RESUMEN
BACKGROUND: Failure-free survival (FFS) rates of low-risk patients with rhabdomyosarcoma improved in Intergroup Rhabdomyosarcoma Study IV after the escalation of cyclophosphamide total dose to 26.4 g/m2. However, this dose may increase the risk of adverse events, including infertility, in some patients. The JRS-I LRA0401 and LRB0402 protocols aimed to reduce the cyclophosphamide dose to 9.6 g/m2 and 17.6 g/m2, respectively, without decreasing the FFS rates. METHODS: Subgroup-A patients received eight cycles (24 weeks) of vincristine, actinomycin D, and 1.2 g/m2/cycle cyclophosphamide. Subgroup-B patients received eight cycles (24 weeks) of vincristine, actinomycin D, and 2.2 g/m2/cycle cyclophosphamide, followed by six cycles (24 weeks) of vincristine and actinomycin D. Group II/III patients in both subgroups received radiotherapy. RESULTS: In subgroup A (n = 12), the 3-year FFS rate was 83% (95% confidence interval [CI], 48-96), and the 3-year overall survival (OS) rate was 100%. Only one isolated local recurrence was observed (8.3%). There were no unexpected grade-4 toxicities and no deaths. In subgroup B (n = 16), the 3-year FFS and OS rates were 88% (95% CI, 59-97) and 94% (95% CI, 63-99), respectively. There were no unexpected grade 4 toxicities and no deaths. CONCLUSIONS: Shorter duration therapy using vincristine, actinomycin D, and lower dose cyclophosphamide with or without radiotherapy for patients with low-risk subgroup A rhabdomyosarcoma (JRS-I LRA0401 protocol) and moderate reduction of cyclophosphamide dose for patients with low-risk subgroup B rhabdomyosarcoma (JRS-I LRB0402 protocol) did not compromise FFS.
RESUMEN
There is emerging evidence that human solid tumor cells originate from cancer stem cells (CSCs). In cancer cell lines, tumor-initiating CSCs are mainly found in the side population (SP) that has the capacity to extrude dyes such as Hoechst 33342. We found that Nanog is expressed specifically in SP cells of human gastrointestinal (GI) cancer cells. Nucleotide sequencing revealed that NanogP8 but not Nanog was expressed in GI cancer cells. Transfection of NanogP8 into GI cancer cell lines promoted cell proliferation, while its inhibition by anti-Nanog siRNA suppressed the proliferation. Immunohistochemical staining of primary GI cancer tissues revealed NanogP8 protein to be strongly expressed in 3 out of 60 cases. In these cases, NanogP8 was found especially in an infiltrative part of the tumor, in proliferating cells with Ki67 expression. These data suggest that NanogP8 is involved in GI cancer development in a fraction of patients, in whom it presumably acts by supporting CSC proliferation.
Asunto(s)
Neoplasias Gastrointestinales/genética , Proteínas de Homeodominio/genética , Seudogenes , Animales , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular , Cartilla de ADN/genética , Neoplasias Gastrointestinales/metabolismo , Neoplasias Gastrointestinales/patología , Proteínas de Homeodominio/antagonistas & inhibidores , Proteínas de Homeodominio/metabolismo , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Proteína Homeótica Nanog , Trasplante de Neoplasias , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , ARN Interferente Pequeño/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Ácido Nucleico , Transfección , Trasplante HeterólogoRESUMEN
AIMS: The aim of this study was to investigate the potential role of HER-2/neu in the stepwise progression of carcinoma ex pleomorphic adenoma (CXPA) and to evaluate its prognostic significance in CXPA. METHODS AND RESULTS: We examined HER2 overexpression and HER2 amplification by immunohistochemistry and chromogenic in-situ hybridization in 31 cases of CXPA with ductal differentiation (eight intraductal, five intracapsular, and 18 extracapsular) and seven cases of atypical pleomorphic adenoma (PA). HER2 overexpression and HER2 amplification were found in 17 (54.8%) and 12 (38.7%) of the 31 CXPA cases, respectively. HER2 amplification was more prevalent in extracapsular CXPAs (9/18 cases; 50%) than intracapsular CXPAs (1/5 cases; 20%), intraductal CXPAs (2/8 cases; 25%), or atypical PAs (0/7 case; 0%). The status of HER2 amplification was essentially retained from the intraductal to the extracapsular component in individual extracapsular CXPAs. In addition, HER2 amplification was significantly associated with a worse prognosis (shorter disease-free survival time and shorter overall survival time) among extracapsular CXPAs (each P < 0.05). CONCLUSIONS: These results suggest that HER2 may play an important role in the progression of CXPA, and that HER2 amplification may be an additional prognostic indicator of CXPA.
