54.6 %, with no significant difference according to vascular reconstruction. CONCLUSION: Parenchyma-sparing hepatectomy combined with vascular reconstruction is a useful option to avoid major hepatectomy among various procedures for resection of CRLM with major vascular invasion.
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PURPOSE: A femoral hernia is a relatively rare condition, and no standard surgical methods have so far been established. In this study, we investigated the development of a femoral hernia after inguinal herniorrhaphy. METHODS: A total of 1,969 patients who underwent surgery for an inguinal hernia from April 1992 to March 2012 were enrolled in this study. The patients were composed of 1,934 (98.2 %) inguinal hernia and 35 (1.8 %) femoral hernia patients. Of these, we retrospectively studied the femoral hernia cases with reference to the use of inguinal herniorrhaphy. RESULTS: Of all 35 femoral hernia cases, six cases (17.1 %) were femoral type recurrences after inguinal herniorrhaphy performed by the conventional or mesh plug methods. The surgical methods used for the 35 cases were mesh plug repair in 15 cases (42.9 %), the Kugel patch method in seven (20.0 %) and conventional repair in 13 patients (37.2 %). Inguinal type recurrences developed in three cases (8.6 %) that were re-repaired by mesh plug repair or sac resection. There were no femoral or inguinal type recurrences after Kugel patch repair for a femoral hernia. CONCLUSIONS: The results of this study suggested the importance of repairing all hernia orifices when repairing a groin hernia. The Kugel patch repair method is available for all inguinal region hernias by the same approach, and it seems to be useful for preventing the development of recurrence after surgery.
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Hérnia Femoral/prevenção & controle , Hérnia Inguinal/cirurgia , Herniorrafia/métodos , Complicações Pós-Operatórias/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Telas CirúrgicasRESUMO
BACKGROUND/AIMS: Therapeutic efficacy of radiofrequency ablation (RFA) for colorectal liver metastases (CRLM) was compared with hepatic resection (HR), focusing on local disease control rate as well as risk factors of recurrence and patients survival. METHODOLOGY: From April 2002 to March 2012, 32 patients underwent RFA and 60 patients underwent HR for CRLM. The rate of local recurrence along the ablated or resected margin was evaluated in these patients. RESULTS: The local recurrence was seen in 8 patients (13.3%) after HR, and 15 (46.9%) after RFA. Multivariate analysis of all patients revealed that RFA as an initial therapy (P < 0.001), venous invasion liver metastases (P = 0.049) were independent risk factors for local recurrence. Subgroup analysis showed that local recurrence rate after RFA was significantly higher than that after HR in patients with tumors 20 mm or larger (P < 0.001), while there was no significant difference in local recurrence rate between RFA and HR in patients with tumors less than 20 mm (P = 0.676). CONCLUSIONS: RFA showed a high risk of local recurrence in comparison to HR especially in patients with tumors larger than 20 mm. Indication of RFA should be restricted drastically considering the limitation of efficacy.
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Ablação por Cateter/métodos , Neoplasias Colorretais/patologia , Hepatectomia/métodos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Idoso , Ablação por Cateter/efeitos adversos , Intervalo Livre de Doença , Feminino , Hepatectomia/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnósticoRESUMO
A 62-year-old man had undergone retroperitoneoscopic radical nephrectomy for left renal cell carcinoma at the age of 57 years. The histopathological diagnosis was clear cell carcinoma of the kidney (G2, pT2a, INF ß). Five years postoperatively, enhanced computed tomography demonstrated strongly enhanced tumors on the pancreatic head and body. No other metastatic lesion was detected. Pancreatic endocrine tumors were not ruled out. The patient underwent enucleation of the pancreatic head tumor and distal pancreatectomy. The histopathological diagnosis of the tumors was metastatic renal cell carcinoma. Patients with renal cell carcinoma should receive a long-term follow-up to detect possible metastatic lesions other than the common metastatic sites such as the lung and bones.
