RESUMEN
BACKGROUND: Up to 6-months oxaliplatin-containing regimen is now widely accepted as a standard adjuvant chemotherapy for stage III colorectal cancer (CRC). However, oral fluoropyrimidine monotherapy is used for some part of patients, especially in Asian countries including Japan, and its optimal duration is yet to be fully investigated. METHODS: A total of 1306 patients with curatively-resected stage III CRC were randomly assigned to receive capecitabine (2500 mg/m2/day) for 14 out of 21 days for 6 (n = 654) or 12 (n = 650) months. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were relapse-free survival (RFS), overall survival (OS), and adverse events. RESULTS: The 3- and 5-year DFS were 70.0% and 65.3% in the 6M group and 75.3% and 68.7% in the 12M group, respectively (p = 0.0549, HR = 0.858, 90% CI: 0.732-1.004). The 5-year RFS was 69.3% and 74.1% in the 6M and 12M groups, respectively (p = 0.0143, HR = 0.796, 90% CI: 0.670-0.945). The 5-year OS was 83.2% and 87.6%, respectively (p = 0.0124, HR = 0.727, 90% CI: 0.575-0.919). The incidence of overall grade 3-4 adverse events was almost comparable in both groups. CONCLUSIONS: Although 12-month adjuvant capecitabine did not demonstrate superior DFS to that of 6-month, the observed better RFS and OS in the 12-month treatment period could be of value in selected cases.
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Adenocarcinoma/tratamiento farmacológico , Antimetabolitos Antineoplásicos/administración & dosificación , Capecitabina/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Adenocarcinoma/patología , Anciano , Quimioterapia Adyuvante , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Duración de la Terapia , Femenino , Humanos , Masculino , Estadificación de Neoplasias , Modelos de Riesgos ProporcionalesRESUMEN
PURPOSE: Prolonged postoperative ileus (POI) is a common complication after open abdominal surgery (OAS). Daikenchuto (DKT), a traditional Japanese medicine that peripherally stimulates the neurogenic pathway, is used to treat prolonged POI in Japan. To analyze whether DKT accelerates the recovery from prolonged POI after OAS, we conducted a secondary analysis of three multicenter randomized controlled trials (RCTs). METHODS: A secondary analysis of the three RCTs supported by the Japanese Foundation for Multidisciplinary Treatment of Cancer (project numbers 39-0902, 40-1001, 42-1002) assessing the effect of DKT on prolonged POI in patients who had undergone OAS for colon, liver, or gastric cancer was performed. The subgroup included 410 patients with no bowel movement (BM) before the first diet, a DKT group (n = 214), and a placebo group (n = 196). Patients received either 5 g DKT or a placebo orally, three times a day. The primary endpoint was defined as the time from the end of surgery to the first bowel movement (FBM). A sensitivity analysis was also performed on the age, body mass index and dosage as subgroup analyses. RESULTS: The primary endpoint was significantly accelerated in the DKT group compared with the placebo group (p = 0.004; hazard ratio 1.337). The median time to the FBM was 113.8 h in the placebo group and 99.1 h in the DKT treatment group. CONCLUSIONS: The subgroup analysis showed that DKT significantly accelerated the recovery from prolonged POI following OAS. TRIAL REGISTRATION NUMBER: UMIN000026292.