Asunto(s)
Adenoma Pleomórfico/genética , Carcinoma/genética , Amplificación de Genes , Receptor ErbB-2/genética , Neoplasias de las Glándulas Salivales/genética , Adenoma Pleomórfico/metabolismo , Adenoma Pleomórfico/patología , Adulto , Anciano , Biomarcadores de Tumor , Carcinoma/metabolismo , Carcinoma/patología , Progresión de la Enfermedad , Femenino , Humanos , Hibridación in Situ , Masculino , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/patologíaRESUMEN
OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMN) are classified into four phenotypes according to the WHO classification. Recently, intestinal-type IPMN has been suggested to grow with a distinct carcinogenetic pathway. Like mucin 2, oligomeric mucus/gel forming (MUC2) and caudal-related homeobox 2 (CDX2), liver-intestine cadherin (LI cadherin) is an intestine-specific marker. We aimed to investigate the roles of LI cadherin expression in IPMN. METHODS: We examined LI cadherin expression in 135 cases of IPMN by immunohistochemical staining and the quantitative real-time reverse-transcription polymerase chain reaction. RESULTS: LI cadherin protein and mRNA levels were significantly higher in intestinal-type IPMN than in nonintestinal-type IPMN (protein level, p < 0.001; mRNA level, p = 0.0312). A positive correlation was found between protein and mRNA of LI cadherin (p = 0.0037). The positivity rates of LI cadherin expression were significantly higher in CDX2-positive cases than in CDX2-negative cases (p < 0.001). In 41 intestinal-type IPMNs, LI cadherin-positive rates tended to increase gradually, from IPMN with low-grade dysplasia (IPMN-L) to IPMN with an associated invasive carcinoma (IPMN-IC) [IPMN-L vs. IPMN with high-grade dysplasia (IPMN-H); p = 0.0357, IPMN-L vs. IPMN-IC; p = 0.0230] and positively correlated with the Ki-67 labeling index (p = 0.0408), whereas this tendency was not recognized in nonintestinal-type IPMNs. CONCLUSIONS: LI cadherin is associated with an intestinal phenotype and an 'intestinal pathway' of carcinogenesis in IPMN.
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Adenocarcinoma Mucinoso/patología , Cadherinas/metabolismo , Carcinoma Ductal Pancreático/patología , Carcinoma Papilar/patología , Neoplasias Pancreáticas/patología , Biomarcadores de Tumor/análisis , Factor de Transcripción CDX2 , Cadherinas/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Diferenciación Celular/fisiología , Proteínas de Homeodominio/metabolismo , Humanos , Mucina 2/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismoRESUMEN
A 66-year-old Japanese woman had been diagnosed with a neuroendocrine tumor of the pancreatic head (G2) 3 years previously and undergone pancreaticoduodenectomy. Nine months postoperatively, recurrence with multiple liver metastases developed and she was referred to our department. A regimen of 10 mg of everolimus for 2 weeks plus 1-week washout was instituted, and no adverse events were observed. Fourteen months after treatment initiation, she developed severe generalized erythema multiforme (EM). Skin biopsy revealed spongiosis in the epidermis and interface change and edema in the superficial dermis. Mast cells were observed from the dermis to the subcutaneous tissue, as well as perivascular eosinophilic infiltration, leading to EM being diagnosed. Oral everolimus was discontinued, and the EM was relieved by treatment including steroid therapy. Everolimus is an inhibitor of the mammalian target of rapamycin, and its indications include neuroendocrine tumors. Skin disorders are commonly seen in the early stages of everolimus treatment, but their severity is almost always mild and never severe. This is the first report on a patient who presented with severe generalized EM more than 1 year after everolimus treatment initiation. Patients on everolimus therapy should be monitored for skin disorders on a long-term basis.
