RESUMEN
Malignant pericardial effusion is an uncommon metastatic manifestation of ovarian carcinoma. Few cases of ovarian serous carcinoma have been previously reported. Ovarian clear cell carcinoma is the second most common histologic subtype in East Asian countries and is a relatively rare in Western countries. Here, we report the case of cardiac tamponade secondary to Ovarian clear cell carcinoma. A 46-year-old woman with recurrent Ovarian clear cell carcinoma presented with worsening cough, palpitations, and shortness of breath during chemotherapy. Chest radiography and computed tomography confirmed a pleural effusion with cardiac tamponade. The patient underwent pericardial fenestration and drainage for cardiac tamponade. Pericardial fluid cytology showed malignant cells forming papillary and ball-like clusters with irregular stacking. The cells had a mirror ball-like appearance and collagenous stroma, in which a homogenous hyaline core was observed in the center of most tumor cell clusters. Based on these findings, a diagnosis of Ovarian clear cell carcinoma metastasis was made. She received palliative care and died 5 months after the operation without recurrent cardiac tamponade. This case suggests that cytological findings from pericardial effusion are useful in diagnosing Ovarian clear cell carcinoma metastasis.
RESUMEN
BACKGROUND: In 2014, the World Health Organization (WHO) released a classification system introducing neuroendocrine neoplasms (NENs) of the female reproductive tract, excluding the ovaries. This study aimed to evaluate whether retrospective adaption of the gastroenteropancreatic (GEP)-NEN classification is feasible for ovarian NENs (O-NENs) and correlates with prognosis. METHODS: Sixty-eight patients diagnosed with carcinoid, small cell carcinoma (pulmonary type), paraganglioma, non-small/large cell neuroendocrine carcinoma (NEC), mixed NEC, or undifferentiated carcinomas at 20 institutions in Japan were included in this retrospective cross-sectional study. We identified O-NENs through central pathological review using a common slide set, followed by reclassification according to WHO 2010 guidelines for GEP-NENs. A proportional hazards model was used to assess the association of prognostic factors (age, stage, performance status, histology, and residual disease) with overall survival (OS) and progression-free survival (PFS). RESULTS: Of the 68 enrolled patients, 48 were eligible for analysis. All carcinoids (n = 32) were reclassified as NET G1/G2, whereas 14 of 16 carcinomas were reclassified as NEC/mixed adeno-NEC (MANEC) (Fisher's exact test; p < 0.01). The OS/PFS was 49.0/42.5 months and 6.5/3.9 months for NET G1/G2 and NEC/MANEC, respectively. Histology revealed that NEC/MANEC was associated with increased risk of death (HR = 48.0; 95% CI, 3.93-586; p < 0.01) and disease progression (HR = 51.6; 95% CI, 5.54-480; p < 0.01). CONCLUSION: Retrospective adaption of GEP-NEN classification to O-NENs is feasible and correlates well with the prognosis of O-NENs. This classification could be introduced for ovarian tumors.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias Gastrointestinales/clasificación , Tumores Neuroendocrinos/clasificación , Neoplasias Ováricas/sangre , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/diagnóstico , Neoplasias Pancreáticas/clasificación , Guías de Práctica Clínica como Asunto , Anciano , Estudios Transversales , Femenino , Humanos , Japón , Persona de Mediana Edad , Neoplasias Ováricas/mortalidad , Pronóstico , Estudios Retrospectivos , Organización Mundial de la SaludRESUMEN
BACKGROUND/AIM: Treatments for controlling delayed nausea after chemotherapy are inadequate, potentially inciting malnutrition. We sought to determine the incidence of nausea, anorexia, and food intake after chemotherapy. PATIENTS AND METHODS: Subjects were females with gynecological cancers who underwent chemotherapy between 2008 and 2013. Nausea, anorexia, and food intake in the acute (day 1) and delayed phases (days 2 and 3) were retrospectively evaluated. RESULTS: Subjects included 156 females. Chemotherapies were highly (HEC; n=24) and moderately emetogenic (MEC; n=132). There were no significant between-group differences for anorexia control during either the acute or the delayed phase and both groups demonstrated significantly worse control of nausea during the delayed phase. In the HEC group, food intake was significantly reduced on days 2 and 3 compared with day 1. CONCLUSION: Rates of nausea, anorexia, and food intake significantly worsened over time, particularly in the MEC group. Current supportive therapies appear inadequate and should be improved.
