RESUMEN
The process of gastric ulcer healing includes cell migration, proliferation, angiogenesis and re-epithelialization. Platelets contain angiogenesis stimulating factors that induce angiogenesis. Thromboxane A2 (TXA2 ) not only induces platelet activity but also angiogenesis. This study investigated the role of TXA2 in gastric ulcer healing using TXA2 receptor knockout (TPKO) mice. Gastric ulcer healing was suppressed by treatment with the TXA2 synthase inhibitor OKY-046 and the TXA2 receptor antagonist S-1452 compared with vehicle-treated mice. TPKO showed delayed gastric ulcer healing compared with wild-type mice (WT). The number of microvessels and CD31 expression were lower in TPKO than in WT mice, and TPKO suppressed the expression of transforming growth factor beta (TGF-ß) and vascular endothelial growth factor A (VEGF-A) in areas around gastric ulcers. Immunofluorescence assays showed that TGF-ß and VEGF-A co-localized with platelets. Gastric ulcer healing was significantly reduced in WT mice transplanted with TPKO compared with WT bone marrow. These results suggested that TP signalling on platelets facilitates gastric ulcer healing through TGF-ß and VEGF-A.
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Neovascularización Patológica/metabolismo , Úlcera Gástrica/tratamiento farmacológico , Tromboxanos/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Ratones Endogámicos C57BL , Activación Plaquetaria/efectos de los fármacos , Prostaglandinas/farmacología , Receptores de Tromboxanos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Úlcera Gástrica/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Sinusoidal obstruction syndrome (SOS) is a major complication of chemotherapy and hematopoietic stem cell transplantation. The early stage of SOS is characterized by liver sinusoidal endothelial cell (LSEC) injury accompanied by platelet aggregation. Thromboxane A2 (TxA2) induces platelet aggregation through the thromboxane prostanoid (TP) receptor. In this study, we explored the role of TP signaling in a monocrotaline (MCT)-induced mouse model of SOS. Relative to wild-type (WT) mice, TP-deficient (TP-/-) mice exhibited more severe MCT-liver injury, as indicated by elevated levels of alanine aminotransferase (ALT) and coagulative necrosis. Extensive accumulation of platelets in the liver was observed in both WT and TP-/- mice. TP expression co-localized with CD31-positive LSECs. MCT treatment caused LSEC destruction, concomitant with elevated expression of matrix metalloproteinases (MMPs) and adhesion molecules in WT mice, and LSEC damage was further exacerbated in TP-/- mice. Viability of isolated LSECs was lower in cells from TP-/- mice, whereas mRNA levels of MMPs and adhesion molecules were higher; U46619, a TxA2 agonist, reduced these levels in WT mice. These data suggest that TP signaling has no effect on platelet accumulation during MCT-induced liver injury, but instead prevents injury by suppressing LSEC damage.
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Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Células Endoteliales/metabolismo , Receptores de Tromboxanos/metabolismo , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Animales , Células Cultivadas , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Monocrotalina , Receptores de Tromboxanos/agonistas , Receptores de Tromboxanos/genética , Transducción de SeñalRESUMEN
BACKGROUND: Ulcerative Colitis (UC) is an inflammatory bowel disease that affects the colon. The development of UC is regulated by immune cells. Previously, we showed that vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase (TK) signaling induces healing of mucosal damage by recruiting VEGFR1+ cells appear to be lineage monocyte cells. Recent studies show that development of UC correlates with the number of regulatory T cells (Tregs). Here, we investigated whether VEGFR1-TK signaling induces healing of UC via accumulation of Tregs or not. METHOD: Acute colitis was induced in C57/Bl6N (wild-type [WT]) and VEGFR1 T K knockout (VEGFR1 T K-/-) mice by administration of 2.0% dextran sulfate sodium (DSS). RESULTS: Total colon length in VEGFR1 T K-/- mice was shorter than that in WT mice. The ulcer length and the disease activity index (DAI) score were significantly higher in VEGFR1 T K-/- mice than in WT mice, whereas CD31 mRNA and protein levels were significantly lower. Accumulation of forkhead box P3+ (Foxp3+) VEGFR1+ Tregs was lower in VEGFR1 T K-/- mice, as was expression of interleukin (IL)-10 and transforming growth factor (TGF)-ß. The survival rate of WT mice treated with an anti-folate receptor 4 (FR4) antibody was 40%, while that of WT mice treated with control IgG was 90%. Moreover, WT mice treated with a neutralizing antibody against C-X-C chemokine receptor type 4 (CXCR4) showed significantly shorter colon length than WT with control antibody. In VEGFR1 T K-/-, infiltration of Foxp3+ Tregs expressing VEGFR1 and CXCR4 into ulcerated areas was lower than that in WT mice. CONCLUSION: VEGFR1-TK signaling plays a critical role in UC healing and angiogenesis via accumulation of VEGFR1+CXCR4+Foxp3+ Tregs in ulcerated tissue. (264 words).