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Antineoplásicos , Eritema Multiforme , Exantema , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Femenino , Humanos , Anciano , Everolimus/efectos adversos , Tumores Neuroendocrinos/tratamiento farmacológico , Antineoplásicos/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Eritema Multiforme/inducido químicamente , Eritema Multiforme/diagnóstico , Exantema/inducido químicamenteRESUMEN
Mitochondria are key organelles for ATP production and apoptosis. Therefore, impairment of mitochondria can modulate or accelerate cancer progression. p32, originally identified as a pre-mRNA splicing factor SF2/ASF-associated protein, is localized predominantly in the mitochondrial matrix and involved in mitochondria respiration. Recently, p32 was implicated in apoptosis and resultantly cancer progression. However, little is known about the expression and function of p32 in human tumors including prostate cancer. Here, we investigated the expression of p32 in 148 prostate carcinoma tissues by immunohistochemistry and found a positive correlation of p32 expression to clinicopathological parameters including follow-up data. p32 is highly expressed in prostate tumor samples and its expression is significantly associated with the Gleason score, pathological stage and relapse. For localized cancers, high p32 is a strong and independent predictor of clinical recurrence in multivariate analysis (P=0.01). In addition, p32 is overexpressed in the prostate cancer cell lines examined. The selective knockdown of p32 by RNA interference inhibits the growth of prostate cancer cell lines but not of a non-cancerous cell line. The p32 RNA interference decreases cyclin D1, increases p21 expression and causes a G1/S cell cycle arrest in prostate cancer cells. These data suggest that p32 is critical for prostate cancer cell proliferation and may be a novel marker of clinical progression in prostate cancer.
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Proteínas Portadoras/análisis , Mitocondrias/química , Proteínas Mitocondriales/análisis , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/patología , Anciano , Biomarcadores de Tumor/análisis , Proteínas Portadoras/fisiología , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Ciclina D1/antagonistas & inhibidores , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Humanos , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/fisiología , Neoplasias de la Próstata/química , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/cirugía , Recurrencia , Factores de TiempoRESUMEN
AIMS: The role of misregulated Wnt/beta-catenin signalling in human ovarian granulosa cell tumour (GCT) has not been well characterized. The aim of this study was to confirm subcellular localization of key molecules of Wnt signalling (beta-catenin and E-cadherin) in human ovarian GCTs. METHODS AND RESULTS: Tissue samples taken from 32 human ovarian GCTs and 19 human normal ovaries containing 68 follicles were stained immunohistochemically using monoclonal anti-beta-catenin and anti-E-cadherin antibodies. None of the 32 GCTs and none of the 68 ovarian follicles showed beta-catenin nuclear expression (0%). On the other hand, 28 of 32 GCTs (88%) and 53 of 68 normal ovarian follicles (78%) showed nuclear expression of E-cadherin in granulosa cells. The ovarian stroma in all 19 normal ovaries showed nuclear expression of E-cadherin but not beta-catenin. Membranous and cytoplasmic expression was observed variously in ovarian GCT, follicles and stroma. CONCLUSIONS: We have confirmed frequent nuclear localization of E-cadherin but not beta-catenin in human ovarian GCT, ovarian follicles and stroma. There is no evidence of misregulated Wnt/beta-catenin signalling (represented by nuclear expression of beta-catenin) in human ovarian GCT. Nuclear translocation of E-cadherin might contribute to ovarian folliculogenesis or granulosa/stromal cell differentiation.
Asunto(s)
Cadherinas/análisis , Núcleo Celular/metabolismo , Células de la Granulosa/metabolismo , Folículo Ovárico/metabolismo , Neoplasias Ováricas/metabolismo , beta Catenina/metabolismo , Cadherinas/metabolismo , Femenino , Tumor de Células de la Granulosa/metabolismo , Tumor de Células de la Granulosa/patología , Células de la Granulosa/patología , Humanos , Folículo Ovárico/patología , Neoplasias Ováricas/patología , Ovario/metabolismo , Ovario/patología , Transducción de SeñalRESUMEN
AIMS: To analyse the correlation between ß-catenin and vascular endothelial growth factor (VEGF) in sporadic desmoid tumours. METHODS AND RESULTS: The correlation between ß-catenin aberrant expression and VEGF overexpression was examined and microvessel density (MVD) assessed by immunohistochemical expression of CD31 in 74 samples (63 primary and 11 recurrent samples, 63 patients) of sporadic desmoid tumours without familial adenomatous polyposis (FAP). ß-catenin gene mutation and mRNA expression of VEGF was then examined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). There was a statistically significant correlation between widespread nuclear expression of ß-catenin and overexpression of VEGF in all desmoid tumours (P = 0.04, Fisher's exact test). MVD in recurrent tumours was significantly higher than that in primary tumours. CONCLUSIONS: Abnormalities of ß-catenin and VEGF overexpression play an important role in the neoplastic progression of sporadic desmoid tumours.