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Anorexia/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Ingestión de Alimentos , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Adulto , Anciano , Anorexia/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Neoplasias de los Genitales Femeninos/complicaciones , Neoplasias de los Genitales Femeninos/epidemiología , Neoplasias de los Genitales Femeninos/patología , Humanos , Persona de Mediana Edad , Náusea/inducido químicamente , Náusea/epidemiología , Náusea/patología , Vómitos/inducido químicamente , Vómitos/epidemiología , Vómitos/patologíaRESUMEN
BACKGROUND: There are few studies on serum vascular endothelial growth factors and receptors (VEGF/VEGFRs) in patients with uterine cervical cancer (CC). The aim of this study was to determine whether VEGF/VEGFRs could be used as prognostic biomarkers in patients with CC. METHODS: A total of 107 patients with stage IB to IIB CC, who underwent radical hysterectomy at Tottori University Hospital between 2006 and 2015, were included in this study. Serum samples were collected prior to radical hysterectomy, and levels of VEGF-A, VEGF-C, VEGFR-1, and VEGFR-2 were analyzed by enzyme-linked immunosorbent assays. We evaluated the association between the levels of these angiogenic factors and clinicopathologic variables. Survival analysis of 93 patients treated between 2006 and 2013 was performed. RESULTS: The levels of VEGF-A in patients with bulky tumor, pelvic lymph-node involvement (PLNI), and parametrial infiltration (PI) were significantly higher than those in patients without these factors (P = 0.022, P = 0.020, and P = 0.0013, respectively). The overall survival (OS) of patients with high VEGF-A and VEGFR-2 defined by median levels was significantly lower than the OS of patients with low levels of VEGF-A and VEGFR-2 (P = 0.014, P = 0.012, respectively). Multivariate analysis revealed that PLNI, serum VEGF-A levels, and serum VEGFR-2 levels were independent prognostic factors for OS (hazard ratio for VEGF-A 3.42, 95% CI 1.07-13.2; hazard ratio for VEGFR-2 6.37, 95% CI 1.59-43.5). CONCLUSION: Our results suggest that serum VEGF-A and VEGFR-2 may be promising prognostic biomarkers for CC.
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Biomarcadores de Tumor/sangre , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/mortalidad , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Femenino , Humanos , Ganglios Linfáticos/patología , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Neoplasias del Cuello Uterino/cirugía , Factor C de Crecimiento Endotelial Vascular/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
Bevacizumab (Bev) is an antiangiogenic drug used to treat various malignances, including ovarian cancer (OC). Bev is generally well-tolerated; however, it has a characteristic toxicity profile. In particular, gastrointestinal perforation (GIP) is a rare but serious side effect that can be lethal. A 55-year-old woman with recurrent OC had an episode of GIP during third-line chemotherapy comprising Bev and topotecan (TPT). Bev was discontinued while TPT was continued as monotherapy. Three months after discontinuation of Bev, the patient presented with left lower abdominal pain and was diagnosed with a second GIP. She had emergent surgery. One year later, she is still alive and healthy, and is continuing TPT. This is the first report of recurrent GIP after discontinuation of Bev. Our case suggests that physicians should be aware of GIP even after the discontinuation of Bev.