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Colitis Ulcerosa/metabolismo , Sulfato de Dextran/toxicidad , Transducción de Señal/fisiología , Linfocitos T Reguladores/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Cicatrización de Heridas/fisiología , Animales , Colitis Ulcerosa/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacosRESUMEN
PURPOSE: Treatment strategies for superficial esophageal squamous cell carcinoma (S-ESCC) are determined mainly on the basis of the depth of invasion. We retrospectively studied the accuracy of the depth of tumor invasion, comprehensively assessed using the Japan Esophageal Society (JES) classification. METHODS: The study group comprised 256 patients who underwent narrow band imaging (NBI) magnifying endoscopy, and endoscopic submucosal dissection for S-ESCC. The depth of invasion of S-ESCC was classified into three groups: EP/LPM, MM/SM1, and SM2. The following variables were studied retrospectively: (1) the diagnostic accuracy of non-magnifying white-light endoscopy, (2) the diagnostic accuracy of type B vessels, (3) the diagnostic accuracy of avascular area (AVA), (4) the diagnostic accuracy of the JES classification, and (5) the diagnostic accuracy of comprehensive diagnosis. The depth of invasion was assessed by white-light non-magnifying endoscopy, followed by NBI magnifying endoscopy. RESULTS: The positive predictive value (PPV) of white-light non-magnifying endoscopy was 86% for EP/LPM, 53% MM/SM1, and 74% for SM2. The PPV of the diagnosis of type B vessels was 93% for EP/LPM, 62% for MM/SM1, and 74% for SM2. The PPV of the AVA diagnosis was 73% for EP/LPM, 89% for MM/SM1, and 100% for SM2. The PPV of diagnosis according to the JES classification was 93% for EP/LPM, 65% for MM/SM1, and 77% for SM2. The PPV of the comprehensive diagnosis was 94% for EP/LPM, 63%, for MM/SM1, and 75% for SM2. CONCLUSIONS: The additional use of NBI magnifying endoscopy can enhance the diagnostic accuracy of the depth of invasion in patients with S-ESCC.
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Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/diagnóstico por imagen , Carcinoma de Células Escamosas de Esófago/patología , Anciano , Anciano de 80 o más Años , Resección Endoscópica de la Mucosa , Mucosa Esofágica/diagnóstico por imagen , Mucosa Esofágica/patología , Mucosa Esofágica/cirugía , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagoscopía/normas , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Imagen de Banda Estrecha , Invasividad Neoplásica/diagnóstico por imagen , Invasividad Neoplásica/patología , Valor Predictivo de las Pruebas , Estudios RetrospectivosRESUMEN
BACKGROUND: Endoscopic submucosal dissection (ESD) has been performed in a high proportion of patients with superficial esophageal squamous-cell carcinoma. Endoscopic aspiration mucosectomy (EAM) is a more straightforward technique that is easier to perform. We retrospectively evaluated the safety and efficacy of EAM and ESD to clarify the advantages and disadvantages of each procedure. METHODS: A total of 374 patients (423 lesions) who underwent endoscopic resection were retrospectively studied. The following variables were evaluated (1) procedure time and adverse events as safety, and (2) en bloc complete resection rate, local recurrence rate, lymph node recurrence rate, overall survival rate, and cause-specific survival rate as efficacy. RESULTS: EAM was performed in 134 patients (149 lesions), and ESD was performed in 240 patients (274 lesions). The procedure times of EAM and ESD were 31.0 ± 22.4 and 85.7 ± 46.5 min (p < 0.001), respectively. The perforation rates were 0 and 6.2% (p = 0.002), respectively. The en bloc complete resection rates were 48.3 and 91.6% (p < 0.001), respectively. The local recurrence rates were 5.5 and 0% (p < 0.001), respectively. For lesions measuring less than 15 mm in diameter, EAM had a relatively good en bloc complete resection rate (EAM, 76.1% vs. ESD, 100%) and a significantly short procedure time (EAM, 25.2 ± 15.2 min vs. ESD, 62.7 ± 35.2 min; p < 0.001). CONCLUSIONS: ESD has a higher en bloc complete resection rate and a better local control rate than EAM. For lesions measuring less than 15 mm in diameter, EAM may be a treatment option.
