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BACKGROUND & AIMS: The Global Leadership Initiative on Malnutrition (GLIM) criteria has been recognised as major diagnostic criteria for malnutrition in adults worldwide; however, its validity in rehabilitation settings remains unclear. This study investigated the concurrent and predictive validity of the GLIM criteria for adult patients in convalescent rehabilitation wards. METHODS: This retrospective cohort study was conducted using pre-established datasets from convalescent rehabilitation wards in a hospital. The inclusion criteria were adults aged ≥18 years admitted to the wards between November 2018 and October 2020 who were available for body composition assessment. Malnutrition diagnoses were determined by registered dietitians (RDs) using the GLIM criteria. The Subjective Global Assessment (SGA) was performed by another RD and used for the malnutrition reference standard. The GLIM criteria sensitivity and specificity were examined for SGA. The odds ratios and hazard ratios of GLIM-defined malnutrition for the total score of the Functional Independence Measure (tFIM) effectiveness and non-home discharge were calculated using univariable and multivariable logistic regression analyses and Cox proportional hazard models. RESULTS: Data from 723 patients were extracted from the dataset. GLIM-defined malnutrition was confirmed in 207 (28.6%) patients, 87 (12.0%) with moderate malnutrition and 120 (16.6%) with severe malnutrition. The SGA graded 146 (20.2%) patients with moderate malnutrition (grade B) and 86 (11.9%) with severe malnutrition (grade C). The GLIM criteria (malnutrition/ no malnutrition) had fair sensitivity (76.7%, 95% confidence interval [CI]: 70.7-82.0%) and good specificity (94.1%, 95% CI: 91.6-96.0%), indicating acceptable concurrent validity. GLIM-defined moderate malnutrition had poorer sensitivity than severe malnutrition (42.5% vs 81.4%). Logistic regression analyses revealed no evidence for the association between GLIM-defined malnutrition and poor tFIM effectiveness (adjusted odds ratio [AOR]: 1.09, 95% CI: 0.71-1.69) and non-home discharge (AOR: 1.19, 95% CI: 0.76-1.84). The Cox proportional hazard analyses also showed no effect of malnutrition on outcomes. CONCLUSION: The GLIM criteria had fair sensitivity and good specificity, indicating acceptable criteria for diagnosing malnutrition in rehabilitation settings. However, its predictive validity for functional recovery and discharge outcomes was insufficient.
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AIM: This retrospective cohort study investigated the relationship between sarcopenia and Activities of Daily Living capacity after discharge from convalescent rehabilitation wards. METHODS: We included consecutive patients discharged from three convalescent rehabilitation wards in a hospital in Japan between December 2018 and October 2020. Sarcopenia was diagnosed based on the criteria of the 2019 Asian Working Group for Sarcopenia, utilizing skeletal muscle mass index and handgrip strength. Statistical analyses were carried out separately for men and women. The primary outcome was a higher motor domain (motor Functional Independence Measure [mFIM]) and a higher cognitive domain (cognitive Functional Independence Measure [cFIM]) of the FIM score 1 month after discharge. The secondary outcomes were higher mFIM and cFIM scores 6 months after discharge, analyzed using binary logistic regression. RESULTS: Among 305 participants (mean age 70.0 years, 148 men), 93 were identified as having sarcopenia. The prevalence of sarcopenia was 16% for outpatient rehabilitation services, 59% for home-visit rehabilitation services and 50% for older adult day care. Logistic regression analyses showed that sarcopenia at discharge was not an independent variable for mFIM at 1 month (odds ratio [OR] 20, 95% confidence interval [CI] 0.31-1300 for men, OR 0.51, 95% CI 0.11-2.4 for women) and cFIM (OR 0.63, 95% CI 0.10-3.8 for men, OR 5.3, 95% CI 0.81-34 for women). At 6 months, sarcopenia at discharge was not an independent variable for mFIM (OR 0.30, 95% CI 0.02-3.6 for men, OR 0.40, 95% CI 0.06-2.5 for women) and cFIM (OR 0.16, 95% CI 0.01-2.4 for men, OR 0.00, 95% CI 0.00-1.1 for women). CONCLUSIONS: Sarcopenia at the time of discharge from convalescent rehabilitation wards does not independently predict FIM 1 month or 6 months after discharge. Geriatr Gerontol Int 2024; 24: 715-721.