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Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Neoplasias Pancreáticas/secundário , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A 71-year-old man, diagnosed with advanced gastric cancer and severe pyloric stenosis, was introducted to our hospital. Para-aortic lymph nodes metastasis and pancreas invasion were seen with enhanced CT scan. Serum AFP showed a high price (1,465.3 ng/mL). Because significant peritoneal metastases were seen in the abdominal cavity, gastrojejunostomy was performed. Overexpression of the HER2 gene was seen by immunostaining for peritoneal dissemination of the omentum. After starting S-1 + CDDP + trastuzumab, the AFP was normalized immediately (7. 6 ng/mL). We then performed colostomy for a sigmoid colon stenosis. S-1 + DOC + trastuzumab was administered afterward, and we performed closure of the colostomy because the stenosis was improved. Macroscopic peritoneal dissemination in the abdomen disappeared. AFP-producing gastric cancer with peritoneal metastasis has a poor prognosis, but chemotherapy, mainly with S-1 and trastuzumab, was effective for it.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , alfa-Fetoproteínas/biossíntese , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos/administração & dosagem , Combinação de Medicamentos , Humanos , Masculino , Ácido Oxônico/administração & dosagem , Neoplasias Gástricas/metabolismo , Tegafur/administração & dosagem , TrastuzumabRESUMO
BACKGROUND: Splenic artery aneurysms usually rupture into the free peritoneal space and rarely into the gastrointestinal tract. We report the case of a patient with a giant splenic artery aneurysm that ruptured in to the stomach with hemorrhagic shock and was successfully treated with emergency surgery. CASE PRESENTATION: A 59-year-old man presented to the emergency department with chest pain and syncope. Contrast-enhanced computed tomography showed splenic artery aneurysm with active contrast extravasation. He developed upper gastrointestinal (UGI) bleeding and hypovolemic shock. We diagnosed a splenic artery aneurysm ruptured in to the stomach, performed emergency distal splenopancreatectomy including the aneurysm and partial gastric resection, and could prevent patient death. CONCLUSIONS: This report shows that splenic artery aneurysm can cause UGI bleeding. Thus, clinicians should be alert about this condition when managing patients with UGI bleeding and/or splenic artery aneurysm.
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BACKGROUND/AIMS: The precise mechanism and prophylactic strategy of deteriorated hepatic function after liver surgery have not been fully understood. The substrate of ADAMTS13, unusually large von Willebrand factor multimers, is produced in vascular endothelial cells at liver injury, leading to platelet aggregation. The decrease of plasma ADAMTS13 activity may involve not only the formation of platelet thrombi in the liver, but also subsequent progression of liver dysfunction through a microcirculatory disturbance. This study evaluated changes of plasma ADAMTS13 activity and its clinical relevance in patients with hepatectomy. METHODOLOGY: Plasma ADAMTS13 activity and its related parameters were sequentially determined after hepatectomy in 70 patients. RESULTS: ADAMTS13 activity significantly decreased preoperative 67.0 +/- 30.6 to 48.1 +/- 24.6% after hepatectomy (p < 0.0001). Pringle's maneuver for longer than 45 minutes (p = 0.0007) and major hepatectomy (p = 0.0002) were significantly associated with the decrease of ADAMTS13 activity to less than 40%. The decreased ADAMTS13 activity reflected postoperative thrombocytopenia (p = 0.0028) and hyperbilirubinemia (p < 0.05). CONCLUSIONS: Plasma ADAMTS13 activity significantly decreased after hepatectomy due to ischemic injury together with liver mass reduction, reflecting a postoperative liver dysfunction. Monitoring of ADAMTS13 activity may be useful to prevent further development of the liver failure after hepatectomy.
