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Background/Aims: Endoscopic self-expandable metal stent (SEMS) placement is currently the standard technique for treating unresectable malignant distal biliary obstructions (MDBO). Therefore, covered SEMS with longer stent patency and fewer migrations are required. This study aimed to assess the clinical performance of a novel, fully covered SEMS for unresectable MDBO. Methods: This was a multicenter single-arm prospective study. The primary outcome was a non-obstruction rate at 6 months. The secondary outcomes were overall survival (OS), recurrent biliary obstruction (RBO), time to RBO (TRBO), technical and clinical success, and adverse events. Results: A total of 73 patients were enrolled in this study. The non-obstruction rate at 6 months was 61%. The median OS and TRBO were 233 and 216 days, respectively. The technical and clinical success rates were 100% and 97%, respectively. Furthermore, the rate of occurrence of RBO and adverse events was 49% and 21%, respectively. The length of bile duct stenosis (<2.2 cm) was the only significant risk factor for stent migration. Conclusions: The non-obstruction rate of a novel fully covered SEMS for MDBO is comparable to that reported earlier but shorter than expected. Short bile duct stenosis is a significant risk factor for stent migration.
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Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer displaying no definitive direction of differentiation. UC has been reported as a highly aggressive malignant neoplasm, with a median overall survival of <1 year, except for several surgical series. On the other hand, UC tissue sometimes contains non-neoplastic osteoclast-like giant cells (OGCs), and such cases have been reported to have relatively longer survival. Thus, the World Health Organization (WHO) classification histologically distinguishes UC with OGCs (UCOGCs) from UC, and UCs were subclassified into three subtypes: anaplastic UC, sarcomatoid UC and carcinosarcoma. However, still less is known about UC due to its rarity, and such situations lead to further difficulties in treatment for UC. To date, only surgical resection can offer curative treatment for patients with UC, and no clear evidence for chemotherapy exists for them. However, a retrospective cohort study and case reports showed that relatively promising results paclitaxel-containing regimens for treatment of patients with unresectable UC. Furthermore, high programmed cell death protein 1 expression has been reported in sarcomatoid UCs and UCOGCs, and promising responses to anti-programmed death-ligand 1 therapy have been described in case reports of UCOGCs. Recent advances in chemotherapeutic agents and molecular technologies are opening up the possibilities for expanded treatments.
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Carcinoma , Neoplasias Pancreáticas , Humanos , Estudios Retrospectivos , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/terapia , Carcinoma/patología , Páncreas/cirugía , Páncreas/patologíaRESUMEN
Although phase III trials have reported improved overall survival in patients with advanced esophageal squamous cell carcinoma following treatment with nivolumab, as compared with chemotherapy (paclitaxel or docetaxel), the treatment was effective only in a limited number of patients. Therefore, the aim of this study is to determine whether there is a correlation between nutritional status (Glasgow prognostic score, prognostic nutritional index, and neutrophil-to-lymphocyte ratio) and prognosis of advanced esophageal cancer in patients treated with taxane or nivolumab therapy. The medical records of 35 patients who received taxane monotherapy (paclitaxel or docetaxel), for advanced esophageal cancer between October 2016 and November 2018 (taxane cohort) were reviewed. The clinical data of 37 patients who received nivolumab therapy between March 2020 and September 2021 (nivolumab cohort) were collected. The median overall survival was 9.1 months for the taxane cohort and 12.5 months for the nivolumab cohort. In the nivolumab cohort, patients with good nutritional status had significantly better median overall survival than those with poor nutritional status (18.1 vs. 7.6 months, respectively, p = 0.009, classified by prognostic nutritional index, 15.5 vs. 4.3 months, respectively, p = 0.012, classified by Glasgow prognostic score), whereas the prognosis of the patients treated with taxane therapy was less affected by the nutritional status. This suggests that the pretreatment nutritional status of patients with advanced esophageal cancer is a key factor for successful outcomes, especially for treatment with nivolumab.