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Actividades Cotidianas , Alta del Paciente , Sarcopenia , Humanos , Masculino , Sarcopenia/epidemiología , Femenino , Anciano , Alta del Paciente/estadística & datos numéricos , Estudios Retrospectivos , Japón/epidemiología , Recuperación de la Función , Anciano de 80 o más Años , Fuerza de la Mano/fisiología , Centros de Rehabilitación , Persona de Mediana EdadRESUMEN
BACKGROUND: The effect of sarcopenia on the recovery of swallowing function, and the interaction among sarcopenia, nutrition care, and rehabilitation therapy are inconclusive. METHODS: This multicenter cohort study was conducted between November 2018 and October 2020 in convalescent rehabilitation hospitals in Japan and included post-stroke patients aged ≥65 years with dysphagia. All participants were assigned to sarcopenia and non-sarcopenia groups. The primary outcome was the achievement of ≥2 Food Intake Level Scale [FILS] gain, and the secondary outcomes included Functional Independence Measure (FIM) gain and efficiency. Considering the effect modification of energy intake and rehabilitation duration, logistic regression analyses were performed. RESULTS: Overall, 153 participants with (median age, 82 years; 57.5% women) and 40 without (median age 75 years; 35.0% women) sarcopenia were included. The non-sarcopenia group had more patients who achieved an FILS gain of ≥2 (75.0%) than the sarcopenia group (51.0%). Sarcopenia was independently associated with a poor FILS gain (odds ratio:0.34, 95% confidence intervals: 0.13-0.86) but not associated with FIM gain or efficiency. This association was not affected by the rehabilitation duration or energy intake. CONCLUSIONS: In conclusion, sarcopenia was negatively associated with the recovery of swallowing function in stroke patients without interaction by energy intake and rehabilitation duration.
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Trastornos de Deglución , Sarcopenia , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Deglución , Femenino , Humanos , Masculino , Recuperación de la Función , Estudios Retrospectivos , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/terapiaRESUMEN
OBJECTIVES: This study aimed to investigate the association between muscle strength and adjusted appendicular skeletal muscle mass (ASM) in patients who have had strokes with the Functional Independence Measure (FIM) and the probability of being discharged. METHODS: A retrospective cohort study was conducted for older patients who have had strokes admitted to convalescent rehabilitation wards between January 2017 and October 2020. Hand-grip strength (HGS) was used to assess muscle strength. ASM was measured with a bioelectrical impedance analysis, and then divided by height-squared, body weight, body mass index (BMI), body fat mass (BFM), and body fat percentage (BFP) to calculate the adjusted ASM. The primary outcome was FIM at the time of discharge, and the secondary outcome was the probability of being discharged to their home. Multivariate analyses were conducted to adjust for confounding effects. RESULTS: The data of 699 participants (female: 47%; median age, 79 y) were analyzed. HGS was independently associated with FIM at the time of discharge in men (partial regression coefficient [B]â¯=â¯0.482; 95% confidence interval [CI], 0.225-0.740) and women (Bâ¯=â¯0.664; 95% CI, 0.263-1.065) and also was independently associated with being discharged to their home in men (odds ratio [OR]: 1.070; 95% CI, 1.030-1.100) and women (OR: 1.070; 95% CI, 1.000-1.130). Conversely, none of the adjusted ASM indices were associated with the outcomes. The cutoff value of HGS for discharge to home was 15.1 kg for men and 9.5 kg for women. CONCLUSIONS: In patients who have had strokes, HGS independently predicted FIM at the time of discharge and the probability of being discharged to their home. The adjusted ASM methods had less predictive value for functional and discharge outcomes.