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Proteínas ADAM/sangue , Hepatectomia , Hepatopatias/sangue , Hepatopatias/cirurgia , Proteína ADAMTS13 , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Feminino , Humanos , Testes de Função Hepática , Modelos Logísticos , Masculino , Pessoa de Meia-IdadeRESUMO
Recent advances in chemotherapy for colorectal cancer prolonged survival. Tumor necrosis may develop as a side effect of chemotherapeutic agents. Recently, radiofrequency ablation sometimes indicated to patients with colorectal liver metastasis, when hepatectomy cannot be performed due to impaired hepatic functional reserve or general condition. We experienced hepatectomy for colorectal liver metastasis containing necrotic foci which was induced by anti-cancer drugs and radiofrequency ablation. Massive liver necrosis and abscess developed in a patient with initially unresectable large liver metastasis 6 months after induction of mFOLFOX6 and bevacizumab. Chemotherapy was discontinued due to systemic inflammatory responses. Extended right hepatectomy resulted in both resection of the tumor and significant improvement of septic condition. Chemotherapy was re-started after the operation. Bevacizumab targeted to tumor-related vascular endotherial cells might be responsible for the massive tumor necrosis. Another patient with chronic renal dysfunction underwent radiofrequency ablation for colorectal liver metastasis 2 cm in diameter in the segment 7. Three months after ablation, the tumor grew very rapidly to 6 cm in diameter. After extended posterior sectorectomy of the liver, blood CEA levels were normalized. Resected specimen showed a massive tumor growth around the necrotic foci of radiofrequency ablation. Hepatectomy played significant roles in these patients with necrotic foci of the liver. Decision and timing of hepatectomy are very important to save the patient.
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Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ablação por Cateter/efeitos adversos , Neoplasias Colorretais/patologia , Hepatectomia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Fígado/patologia , Idoso , Anticorpos Monoclonais Humanizados , Bevacizumab , Neoplasias Colorretais/terapia , Fluoruracila/efeitos adversos , Humanos , Leucovorina/efeitos adversos , Neoplasias Hepáticas/patologia , Masculino , Necrose , Compostos Organoplatínicos/efeitos adversosRESUMO
BACKGROUND: Skeletal muscle metastasis from gastric cancer is extremely rare and often accompanied with synchronous metastasis to any other organs. We herein report a case of rapidly developing multiple skeletal metastases from gastric cancer without any other organ metastases. CASE PRESENTATION: A 47-year-old man underwent distal gastrectomy for advanced gastric cancer. Pathological diagnosis was poorly differentiated adenocarcinoma, T2N1M0, Stage IIA. The patient presented with a history of left dorsal tenderness 12 months after the operation. A computed tomography (CT) revealed a solid mass in the left latissimus dorsi muscle. Pathological examination of the ultrasound guided needle biopsy specimen revealed poorly differentiated adenocarcinoma similar to the previously resected gastric cancer, and the tumor was diagnosed as metastasis of gastric cancer. Thereafter, the systemic chemotherapy was administrated. However, the metastases were extended to the paraspinal muscle and quadriceps, and the patient died 7 months after the recurrence. CONCLUSIONS: The prognosis of patients with skeletal muscle metastasis may be extremely poor, even in patients without any other organ metastases. The development of further chemotherapeutic agents and regimens is therefore needed.
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The long-term durability of agarose microencapsulated islets against autoimmunity was evaluated in NOD mice. Islets were isolated from 6-8-week-old prediabetic male NOD mice and microencapsulated in 5% agarose hydrogel. Microencapsulated or nonencapsulated islets were transplanted into the omental pouch of spontaneously diabetic NOD mice. Although the diabetic NOD mice that received nonencapsulated islets experienced a temporary reversal of their hyperglycemic condition, all 10 of these mice returned to hyperglycemia within 3 weeks. In contrast, 9 of 10 mice transplanted with microencapsulated islets maintained normoglycemia for more than 100 days. Islet grafts were removed at 100, 150, 200, 300, and 400 days posttransplantation. A prompt return to hyperglycemia was observed in the mice after graft removal, indicating that the encapsulated islet grafts were responsible for maintaining euglycemia. Histological examination revealed viable islets in the capsules at all time points of graft removal. In addition, beta-cells within the capsules remained well granulated as revealed by the immunohistochemical detection of insulin. No immune cells were detected inside the microcapsules and no morphological irregularities of the microcapsules were observed at any time point, suggesting that the microcapsules successfully protected the islets from cellular immunity. Sufficient vascularization was evident close to the microcapsules. Considerable numbers of islets showed central necrosis at 400 days posttransplantation, although the necrotic islets made up only a small percentage of the islet grafts. Islets with central necrosis also showed abundant insulin production throughout the entire islets, except for the necrotic part. These results demonstrate the long-term durability of agarose microcapsules against autoimmunity in a syngeneic islet transplantation model in NOD mice.