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Fibromatosis Agresiva/genética , Fibromatosis Agresiva/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Proteínas Wnt/genética , beta Catenina/genética , Adolescente , Adulto , Anciano , Núcleo Celular/metabolismo , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Fibromatosis Agresiva/patología , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Wnt/metabolismo , Adulto Joven , beta Catenina/biosíntesisRESUMEN
AIMS: To investigate nuclear atypical in papillary gastric adenocarcinoma (PGA). METHOD AND RESULTS: Hundred cases of PGA were classified into two groups according to nuclear pleomorphism and nuclear polarity; these groups were designated as high nuclear grade and low nuclear grade. Correlations between nuclear grade and clinicopathological features were evaluated for prognostic value. In order to evaluate which types of biological factors influence nuclear atypia, the expression of gastric-type mucin phenotype, p53, HER2 and Ki-67 detected by immunohistochemistry and DNA ploidy detected by laser scanning cytometry. The high nuclear grade group correlated with deeper wall invasion, the presence of lymphatic and venous invasion and the positivity of lymph node metastasis. High nuclear grade was an independent prognostic factor for disease-free survival. Moreover, significant correlations were observed between high nuclear grade and positivity of gastric-type mucin phenotype, p53 and HER2 and DNA aneuploidy. CONCLUSION: Nuclear grade could be a new and useful morphological predictor for high malignant potential in PGA.
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Adenocarcinoma Papilar/patología , Núcleo Celular/patología , Neoplasias Gástricas/patología , Adenocarcinoma Papilar/genética , Adenocarcinoma Papilar/mortalidad , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Femenino , Humanos , Inmunohistoquímica , Citometría de Barrido por Láser , Masculino , Clasificación del Tumor , Estadificación de Neoplasias , Ploidias , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidadRESUMEN
AIMS: Hitherto, biliary intraepithelial neoplasia (BilIN) has been described in chronic biliary disease but rarely in non-biliary liver cirrhosis (LC). Intraepithelial neoplasia of the pancreas shows alterations in the expression of cell cycle and mucin core proteins. The aim of this study was to evaluate BilIN and reactive biliary lesions in biliary disease and non-biliary LC. METHODS AND RESULTS: BilIN was found in 51% (33 of 65) of liver tissue cases of biliary disease, and in 11% (34 of 310) of the LC group. Immunohistologically, MUC5AC, an 'early phase' protein, and Ki67, reflecting 'late phase' expression, were identified with increasing degrees of dysplasia in both groups, but that expression was significantly higher in the biliary disease group. 'Early phase' cell cycle proteins, p16 (decrease) and p21 (increase) altered in both biliary and LC groups with increasing degrees of dysplasia. CONCLUSIONS: We found BilIN in the large bile ducts of hepatitis B virus- and hepatitis C virus-related LC as well as in cases related to a biliary aetiology. The LC group was significantly less likely to show changes in the expression of MUC5AC and proliferative activity than the biliary group. Alterations in p16 and p21 reflected increasing degrees of dysplasia in both groups.
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Enfermedades de las Vías Biliares/patología , Neoplasias del Sistema Biliar/patología , Carcinoma in Situ/patología , Cirrosis Hepática/patología , Enfermedades de las Vías Biliares/metabolismo , Neoplasias del Sistema Biliar/metabolismo , Carcinoma in Situ/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Humanos , Inmunohistoquímica , Cirrosis Hepática/metabolismo , Mucina 5AC/biosíntesis , Proteínas de Neoplasias/biosíntesisRESUMEN
AIMS: Histone deacetylases (HDACs) play important roles in many types of cancer. Recently, it has been reported that HDAC1 expression in prostate cancer is significantly higher than in benign prostate cell lines and tissues. The expression of HDAC1 in association with the clinicopathological data was investigated to define its functional and pathological roles in prostate cancer. METHODS AND RESULTS: HDAC1 expression was examined immunohistochemically in 148 patients with prostate cancer. Strong expression of HDAC1 in benign prostate glands, high-grade prostatic intraepithelial neoplasia (PIN) and prostate cancer was observed in 17/148 (11%), 19/71 (27%) and 69/148 (47%) patients. Strong HDAC1 expression was correlated with high Gleason score (P = 0.025) and high pT stage (P = 0.012). Patients with strong HDAC1 expression had higher biochemical recurrence rates (P = 0.0010). Furthermore, strong HDAC1 expression had a significant impact on patient biochemical recurrence rates in multivariate analysis (P = 0.004). CONCLUSIONS: These results indicate that overexpression of HDAC1 contributes to progression and poor prognosis in prostate cancer. The findings may play an important role in the emergence of effective new approaches for therapy and prognostic markers of prostate cancer.