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Antineoplásicos Inmunológicos , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Nivolumab/uso terapéutico , Neoplasias Esofágicas/patología , Docetaxel/uso terapéutico , Estado Nutricional , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Escamosas de Esófago/patología , Estudios Retrospectivos , Paclitaxel/uso terapéuticoRESUMEN
Objectives: Chemoradiotherapy (CRT) or radiotherapy (RT) alone is often the treatment of choice for elderly patients with esophageal cancer with the expectation of organ preservation. However, salvage treatment remains a problem when endoscopic resection is not indicated for local failure after CRT/RT. Photodynamic therapy (PDT) is indicated for local failure after CRT/RT, but there are few reports on its efficacy and safety in elderly patients. This study aimed to assess the outcome of PDT for local failure after CRT/RT for esophageal cancer in elderly patients. Methods: This retrospective single-center study included 42 patients who first underwent PDT between April 2013 and June 2021. Patients aged ≥80 and <80 years were classified into the elderly and nonelderly groups, respectively. Local complete response rate, overall survival, progression-free survival, and incidence of adverse events related to PDT were compared retrospectively between the groups. Results: The local complete response rate was 93.3% in the elderly group and 85.7 in the non-elderly group. The 2-year overall survival rate was 68.6% and 72.5%, and the 2-year progression-free survival rate was 49.5% and 70.0% in the elderly and nonelderly groups, respectively. There was no significant difference in any of these outcomes between the groups. In terms of adverse events, pneumonia and delirium tended to occur more frequently in the elderly group, but there were no serious adverse events in either group. Conclusion: The outcome of salvage PDT in the local control was comparable between the elderly and nonelderly patients for local failure after CRT/RT for esophageal cancer.
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In Japan, South Korea, and Taiwan, nivolumab might provide overall survival benefits for patients with advanced gastric cancer. However, it is effective only in a limited number of patients. The Glasgow prognostic score is an indicator of the systematic inflammatory response and nutritional status. This study aimed to investigate the ability of the Glasgow prognostic score and other markers to predict the outcomes of patients treated with nivolumab. We reviewed the medical records of patients treated for advanced gastric cancer and who received nivolumab between February 2015 and June 2019 at Hyogo Cancer Center. The patients were categorized into two groups according to their Glasgow prognostic scores. Overall, 53.3% and 46.7% of the patients were assigned to groups with Glasgow prognostic scores of 0 and 1/2, respectively. The median durations of progression-free and overall survival of the participants were 2.3 and 5.7 months, respectively. The patients with a Glasgow prognostic score of 0 had significantly higher median overall survival than those with scores of 1 or 2 (16.4 vs. 4.2 months; p = 0.0006). This observation suggests that a pretreatment Glasgow prognostic score of 0 is associated with better outcomes, and this scoring system may be used as a predictor of outcomes in patients with advanced gastric cancer treated with nivolumab.
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Antineoplásicos Inmunológicos/administración & dosificación , Proteína C-Reactiva/análisis , Nivolumab/administración & dosificación , Proyectos de Investigación , Albúmina Sérica/análisis , Neoplasias Gástricas/sangre , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Supervivencia sin Progresión , Estudios RetrospectivosRESUMEN
BACKGROUND: Delayed perforation is a rare but severe complication of endoscopic submucosal dissection (ESD) for early gastric neoplasm (EGN). The aim of this study was to clarify clinical factors related to delayed perforation after ESD. METHODS: A total of 1158 consecutive patients with 1199 EGNs underwent ESD at our hospital between January 2000 and December 2015. Univariate analysis was used to identify clinicopathological factors related to delayed perforation. Moreover, duration of cautery needed for hemostasis was measured by comparison between perforated and nonperforated points in patients with delayed perforation. RESULTS: Delayed perforation occurred in 5 of 1158 consecutive patients with 1199 EGNs who underwent ESD (0.42%). All cases were diagnosed within 24 h after ESD and recovered with conservative management. On univariate analysis, location in the upper stomach was the factor most significantly associated with delayed perforation (P < 0.01). Duration of cautery needed for hemostasis was significantly longer at perforated points (9 s) than at nonperforated points (3.5 s) in five patients. CONCLUSIONS: Location in the upper stomach was the risk factor most prominently associated with delayed perforation after ESD for EGNs. In addition, delayed perforation appears associated with excessive electrocautery for hemostasis.