Assuntos
Diabetes Mellitus Tipo 1/terapia , Transplante das Ilhotas Pancreáticas/métodos , Ilhotas Pancreáticas/imunologia , Omento , Alginatos/química , Alginatos/uso terapêutico , Animais , Autoimunidade/efeitos dos fármacos , Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Sobrevivência de Enxerto/fisiologia , Ilhotas Pancreáticas/química , Ilhotas Pancreáticas/fisiologia , Transplante das Ilhotas Pancreáticas/imunologia , Transplante das Ilhotas Pancreáticas/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Sefarose/química , Sefarose/uso terapêutico , Fatores de Tempo , Transplante HomólogoRESUMO
AIM: To evaluate the efficacy of technical modifications of total hepatic vascular exclusion (THVE) for hepatectomy involving inferior vena cava (IVC). METHODS: Of 301 patients who underwent hepatectomy during the immediate previous 5-year period, 8 (2.7%) required THVE or modified methods of IVC cross-clamping for resection of liver tumors with massive involvement of the IVC. Seven of the patients had diagnosis of colorectal liver metastases and 1 had diagnosis of hepatocellular carcinoma. All tumors involved the IVC, and THVE was unavoidable for combined resection of the IVC in all 8 of the patients. Technical modifications of THVE were applied to minimize the extent and duration of vascular occlusion, thereby reducing the risk of damage. RESULTS: Broad dissection of the space behind the IVC coupled with lifting up of the liver from the retrocaval space was effective for controlling bleeding around the IVC before and during THVE. The procedures facilitate modification of the positioning of the cranial IVC cross-clamp. Switching the cranial IVC cross-clamp from supra- to retrohepatic IVC or to the confluence of hepatic vein decreased duration of the THVE while restoring hepatic blood flow or systemic circulation via the IVC. Oblique cranial IVC cross-clamping avoided ischemia of the remnant hemi-liver. With these technical modifications, the mean duration of THVE was 13.4 ± 8.4 min, which was extremely shorter than that previously reported in the literature. Recovery of liver function was smooth and uneventful for all 8 patients. There was no case of mortality, re-operation, or severe complication (i.e., Clavien-Dindo grade of III or more). CONCLUSION: The retrocaval liver lifting maneuver and modifications of cranial cross-clamping were useful for minimizing duration of THVE.
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BACKGROUND: Among young residents, there seems to be a decreasing desire to become surgeons, resulting in a decrease in the number of surgeons. There is concern regarding a shortage of hepatobiliary pancreatic (HBP) surgery residents in Japan. A questionnaire survey was designed to assess the work motivations of Japanese gastrointestinal (GI) and HBP surgeons. METHODS: Questionnaires assessing seven domains related to motivation (aptitude, satisfaction/dissatisfaction, knowledge/skill, evaluation/approval, self-management, community/expectation from other parties, and emotion) were sent to GI and HBP surgeons throughout Japan. Differences between HBP and GI surgeons were analyzed. RESULTS: Responses were received from 27 institutions in Japan between May and August 2014. Mid-career and senior HBP surgeons (11-20 years after graduation) working in university hospitals were significantly less satisfied with their work than GI surgeons (P = 0.036). Evaluation/approval factors were significantly lower in senior HBP surgeons than in GI surgeons 16-20 years after graduation (P = 0.048). CONCLUSIONS: The future satisfaction of young residents seeking to become HBP surgeons should be enhanced, providing an appealing workplace for young residents and preventing discontinuation by mid-career and senior surgeons.