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Resección Endoscópica de la Mucosa/efectos adversos , Resección Endoscópica de la Mucosa/métodos , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/cirugía , Anciano , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Complicaciones Posoperatorias , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The significance of the relationship between the nervous and immune systems with respect to disease course is increasingly apparent. Immune cells in the liver and spleen are responsible for the development of acute liver injury, yet the regulatory mechanisms of the interactions remain elusive. Calcitonin gene-related peptide (CGRP), which is released from the sensory nervous system, regulates innate immune activation via receptor activity-modifying protein 1 (RAMP1), a subunit of the CGRP receptor. Here, we show that RAMP1 in Kupffer cells (KCs) plays a critical role in the etiology of immune-mediated hepatitis. RAMP1-deficient mice with concanavalin A (ConA)-mediated hepatitis, characterized by severe liver injury accompanied by infiltration of immune cells and increased secretion of pro-inflammatory cytokines by KCs and splenic T cells, showed poor survival. Removing KCs ameliorated liver damage, while depleting T cells or splenectomy led to partial amelioration. Adoptive transfer of splenic T cells from RAMP1-deficient mice led to a modest increase in liver injury. Co-culture of KCs with splenic T cells led to increased cytokine expression by both cells in a RAMP1-dependent manner. Thus, immune-mediated hepatitis develops via crosstalk between immune cells. RAMP1 in KCs is a key regulator of immune responses.
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Hepatitis/inmunología , Macrófagos del Hígado/inmunología , Proteína 1 Modificadora de la Actividad de Receptores/inmunología , Animales , Péptido Relacionado con Gen de Calcitonina/inmunología , Células Cultivadas , Concanavalina A/inmunología , Citocinas/inmunología , Eliminación de Gen , Hepatitis/genética , Hepatitis/patología , Inmunidad Innata , Macrófagos del Hígado/metabolismo , Macrófagos del Hígado/patología , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 1 Modificadora de la Actividad de Receptores/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
PURPOSE: This study was designed to retrospectively analyze the safety and efficacy of chemoradiation therapy with nedaplatin and 5-fluorouracil in elderly patients with esophageal squamous cell carcinoma. METHODS AND MATERIALS: Eligible patients were aged 76 years or older, had a histopathologic diagnosis of esophageal squamous cell carcinoma, and were treated at the Kitasato University Hospital between January 2010 and March 2016. Chemotherapy consisted of nedaplatin in an intravenous dose of 90 mg/m2 on day 1 and 5-fluorouracil in an intravenous dose of 800 mg/m2 on days 1 to 5, repeated every 4 weeks for 2 cycles. Radiation therapy consisted of 50.4 Gy in 28 fractions for thoracic tumors and 61.2 Gy for cervical tumors. RESULTS: Twenty-five patients were studied. Patient characteristics were as follows: median age 79 years (range, 76-85 years), clinical stage I/II/III/IV (7/8/8/2, respectively), and surgically resectable/unresectable (17/8, respectively). The completion rates of radiation therapy and chemoradiation therapy were 100% and 84%, respectively. Grade ≥3 acute toxicities included neutropenia (76%), leukopenia (72%), thrombocytopenia (32%), anemia (28%), anorexia (32%), oral mucositis (20%), febrile neutropenia (12%), and esophagitis (8%). Grade ≥3 late toxicities included esophageal stenosis (12%) and pleural effusion (4%). The complete response rate was 64%. In the median follow-up period of 18.9 months, the 1-year overall survival rate was 68%. CONCLUSIONS: Definitive chemoradiation therapy with nedaplatin and 5-fluorouracil may be a feasible treatment option for elderly patients with esophageal squamous cell carcinoma.