RESUMEN
OBJECTIVES: The aim of this study was to evaluate the diagnostic significance of high-risk human papillomavirus (hrHPV) testing for managing women with atypical glandular cells (AGC) and to explore the distribution of hrHPV genotypes. METHODS: We analyzed cytologic and histopathologic diagnoses in patients referred to our institution due to AGC or atypical squamous cells of undetermined significance (ASC-US). All patients underwent hrHPV testing and genotyping, and positive (PPV) and negative predictive values (NPV) for cervical intraepithelial neoplasia (CIN) 2 or worse [CIN2+/adenocarcinoma in situ (AIS)+] were calculated. RESULTS: Among 41 cases previously diagnosed with AGC, 22 (53%) were classified as CIN2+ (2 squamous cell carcinomas), whereas only 2 were AIS or adenocarcinoma. Twenty-seven (65.8%) cases in the AGC group were hrHPV positive. The most frequent genotypes in both the ASC-US and AGC groups were HPV16 and HPV52. The PPV of hrHPV testing for CIN2+/AIS+ was significantly higher in the AGC than in the ASC-US group (74.1 vs. 35.0%; p = 0.0005). The NPV for CIN2+/AIS+ was significantly lower in the AGC than in the ASC-US group (74.4 vs. 100%; p = 0.0441). CONCLUSION: In patients with AGC, both glandular and squamous lesions must be monitored. hrHPV testing is useful for detecting CIN2+/AIS+ in AGC.
Asunto(s)
Adenocarcinoma/virología , Células Escamosas Atípicas del Cuello del Útero/virología , Carcinoma de Células Escamosas/virología , ADN Viral/genética , Pruebas de ADN del Papillomavirus Humano , Papillomaviridae/genética , Infecciones por Papillomavirus/virología , Displasia del Cuello del Útero/virología , Neoplasias del Cuello Uterino/virología , Adenocarcinoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Células Escamosas Atípicas del Cuello del Útero/patología , Carcinoma de Células Escamosas/patología , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Prueba de Papanicolaou , Infecciones por Papillomavirus/patología , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Neoplasias del Cuello Uterino/patología , Frotis Vaginal , Adulto Joven , Displasia del Cuello del Útero/patologíaRESUMEN
BACKGROUND: Bevacizumab, which targets vascular endothelial growth factor (VEGF)-A, has recently been proven to be effective for the treatment of epithelial ovarian cancer (EOC). Thus, interest in VEGF-A has increased. There are few reports on concomitant detection of both ligands and its soluble receptors in serum samples, and the significance of serum VEGF-A in EOC is unclear, unlike the situation with tissue samples. We conducted the present study to explore the levels of serum VEGF family and its receptors and to evaluate their utility as prognostic biomarkers. METHODS: A total of 128 patients with EOC, who were consecutively treated at Tottori University Hospital between 2006 and 2012, were included. Blood samples were collected before initial surgery. Serum concentrations of VEGF-A, VEGF-C, VEGFR-1, and VEGFR-2 were analyzed by enzyme-linked immunosorbent assay. We also examined the mRNA and protein expression of VEGF-A in tumor tissue from 30 cases by real-time reverse transcription polymerase chain reaction and immunohistochemistry. RESULTS: The levels of VEGF-A in patients with stage III/IV disease were significantly higher than those with stage I/II disease (P = 0.0036). On the other hand, the level of VEGFR-2 in stage III/IV was significantly lower than that in stage I/II (P = 0.0026). With the cutoff value of VEGF/VEGFRs at the median level, the overall survival (OS) for patients with high VEGF-A levels was significantly lower than those with low levels (P = 0.015). Patients with high VEGFR-2 levels showed better prognosis than those with low VEGFR-2 levels (P = 0.023). Multivariate analysis revealed that International Federation of Gynecology and Obstetrics stage and serum VEGF-A were independent prognostic factors for OS [hazard ratio 2.01, 95% confidence interval (1.13-3.63), P = 0.017]. There was no significant correlation between mRNA or protein expression and serum levels of VEGF-A. CONCLUSIONS: Serum VEGF-A is an independent prognostic factor for OS in patients with EOC, implying that serum VEGF-A is a prognostic biomarker for EOC. Further study to validate the data is needed.