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Atitude do Pessoal de Saúde , Escolha da Profissão , Internato e Residência/estatística & dados numéricos , Cirurgiões/provisão & distribuição , Inquéritos e Questionários , Adulto , Procedimentos Cirúrgicos do Sistema Biliar , Estudos Transversais , Procedimentos Cirúrgicos do Sistema Digestório , Educação de Pós-Graduação em Medicina , Feminino , Humanos , Japão , Satisfação no Emprego , Masculino , Motivação , Pancreatectomia , Satisfação Pessoal , Estatísticas não ParamétricasRESUMO
BACKGROUND: Chemokines and chemokine receptors are critical in leukocyte recruitment, activation, and differentiation. Among them, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 3 (CXCR3) have been reported to play important roles in alloimmune responses and may be potential targets for posttransplant immunosuppression. METHODS: Fully major histocompatibility complex (MHC)-mismatched murine cardiac and islet transplant models were used to test the effect in vivo of a novel, small-molecule compound TAK-779 by targeting CCR5 and CXCR3 in acute allograft rejection. An MHC class II mismatched cardiac transplant model was used to evaluate its efficacy in chronic allograft rejection. Intragraft expression of cytokines, chemokines, and chemokine receptors was measured by quantitative real-time polymerase chain reaction and by histological analysis. RESULTS: Treatment of TAK-779 significantly prolonged allograft survival across the MHC barrier in two distinct transplant models. The treatment downregulated local immune activation as observed by the reduced expression of several chemokines, cytokines, and chemokine receptors. Thereby, the recruitment of CD4, CD8, and CD11c cells into transplanted allografts were inhibited. Furthermore, TAK-779 treatment significantly attenuated the development of chronic vasculopathy, fibrosis, and cellular infiltration. CONCLUSIONS: Antagonism of CCR5 and CXCR3 has a substantial therapeutic effect on inhibiting both acute and chronic allograft rejection. CCR5 and CXCR3 are functional in the process of allograft rejection and may be potential targets in clinical transplantation in the future.
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Amidas/farmacologia , Antagonistas dos Receptores CCR5 , Rejeição de Enxerto , Sobrevivência de Enxerto , Transplante de Coração/métodos , Transplante das Ilhotas Pancreáticas/métodos , Compostos de Amônio Quaternário/farmacologia , Receptores CCR5/química , Receptores de Quimiocinas/química , Amidas/química , Animais , Antígeno CD11c/biossíntese , Antígenos CD4/biossíntese , Antígenos CD8/biossíntese , Transplante de Células , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase , Compostos de Amônio Quaternário/química , RNA Mensageiro/metabolismo , Receptores CXCR3 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Resultado do Tratamento , Regulação para CimaRESUMO
Liver tissue engineering using hepatocyte transplantation has been proposed as a therapeutic alternative to liver transplantation toward several liver diseases. We have previously reported that stable liver tissue with the potential for liver regeneration can be engineered at extrahepatic sites by transplanting mature hepatocytes into an extracellular matrix. The present study was aimed at assessing the liver tissue persistence after induced regeneration by hepatectomy and repeat regeneration potential induced by repeat hepatectomy. Mouse isolated hepatocytes mixed in EHS extracellular matrix gel were transplanted under both kidney capsules of isogenic mice. The hepatocyte survival persisted for over 25 weeks. In some of the mice, we confirmed that the grafted hepatocytes developed a thin layer of liver tissues under the kidney capsule, determined by specific characteristics of differentiated hepatocytes in cord structures between the capillaries. We then assessed the regenerative potential and persistence of the exogenous liver tissue. To induce liver regeneration, we performed a two-thirds hepatectomy at 70 days after hepatocyte transplantation. Three weeks after this procedure, the engineered liver tissues showed active regeneration, reaching serum marker protein levels of 261 +/- 42% of the prehepatectomy level. We found that the regenerated liver tissue was stably maintained for 100 days (length of the experiment). Repeat regeneration potential was established by performing a repeat hepatectomy (that had been two-thirds hepatectomized at day 70) 60 days after the initial hepatectomy. Again, the regenerated engineered liver tissues showed active regeneration as there was an approximately twofold increase in the serum marker protein levels. The present studies demonstrate that liver tissue, which was recognized as a part of the host naive liver in terms of the regeneration profile, could be engineered at a heterologous site that does not have access to the portal circulation.