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Esophagectomy with extended lymphadenectomy and gastric conduit reconstruction is a radical procedure for the treatment of esophageal cancer that is associated with a high morbidity rate. Gastric conduit necrosis is a fatal complication that occurs in 2% of patients. Conventionally, two-stage salvage surgery consisting of removal of the necrotic gastric conduit followed by reconstruction has been performed; however, this procedure has a high morbidity rate. We describe a 61-year-old man who underwent minimally invasive esophagectomy complicated by slowly progressive gastric conduit necrosis associated with complete neck drainage and a stable overall condition. There was a 2 cm gap in the anastomosis. Because there was no evidence of residual gastric conduit necrosis, a removable, covered self-expanding metal stent (SEMS) was inserted to bridge the anastomosis. The stent was fixed to the patient's ear with silk thread through the lasso on its proximal end to prevent migration. Eight weeks after insertion, the stent was removed easily without any associated complications. The anastomotic defect was completely bridged with granulation tissue, showing progressive epithelialization without leakage or stenosis. The patient was discharged home in good general health. This is the first report of the successful conservative management of esophago-gastric conduit anastomosis disruption with SEMS placement.
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Carcinoma de Células Escamosas/cirugía , Neoplasias Esofágicas/cirugía , Esofagectomía , Esofagoscopía/instrumentación , Procedimientos de Cirugía Plástica/instrumentación , Complicaciones Posoperatorias/cirugía , Stents , Estómago/cirugía , Anastomosis Quirúrgica , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Humanos , Masculino , Persona de Mediana Edad , Necrosis , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Diseño de Prótesis , Procedimientos de Cirugía Plástica/efectos adversos , Reoperación , Estómago/patología , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVE: The reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from 1997 to 2011 were reviewed to assess serious adverse events induced by the administration of antipsychotics to children. METHODS: Following pre-processing of FAERS data by elimination of duplicated records as well as adjustments to standardize drug names, reports involving haloperidol, olanzapine, quetiapine, clozapine, ziprasidone, risperidone, and aripiprazole were analyzed in children (age 0-12). Signals in the data that signified a drug-associated adverse event were detected via quantitative data mining algorithms. The algorithms applied to this study include the empirical Bayes geometric mean, the reporting odds ratio, the proportional reporting ratio, and the information component of a Bayesian confidence propagation neural network. Neuroleptic malignant syndrome (NMS), QT prolongation, leukopenia, and suicide attempt were focused on as serious adverse events. RESULTS: In regard to NMS, the signal scores for haloperidol and aripiprazole were greater than for other antipsychotics. Significant signals of the QT prolongation adverse event were detected only for ziprasidone and risperidone. With respect to leukopenia, the association with clozapine was noteworthy. In the case of suicide attempt, signals for haloperidol, olanzapine, quetiapine, risperidone, and aripiprazole were detected. CONCLUSIONS: It was suggested that there is a level of diversity in the strength of the association between various first- and second-generation antipsychotics with associated serious adverse events, which possibly lead to fatal outcomes. We recommend that research be continued in order to gather a large variety and quantity of related information, and that both available and newly reported data be placed in the context of multiple medical viewpoints in order to lead to improved levels of care.
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Bases de Datos Factuales , Algoritmos , Antipsicóticos/efectos adversos , Aripiprazol , Benzodiazepinas/efectos adversos , Minería de Datos , Dibenzotiazepinas/efectos adversos , Haloperidol/efectos adversos , Humanos , Olanzapina , Piperazinas/efectos adversos , Fumarato de Quetiapina , Quinolonas/efectos adversos , Tiazoles/efectos adversosRESUMEN
We report a rare case of polypoid leiomyosarcoma of the esophagus that was treated by endoscopic submucosal dissection (ESD). A 63-year-old man with complaints of progressive dysphagia was referred to Hyogo Cancer Center for treatment of esophageal tumor. Esophagoscopy revealed a polypoid tumor 25 mm in diameter on the left side of the upper esophagus. Despite several biopsy specimens, the diagnosis could not be confirmed. Computed tomography showed a protruded, homogeneously enhancing mass in the upper esophagus, but no lymph node enlargement or metastasis. After 1.5 months, the esophagogram showed a filling defect 47 mm in diameter in the upper esophagus. Given this rapid tumor growth, en bloc resection was done by ESD for therapeutic diagnosis. After this treatment, the tumor seemed to grow larger, showing a short stalk and occupying the esophageal lumen. Histopathologically, the tumor comprised pleomorphic spindle cells with mitosis. Tumor invasion involved the lumina propria mucosae and contact with the muscularis mucosae, but not involving the submucosa. Immunohistochemical examination showed positive staining for smooth muscle actin and HHF35, but negative for desmin, caldesmon, CD34, c-kit, DOG1, ALK, S-100 protein and cytokeratin. These histopathological findings were compatible with a diagnosis of esophageal leiomyosarcoma derived from the muscularis mucosae.