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Fuerza de la Mano , Accidente Cerebrovascular , Anciano , Femenino , Fuerza de la Mano/fisiología , Humanos , Masculino , Fuerza Muscular , Músculo Esquelético , Músculos , Pronóstico , Estudios Retrospectivos , Accidente Cerebrovascular/complicacionesRESUMEN
Malnutrition and sarcopenia often coexist in rehabilitation patients, although they are often overlooked and undertreated in clinical practice. This cross-sectional study aimed to clarify the prevalence of the coexistence of malnutrition and sarcopenia (Co-MS) and its associated factors in convalescent rehabilitation wards in Japan. Consecutive patients aged ≥ 65 years in convalescent rehabilitation wards between November 2018 and October 2020 were included. Malnutrition and sarcopenia were determined by the Global Leadership Initiative on Malnutrition (GLIM) criteria and the Asian Working Group for Sarcopenia (AWGS 2019) criteria, respectively. Patients who presented both with malnutrition and sarcopenia were classified as Co-MS. Potentially associated factors included age, sex, days from onset to admission of rehabilitation wards, reason for admission, pre-morbid functional dependency, comorbidity, activities of daily living, swallowing ability, and oral function and hygiene. The prevalence of malnutrition, sarcopenia, and Co-MS was calculated. Binary logistic regression analyses were performed to compute odds ratios (ORs) and the 95% confidence interval (CI) of possible associated factors for each condition. Overall, 601 patients were eligible for the analysis (median 80 years old, 355 female patients, 70% cerebrovascular disease). Co-MS, malnutrition, and sarcopenia were found in 23.5%, 29.0%, and 62.4% of the enrolled patients, respectively. After adjustment, onset-admission interval (OR = 1.04; 95% CI = 1.02 to 1.06), hospital-associated deconditioning (OR = 4.62; 95% CI = 1.13 to 18.8), and swallowing ability (Food Intake LEVEL Scale) (OR = 0.83; 95% CI = 0.73 to 0.93) were identified as independent explanatory factors of Co-MS. In conclusion, Co-MS was prevalent in geriatric rehabilitation patients; thus, healthcare professionals should be aware of the associated factors to detect the geriatric rehabilitation patients who are at risk of both malnutrition and sarcopenia, and to provide appropriate treatments.
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Evaluación Geriátrica , Desnutrición/complicaciones , Desnutrición/epidemiología , Sarcopenia/complicaciones , Sarcopenia/epidemiología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Oportunidad Relativa , PrevalenciaRESUMEN
This cross-sectional study investigated the proportion of patients' recovery from sarcopenia status and the relationship between improvement in sarcopenia (IS) and function and discharge outcome in hospitalized patients with stroke. This study included patients with stroke, aged 65 years or more, with a diagnosis of sarcopenia, who were admitted to a convalescent rehabilitation ward. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 criteria. Patients were divided according to the presence or absence of sarcopenia at discharge: IS group and non-improvement in sarcopenia (NIS) group. Among the 227 participants (mean age: 80.5 years; 125 females), 30% (69/227) of the patients were in the IS group, while 70% (158/227) were in the NIS group. The IS group showed a higher Functional Independence Measure (FIM) than the NIS group (median 112 vs. 101, p = 0.003). The results demonstrated that IS was independently associated with higher FIM (partial regression coefficient, 5.378; 95% confidence interval (CI), 0.709-10.047). The IS group had higher odds of home discharge than the NIS group (odds ratio, 2.560; 95% CI, 0.912-7.170). In conclusion, recovery from sarcopenia may be associated with better function in patients with stroke.