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Histona Desacetilasa 1/metabolismo , Neoplasias de la Próstata/enzimología , Anciano , Progresión de la Enfermedad , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Neoplasia Intraepitelial Prostática/metabolismo , Neoplasia Intraepitelial Prostática/patología , Neoplasias de la Próstata/patologíaRESUMEN
AIMS: Activation-induced cytidine deaminase (AID) is a DNA/RNA-editing enzyme that is essential for hypermutation and class-switch recombination in immunoglobulin genes. The aim of this study was to investigate the expression of AID and its association with p53 mutation in ulcerative colitis (UC)-associated carcinogenesis. METHODS AND RESULTS: The expression of AID was examined in 25 patients with UC-associated neoplasia, 20 UC patients without neoplasia, 18 patients with non-inflamed colorectal mucosa unaffected by UC, and 19 patients with sporadic colorectal cancer, by immunohistochemistry and quantitative reverse transcription polymerase chain reaction analysis. Mutational analysis and immunohistochemistry for p53 were also performed. The degree of AID expression was not different between UC-associated neoplasia and sporadic colorectal cancer. However, AID was expressed in both UC-associated neoplasia and UC without neoplasia. Whereas AID expression in UC-associated neoplasia was not correlated with the grade of dysplasia, expression in non-neoplastic mucosa of UC was correlated with the histological grade of inflammation. In UC-associated neoplasia, there was no significant correlation between AID expression and p53 mutation. CONCLUSIONS: AID is associated with inflammation in UC, whereas it may not specifically contribute to carcinogenesis in UC.
Asunto(s)
Biomarcadores de Tumor/análisis , Transformación Celular Neoplásica/metabolismo , Colitis Ulcerosa/enzimología , Neoplasias del Colon/enzimología , Citidina Desaminasa/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Transformación Celular Neoplásica/genética , Colitis Ulcerosa/genética , Colitis Ulcerosa/patología , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Análisis Mutacional de ADN , Femenino , Humanos , Inmunohistoquímica , Inflamación/enzimología , Inflamación/genética , Inflamación/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína p53 Supresora de Tumor/genética , Adulto JovenRESUMEN
OBJECTIVES: Gastrointestinal stromal tumor (GIST) is characterized by KIT or PDGFRA gene mutation. Although chromosomal losses of 22q are frequent in GIST, it is unclear which tumor suppressor genes might be inactivated in association with such losses. The INI1 gene, located at 22q11.23, is a tumor suppressor gene that is frequently altered in malignant rhabdoid tumor. METHODS: To elucidate the hypothesis that the INI1 gene might be altered along with 22q loss in GIST, we examined the loss of heterozygosity (LOH) at 22q11.23, homozygous deletion and mutation of the INI1 gene, and its gene product expression as well as mutations of KIT and PDGFRA in 27 cases of GIST. RESULTS: Among the 27 informative cases, 19 (70.4%) showed LOH of at least one of the microsatellite markers on 22q11.23. None of the cases (0%) showed homozygous deletion or mutation of the INI1 gene. Immunohistochemically, the INI1 expression was focally reduced in 17/27 (63%) cases, and the INI1 protein level and INI1 mRNA level were each correlated with the presence of 22q11.23 LOH. Although the 22q11.23 LOH was more frequently present in high- than in low-grade tumors, INI1 expression level was not correlated with tumor grade, tumor size, proliferative activity and the expression levels of cyclin D1 and p16INK4a. KIT mutations were found in 18/27 (66.7%) GISTs; however, the KIT genotype was not correlated with the status of LOH at 22q11.23. CONCLUSIONS: The results suggest that 22q11.23 LOH is frequently present in GIST irrespective of KIT genotype and it might play a role in part of the development of GIST. However, the hemiallelic loss of INI1 gene causing reduced expression of INI1 protein probably does not have a major impact in the progression of GIST.