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Abdomen/cirugía , Ileus/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Complicaciones Posoperatorias/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Panax , Resultado del Tratamiento , Zanthoxylum , ZingiberaceaeRESUMEN
BACKGROUND: Although colorectal cancer comprises several histological subtypes, the influences of histological subtypes on disease progression and treatment responses remain controversial. OBJECTIVE: We sought to evaluate the prognostic relevance of mucinous and poorly differentiated histological subtypes of colorectal cancer by the propensity score weighting analysis of prospectively collected data from multi-institute phase III trials. DESIGN: Independent patient data analysis of a pooled database from 3 phase III trials was performed. SETTINGS: An integrated database of 3 multicenter prospective clinical trials (the Japanese Foundation for Multidisciplinary Treatment of Cancer 7, 15, and 33) was the source of study data. INTERVENTIONS: Surgery alone or postoperative adjuvant chemotherapy was offered in patients with resectable colorectal cancer. MAIN OUTCOME MEASURES: To balance essential variables more strictly for the comparison analyses, propensity score weighting was conducted with the use of a multinomial logistic regression model. We evaluated the clinical signatures of mucinous and poorly differentiated subtypes with regard to postoperative survival, recurrence, and chemosensitivity. RESULTS: Of 5489 patients, 136 (2.5%) and 155 (2.8%) were pathologically diagnosed with poorly differentiated and mucinous subtypes. The poorly differentiated subtypes were associated with a poorer prognosis than the "others" group (HR, 1.69; 95% CI, 1.00-2.87; p = 0.051), particularly in the patient subgroup of adjuvant chemotherapy (HR, 2.16). Although the mucinous subtype had a marginal prognostic impact among patients with stage I to III colorectal cancer (HR, 1.33; 95% CI, 0.90-1.96), it was found to be an independent prognostic factor in the subpopulation of patients with stage II disease, being associated with a higher prevalence of peritoneal recurrence. LIMITATIONS: The treatment regimens of postoperative chemotherapy are now somewhat outdated. CONCLUSIONS: Both mucinous and poorly differentiated subtypes have distinct clinical characteristics. Patients with the mucinous subtype require special attention during follow-up, even for stage II disease, because of the risk of peritoneal or local recurrence. See Video Abstract at http://links.lww.com/DCR/A531.
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Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Adenocarcinoma/mortalidad , Adenocarcinoma/terapia , Adulto , Anciano , Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Ensayos Clínicos Fase III como Asunto , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/terapia , Bases de Datos Factuales , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Pronóstico , Puntaje de Propensión , Análisis de SupervivenciaRESUMEN
BACKGROUND: Most previous reports to analyze risk factors for peritoneal recurrence in patients with colon cancer have been observational studies of a population-based cohort. OBJECTIVE: This study aimed to determine the risk factors for peritoneal recurrence in patients with stage II to III colon cancer who underwent curative resection. DESIGN: This was a pooled analysis using a combined database obtained from 3 large phase III randomized trials (N = 3714). SETTINGS: Individual patient data were collected from the Japanese Foundation for Multidisciplinary Treatment of Cancer clinical trials 7, 15, and 33, which evaluated the benefits of postoperative 5-fluorouracil-based adjuvant therapies in patients with locally advanced colorectal cancer. PATIENTS: We included patients who had stage II to III colon cancer and underwent curative resection with over D2 lymph node dissection. MAIN OUTCOME MEASURES: Main outcomes measured were risk factors for peritoneal recurrence without other organ metastasis after curative surgery. RESULTS: Peritoneal recurrence occurred in 2.3% (86/3714) of all patients undergoing curative resection. Mean duration from operation to peritoneal recurrence was 17.0 ± 10.3 months. Of these patients with peritoneal recurrence, 29 patients (34%) had recurrence in ≥1 other organ. Multivariate analysis showed that age (≥60 y: HR = 0.531; p = 0.0182), pathological T4 (HR = 3.802; p < 0.0001), lymph node involvement (HR = 3.491; p = 0.0002), and lymphadenectomy (D2: HR = 1.801; p = 0.0356) were independent predictors of peritoneal recurrence. The overall survival was lower in patients who developed peritoneal recurrence than in those with other recurrence (HR = 1.594; p = 0.002). LIMITATIONS: The regimens of adjuvant chemotherapy were limited to oral 5-fluorouracil. CONCLUSIONS: Our findings clarified the risk factors for peritoneal recurrence in patients who underwent curative resection for colon cancer. See Video Abstract at http://links.lww.com/DCR/A609.