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Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Esofagoscopía/métodos , Leiomiosarcoma/patología , Leiomiosarcoma/cirugía , Biopsia con Aguja , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Neoplasias Esofágicas/diagnóstico por imagen , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Leiomiosarcoma/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Membrana Mucosa/patología , Membrana Mucosa/cirugía , Pólipos/diagnóstico por imagen , Pólipos/patología , Pólipos/cirugía , Medición de Riesgo , Factores de Tiempo , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption. AIM: We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM)-induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P-glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver. METHODS: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs. RESULTS: INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa. CONCLUSIONS: INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs.
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Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Antiinflamatorios no Esteroideos/toxicidad , Sistema Enzimático del Citocromo P-450/genética , Indometacina/toxicidad , Enfermedades Intestinales/inducido químicamente , Enfermedades Intestinales/genética , Úlcera/inducido químicamente , Úlcera/genética , Animales , Hidrocarburo de Aril Hidroxilasas/genética , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP3A/genética , Familia 2 del Citocromo P450 , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Enfermedades Intestinales/metabolismo , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Esteroide 16-alfa-Hidroxilasa/genética , Úlcera/metabolismo , Vancomicina/administración & dosificación , Vancomicina/sangre , Vancomicina/farmacocinéticaRESUMEN
OBJECTIVE: Definitive chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and cisplatin (CDDP) is one of the standard therapies for esophageal squamous cell carcinoma (ESCC); however, inter-individual variations in clinical outcomes have yet to be investigated. In the present study, single nucleotide polymorphisms (SNPs) in SLC23A2 gene were retrospectively evaluated in 49 Japanese patients with ESCC who were treated with a definitive 5-FU/CDDP-based CRT, and the predictive values for the clinical response, severe acute toxicities, and long-term survival were assessed. METHODS: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course being repeated after a 2-week interval. The SLC23A2 SNPs rs2681116, rs13037458, rs1715364, rs4987219, and rs1110277 were evaluated. RESULTS: The rs2681116 and rs13037458 had a tendency to predict the clinical response (p=0.144 and 0.085, respectively) and long-term survival (p=0.142 and 0.056, respectively). The rs4987219 and rs1110277 correlated with severe acute leukopenia (p=0.025) and stomatitis (p=0.019), respectively. CONCLUSIONS: Further investigations with a larger number of patients or an in vitro study are needed to confirm the predictive values of genetic polymorphisms in SLC23A2.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Cisplatino/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Fluorouracilo/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Transportadores de Sodio Acoplados a la Vitamina C/genética , Anciano , Pueblo Asiatico , Carcinoma de Células Escamosas de Esófago , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
CYP3A and P-glycoprotein (P-gp) play important roles in drug metabolism and excretion; however, their functions in pathological conditions remain unclear. Hepatobiliary abnormalities have been described in patients with ulcerative colitis, which may affect drug metabolism and excretion in the liver and small intestine. We examined the functions of CYP3A and P-gp in the liver and small intestine of mice with dextran sodium sulfate (DSS)-induced colitis. Up to day 7, inflammatory markers were significantly increased in the livers of DSS-treated mice, accompanied by decreased CYP3A. Additionally hepatobiliary transporters and Pregnane X receptor, which regulates the transcriptional activation of CYP3A, were reduced. Both CYP3A and P-gp were significantly decreased in the upper small intestine of DSS-treated mice on day 7. This was associated with the increased expression of inducible nitric oxide synthase, but not changes in nuclear receptor expression. On day 7 of DSS treatment, the concentrations of cyclosporine A (CsA), a substrate of both CYP3A and P-gp, were significantly higher than controls. These results indicated the existence of a second inflammatory response in the liver and upper small intestine of mice with DSS-induced colitis, and bioavailability of CsA was increased by the dysfunction of CYP3A and P-gp in these organs.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Colitis Ulcerosa/metabolismo , Ciclosporina/sangre , Citocromo P-450 CYP3A/fisiología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Disponibilidad Biológica , Colitis Ulcerosa/inducido químicamente , Citocromo P-450 CYP3A/metabolismo , Sulfato de Dextran , Regulación hacia Abajo , Humanos , Intestino Delgado/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/metabolismo , Receptor X de Pregnano , Receptores de Esteroides/metabolismoRESUMEN
Squamous cell carcinoma (Sqc) of the pancreas is considered to be extremely rare. We report the case of a 79-year-old male with Sqc of the pancreas complicated by massive gastric ulcer fistula and multiple lymph node metastases. After completing two courses of S-1 chemotherapy, the gastric ulcer fistula and lymph node metastases improved. Sqc of the pancreas is usually associated with a poor prognosis. Various therapeutic regimens have been used for this type of cancer, but none has been proven effective. To the best of our knowledge, this report is the first on the effective response of pancreatic Sqc treated by S-1 chemotherapy.