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Hepatócitos/transplante , Regeneração Hepática/fisiologia , Ensaio de Cápsula Sub-Renal/métodos , Engenharia Tecidual , Animais , Sobrevivência de Enxerto/fisiologia , Hepatectomia , Hepatócitos/citologia , Humanos , Camundongos , Camundongos Transgênicos , alfa 1-Antitripsina/biossíntese , alfa 1-Antitripsina/genéticaRESUMO
CD45 is known to have tyrosine phosphatase activity for signal transduction of T cells. Immunomodulation of CD45 has been tried to prevent T cell-mediated graft rejection in organ transplantation. In vitro study showed that blockade of CD45RB, an alternative splicing isoform of CD45, inhibited proliferative response of T cells after allogeneic stimulation. Treatment with a monoclonal antibody (mAb) against CD45RB induced long-term allograft acceptance in some mouse organ transplantation models. In a rat heart allograft model, a single injection of anti-rat CD45 (RT7) mAb which bound to allomorphic region of RT7 also induced allograft acceptance. CD45/RT7 is also a useful tool of targeting hematopoietic cells, because of the selective expression on all hematopoietic cells. There are two allomorphic forms of CD45 (RT7a and RT7b) in the rat. Using RT7 system, a rat heart allograft model from RT7a donors to RT7b recipients was designed to test functional relevance of graft-associated hematopoietic cells (microchimerism) to allograft acceptance. Then donor-derived hematopoietic cells were selectively depleted using anti-RT7a mAb in vivo. Depletion on day 0 prevented allograft acceptance and was associated with severe acute or chronic graft rejection, while depletion on day 18 after transplantation showed no effect. This experimental study showed a crucial role of microchimerism in induction phase of allograft acceptance. In conclusion, the CD45/RT7 system is not only a target molecule for tolerance induction, but also an useful tool for experimental models in transplantation immunology. In this review, we introduce basic properties of CD45 and recent results with manipulation of CD45.
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Antígenos Comuns de Leucócito , Tolerância ao Transplante/imunologia , Animais , Medula Óssea/metabolismo , Humanos , Leucócitos/imunologiaRESUMO
Oxaliplatin-based chemotherapy is widely used to treat advanced colorectal cancer (CRC). Sinusoidal obstruction syndrome (SOS) due to oxaliplatin is a serious type of chemotherapy-associated liver injury (CALI) in CRC patients. SOS is thought to be caused by the sinusoidal endothelial cell damage, which results in the release of unusually-large von Willebrand factor multimers (UL-VWFMs) from endothelial cells. To investigate the pathophysiology of CALI after oxaliplatin-based chemotherapy, we analyzed plasma concentration of von Willebrand factor (VWF) and the distribution of VWFMs in CRC patients. Twenty-three patients with advanced CRC who received oxaliplatin-based chemotherapy with (n = 6) and without (n = 17) bevacizumab were analyzed. CALI (n = 6) and splenomegaly (n = 9) were found only in patients who did not treated with bevacizumab. Plasma VWF antigen (VWF:Ag) and serum aspartate aminotransferase (AST) levels increased after chemotherapy only in patients without bevacizumab. VWFM analysis in patients who did not receive bevacizumab showed the presence of UL-VWFMs and absence of high molecular weight VWFMs during chemotherapy, especially in those with CALI. In addition, plasma VWF:Ag and AST levels increased after chemotherapy in patients with splenomegaly (n = 9), but not in patients without splenomegaly (n = 14). Histological findings in the liver tissue of patients who did not receive bevacizumab included sinusoidal dilatation and microthrombi in the sinusoids. Many microthrombi were positive for both anti-IIb/IIIa and anti-VWF antibodies. Plasma UL-VWFM levels might be increased by damage to endothelial cells as a result of oxaliplatin-based chemotherapy. Bevacizumab could prevent CALI and splenomegaly through inhibition of VWF-rich platelet thrombus formation.