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Estado Funcional , Estado Nutricional , Sarcopenia/rehabilitación , Rehabilitación de Accidente Cerebrovascular/estadística & datos numéricos , Accidente Cerebrovascular/fisiopatología , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Oportunidad Relativa , Alta del Paciente , Recuperación de la Función , Sarcopenia/complicaciones , Sarcopenia/fisiopatología , Accidente Cerebrovascular/complicaciones , Rehabilitación de Accidente Cerebrovascular/métodos , Resultado del TratamientoRESUMEN
A 50-year-old male was examined at another hospital for fever, general fatigue and slight abdominal pain. He was treated with antibiotics and observed. However, his symptoms did not lessen, and laboratory tests revealed liver dysfunction, jaundice and an increased inflammatory response. He was then admitted to our hospital and underwent an abdominal computed tomography scan and magnetic resonance cholangiopancreatography (MRCP), which revealed common bile duct (CBD) stones. He was diagnosed with mild acute cholangitis. As the same time, he was admitted to our hospital and an emergency endoscopic retrograde cholangiopancreatography was performed. Vater papilla opening in the third portion of the duodenum and presence of a peripapillary duodenal diverticulum made it difficult to perform cannulation of the CBD. In addition, MRCP revealed that the CBD was extremely narrow (diameter 5 mm). We therefore performed laparoscopic cholecystectomy and endoscopic sphincterotomy using the rendezvous technique for choledocholithiasis simultaneously rather than laparoscopic CBD exploration. After the operation, the patient was discharged with no complications. Although the rendezvous technique has not been very commonly used because several experts in the technique and a large operating room are required, this technique is a very attractive and effective approach for treating choledocholithiasis, for which endoscopic treatment is difficult.
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BACKGROUND: Group-specific component (Gc)-globulin-derived macrophage-activating factor (GcMAF) generated by a cascade of catalytic reactions with deglycosidase enzymes exerts antitumor activity. We hypothesized that degalactosyl Gc-globulin (DG3), a precursor of GcMAF, also plays a role in recovery from cancer as well as GcMAF due to progression of deglycosylation by generally resident sialidases and mannosidases. MATERIALS AND METHODS: We prepared the subtypes of DG3, such as 1f1f and 1s1s and its 22 homodimers, by using vitamin D3-binding Sepharose CL-6B and examined their antitumor activity in mice bearing Lewis lung carcinoma cells, by counting the number of nodules formed in their lungs. RESULTS: Antitumor activity of DG3 was observed regardless of its subtype, being equivalent to that of GcMAF. The injection route of DG3 affected its antitumor activity, with subcutaneous and intramuscular administration being more favorable than the intraperitoneal or intravenous route. In order to obtain significant antitumor activity, more than 160 ng/kg of DG3 were required. CONCLUSION: DG3 proved to be promising as an antitumor agent, similarly to GcMAF.
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Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Galactosa/metabolismo , Factores Activadores de Macrófagos/administración & dosificación , Proteína de Unión a Vitamina D/administración & dosificación , Animales , Carcinoma Pulmonar de Lewis/metabolismo , Femenino , Humanos , Inyecciones Intramusculares , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Inyecciones Subcutáneas , Factores Activadores de Macrófagos/farmacología , Ratones , Ratones Endogámicos C57BL , Proteína de Unión a Vitamina D/química , Proteína de Unión a Vitamina D/farmacologíaRESUMEN
BACKGROUND: The 1f1f subtype of the group-specific component (Gc) protein is converted into Gc protein-derived macrophage-activating factor (GcMAF) by enzymatic processing with ß-galactosidase and sialidase. We previously demonstrated that preGc(1f1f)MAF, a full Gc(1f1f) protein otherwise lacking a galactosyl moiety, can be converted to GcMAF by treatment with mouse peritoneal fluid. Here, we investigated the effects of the ß-galactosidase-treated 1s1s and 22 subtypes of Gc protein (preGc(1s1s)MAF and preGc22MAF) on the phagocytic activation of mouse peritoneal macrophages. RESULTS: We demonstrated the presence of Gal-GalNAc disaccharide sugar structures in the Gc(1s1s) protein by western blotting using peanut agglutinin and Helix pomatia agglutinin lectin. We also found that preGc(1s1s)MAF and preGc22MAF significantly enhanced the phagocytic activity of mouse peritoneal macrophages in the presence and absence of mouse peritoneal fluid. CONCLUSION: We demonstrate that preGc(1s1s)MAF and preGc22MAF proteins can be used as effective macrophage activators.