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Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Ácido Oxónico/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Tegafur/uso terapéutico , Anciano , Combinación de Medicamentos , Humanos , Masculino , Inducción de RemisiónRESUMEN
A 61-year-old female was admitted to our hospital for esophageal cancer treatment. Esophagectomy with 2-field lymphadenectomy was performed. Postoperative findings revealed the lesion was a poorly differentiated squamous cell carcinoma invading into the diaphragm and there were no carcinoma cells on the surgical margins. Eight months after surgery, a recurrence was suspected by the presence of tumors at the pericardia, right axillary lymph node and around the descending aorta. The patient was re-admitted for chemotherapy and administrated fluorouracil and cisplatin 4 days after admission. After 7 days, she complained of dysphagia. Esophagogastroduodenoscopy showed no abnormal lesion that could cause the symptom. Computed tomography revealed massive progression of the pericardial tumor, bilateral pleural effusion and congested liver. Echocardiography showed the diffuse pericardial tumor caused restriction of ventricular dilation and hemodynamics of constrictive pericarditis. The patient died 29 days after re-admission. Autopsy revealed squamous cell carcinoma involving the mediatinum and pericardium. The pericardium was completely full of cancer tissue but no fluid. We concluded that the direct cause of death was neoplastic constrictive pericarditis.
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Carcinoma de Células Escamosas/complicaciones , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/patología , Neoplasias Cardíacas/complicaciones , Neoplasias Cardíacas/patología , Pericarditis Constrictiva/etiología , Pericardio , Resultado Fatal , Femenino , Humanos , Persona de Mediana Edad , Invasividad NeoplásicaRESUMEN
BACKGROUND: Genotypes of tumor necrosis factor alpha (TNF-α) and its surface receptors, TNFRSF1A and TNFRSF1B, have been examined in terms of the progression, metastasis, clinical efficacy, and prognosis of various cancers; however, little is known about their effects on clinical outcome in patients with esophageal squamous cell carcinoma (ESCC). In this study, TNF-α and TNFRSF1A genotypes were retrospectively evaluated in terms of predicting clinical response, long-term survival, and severe acute toxicities in 46 male Japanese ESCC patients treated with definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT). METHODS: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course being repeated after a 2-week interval. The TNF-α -1031T>C (rs1799964), -863C>A (rs1800630), -857C>T (rs1799724), -308G>A (rs1800629), -238G>A (rs361525), TNFRSF1A -609G>T (rs4149570), and 36A>G (rs767455) genotypes were evaluated. RESULTS: The TNF-α -857C>T genotype was found to be predictive of clinical response, i.e., complete response or not (P = 0.010, Fisher's exact test), but had no effect on long-term survival (CC(-857) vs. CT(-857) + TT(-857), P = 0.072, Fisher's exact test, P = 0.070, Log-rank test). CONCLUSIONS: The TNF-α -857C>T genotype was found to be predictive of clinical response and was more likely to predict long-term survival in Japanese ESCC patients receiving definitive 5-FU/CDDP-based CRT. Further clinical investigations with a larger number of patients or experiments in vitro should be performed to assess the predictive value of this genotype following CRT.