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Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/efeitos adversos , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Hepatopatia Veno-Oclusiva/prevenção & controle , Compostos Organoplatínicos/efeitos adversos , Esplenomegalia/prevenção & controle , Trombose/prevenção & controle , Adulto , Idoso , Antineoplásicos/administração & dosagem , Aspartato Aminotransferases/sangue , Autoanticorpos/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Plaquetas/patologia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Progressão da Doença , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Hepatopatia Veno-Oclusiva/sangue , Hepatopatia Veno-Oclusiva/etiologia , Hepatopatia Veno-Oclusiva/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Esplenomegalia/sangue , Esplenomegalia/etiologia , Esplenomegalia/patologia , Trombose/sangue , Trombose/etiologia , Trombose/patologia , Fator de von Willebrand/metabolismoRESUMO
A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) specifically cleaves unusually-large von Willebrand factor (VWF) multimers under high shear stress, and down-regulates VWF function to form platelet thrombi. Deficiency of plasma ADAMTS13 activity induces a life-threatening systemic disease, termed thrombotic microangiopathy (TMA) including thrombotic thrombocytopenic purpura (TTP). Children with advanced biliary cirrhosis due to congenital biliary atresia sometimes showed pathological features of TMA, with a concomitant decrease of plasma ADAMTS13 activity. Disappearance of their clinical findings of TTP after successful liver transplantation suggested that the liver is a major organ producing plasma ADAMTS13. In situ hybridization analysis showed that ADAMTS13 was produced by hepatic stellate cells. Subsequently, it was found that ADADTS13 was not merely responsible to development of TMA and TTP, but also related to some kinds of liver dysfunction after liver transplantation. Ischemia-reperfusion injury and acute rejection in liver transplant recipients were often associated with marked decrease of ADAMTS13 and concomitant formation of unusually large VWF multimers without findings of TMA/TTP. The similar phenomenon was observed also in patients who underwent hepatectomy for liver tumors. Imbalance between ADAMTS13 and VWF in the hepatic sinusoid might cause liver damage due to microcirculatory disturbance. It can be called as "local TTP like mechanism" which plays a crucial role in liver dysfunction after liver transplantation and surgery.
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BACKGROUND: The recurrence of autoimmunity and allograft rejection act as major barriers to the widespread use of islet transplantation as a cure for type 1 diabetes. The aim of this study was to evaluate the feasibility of immunoisolation by use of an agarose microcapsule to prevent autoimmune recurrence after islet transplantation. METHODS: Highly purified islets were isolated from 6- to 8-week-old prediabetic male nonobese diabetic (NOD) mice and microencapsulated in 5% agarose hydrogel as a semipermeable membrane. Islet function was evaluated by a syngeneic islet transplantation model, in which islets were transplanted into spontaneously diabetic NOD mice. RESULTS: The nonencapsulated islet grafts were destroyed and diabetes recurred within 2 weeks after transplantation in all 12 mice. In contrast, 13 of the 16 mice that underwent transplantation with microencapsulated islets maintained normoglycemia for more than 100 days after islet transplantation. Histologic examination of the nonencapsulated islet grafts showed massive mononuclear cellular infiltration with beta-cell destruction. In contrast, the microencapsulated islets showed well-granulated beta cells with no mononuclear cellular infiltration around the microcapsules or in the accompanying blood capillaries between the microcapsules. CONCLUSIONS: Agarose microcapsules were able to completely protect NOD islet isografts from autoimmune destruction in the syngeneic islet transplantation model.