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Adenocarcinoma Mucinoso/epidemiología , Adenocarcinoma/epidemiología , Neoplasias del Colon/patología , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Peritoneales/epidemiología , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Adenocarcinoma Mucinoso/secundario , Adenocarcinoma Mucinoso/terapia , Anciano , Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Colectomía , Neoplasias del Colon/terapia , Femenino , Fluorouracilo/uso terapéutico , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Peritoneales/secundario , Factores de RiesgoRESUMEN
The tumor microenvironment (TME) promotes tumor growth and metastasis. We previously established the color-coded EL4 lymphoma TME model with red fluorescent protein (RFP) expressing EL4 implanted in transgenic C57BL/6 green fluorescent protein (GFP) mice. Color-coded imaging of the lymphoma TME suggested an important role of stromal cells in lymphoma progression and metastasis. In the present study, we used color-coded imaging of RFP-lymphoma cells and GFP stromal cells to identify yellow-fluorescent genetically recombinant cells appearing only during metastasis. The EL4-RFP lymphoma cells were injected subcutaneously in C57BL/6-GFP transgenic mice and formed subcutaneous tumors 14 days after cell transplantation. The subcutaneous tumors were harvested and transplanted to the abdominal cavity of nude mice. Metastases to the liver, perigastric lymph node, ascites, bone marrow, and primary tumor were imaged. In addition to EL4-RFP cells and GFP-host cells, genetically recombinant yellow-fluorescent cells, were observed only in the ascites and bone marrow. These results indicate genetic exchange between the stromal and cancer cells. Possible mechanisms of genetic exchange are discussed as well as its ramifications for metastasis. J. Cell. Biochem. 118: 4216-4221, 2017. © 2017 Wiley Periodicals, Inc.
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Linfoma/genética , Metástasis de la Neoplasia , Recombinación Genética , Células del Estroma , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Linfoma/patología , Ratones , Ratones Transgénicos , Microambiente TumoralRESUMEN
Paclitaxel is a standard second-line gastric cancer treatment in Japan. Trastuzumab could be active as second-line chemotherapy for taxane/trastuzumab-naïve patients with epidermal growth factor 2 (HER2)-positive advanced gastric cancer. Patients aged ≥20 years with HER2-positive, previously treated (except for trastuzumab and taxane), unresectable or recurrent gastric adenocarcinoma underwent combined trastuzumab (first and subsequent doses of 8 and 6 mg kg-1 , respectively, every 3 weeks) and paclitaxel (days 1, 8, 15, every 4 weeks) treatment. Study endpoints were best overall response, progression-free survival, overall survival, and safety. From September 2011 to March 2012, 47 Japanese patients were enrolled. Forty patients discontinued treatment after a median of 128.5 (range 4-486) days. Complete and partial responses were obtained in one and 16 patients (response rate of 37% [95% CI 23-52]), respectively. Median progression-free survival and overall survival were 5.1 (95% CI 3.8-6.5) and 17.1 (95% CI 13.5-18.6) months, respectively. Grade 3/4 adverse events were neutropenia (32.6%), leukopenia (17.4%), anemia (15.2%) and hypoalbuminemia (8.7%). There was no clinically significant cardiotoxicity or cumulative toxicity. Three (disturbed consciousness, pulmonary fibrosis, and rapid disease progression) grade 5 events occurred. In conclusion, trastuzumab combined with paclitaxel was well tolerated and was a promising regimen for patients with HER2-positive, previously treated, advanced or recurrent gastric cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Paclitaxel/administración & dosificación , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Trastuzumab/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Paclitaxel/efectos adversos , Neoplasias Gástricas/metabolismo , Análisis de Supervivencia , Trastuzumab/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Six months of adjuvant chemotherapy is regarded as the standard of care for patients with stage III colon cancer. However, whether longer treatment can improve prognosis has not been fully investigated. We conducted a phase III study comparing 6 and 12 months of adjuvant capecitabine chemotherapy for stage III colon cancer, and report here the results of our preplanned safety analysis. METHODS: Patients aged 20-79 years with curatively resected stage III colon cancer were randomly assigned to receive 8 cycles (6 months) or 16 cycles (12 months) of capecitabine (2500 mg/m2/day on days 1-14 of each 21-day cycle). Treatment exposure and adverse events (AEs) were evaluated. RESULTS: A total of 1304 patients (642 and 636 in the 6-month and 12-month groups, respectively) were analyzed. The most common AE was hand-foot syndrome (HFS). HFS, leukocytopenia, neutropenia, and hyperbilirubinemia (any grade) occurred more frequently in the 12-month group than in the 6-month group. HFS was the only grade ≥3 AE to have a significantly higher incidence in the 12-month group (23 vs 17%, p = 0.011). The completion rate for 8 cycles was 72% in both groups, while that for 16 cycles was 46% in the 12-month group. HFS was the most common AE requiring dose reduction and treatment discontinuation. CONCLUSIONS: Twelve months of adjuvant capecitabine demonstrated a higher cumulative incidence of HFS compared to the standard 6-month treatment period, while toxicities after 12 months of capecitabine were clinically acceptable. TRIAL REGISTRATION: UMIN-CTR, UMIN000001367.