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Carcinoma de Células Escamosas/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Neoplasias Esofágicas/genética , Pronóstico , Factor de Necrosis Tumoral alfa/genética , Anciano , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Terapia Combinada , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Non-steroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal injury is a serious clinical event with recent advances of diagnostic technologies, but a successful therapeutic method to treat such injuries is still lacking. Licorice, a traditional herbal medicine, and its derivatives have been widely used for the treatment of a variety of diseases due to their extensive biological actions. However, it is unknown whether these derivatives have an effect on NSAIDs-induced small intestinal damage. Previously, the anti-inflammatory effects of three compounds extracted from the licorice root, glycyrrhizin, 18ß-glycyrrhetinic acid, and dipotassium glycyrrhizinate, were compared in vitro cell culture. The most prominent inhibitory effect on the tumor necrosis factor-α (TNF-α) production was observed with the administration of 18ß-glycyrrhetinic acid as an active metabolite of glycyrrhizin. In this study, a complex compound of 18ß-glycyrrhetinic acid and hydroxypropyl γcyclodextrin was examined to improve the oral bioavailability. After administration of this complex to indomethacin treated mice, a significantly high plasma concentration of 18ß-glycyrrhetinic acid was detected using the tandem mass spectrometry coupled with the HPLC. Furthermore, the complex form of 18ß-glycyrrhetinic acid and hydroxypropyl γcyclodextrin reduced mRNA expressions of TNF-α, interleukin (IL)-1ß, and IL-6, which was histologically confirmed in the improvement of indomethacin-induced small intestinal damage. These results suggest that the complex of 18ß-glycyrrhetinic acid and hydroxypropyl γcyclodextrin has the potential therapeutic value for preventing the adverse effects of indomethacin-induced small intestinal injury.
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Ácido Glicirretínico/análogos & derivados , Indometacina/efectos adversos , Intestino Delgado/efectos de los fármacos , Intestino Delgado/lesiones , gamma-Ciclodextrinas/farmacología , Animales , Disponibilidad Biológica , Regulación de la Expresión Génica/efectos de los fármacos , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacocinética , Ácido Glicirretínico/farmacología , Interleucina-1beta/genética , Interleucina-6/genética , Intestino Delgado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/genética , ARN Mensajero/metabolismo , Solubilidad , Factor de Necrosis Tumoral alfa/genética , gamma-Ciclodextrinas/química , gamma-Ciclodextrinas/farmacocinéticaRESUMEN
In our previous study, it was found that linoleoyl ethanolamide (LE) is present in sake lees, which are produced as a byproduct during the making of Japanese sake. LE is a fatty acid ethanolamide, which have been demonstrated to exert a variety of biological functions, and in this study, the anti-inflammatory effects of LE were examined using in vitro cell culture and in vivo animal experiments. In mouse RAW264.7 macrophages, LE suppressed the lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6. In addition, LE inhibited LPS-induced increases in the levels of cyclooxygenase enzyme-2 and prostaglandin E(2), which are indicators of inflammation. The inhibitory effect of LE on the release of TNF-α was stronger than that of dipotassium glycyrrhizinate, which is widely used in external human skin care treatments. LE also suppressed the LPS-induced activation of Toll-like receptor 4 signaling and nuclear translocation of nuclear factor-κB (NF-κB) p65. In a contact dermatitis animal model, applying LE to affected ear skin ameliorated 2,4-dinitrofluorobenzene-induced contact dermatitis and pro-inflammatory cytokine expression at inflamed sites. These results indicate that LE exerts anti-inflammatory effects by inhibiting NF-κB signaling, and LE is proposed to be a useful therapeutic agent against contact dermatitis.
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Antiinflamatorios/farmacología , Dermatitis por Contacto/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Ácidos Linoleicos/farmacología , Alcamidas Poliinsaturadas/farmacología , Animales , Línea Celular , Citocinas/metabolismo , Dermatitis por Contacto/patología , Dinitrofluorobenceno/toxicidad , Modelos Animales de Enfermedad , Femenino , Ácido Glicirrínico/farmacología , Inflamación/patología , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVE: Chemotherapy-related toxicities are difficult to predict before treatment. In this study, we investigated whether thyroid hormone receptor beta (THRB) genetic polymorphisms can serve as a potential biomarker in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Forty-nine Japanese patients with ESCC who received a definitive chemoradiotherapy (CRT) with 5-fluorouracil and cisplatin in conjunction with concurrent irradiation were retrospectively analyzed. Severe acute toxicities, including leukopenia, stomatitis, and cheilitis, were evaluated according to 6 single nucleotide polymorphisms (SNPs) in the gene; the intronic SNPs of rs7635707 G/T, rs6787255 A/C, rs9812034 G/T, and rs9310738 C/T and the SNPs in the 3'-untranslated region (3'-UTR) of rs844107 C/T and rs1349265 G/A. RESULTS: Distribution of the 4 intronic SNPs, but not the 2 SNPs in the 3'-UTR, showed a significant difference between patients with and without severe acute leukopenia. Stomatitis and cheilitis were not associated with any of the 6 analyzed SNPs. Frequency of haplotype of the 4 intronic SNPs reached approximately 97% with the 2 major haplotypes G-A-G-C (73.4%) and T-C-T-T (23.5%). CONCLUSIONS: THRB intronic SNPs can provide useful information on CRT-related severe myelotoxicity in patients with ESCC. Future studies will be needed to confirm these findings.