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Activación de Macrófagos/fisiología , Factores Activadores de Macrófagos/metabolismo , Proteína de Unión a Vitamina D/metabolismo , beta-Galactosidasa/metabolismo , Animales , Western Blotting , Humanos , Macrófagos/metabolismo , Ratones , Fagocitosis/fisiologíaRESUMEN
BACKGROUND: A high incidence of recurrence after treatment is the most serious problem in hepatocellular carcinoma (HCC). Therefore, a new strategy for the treatment of the disease is needed. The aim of the present study was to investigate whether vitamin D binding protein-macrophage activating factor (DBP-maf) is able to inhibit the growth of HCC. METHODS: The effects of DBP-maf on endothelial cells and macrophage were evaluated by WST-1 assay and phagocytosis assay, respectively. Human HCC cells (HepG2) were implanted into the dorsum of severe combined immunodeficiency (SCID) mice. These mice were divided into control and DBP-maf treatment groups (n = 10/group). The mice in the treatment group received 40 ng/kg/d of DBP-maf for 21 d. RESULTS: DBP-maf showed anti-proliferative activity against endothelial cells and also activated phagocytosis by macrophages. DBP-maf inhibited the growth of HCC cells (treatment group: 126 ± 18mm(3), untreated group: 1691.5 ± 546.9mm(3), P = 0.0077). Histologic examinations of the tumors revealed the microvessel density was reduced and more macrophage infiltration was demonstrated in the tumor of mice in the treatment group. CONCLUSION: DBP-maf has at least two novel functions, namely, an anti-angiogenic activity and tumor killing activity through the activation of macrophages. DBP-maf may therefore represent a new strategy for the treatment of HCC.
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Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Factores Activadores de Macrófagos/uso terapéutico , Proteína de Unión a Vitamina D/uso terapéutico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Humanos , Factores Activadores de Macrófagos/farmacología , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones SCID , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Fagocitosis/efectos de los fármacos , Ratas , Proteína de Unión a Vitamina D/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The 1f1f subtype of the Gc protein (Gc(1f1f) protein) was converted into Gc-derived macrophage-activating factor (GcMAF) by enzymatic processing in the presence of ß-galactosidase of an activated B-cell and sialidase of a T-cell. We hypothesized that preGc(1f1f)MAF, the only Gc(1f1f) protein lacking galactose, can be converted to GcMAF in vivo because sialic acid is cleaved by residual sialidase. Hence, we investigated the effect of preGc(1f1f)MAF on the phagocytic activation of mouse peritoneal macrophages. RESULTS: We examined the sugar moiety of preGc(1f1f)MAF with a Western blot using peanut agglutinin (PNA) and Helix pomatia agglutinin (HPA) lectin. We also found that preGc(1f1f)MAF significantly enhanced phagocytic activity in mouse peritoneal macrophages but only in the presence of the mouse peritoneal fluid; the level of phagocytic activity was the same as that observed for GcMAF. CONCLUSION: PreGc(1f1f)MAF can be used as an effective macrophage activator in vivo.