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Biomarcadores de Tumor/sangre , Neoplasias Glandulares y Epiteliales/sangre , Neoplasias Ováricas/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Pronóstico , ARN Mensajero/sangre , ARN Mensajero/genética , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
A new cell line of human ovarian clear cell carcinoma (CCC), TU-OC-2, was established and characterized. The cells were polygonal in shape, grew in monolayers without contact inhibition and were arranged in islands like pieces of a jigsaw puzzle. The chromosome numbers ranged from 41 to 96. A low rate of proliferation was observed and the doubling time was 37.5 h. The IC50 values of cisplatin, 7-ethyl-10-hydroxycamptothecin (SN38), which is an active metabolite of camptothecin, and paclitaxel were 7.7 µM, 17.7 nM and 301 nM, respectively. The drug sensitivity assay indicated that TU-OC-2 was sensitive to SN38, but resistant to cisplatin and paclitaxel. Mutational analysis revealed that TU-OC-2 cells have no mutations of PIK3CA in exons 9 and 20 and of TP53 in exons 4-9. We observed the loss of ARID1A protein expression in TU-OC-2 cells by western blot analysis and in the original tumor tissue by immunohistochemistry. This cell line may be useful for studying the chemoresistant mechanisms of CCC and exploring novel therapeutic targets such as the ARID1A-related signaling pathway.
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Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patología , Línea Celular Tumoral , Eliminación de Gen , Expresión Génica , Proteínas Nucleares/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Factores de Transcripción/genética , Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Camptotecina/farmacología , Cromosomas , Cisplatino/farmacología , Proteínas de Unión al ADN , Resistencia a Antineoplásicos , Femenino , Humanos , Irinotecán , Paclitaxel/farmacología , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
A new cell line of human malignant peritoneal mesothelioma (MPM), TU-MM-1, was established and characterized. The cells showed polygonal morphology, grew in monolayers without contact inhibition and were arranged like a jigsaw puzzle. The chromosome numbers ranged from 41 to 44. A low rate of proliferation was observed and the doubling time was 67.9 h. Genomic DNA sequencing revealed that TU-MM-1 cells harbored missense mutations in APC, LATS2, BRCA1/2, and TP53, and mutation of a splice donor site in BAP1 and loss of CDKN2A gene. We observed the absence of BAP1 and p16(INK4a) proteins, underexpression of LATS2 protein, and overexpression of p53 protein in TU-MM-1 cells in western blot analysis. Heterotransplantation to nude mice produced tumors that had the characteristics of the original tumor. This cell line may be useful for studying biological properties and contribute to novel treatment strategies.
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Análisis Mutacional de ADN/métodos , Genoma Humano/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Neoplasias Peritoneales/genética , Análisis de Secuencia de ADN/métodos , Proteína de la Poliposis Adenomatosa del Colon/genética , Animales , Proteína BRCA1/genética , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Neoplasias Pulmonares/patología , Mesotelioma/patología , Mesotelioma Maligno , Ratones Endogámicos BALB C , Mutación , Trasplante de Neoplasias , Neoplasias Peritoneales/patología , Proteínas Serina-Treonina Quinasas/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
OBJECTIVE: To assess the relationship between pre- and postoperative high-risk human papillomavirus (hrHPV) genotypes and hrHPV type-specific persistence and reappearance of abnormal cytology after successful conization. METHODS: A retrospective analysis was performed of 211 patients who were undergoing conization after hrHPV genotype testing at Tottori University Hospital between July 2009 and June 2013. Of the 211 women, 129 underwent pre- and postoperative hrHPV genotype testing and were diagnosed with cervical intraepithelial neoplasia (CIN) grades 1-3 with negative margins. RESULTS: The postoperative pathological diagnosis was CIN 1 in 8 patients, CIN 2 in 12, CIN 3 in 108 and adenocarcinoma in situ in 1 patient. Before conization, the most frequent hrHPV genotypes were HPV16 (n = 52; 40.3 %), followed by HPV52 (n = 32; 24.8 %) and HPV58 (n = 28; 21.7 %), while HPV18 was detected in 6 cases (4.7 %). Of the 23 postoperative hrHPV-positive cases, the same genotypes were detected in 10 cases while a different genotype was detected in 11 cases; type did not affect the frequency of persistent postoperative infection. The 3-year cumulative risk for the reappearance of abnormal cytology was significantly higher in postoperative hrHPV-positive patients than in postoperative hrHPV-negative patients (31.6 vs 9.7 %, P = 0.0014). A high-grade squamous intraepithelial lesion (HSIL) was observed during the follow-up period in one patient with persistent HPV16 infection. CONCLUSIONS: Postoperative hrHPV infection was a significant positive predictor for the reappearance of abnormal cytology and HPV16 infection-induced HSIL after treatment. Therefore, our study suggests that hrHPV genotype testing may be useful to follow-up CIN patients.