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Capecitabina/efectos adversos , Capecitabina/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Capecitabina/administración & dosificación , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Relación Dosis-Respuesta a Droga , Femenino , Síndrome Mano-Pie/etiología , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
PURPOSE: Although S-1 based chemotherapy for patients with advanced gastric cancer has generally been accepted in Japan, discontinuations of treatment have been reported due to grade 3 or more adverse events. The present randomized phase II study was conducted to test whether alternate-day administration of S-1 would be comparably efficient and reduce adverse events compared with conventional daily administration in the first-line chemotherapy for advanced gastric cancer. METHODS: 132 patients with advanced gastric cancer were randomly assigned to 1:2 ratios to receive treatment with daily at a standard dose of 80 mg/m2/day or alternate-day administration group received S-1 on 4 days a week. The primary end point was progression-free survival (PFS), and the secondary end points were safety, overall survival, time to treatment failure (TTF), disease control rate, and response rate. RESULTS: The 6-month PFS rate of the alternate-day administration group was 20.9% and failed to show significant difference from the pre-specified threshold at 15% (p = 0.117), whereas that of the daily administration group was 39.1% and significantly higher than the threshold (p = 0.001). The hazard ratio of the alternate-day administration group compared with the daily administration group was 1.753 (95% confidence interval (CI) 1.15-2.68, p = 0.010). With regard to OS, the hazard ratio of the alternate-day administration group compared with the daily administration group was 1.487 (95% CI 0.97-2.29, p = 0.072). The median TTF were 4.2 and 2.8 months in the daily and alternate-day administration group, respectively (p = 0.007). CONCLUSION: The alternate-day administration of S-1 was not recommended as the first-line therapy for patients with advanced gastric cancer.
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Antimetabolitos Antineoplásicos/administración & dosificación , Ácido Oxónico/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Tegafur/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Ácido Oxónico/efectos adversos , Neoplasias Gástricas/mortalidad , Tegafur/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Human epidermal growth factor (HER) 2 positivity and its association with clinicopathological factors remain unclear in Japanese gastric cancer (GC) patients. We performed a prospective, multicenter, observational cohort study to evaluate HER2 protein expression and gene amplification in Japanese metastatic and recurrent GC patients, and explored its correlations with clinicopathological features. METHODS: HER2 protein expression and gene amplification were centrally assessed in formalin-fixed, paraffin-embedded GC tissue by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Patient information was collected, and associations between clinicopathological factors and HER2 positivity (IHC score 3+ and/or FISH positive) and low HER2 expression (IHC score 0/FISH positive or IHC score 1+/FISH positive) were examined. RESULTS: From September 2011 to June 2012, 1461 patients were registered across 157 sites, and the HER2 status of 1427 patients was evaluated. The rate of HER2 positivity was 21.2 %, whereas the rate of high HER2 expression (IHC score 2+/FISH positive or IHC score 3+) was 15.6 % and that of low HER2 expression was 7.0 %. Multiple logistic regression analysis identified intestinal type, absence of peritoneal metastasis, and hepatic metastasis as significant independent factors related to HER2 positivity. The intestinal type was confirmed to be the GC subtype predominantly associated with lower HER2 expression. Sampling conditions including number of biopsy samples, formalin concentration, and formalin-fixation time did not significantly affect HER2 positivity. CONCLUSIONS: HER2 expression in Japanese patients was comparable to that in other populations examined. Intestinal type was an independent factor related to HER2 positivity and low HER2 expression.