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Activación de Macrófagos/efectos de los fármacos , Factores Activadores de Macrófagos/farmacología , Macrófagos Peritoneales/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Precursores de Proteínas/farmacología , Animales , Evaluación Preclínica de Medicamentos , Femenino , Galactosa/metabolismo , Glicosilación , Factores Activadores de Macrófagos/biosíntesis , Factores Activadores de Macrófagos/química , Macrófagos Peritoneales/fisiología , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Ácido N-Acetilneuramínico/metabolismo , Neuraminidasa/metabolismo , Precursores de Proteínas/química , Procesamiento Proteico-Postraduccional , Proteína de Unión a Vitamina D/química , Proteína de Unión a Vitamina D/metabolismoRESUMEN
Pancreatitis is a relatively rare complication in systemic lupus erythematosus (SLE). Herein we report a case of SLE with the initial development of acute pancreatitis, subsequently complicated by bleeding pseudoaneurysms. A 55-year-old Japanese woman was admitted to our hospital for the treatment of SLE. During the course of treatment, she complained of upper abdominal pain. An abdominal computed tomography (CT) scan showed that the pancreas was diffusely enlarged, and she was diagnosed with acute pancreatitis. Her pancreatitis was resistant to glucocorticoid therapy and was subsequently associated with pancreatic pseudocysts and recurrent rupture of the pseudoaneurysms. After surgical drainage of the hemorrhagic pseudocysts, the patient's clinical condition gradually improved with intensive therapies. Our case indicates that lupus pancreatitis can be associated with the potentially fatal complication of recurrent bleeding of pseudoaneurysms.
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Aneurisma Falso/etiología , Aneurisma Roto/etiología , Lupus Eritematoso Sistémico/complicaciones , Pancreatitis/etiología , Arteria Esplénica , Aneurisma Falso/diagnóstico , Aneurisma Falso/terapia , Aneurisma Roto/diagnóstico , Aneurisma Roto/terapia , Angiografía , Antibacterianos/uso terapéutico , Embolización Terapéutica , Femenino , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Imagen por Resonancia Magnética , Persona de Mediana Edad , Pancreatitis/diagnóstico , Pancreatitis/tratamiento farmacológico , Prednisolona/administración & dosificación , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Bilioenterostomy is a common surgical technique that is widely used. Recently, clinical studies have revealed that biliary carcinomas can occur after bilioenterostomy. The present study was designed to evaluate whether hochu-ekki-to (TJ-41), a Japanese herbal drug, could prevent chemically induced biliary carcinomas in bilioenterostomized hamsters. MATERIALS AND METHODS: Syrian golden hamsters were subjected to choledochojejunostomy and then received subcutaneous injections of N-nitrosobis(2-oxopropyl) amine every 2 weeks at a dose of 10 mg/kg. N-nitrosobis(2-oxopropyl) amine administration was started 4 weeks after surgery. The animals were simultaneously p.o. administered TJ-41 in water every day at a dose of 1000 mg/kg (TJ-41 group). The control hamsters were administered water alone. The hamsters were sacrificed 22 weeks after surgery, and the development of biliary carcinomas, the presence and degree of cholangitis, and the cell kinetic status of the biliary epithelium were evaluated histologically. RESULTS: Intrahepatic bile duct carcinomas developed in 15/17 (88%) hamsters in the control group and in only 8/17 (47%) hamsters in the TJ-41 group (P < 0.05). The degree of cholangitis was not different between the two groups. However, the proliferating cell nuclear antigen labeling index of the biliary epithelium in the TJ-41 group (6.46%) was significantly lower than the controls (9.67%) (P < 0.05). These findings indicated that TJ-41 reduced accelerated biliary epithelial cell kinetics after bilioenterostomy, resulting in the prevention of carcinogenesis. CONCLUSION: TJ-41 has a preventive effect on chemically induced carcinoma of the biliary tract after bilioenterostomy.