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Proteínas Cromosómicas no Histona/genética , Cromosomas Humanos Par 22/genética , Proteínas de Unión al ADN/genética , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Pérdida de Heterocigocidad/genética , Factores de Transcripción/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Cromosómicas no Histona/metabolismo , Ciclina D1/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , ARN Mensajero/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Proteína SMARCB1 , Factores de Transcripción/metabolismoRESUMEN
Perivascular epithelioid cell tumor (PEComas), other than angiomyolipoma, clear cell 'sugar' tumor of the lung, and lymphangioleiomyomatosis, is an uncommon mesenchymal neoplasm that arises in the soft tissue and visceral organs. We report herein two cases of sclerosing PEComa; a distinctive variant of PEComa, which is characterized by extensive stromal hyalinization, occurring in the uterus and broad ligament. The patients were 34- and 51-year-old females with no family history of tuberous sclerosis complex. Macroscopically, the tumors had white to gray cut surfaces and were microscopically composed of predominantly spindle- to polygon-shaped cells with clear to slightly eosinophilic cytoplasm and pleomorphic nuclei focally arranged in a perivascular pattern, accompanied by marked stromal hyalinization. These tumor cells were immunohistochemically positive for HMB45 and α-smooth muscle actin. Although this variant of PEComa is very rare, this entity should be considered as a potential primary neoplasm of the female genital organs.
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Neoplasias de Células Epitelioides Perivasculares/patología , Neoplasias Uterinas/patología , Adulto , Biomarcadores de Tumor/análisis , Ligamento Ancho/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Neoplasias de Células Epitelioides Perivasculares/metabolismo , Neoplasias de Células Epitelioides Perivasculares/cirugía , Esclerosis , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/cirugíaRESUMEN
Aberrant activation of the Wnt signaling pathway has been implicated in tumorigenesis of a wide range of tumors, including colorectal cancer. Regarding endometrial stromal tumors and related high-grade sarcomas, there have been some reports regarding nuclear accumulation of beta-catenin. To clarify the function of the aberrant Wnt signaling pathway in these tumors, we searched for mutations of the CTNNB1 (beta-catenin) gene and APC gene by PCR direct sequencing and analyzed the methylation status of SFRP genes. We also examined overexpression of cyclin D1 and MMP-7, which are direct target genes of beta-catenin. Eight endometrial stromal nodules, 16 low-grade endometrial stromal sarcomas, and 13 undifferentiated endometrial sarcomas were examined. PCR and direct sequencing revealed no mutation of the beta-catenin gene or the APC gene. Concerning the promoter methylation status of SFRP genes, methylation-specific PCR revealed no significant difference between the group with nuclear beta-catenin expression and that without nuclear beta-catenin expression. Immunohistochemistry revealed overexpression of cyclin D1 in 2 out of 8 endometrial stromal nodules, 1 out of 17 low-grade endometrial stromal sarcomas, and 6 out of 13 undifferentiated endometrial sarcomas, and these 6 undifferentiated endometrial sarcomas simultaneously expressed nuclear beta-catenin. Interestingly, all six undifferentiated endometrial sarcoma cases with cyclin D1 overexpression histologically featured rather uniform nuclei. In contrast, the six cases of undifferentiated endometrial sarcoma with highly pleomorphic nuclei were all negative for cyclin D1. In conclusion, among endometrial stromal tumors and related sarcomas, undifferentiated endometrial sarcomas featuring uniform nuclei were characterized by frequent coincident expression of beta-catenin and cyclin D1. This finding raises the possibility that cyclin D1 is upregulated by beta-catenin in these high-grade sarcomas previously called high-grade endometrial stromal sarcoma.
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Ciclina D1/biosíntesis , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Sarcoma Estromático Endometrial/metabolismo , Sarcoma Estromático Endometrial/patología , beta Catenina/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Núcleo Celular/patología , Proteínas Co-Represoras , Ciclina D1/genética , Metilación de ADN , Análisis Mutacional de ADN , Proteínas de Unión al ADN , Neoplasias Endometriales/genética , Femenino , Genes APC , Glicoproteínas/biosíntesis , Glicoproteínas/genética , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular , Metaloproteinasa 7 de la Matriz/biosíntesis , Metaloproteinasa 7 de la Matriz/genética , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sarcoma Estromático Endometrial/genética , Transducción de Señal/fisiología , Factores de Transcripción/genética , Adulto Joven , beta Catenina/genéticaRESUMEN
Synovial sarcoma is classified as a tumor of uncertain differentiation, and some synovial sarcomas have rhabdoid cells. In previous studies, all malignant rhabdoid tumors and renal medullary carcinomas, some extraskeletal myxoid chondrosarcomas, almost all epithelioid sarcomas and half of epithelioid malignant peripheral nerve sheath tumors showed a loss of SMARCB1/INI1 protein expression in tumor cells and all of these tumors are also known to have rhabdoid cells. We analyzed the immunohistochemical and mRNA expression of SMARCB1/INI1 in 95 synovial sarcomas (73 monophasic fibrous type, 18 biphasic type and 4 poorly differentiated type) and 30 spindle cell sarcomas (3 adult fibrosarcomas, 7 fibrosarcomas arising in dermatofibrosarcoma protuberans, 10 leiomyosarcomas and 10 malignant peripheral nerve sheath tumors) resembling monophasic fibrous synovial sarcoma. The results have shown that 66 of the 95 synovial sarcoma cases (69%) had reduced SMARCB1/INI1 protein expression, whereas the remaining 29 cases (31%) and all 30 spindle cell sarcomas showed preserved this protein expression. No case with a complete loss of SMARCB1/INI1 protein expression was recognized. The median values of SMARCB1/INI1 mRNA expression in non-tumor skeletal muscle and synovial sarcoma with reduced protein expression were 12.86 and 134.01, respectively, and a statistically significant difference was detected between these two groups (P=0.0000004). However, there was no statistically significant difference of prognosis between the synovial sarcoma group with reduced and that with preserved SMARCB1/INI1 protein expression (P=0.46). Therefore, it was suggested that there is a post-transcriptional SMARCB1/INI1 regulatory mechanism in the tumor cells of synovial sarcoma.