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Biomarcadores de Tumor/metabolismo , Neoplasias Hepáticas/secundario , Recurrencia Local de Neoplasia/patología , Neoplasias Peritoneales/secundario , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Hibridación Fluorescente in Situ , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Estadificación de Neoplasias , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/metabolismo , Pronóstico , Receptor ErbB-2/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adulto JovenRESUMEN
We report here a color-coded imaging model in which metastatic niches in the lung and liver of breast cancer can be identified. The transgenic green fluorescent protein (GFP)-expressing nude mouse was used as the host. The GFP nude mouse expresses GFP in all organs. However, GFP expression is dim in the liver parenchymal cells. Mouse mammary tumor cells (MMT 060562) (MMT), expressing red fluorescent protein (RFP), were injected in the tail vein of GFP nude mice to produce experimental lung metastasis and in the spleen of GFP nude mice to establish a liver metastasis model. Niche formation in the lung and liver metastasis was observed using very high resolution imaging systems. In the lung, GFP host-mouse cells accumulated around as few as a single MMT-RFP cell. In addition, GFP host cells were observed to form circle-shaped niches in the lung even without RFP cancer cells, which was possibly a niche in which future metastasis could be formed. In the liver, as with the lung, GFP host cells could form circle-shaped niches. Liver and lung metastases were removed surgically and cultured in vitro. MMT-RFP cells and GFP host cells resembling cancer-associated fibroblasts (CAFs) were observed interacting, suggesting that CAFs could serve as a metastatic niche.
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Neoplasias de la Mama/genética , Neoplasias Hepáticas/patología , Imagen Molecular/métodos , Microambiente Tumoral/genética , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Proteínas Luminiscentes/metabolismo , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Proteína Fluorescente RojaRESUMEN
BACKGROUND: This multi-center, phase III trial assesses the efficacy of daikenchuto (TU-100) on gastrointestinal disorders after hepatic resection (UMIN Registration No. 000003103). MATERIALS AND METHODS: A total of 231 patients, who underwent hepatic resection at 26 Japanese centers, were enrolled. Patients were randomly assigned to receive either oral doses (15 g/day, three times a day) of TU-100 or placebo control from preoperative day 3 to postoperative day 10, except on the day of surgery. Primary end points were the time from extubation until the first postoperative bowel movement (FBM-T), serum C-reactive protein (CRP) and ammonia levels. RESULTS: Finally, 209 patients (TU-100: n = 108, placebo: n = 101) were included in the statistical analysis. The median FBM-T was 88.2 h (95 % CI 74.0-94.1) in the TU-100 group and 93.1 h (95 % CI 83.3-99.4) in the placebo group, demonstrating that TU-100 accelerated the time to first bowel movement significantly more than placebo control. Serum CRP levels did not differ significantly during the study period, although serum CRP levels in the TU-100 group tended to be lower than those in the placebo group in patients with grade B liver damage. Meanwhile, the two groups had similar serum ammonia levels. TU-100-related serious adverse events did not occur during the study. CONCLUSIONS: TU-100 appears to improve gastrointestinal dysmotility and reduce serum CRP levels in patients with grade B liver damage after hepatectomy. TU-100 is an effective treatment option after hepatic resection in patients with liver cancer.