RESUMEN
BACKGROUND: Gastric cancer treatment guidelines recommend additional surgery as the standard treatment for lesions for which endoscopic submucosal dissection (ESD) is not indicated. However, the incidence of lymph-node metastasis is low in most patients. METHODS AND MATERIALS: The study comprised 231 patients (231 lesions) who underwent ESD for early gastric cancer (EGC) in our hospital from September 2002 through March 2015 and were found to have lesions for which endoscopic treatment is not indicated on histopathological evaluation after ESD. The patients were divided into the additional operation group and the follow-up group, and long-term outcomes were studied retrospectively. Risk factors for metastasis and recurrence were also studied (capture rate, 98.7%). RESULTS: The median follow-up was 48 months. There were 174 men and 57 women with a median age of 72 years. The additional operation group comprised 118 patients, and the follow-up group comprised 113 patients. The rates of 5-year cause-specific survival and 5-year overall survival were significantly higher in the additional operation group (100 and 96.0%, respectively) than in the follow-up group (92.6 and 73.3%, respectively; p = 0.010, p < 0.001). In the follow-up group, 5 patients (4.4%) died of gastric cancer (p = 0.021). Among elderly patients 75 years or older, long-term outcomes did not differ significantly between the groups. Sixteen patients had metastasis or recurrence, and the presence of lymphatic involvement was an independent risk factor for metastasis, recurrence, or both (p = 0.003; odds ratio 10.594; 95% confidence interval 2.294-48.927). CONCLUSIONS: In patients with EGC who are confirmed to have lesions for which endoscopic treatment is not indicated on histopathological evaluation after ESD, additional surgery should be aggressively performed if the patient can tolerate such treatment. In elderly patients aged 75 years or older and patients with serious underlying diseases, follow-up observation was suggested to be one option in patients who give informed consent after receiving an explanation of the risk of recurrence.
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Resección Endoscópica de la Mucosa , Gastrectomía , Neoplasias Gástricas/cirugía , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Oportunidad Relativa , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
In Table 1, the second item in the right-hand column "Extra-indication" should be changed to "Out of indication". The correct version of Table 1 is displayed.
RESUMEN
OBJECTIVE: To evaluate the clinical outcomes in patients with cancer of an unknown primary site (CUP), who were treated by gastrointestinal oncologists. METHODS: We retrospectively studied 29 patients with CUP who were presented at the Department of Gastroenterology, Kitasato University Hospital from October 2005 to October 2013, and were treated by the gastrointestinal oncologists. The patients were divided into two groups, namely chemotherapy group and symptomatic therapy group, and the clinical characteristics and survival times were compared. The clinical course was studied according to the histologic type (adenocarcinoma or non-adenocarcinoma), prognostic subset (favorable or unfavorable), and the presence or absence of chemotherapy. RESULTS: The chemotherapy group comprised 19 patients, and the symptomatic therapy group comprised 10 patients. The median survival time was 11 months in the chemotherapy group and 3 months in the symptomatic therapy group. Twenty-two patients had adenocarcinoma, and 7 had non-adenocarcinoma. Of the 22 patients with adenocarcinoma, 2 belonged to the favorable prognostic subset and received chemotherapy. One of these patients died of cancer at 47 months, and the other was alive and disease free at 58 months. Among the 20 patients with adenocarcinoma in the unfavorable prognostic subset, 16 received chemotherapy and had a median survival of 16 months. Seven (44%) of these patients survived for at least 21 months, and 3 patients who could receive 3 or more regimens survived for at least 46 months. CONCLUSION: It might be appropriate for gastrointestinal oncologists to treat CUP on the basis of clinical experience, depending on the situation.