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Proteínas Cromosómicas no Histona/biosíntesis , Proteínas de Unión al ADN/biosíntesis , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patología , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/patología , Factores de Transcripción/biosíntesis , Biomarcadores de Tumor/análisis , Western Blotting , Humanos , Inmunohistoquímica , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína SMARCB1 , Sarcoma Sinovial/mortalidad , Análisis de SupervivenciaRESUMEN
8-Hydroxy-guanine (8-OH-G) mismatches readily with adenine residues, leading to a G : C to T : A transversion mutation. The human mutY homologue (MUTYH) excises adenine misincorporated opposite 8-OH-G during replication and suppresses mutations caused by reactive oxygen species. We defined the expression of 8-hydroxydeoxyguanosine (8-OHdG) and MUTYH in ulcerative colitis (UC)-associated neoplasia by immunohistochemistry and compared this with expression in UC patients without neoplasia and patients unaffected by UC. We also performed mutation analyses for MUTYH and K-ras. 8-OHdG was expressed more intensely in the mucosa of UC-associated neoplasia and UC without neoplasm than in the mucosa unaffected by UC. Immunohistochemistry with two different types of MUTYH antibody showed that UC-associated neoplasia and UC without neoplasia exhibited strong cytoplasmic expression and attenuated nuclear expression of MUTYH when compared with patients unaffected by UC. No pathological MUTYH mutations were detected in any of the UC-associated neoplasia cases. However, K-ras mutation was detected in two cases, one of which showed G : C to T : A transversion mutation and attenuated nuclear staining of MUTYH. In conclusion, inflamed mucosa of UC is exposed to oxidative damage. An increase in cytoplasmic MUTYH, rather than its mutation, may contribute to the promotion of carcinogenesis in UC.
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Colitis Ulcerosa/genética , Neoplasias del Colon/genética , ADN Glicosilasas/genética , Desoxiguanosina/análogos & derivados , Mutación , 8-Hidroxi-2'-Desoxicoguanosina , Anciano , Anciano de 80 o más Años , Núcleo Celular/metabolismo , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/patología , Colon , Neoplasias del Colon/complicaciones , Neoplasias del Colon/patología , Citoplasma/metabolismo , ADN Glicosilasas/análisis , Análisis Mutacional de ADN , Desoxiguanosina/análisis , Desoxiguanosina/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Genes ras , Humanos , Inmunohistoquímica , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Adulto JovenRESUMEN
PURPOSE: Of the various microtubule-associated molecules, beta-tubulin III has been reported to be closely associated with the therapeutic efficacy of taxane-based chemotherapy against ovarian cancer. Stathmin and microtubule-associated protein 4 (MAP4) have been reported to play an important role in microtubule stabilization. In this study, we investigated whether expression of these microtubule-associated factors affects the therapeutic efficacy of taxane-based chemotherapy in ovarian clear cell adenocarcinoma. EXPERIMENTAL DESIGN: Drug sensitivity of paclitaxel or cisplatin was assessed in ovarian cancer cell lines treated with small interfering RNA of tubulin isoforms, MAP4, and stathmin. We examined 94 surgically resected ovarian clear cell adenocarcinoma specimens from patients treated with taxane-containing regimens (n=44) and with taxane-free regimens (n=50), using immunohistochemistry to detect expression of beta-tubulin III, stathmin, and MAP4. RESULTS: Knockdown of beta-tubulin III and IV specifically conferred drug resistance to paclitaxel in one ovarian cancer cell line, but not to other molecules. Estimated overall survival revealed a significant synergistic effect between taxane and beta-tubulin III in patients with ovarian clear cell adenocarcinoma. Of three microtubule-related molecules, among the taxane-based chemotherapy group, cases with higher beta-tubulin III expression were associated with a significantly more favorable prognosis compared with those having lower beta-tubulin III expression. By contrast, there was no statistical significance in the synergistic relationships between stathmin and taxane or between MAP4 and taxane. CONCLUSIONS: Taxane-based chemotherapy was effective for patients with ovarian clear cell adenocarcinomas who were positive for beta-tubulin III but not for those who were negative for these proteins.