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Enfermedades Gastrointestinales/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Naftoquinonas/administración & dosificación , Anciano , Anciano de 80 o más Años , Amoníaco/sangre , Pueblo Asiatico , Proteína C-Reactiva/metabolismo , Femenino , Hepatectomía/métodos , Humanos , Hígado/metabolismo , Hígado/cirugía , Masculino , Medicina Tradicional de Asia Oriental/métodos , Persona de Mediana Edad , Periodo PosoperatorioRESUMEN
OBJECTIVE: Cancer-related fatigue (CRF) is a common and one of the most important issues in palliative medicine, and it has been demonstrated to have a significant impact on patient quality of life (QoL). The present pilot randomized controlled study evaluated the efficacy and toxicity of methylprednisolone (MP) for CRF in advanced cancer patients. METHOD: Our study was planned as a randomized, double-blind, multicenter, placebo-controlled trial. Patients were randomly assigned to an MP group, who received 32 mg/day of MP orally for 7 days, and a placebo group. The primary endpoint was an improvement in visual analog scale (VAS) score for fatigue from baseline to day 7. The secondary endpoints were improvements in appetite loss and QoL as well as evaluating the safety of corticosteroids as palliative therapy. RESULTS: It was not possible to complete patient registration. In total, 35 patients were randomly assigned to an MP group (n = 18) and a placebo group (n = 17). The mean changes in VAS score for fatigue were -9.06 in the placebo group and -1.56 in the MP group, and for appetite loss -6.44 in the placebo group and -8.06 in the MP group. In addition, there was no evidence that methylprednisolone improved appetite loss or QoL compared to placebo. The incidence of adverse effects was not greater in the MP group. Significant of Result: We conclude that our sample size was too small to prove the efficacy of methylprednisolone in improving fatigue. Our results were reported as a pilot study performed to support a subsequent larger trial.
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Fatiga/tratamiento farmacológico , Trastornos de Alimentación y de la Ingestión de Alimentos/tratamiento farmacológico , Metilprednisolona/uso terapéutico , Neoplasias/tratamiento farmacológico , Cuidados Paliativos/métodos , Calidad de Vida , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Fatiga/etiología , Trastornos de Alimentación y de la Ingestión de Alimentos/etiología , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Masculino , Metilprednisolona/administración & dosificación , Metilprednisolona/efectos adversos , Persona de Mediana Edad , Neoplasias/complicaciones , Proyectos Piloto , Resultado del TratamientoRESUMEN
OBJECTIVE: Dihydropyrimidine dehydrogenase (DPYD) genotype is closely associated with fluoropyrimidine (FP)-induced toxicities in Caucasian population and European Medicines Agency now recommends DPYD genotype-based FP dosing strategy. PATIENTS AND METHODS: The current study aimed to investigate their impact on FP-related toxicities in an Asian population using genome-wide association study (GWAS) data set from 1364 patients with colon cancer. RESULTS: Among 82 variants registered in the Clinical Pharmacogenetics Implementation Consortium, 74 DPYD variants were directly genotyped in GWAS cohort; however, only 7 nonsynonymous DPYD variants (CPIC variants) were identified and none of the four recurrent DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G, c.1236G>A) were included. Seven CPIC variants were investigated for their association with the incidence of FP-related toxicities; however, none of these variants revealed a significant correlation with FP-related toxicities. CONCLUSION: These data suggested that the DPYD genotype registered in CPIC plays a minor role in FP-related toxicities in an Asian population.