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Liver metastases from colorectal cancer (CRC) are a clinically significant problem. The renin-angiotensin system is involved in tumor growth and metastases. This study was designed to evaluate the role of angiotensin II subtype receptor 1a (AT1a) in the formation of liver metastasis in CRC. A model of liver metastasis was developed by intrasplenic injection of mouse colon cancer (CMT-93) into AT1a knockout mice (AT1aKO) and wild-type (C57BL/6) mice (WT). Compared with WT mice, the liver weight and liver metastatic rate were significantly lower in AT1aKO. The mRNA levels of CD31, transforming growth factor- ß1 (TGF-ß1), and F4/80 were suppressed in AT1aKO compared with WT. Double immunofluorescence analysis showed that the number of accumulated F4/80+ cells expressing TGF-ß1 in metastatic areas was higher in WT than in AT1aKO. The AT1aKO bone marrow (BM) (AT1aKO-BM)âWT showed suppressed formation of liver metastasis compared with WT-BMâWT. However, the formation of metastasis was further suppressed in WT-BMâAT1aKO compared with AT1aKO-BMâWT. In addition, accumulated F4/80+ cells in the liver metastasis were not BM-derived F4/80+ cells, but mainly resident hepatic F4/80+ cells, and these resident hepatic F4/80+ cells were positive for TGF-ß1. Angiotensin II enhanced TGF-ß1 expression in Kupffer cells. Treatment of WT with clodronate liposomes suppressed liver metastasis by diminishing TGF-ß1+ F4/80+ cells accumulation. The formation of liver metastasis correlated with collagen deposition in the metastatic area, which was dependent on AT1a signaling. These results suggested that resident hepatic macrophages induced liver metastasis formation by induction of TGF-ß1 through AT1a signaling.
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Neoplasias Colorrectales/metabolismo , Macrófagos del Hígado/fisiología , Neoplasias Hepáticas Experimentales/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Proteínas Angiogénicas/metabolismo , Angiotensina II/fisiología , Animales , Línea Celular Tumoral , Colágeno Tipo I/metabolismo , Neoplasias Colorrectales/patología , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas Experimentales/secundario , Masculino , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND/AIMS: Few studies have classified risk factors according to the onset time of bleeding after endoscopic submucosal dissection (post-ESD bleeding). METHODS: We studied 1767 consecutive lesions in patients who underwent ESD for early gastric cancer from December 2006 through June 2016. Patients who had a remnant stomach or who had undergone reconstruction with a gastric tube were excluded. Post-ESD bleeding was classified into acute bleeding (0-5 days after ESD) and delayed bleeding (6 or more days after ESD), and the risk factors for each type of bleeding were compared. RESULTS: Post-ESD bleeding occurred in 150 (8.5%) of 1767 lesions. Bleeding was acute in 129 lesions (7.3%) and delayed in 21 (1.2%). Acute post-ESD bleeding was frequently associated with lesions located in the distal stomach, expanded indications or non-indicated lesions, a specimen diameter of ≥40 mm, and antithrombotic therapy. Delayed post-ESD bleeding was often associated with lesions located in the proximal stomach, hemodialysis, and antithrombotic therapy. Among 334 lesions in patients who received antithrombotic therapy, post-ESD bleeding occurred in 47 lesions (14.1%). Independent risk factors for post-ESD bleeding were a specimen diameter of ≥40 mm and treatment with 2 or more antithrombotic agents. CONCLUSIONS: Acute post-ESD bleeding and delayed post-ESD bleeding were associated with different clinical characteristics. Antithrombotic therapy is a risk factor for post-ESD bleeding in both the acute and delayed phases.
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Resección Endoscópica de la Mucosa/efectos adversos , Fibrinolíticos/efectos adversos , Hemorragia Posoperatoria/etiología , Neoplasias Gástricas/cirugía , Anciano , Anciano de 80 o más Años , Femenino , Fibrinolíticos/uso terapéutico , Estudios de Seguimiento , Mucosa Gástrica/cirugía , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Hemorragia Posoperatoria/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
Perforation is an important procedural complication of endoscopic submucosal dissection (ESD) for early gastric cancer. Although the incidence of delayed perforation after ESD is low, extreme caution is necessary because many cases require surgical intervention. Among 1984 lesions of early gastric cancer treated in our hospital by ESD in 1588 patients from September 2002 through March 2015, delayed perforation developed in 4 patients (4 lesions, 0.25%). A diagnosis of delayed perforation requires prompt action, including surgical intervention when required.