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Adenocarcinoma de Células Claras/tratamiento farmacológico , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/uso terapéutico , Tubulina (Proteína)/fisiología , Adenocarcinoma de Células Claras/química , Adenocarcinoma de Células Claras/mortalidad , Adulto , Anciano , Línea Celular Tumoral , Cisplatino/uso terapéutico , Femenino , Humanos , Inmunohistoquímica , Proteínas Asociadas a Microtúbulos/análisis , Persona de Mediana Edad , Neoplasias Ováricas/química , Neoplasias Ováricas/mortalidad , Estatmina/análisis , Tubulina (Proteína)/análisisRESUMEN
We report the case of a patient demonstrating multiple gastric carcinoids with hypergastrinemia. A 50-year-old Japanese woman was admitted to our hospital for the further examination of multiple carcinoids of the stomach with hypergastrinemia, although she was asymptomatic. However, based on our clinical examination, this case seemed to be neither type I nor II carcinoid. We performed a total gastrectomy with D1 lymph node dissection. A pathological examination showed numerous endocrine micronests, hyperplasia of the parietal cells extending to the foveolar neck region, and numerous dilated oxyntic glands filled with eosinophilic secretions. Many parietal cells exhibited vacuolated cytoplasms and apical snouts. Furthermore, the dilated glands at the base of the mucosa had hyperchromatic nuclei and ciliated surfaces. The postoperative serum gastrin level was soon normalized to 47 pg/ml. This is only the third reported case of multiple gastric carcinoids with hypergastrinemia due to an intrinsic abnormality in the acid secretion of the parietal cells.
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Tumor Carcinoide/metabolismo , Gastrinas/biosíntesis , Neoplasias Gástricas/metabolismo , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/patología , Femenino , Gastrectomía , Ácido Gástrico/metabolismo , Gastrinas/sangre , Humanos , Escisión del Ganglio Linfático , Persona de Mediana Edad , Células Parietales Gástricas/patología , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologíaRESUMEN
The expression of chemokine receptor CXCR4 has been associated with poor prognosis and VEGF expression in several kinds of human malignancy. We measured CXCR4 expression levels in soft-tissue sarcoma and compared them with VEGF expression or microvessel density (MVD). We used real-time quantitative PCR to examine the CXCR4 and VEGF expression levels in a total 176 tumors, including 24 intermediate tumors, 24 malignant round-cell tumors (MRCTs) and 128 malignant non-round-cell tumors (MNRCTs). We also assessed their immunohistochemical expression of CXCR4 and VEGF, MVD and proliferative activities, as measured by the MIB-1-labeling index (LI). Furthermore, we evaluated their significance with respect to patient survival rates in MNRCTs, using the Cox regression model. Within the different types of tumor tissue, the expression levels of CXCR4 (p < 0.0001) and VEGF (p < 0.0001) in MNRCTs were significantly higher than those in intermediate tumors or MRCTs. Immunohistochemical expression levels of CXCR4 and VEGF were significantly correlated with their mRNA expression levels (p < 0.0001). Significant positive correlation was found between CXCR4 and VEGF expression in 112 primary MNRCTs (r = 0.434, p < 0.0001). Moreover, both univariate (p < 0.0001) and Cox multivariate analysis (p = 0.0001) revealed that overexpression of CXCR4 was an independent adverse prognostic factor, in addition to high stage according to the American Joint Committee on Cancer and a high MIB-1-LI. Determination of the CXCR4 expression level as a novel marker can provide useful prognostic information for patients and it could be a candidate for molecular targeting therapy in MNRCTs of soft-tissue sarcomas.