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Dihidrouracilo Deshidrogenasa (NADP) , Fluorouracilo , Humanos , Dihidrouracilo Deshidrogenasa (NADP)/genética , Fluorouracilo/efectos adversos , Estudio de Asociación del Genoma Completo , Genotipo , Antimetabolitos Antineoplásicos/efectos adversos , CapecitabinaRESUMEN
Pancreatic-cancer-patient tumor specimens were initially established subcutaneously in NOD/SCID mice immediately after surgery. The patient tumors were then harvested from NOD/SCID mice and passaged orthotopically in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP). The primary patient tumors acquired RFP-expressing stroma. The RFP-expressing stroma included cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). Further passage to transgenic nude mice ubiquitously expressing green fluorescent protein (GFP) resulted in tumors that acquired GFP stroma in addition to their RFP stroma, including CAFs and TAMs as well as blood vessels. The RFP stroma persisted in the tumors growing in the GFP mice. Further passage to transgenic nude mice ubiquitously expressing cyan fluorescent protein (CFP) resulted in tumors acquiring CFP stroma in addition to persisting RFP and GFP stroma, including RFP- and GFP-expressing CAFs, TAMs and blood vessels. This model can be used to image progression of patient pancreatic tumors and to visually target stroma as well as cancer cells and to individualize patient therapy.
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Diagnóstico por Imagen/métodos , Colorantes Fluorescentes , Neoplasias Pancreáticas/irrigación sanguínea , Neoplasias Pancreáticas/patología , Microambiente Tumoral , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Proteínas Fluorescentes Verdes/biosíntesis , Humanos , Proteínas Luminiscentes/biosíntesis , Macrófagos , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Ratones Transgénicos , Trasplante de Neoplasias , Neoplasias Pancreáticas/metabolismo , Trasplante Heterólogo , Proteína Fluorescente RojaRESUMEN
The tumor microenvironment (TME) is critical for tumor growth and progression. However, the formation of the TME is largely unknown. This report demonstrates a color-coded imaging model in which the development of the TME can be visualized. In order to image the TME, a green fluorescent protein (GFP)-expressing mouse was used as the host which expresses GFP in all organs but not the parenchymal cells of the liver. Non-colored HCT-116 human colon cancer cells were injected in the spleen of GFP nude mice which led to the formation of experimental liver metastasis. TME formation resulting from the liver metastasis was observed using the Olympus OV100 small animal fluorescence imaging system. HCT-116 cells formed tumor colonies in the liver 28 days after cell transplantation to the spleen. GFP-expressing host cells were recruited by the metastatic tumors as visualized by fluorescence imaging. A desmin positive area increased around and within the liver metastasis over time, suggesting cancer-associated fibroblasts (CAFs) were recruited by the liver metastasis which have a role in tumor progression. The color-coded model of the TME enables its formation to be visualized at the cellular level in vivo, in real-time. This imaging model of the TME should lead to new visual targets in the TME.
Asunto(s)
Neoplasias del Colon/patología , Fibroblastos/patología , Neoplasias Hepáticas/secundario , Animales , Fibroblastos/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Células HCT116 , Humanos , Riñón/patología , Hígado/patología , Neoplasias Hepáticas/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Ratones Transgénicos , Microscopía Fluorescente , Trasplante de Neoplasias , Bazo/patologíaRESUMEN
We report here that XPA1 human pancreatic cancer cells are dimorphic. After injection in the spleen, XPA1 cells isolated from the primary tumor in the spleen were predominantly round; while cells isolated from the resulting liver metastasis and ascites were comprised of both round- and spindle-shaped cell types. Cancer cells previously grown in the spleen and re-implanted in the spleen developed large primary tumors in the spleen only. Cancer cells isolated from liver metastasis and re-transplanted to the spleen resulted in a primary tumor in the spleen and liver metastasis. Cancer cells derived from ascites and re-transplanted to the spleen developed primary tumors in the spleen and distant metastasis in the liver, lung, and diaphragm in addition to ascites formation. Spindle and round cells were differentially labeled with fluorescent proteins of different colors. After co-injection of the two cell types in the spleen, cells were isolated from the primary tumors, liver metastasis, and ascites and analyzed by color-coded fluorescence microscopy and fluorescence-activated cell sorting (FACS). No significant differences between the percentages of spindle-shaped and round cancer cells in the primary tumor and the liver metastasis were observed. However, spindle-shaped cancer cells were enriched in the ascites. One hundred percent of the spindle-shaped and round cancer cells expressed CD44, suggesting that morphology and metastatic behavior rather than CD44 expression can distinguish the stem-like cells of the XPA1 pancreatic cancer cell line. The spindle-shaped cancer cells had the greater capability for distant metastasis and ascites formation, suggesting they are stem-like cells, which can be readily targeted for therapy.