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Adenocarcinoma in Situ/virología , ADN Viral/análisis , Recurrencia Local de Neoplasia/virología , Papillomaviridae/genética , Infecciones por Papillomavirus/virología , Lesiones Intraepiteliales Escamosas de Cuello Uterino/virología , Displasia del Cuello del Útero/virología , Neoplasias del Cuello Uterino/virología , Adenocarcinoma in Situ/cirugía , Adolescente , Adulto , Anciano , Conización , Femenino , Genotipo , Papillomavirus Humano 16/aislamiento & purificación , Papillomavirus Humano 18/aislamiento & purificación , Humanos , Persona de Mediana Edad , Papillomaviridae/aislamiento & purificación , Papillomaviridae/fisiología , Infecciones por Papillomavirus/complicaciones , Estudios Retrospectivos , Neoplasias del Cuello Uterino/cirugía , Frotis Vaginal , Activación Viral , Adulto Joven , Displasia del Cuello del Útero/cirugíaRESUMEN
BACKGROUND: It is unclear whether the incidence of febrile seizure (FS) in children with Down syndrome (DS) is higher or lower than in the general population. In this study, we investigated the incidence of FS in DS patients using mailed questionnaires. METHODS: The questionnaires were distributed to parents or caregivers of DS patients attending Osaka Medical College Hospital and six other facilities. The questionnaires were returned by mail from February 2012 to September 2013 from 323 families of DS patients (176 male, 147 female; age range, 3 months-47 years; median age, 5.0 years). To assess the incidence of FS in DS, we performed the following two analyses: (i) we calculated the incidence of FS among DS patients between the ages of 4 and 20 years (n = 199; 113 male, 86 female), and (ii) we extracted families with both DS and healthy siblings between the ages of 4 and 20 years (n = 150; 77 male, 73 female) and compared the incidence of FS in these sibling groups. RESULTS: Five DS patients had a past history of FS. The incidence of FS in DS was 2.5%. The incidence of FS was significantly lower in DS patients compared with healthy siblings (P < 0.003; OR, 0.14). CONCLUSION: The incidence of FS is lower in DS patients than in the general population.
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Síndrome de Down/complicaciones , Convulsiones Febriles/epidemiología , Encuestas y Cuestionarios , Adolescente , Adulto , Niño , Preescolar , Síndrome de Down/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Japón/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Convulsiones Febriles/complicaciones , Hermanos , Adulto JovenRESUMEN
Patients with clear cell carcinoma of the ovary (OCCC) have poor survival due to resistance to standard chemotherapy. OCCC has frequent activating mutations of the PIK3CA gene. The present study was conducted to clarify the efficacy of the inhibition of the PI3K-AKT-mTOR pathway in OCCC. We used 8 OCCC cell lines and 5 ovarian serous adenocarcinoma (OSAC) cell lines. The mutation status of the PIK3CA and KRAS genes was examined by direct sequencing. The IC50 values of NVP-BEZ235 (BEZ235) and temsirolimus were determined by WST-8 assay. Protein expression levels of PI3K-AKT-mTOR pathway molecules were examined by western blotting. Cell cycle distribution was analyzed by flow cytometry. Annexin V staining was used for detecting apoptosis. We also investigated the effects of BEZ235 on OCCC tumor growth in a nude mouse xenograft model. Four of the 8 OCCC cell lines showed a PIK3CA mutation while none of the 5 OSAC cell lines showed a mutation. The IC50 values of BEZ235 for the OCCC cell lines were lower than these values for the OSAC cell lines. The IC50 value of temsirolimus was higher than BEZ235 in the OCCC cell lines. The PIK3CA mutation was more frequently noted in OCCC than OSAC cells, but the sensitivity of these cell lines to BEZ235 or temsirolimus was not related to the mutation status. pHER3 and pAkt proteins were expressed more frequently in OCCC compared with OSAC. However, protein expression levels were distributed widely, and were not related to the sensitivity. Treatment with BEZ235 suppressed expression of pAkt, although treatment with temsirolimus did not. OCCC cells exhibited G1 phase arrest after treatment with BEZ235 and apoptosis with a higher concentration of the agent. BEZ235 significantly inhibited tumor growth in mice bearing OVISE and TU-OC-1 cell tumors. The present study indicated that the PI3K-AKT-mTOR pathway is a potential target for OCCC, and that BEZ235 warrants investigation as a therapeutic agent.