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Neoplasias de los Conductos Biliares/prevención & control , Medicamentos Herbarios Chinos/uso terapéutico , Fitoterapia/métodos , Animales , Neoplasias de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Proliferación Celular/efectos de los fármacos , Coledocostomía/efectos adversos , Cricetinae , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Células Epiteliales/patología , Femenino , Inyecciones Subcutáneas , Mesocricetus , NitrosaminasRESUMEN
The present study was designed to evaluate whether etodolac, a cyclooxgenase-2 (COX-2)-specific inhibitor, could prevent chemically induced biliary carcinogenesis in bilioenterostomized hamsters. Syrian golden hamsters were subjected to choledochojejunostomy and then received subcutaneous injections of N-nitrosobis(2-oxopropyl)amine (BOP) every 2 weeks at a dose of 10 mg/kg body wt. BOP administration was started 4 weeks after surgery, and continued for 18 weeks. The animals were simultaneously orally administered etodolac three times per week at a dose of 10 mg/kg body wt in 0.5% methylcellose solution (etodolac group). The control hamsters were administered methylcellose solution alone. The hamsters were killed 22 weeks after surgery, and the biliary carcinomas were evaluated histologically. The presence and degree of cholangitis and the cell kinetic status of the biliary epithelium were also evaluated with special reference to biliary carcinogenesis. Intrahepatic bile duct carcinomas developed in 15 of 17 (88%) hamsters in the control group, and in only six of 18 (33%) hamsters in the etodolac group (P < 0.01). The incidence and number of developing biliary carcinomas were well correlated with the degree of cholangitis, and severe cholangitis was evident in the controls. The cell kinetic study demonstrated that the proliferating cell nuclear antigen-labeling index of the biliary epithelium was 9.67 and 5.14% in the control and etodolac groups, respectively (P < 0.05). The mean levels of prostaglandin E(2) (PGE(2)) products in the liver tissue were 14.14 +/- 3.31 pg/total protein (TP) mg in the control group, and 7.46 +/- 2.34 pg/TP mg in the etodolac group (P < 0.05). These findings indicated that etodolac reduced both the occurrence of severe cholangitis and the acceleration of biliary epithelial cell kinetics after bilioenterostomy, resulting in the prevention of BOP-induced biliary carcinogenesis in hamsters. In conclusion, COX-2-specific inhibitor (etodolac) may be a possible agent against not only reflux cholangitis, but also biliary carcinoma after bilioenterostomy.
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Neoplasias del Sistema Biliar/prevención & control , Carcinoma/prevención & control , Inhibidores de la Ciclooxigenasa/farmacología , Etodolaco/farmacología , Prostaglandina-Endoperóxido Sintasas/metabolismo , Animales , Neoplasias del Sistema Biliar/inducido químicamente , Neoplasias del Sistema Biliar/patología , Carcinoma/inducido químicamente , Carcinoma/patología , Coledocostomía/métodos , Cricetinae , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/efectos adversos , Dinoprostona/metabolismo , Etodolaco/administración & dosificación , Etodolaco/efectos adversos , Femenino , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Mesocricetus , Nitrosaminas/toxicidad , Páncreas/efectos de los fármacos , Páncreas/enzimología , Páncreas/patologíaRESUMEN
Apoptosis and angiogenesis are critical biologic processes that are altered during carcinogenesis. Both apoptosis and angiogenesis may play an important role in pancreatic carcinogenesis. Despite numerous advances in the diagnosis and treatment of pancreatic cancer, its prognosis remains dismal and a new therapeutic approach is much needed. Recent research has revealed that apoptosis and angiogenesis are closely interrelated. Several reports show that a tumor suppresser gene that is expressed in pancreatic carcinoma and related to malignant potential can induce apoptosis and also inhibit angiogenesis. At present, it is generally accepted that tumor growth in cancers, including pancreatic cancer, depends on angiogenesis. We have identified 2 new angiogenesis inhibitors from a conditioned medium of human pancreatic carcinoma cell line (BxPC-3): antiangiogenic antithrombin III (aaAT-III) and vitamin D binding protein-macrophage activating factor (DBP-maf). These molecules were able to regress tumors in severe combined immunodeficiency disease (SCID) mice, demonstrating potent inhibition of endothelial cell proliferation. Moreover, the angiogenesis inhibitors induced tumor dormancy in the animal model. These results suggest that antiangiogenic therapy using angiogenesis inhibitors may become a new strategy for treatment of pancreatic cancer in the near future.