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Quimioradioterapia/efectos adversos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/radioterapia , Polimorfismo de Nucleótido Simple , Receptores beta de Hormona Tiroidea/genética , Regiones no Traducidas 3' , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Pueblo Asiatico/genética , Queilitis/inducido químicamente , Cisplatino/administración & dosificación , Carcinoma de Células Escamosas de Esófago , Femenino , Fluorouracilo/administración & dosificación , Frecuencia de los Genes , Haplotipos/genética , Humanos , Intrones , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estomatitis/inducido químicamenteRESUMEN
BACKGROUND: Reports have been accumulating that genetic properties are predictive of clinical response after and/or toxicity during cancer chemotherapy, but little information is available concerning effects on long-term survival. In this study, 49 Japanese patients with esophageal squamous cell carcinoma (ESCC) were followed up for 5 years after treatment with a definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT), and the effects of genotypes of vascular endothelial growth factor (VEGF) were retrospectively revaluated in terms of prediction of long-term survival. METHODS: A course consisted of the continuous infusion of 5-FU at 400 mg/m(2)/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m(2)/day on days 1 and 8, and radiation at 2 Gy/day on days 1 to 5, 8 to 12, and 15 to 19, with a second course repeated after a 2-week interval. The VEGF genotypes -1498T/C, -1154G/A, -634C/G, -7C/T, 936C/T, and 1612G/A were evaluated. RESULTS: The complete response (CR) rate was 46.9% (23/49). The 5-year survival rate was 42.9 % (21/49). There were 7 patients with a CR, but survival of less than 5 years. They died from myocardial infarction (N=1), sudden cardiac death after suffering from heart failure (N=1), acute myeloid leukemia that developed from myelodysplastic syndromes (N=1), factors not specified (N=2), oropharynx cancer (N=1), and tongue cancer (N=1). VEGF -634C/G had no effect on clinical response, but long-term survival depended on the genotype (p=0.033, Fisher's; p=0.038, Cochran-Armitage; p=0.079, Log-rank). The genotype frequency of 7 patients with a CR, but survival of less than 5 years was different from that for the other 42 patients (p=0.032, Fisher's). None of the other 5 genotypes evaluated affected either clinical response or survival. CONCLUSIONS: VEGF -634C/G is possibly predictive of long-term survival after treatment with a definitive 5-FU/CDDP-based CRT. Further clinical studies with a larger number of cases are needed to clarify the effects of this genotype.
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Carcinoma de Células Escamosas , Cisplatino/administración & dosificación , Neoplasias Esofágicas , Fluorouracilo/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas de Esófago , Femenino , Genotipo , Humanos , Japón , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: Helicobacter pylori is known to affect the host's nutritional status. This study was performed to elucidate the relationship between H. pylori status and the dynamics of the ghrelin system, in the context of ghrelin O-acyltransferase (GOAT) expression. METHODS: We conducted a clinical study of 30 subjects focusing on the following points: 1) the effects of H. pylori infection on the concentrations of circulating ghrelin isoforms and on ghrelin and GOAT mRNA expression in the gastric mucosa, and 2) the effects of H. pylori eradication on the same parameters. RESULTS: The plasma acyl-ghrelin and desacyl-ghrelin concentrations of 16 H. pylori positive participants were significantly lower than those of 14 H. pylori negative controls. The acyl-ghrelin/desacyl-ghrelin ratio was not significantly different between the H. pylori positive and H. pylori negative participants. The levels of ghrelin and GOAT mRNA in the gastric mucosa were significantly lower in the H. pylori positive participants than in the H. pylori negative controls. In 11 subjects in whom H. pylori eradication was successful, their plasma acyl-ghrelin levels tended to increase after H. pylori eradication, but the difference was not significant; however, their plasma desacyl-ghrelin levels were significantly reduced. Although gastric ghrelin mRNA expression increased significantly after H. pylori eradication, gastric GOAT mRNA expression tended to increase but was not significantly altered. CONCLUSION: H. pylori status might affect the host's nutritional status through changes in the plasma levels of ghrelin isoforms and the gastric expression levels of ghrelin and GOAT mRNA.