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Adenocarcinoma de Células Claras/patología , Imidazoles/farmacología , Neoplasias Ováricas/patología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Quinolinas/farmacología , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adenocarcinoma de Células Claras/tratamiento farmacológico , Animales , Línea Celular Tumoral , Cistadenoma Seroso/tratamiento farmacológico , Cistadenoma Seroso/patología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , Neoplasias Experimentales , Neoplasias Ováricas/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Toriello-Carey syndrome is rare condition characterized by agenesis of the corpus callosum, the Pierre Robin sequence, and facial anomalies such as telecanthus, short palpebral fissures, and a small nose with anteverted nares [Toriello and Carey, 1988]. In addition, tracheal and laryngeal anomalies are common complications in patients with Toriello-Carey syndrome, and these anomalies can lead to death [Kataoka et al., 2003]. Congenital tracheal stenosis is a life-threatening condition with high mortality. Even if surgery is successful, several serious complications can result in a high risk of mortality. We describe a case of a Japanese boy with Toriello-Carey syndrome who had severe congenital tracheal stenosis, in whom surgical tracheal plasty was avoided because of adequate respiratory care, allowing the patient to be alive at 18 months of age.
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Agenesia del Cuerpo Calloso/diagnóstico , Constricción Patológica/diagnóstico , Anomalías Craneofaciales/diagnóstico , Cardiopatías Congénitas/diagnóstico , Deformidades Congénitas de las Extremidades/diagnóstico , Síndrome de Pierre Robin/diagnóstico , Tráquea/anomalías , Anomalías Urogenitales/diagnóstico , Encéfalo/patología , Facies , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Fenotipo , Síndrome , Tomografía Computarizada por Rayos XRESUMEN
A new cell line of human ovarian clear cell adenocarcinoma (CCC), TU-OC-1, was established and characterized. The cells showed a polygonal-shaped morphology and grew in monolayers without contact inhibition and were arranged like a jigsaw puzzle. The chromosome numbers ranged from 64 to 90. A low rate of proliferation was observed, similar to other CCC cell lines tested (OVTOKO, RMG-I, and OVAS), and the doubling time was 38.4 h. The respective IC50 values of cisplatin and paclitaxel were 12.2 µM and 58.3 nM. Mutational analysis revealed that TU-OC-1 cells harbored a PIK3CA mutation at codon 542 (E542K) in exon 9, which is a mutation hot spot on this gene. We observed that phosphorylated Akt protein was overexpressed in TU-OC-1 cells by western blot analysis. Heterotransplantation to nude mice produced tumors that reflected the original. This cell line may be useful to study the chemoresistant mechanisms of CCC and contribute to novel treatment strategies.