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Apoptosis , Neovascularización Patológica/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/etiología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Línea Celular Tumoral , Humanos , Factores Activadores de Macrófagos , Ratones , Ratones SCID , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/patología , Proteína de Unión a Vitamina DRESUMEN
We have isolated a selectively deglycosylated form of vitamin D binding protein (DBP-maf) generated from systemically available DBP by a human pancreatic cancer cell line. DBP-maf is antiproliferative for endothelial cells and antiangiogenic in the chorioallantoic membrane assay. DBP-maf administered daily was able to potently inhibit the growth of human pancreatic cancer in immune compromised mice (T/C=0.09). At higher doses, DBP-maf caused tumor regression. Histological examination revealed that treated tumors had a higher number of infiltrating macrophages as well as reduced microvessel density, and increased levels of apoptosis relative to untreated tumors. Taken together, these data suggest that DBP-maf is an antiangiogenic molecule that can act directly on endothelium as well as stimulate macrophages to attack both the endothelial and tumor cell compartment of a growing malignancy.
Asunto(s)
Factores Activadores de Macrófagos/farmacología , Neovascularización Patológica/prevención & control , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/patología , Proteína de Unión a Vitamina D/farmacología , Alantoides/citología , Alantoides/efectos de los fármacos , Animales , Bovinos , División Celular/efectos de los fármacos , Embrión de Pollo/metabolismo , Corion/citología , Corion/efectos de los fármacos , Medios de Cultivo Condicionados , Endotelio Vascular/metabolismo , Humanos , Inmunidad Celular , Activación de Macrófagos , Macrófagos , Masculino , Ratones , Ratones SCID , Neuraminidasa/metabolismo , Neoplasias Pancreáticas/metabolismo , Tasa de Supervivencia , Células Tumorales Cultivadas/trasplante , beta-Galactosidasa/metabolismoRESUMEN
BACKGROUND/AIMS: Ets-1 regulates the expression of a number of genes related to remodeling of the extracellular matrix. Ets-1 is associated with the occurrence of invasive processes, proliferation and differentiation. Less is known about the biological functions of Ets-1 in human hepatocellular carcinoma. In an attempt at elucidation, we examined immunohistochemically hepatocellular carcinoma followed by application of genetic techniques. METHODOLOGY: We performed immunohistochemical analysis on tissue from 59 Japanese patients undergoing surgical resection of hepatocellular carcinoma using the antibody against human Ets-1. We compared Ets-1 expression in relation to clinicopathological findings. In situ hybridization and reverse transcription-polymerase chain reaction were also performed to confirm the expression of Ets-1 messenger RNA in hepatocellular carcinoma tissues. RESULTS: In specimens from 59 patients with hepatocellular carcinoma, 41 (70%) showed positive staining for Ets-1 protein. The expression of Ets-1 messenger RNA was also observed in hepatocellular carcinoma tissues by in situ hybridization and reverse transcription-polymerase chain reaction. The expression of Ets-1 correlated with histological differentiation of hepatocellular carcinoma (P < 0.05). Ets-1 was positive in 2 (50%) of the 4 well-differentiated hepatocellular carcinomas and in 28 (64%) of the 44 moderately differentiated hepatocellular carcinomas, whereas all the 11 poorly differentiated hepatocellular carcinomas were positive for Ets-1 staining. Ets-1 protein was expressed more strongly at the peripheral than the central area of the tumor. Otherwise, no particular correlation was evident in terms of clinicopathological factors. CONCLUSIONS: We found Ets-1 to be expressed in human hepatocellular carcinoma, particularly at the peripheral area of the tumor. As this expression is linked to cell differentiation, this gene may yield biological information relative to this malignant tumor of the liver.