Asunto(s)
Metástasis de la Neoplasia , Células Madre Neoplásicas/citología , Neoplasias Pancreáticas/patología , Animales , Línea Celular Tumoral , Separación Celular , Humanos , Inmunohistoquímica , Ratones , Ratones Desnudos , Microscopía FluorescenteRESUMEN
Aromatase inhibitor shows efficacy for hormone receptor positive postmenopausal breast cancer. We evaluated the activity of 24 weeks of aromatase inhibition with exemestane for primary breast cancer in a neoadjuvant setting. Patients with stage II/IIIA invasive breast cancer with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive status were eligible. Primary endpoints were objective response rate (ORR) and safety. A steroidal aromatase inhibitor exemestane of 25 mg/day was administered for 16 weeks with an 8-week extension. Secondary endpoints were rates of breast-conserving surgery (BCS), and change of Ki67 index and ER/PgR expression in central laboratory analyses. Between March 2006 and December 2007, 116 patients were enrolled. Among those, 102 patients completed 24 weeks of administration. The ORR was 47% (55/116) at Week 16 and 51% (59/116) at Week 24, respectively. No serious toxicity was seen. ORR was associated with ER Allred scores but not with PgR scores. The significant reduction in Ki67 index was confirmed. No progression was experienced in tumors with less than 15% Ki67 index. Pathological response was observed in 28 (30%) of 94 evaluated cases. No statistical correlation between pre-treatment Ki67 index and pathological response was detected; however, a trend of correlation was found between the post-treatment preoperative endocrine prognostic index (PEPI), a prognostic score and the pathological response. At diagnosis, 59 patients (51%) would have required mastectomy but 40 patients were converted to BCS, showing an increase in the rate of BCS (77%). The 24-week aromatase inhibition provided preferable clinical benefits with significant reduction in Ki67 index. More precise mechanisms of the response need to be investigated.
Asunto(s)
Androstadienos/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Aromatasa/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Antígeno Ki-67/metabolismo , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Metástasis Linfática , Mastectomía Segmentaria , Persona de Mediana Edad , Estadificación de Neoplasias , Posmenopausia , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The pharmacokinetics of irinotecan vary markedly between individuals. This study sought to compare tailored irinotecan and S-1 therapy with S-1 monotherapy for the treatment of patients with advanced/recurrent gastric cancer. Patients with advanced/recurrent gastric cancer were randomized to receive tailored irinotecan and S-1 (arm A) therapy or S-1 therapy alone (arm B). Arm A received S-1 (80-120 mg/m(2)/day) for 14 days, with irinotecan on days 1 and 15. The initial irinotecan dose of 75 mg/m(2) (level 0) was adjusted for toxicity during an earlier course. In arm B, S-1 (80-120 mg/day) was administered alone for 28 days, followed by 14 days without therapy. Ninety-five patients were randomized (48 patients to arm A and 47 patients to arm B). The response rate of the primary tumor (Japanese criteria) was 25.0% in arm A (12 of 48 patients) and 14.9% in arm B (seven of 47 patients), whereas the response rates according to Response Evaluation Criteria In Solid Tumors were 27.8% (10 of 36) versus 21.9% (seven of 32). Hematological toxicity, anorexia, and diarrhea were significantly more common in arm A, but both arms had similar grades 3-4 toxicities. These findings suggest the usefulness of tailored irinotecan and S-1 therapy for gastric cancer.