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Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patología , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Fosfatidilinositol 3-Quinasas/genética , Anciano , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Fosfatidilinositol 3-Quinasa Clase I , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Trasplante HeterólogoRESUMEN
OBJECTIVE: This study was aimed to elucidate the roles of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3K)/Akt pathways in regulating cytotoxicity induced by cisplatin (CDDP) in ovarian carcinoma cells. METHODS: We treated 7 ovarian cancer cell lines with CDDP alone or with CDDP and either a PI3K inhibitor (LY294002), a MEK inhibitor (PD98059), or a MEK/ERK activator (phorbol 12-myristate 13-acetate [PMA]) and assessed cell viability, expression of MEK/ERK and PI3K/Akt, cell cycle distribution, and apoptosis. We also investigated the effect of combination treatment on survival in a xenograft model. RESULTS: The cell lines showed half-maximal inhibitory concentrations (IC50) of CDDP from 2.4 to 26.9 µmol/L. KFr, a CDDP-resistant cell line developed from KF cells, showed an IC50 of CDDP of 9.6 µmol/L. Five of the cell lines with IC50 values of 9.6 µmol/L or greater were defined as CDDP-resistant. Cisplatin and LY294002 had an additive effect on inhibiting cell growth, and CDDP and PD98059 had and antagonistic effect on cell growth in all cell lines. In CDDP-resistant cells, CDDP and PMA dramatically suppressed the cell growth, up-regulated the expression of phosphorylated ERK and cleaved caspase-9, down-regulated the expression of checkpoint kinases, and increased the proportion of cells in the synthesis-phase fraction and apoptotic cells. The treatment of nude mice with CDDP and PMA prolonged survival in an ovarian cancer xenograft model. CONCLUSIONS: The present study indicates that further study is warranted to determine the effectiveness of combination treatment with CDDP and PMA for platinum-resistant ovarian carcinoma.
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Adenocarcinoma/tratamiento farmacológico , Cromonas/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Flavonoides/uso terapéutico , Morfolinas/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Acetato de Tetradecanoilforbol/análogos & derivados , Animales , Antineoplásicos/uso terapéutico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Cromonas/farmacología , Cisplatino/uso terapéutico , Sinergismo Farmacológico , Femenino , Flavonoides/farmacología , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Desnudos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Morfolinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fase S/efectos de los fármacos , Acetato de Tetradecanoilforbol/farmacología , Acetato de Tetradecanoilforbol/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A new line of human ovarian serous adenocarcinoma cells, TU-OS-4, was established and characterized. The cells showed a short, spindle-shaped morphology and grew in monolayers without contact inhibition while forming an arrangement resembling a jigsaw puzzle. Chromosome numbers ranged from 55 to 73. The proliferation rate was lower than other serous adenocarcinoma cell lines tested (KF, SHIN-3, and SK-OV-3), and the doubling time was 53.3 h. Western blot analysis showed that TU-OS-4 cells overexpressed epidermal growth factor receptor, human epidermal growth factor receptor (HER) 2, and phosphorylated HER2 protein. The IC(50) values to cisplatin, paclitaxel, and lapatinib were 25.8 µM, 686 nM, and 183 nM, respectively. Heterotransplantation in nude mice reflected the original tumor of the cells. These results suggested that this cell line would be useful to study chemoresistant mechanisms and contribute to establishing novel treatment strategies for patients with ovarian cancer.
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Antineoplásicos/farmacología , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Técnicas Citológicas/métodos , Receptores ErbB/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Receptor ErbB-2/metabolismo , Anciano , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Receptores ErbB/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lapatinib , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Quinazolinas/farmacología , Receptor ErbB-2/genética , Transducción de Señal/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: The mTOR pathway is thought to be a central regulator of proliferation and survival of cells. Rapamycin and its analogs are undergoing clinical trials in patients with epithelial ovarian cancer. This study aimed to assess the potential to use rapamycin and anticancer agents in combination for first- and second-line chemotherapy to treat ovarian cancer. EXPERIMENTAL DESIGN: We used six ovarian serous adenocarcinoma cell lines (KF, KOC-2S, SHIN-3, SK-OV-3, TU-OS-3, and TU-OS-4) in this study. We treated the cells with rapamycin and anticancer agents, then assessed cell viability, apoptosis, and the expression of protein in apoptotic pathways and molecules downstream of the mTOR signaling pathways. We also investigated the effect of these drug combinations on survival in nude mouse xenograft models. RESULTS: Synergistic effects were observed in five cell lines from the combination of etoposide and rapamycin. However, we observed antagonistic effects when rapamycin was combined with gemcitabine, cisplatin, or paclitaxel on more than two cell lines. Rapamycin dramatically enhanced apoptosis induced by etoposide and the expression of cleaved caspase 9. This effect was associated with upregulation of phosphorylated c-Jun and downregulation of Bcl-xL. The synergistic interaction of rapamycin and etoposide was lower when the c-Jun pathway was suppressed by a c-Jun N-terminal kinase inhibitor (SP600125). Finally, treating nude mice with rapamycin and etoposide significantly prolonged survival in the model mice with ovarian cancer xenografts. CONCLUSIONS: Chemotherapy with rapamycin and etoposide combined is worth exploring as a treatment modality for women with epithelial ovarian cancer.
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Antineoplásicos/farmacología , Etopósido/farmacología , Neoplasias Ováricas/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Proteínas Proto-Oncogénicas c-jun/genética , Transducción de Señal/genética , Sirolimus/farmacología , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We established an extensive and rapid system using suspension array to detect 61 representative mitochondrial DNA (mtDNA) heteroplasmic or homoplasmic point mutations (29 for Series A and 32 for Series B) in 22 genes: 1 each in MT-RNR1, -TV, -ND1, -TQ, -TW, -TC, and -TH genes; 2 each in MT-TN, -TG, -ND4, -TL2, -TE, and -CYB genes; 3 each in MT-ATP6, -ND3, and -ND5 genes; 4 each in MT-CO1 and -TK genes; 5 each in MT-TI, -TS1, and -ND6 genes; and 10 in the MT-TL1 gene. We carefully selected 5'-biotinylated primers and pooled primers for use in two sets of multiplex-PCR amplifications. To detect both mutant and wild-type mtDNA, even when polymorphisms were present near the target mutation sites, we designed specific oligonucleotide probes. By using the mtDNA point mutation detection system of Series A (29 mutations) and Series B (32 mutations), we screened a total of 3103 mutant sites in 107 DNA samples for Series A and 13,101 mutant sites in 397 DNA samples for Series B. We succeeded in determining 99.4% (Series A) and 99.6% (Series B) of the targeted mutant sites by use of the system. The 22 samples with the m.3243A>G heteroplasmic mutation revealed positive signals with both mutant- and wild-type-specific probes in this detection system with a detection limit of approximately 2%. This genetic screening platform is useful to reach a definitive diagnosis for mitochondrial diseases.
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ADN Mitocondrial/genética , Pruebas Genéticas/métodos , Mutación Puntual , Reacción en Cadena de la Polimerasa/métodos , Cartilla de ADN/genética , Humanos , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: Preoperative and intraoperative assessments of myometrial invasion (MI) are commonly used for planning surgical procedures such as dissection of the para-aortic node; however, the assessments often differ from the final diagnosis determined by pathological examination. The present study evaluated the accuracy of preoperative and intraoperative assessments of MI. METHODS: A total of 191 patients with endometrial cancer, who underwent hysterectomy from 1995 to 2007 in Tottori University Hospital, were included in this study. One hundred seventy-four patients underwent endometrial curettage or Pipelle biopsy preoperatively. Histological grade was compared between preoperation and postoperation. Magnetic resonance imaging (MRI) was performed before surgery, and the depth of MI was assessed as 3 levels (no MI, <50%, and >50%). During surgery, the uterine wall was incised at the most invasive part, and then, intraoperative gross assessment was evaluated as less than or greater than 50%. RESULTS: Histological evaluation revealed that 34 patients had no invasion, 97 had less than 50% MI, and 60 had greater than 50% MI. On MRI assessment, 135 patients had correct diagnoses, and the accuracy was 70.7%. Regarding the diagnosis of greater than 50% MI depth, the accuracy, the sensitivity, and the specificity of the MRI assessment were 83.2%, 75.0%, and 85.7%, respectively. Seventeen patients were overestimated, and 15 patients were underestimated by the MRI assessment. On intraoperative gross assessment, 162 patients had correct diagnoses, 8 patients were overestimated, and the remaining 21 patients were underestimated. The accuracy of the gross assessment was 84.8%, the sensitivity was 65.0%, and the specificity was 93.9%. The preoperative grading accuracy was 71.8% (125/174). A discrepancy between preoperative and postoperative grades was more frequent in a low-grade tumor. The incidence of underdiagnosis was significantly higher in patients with a grade 3 (G3) tumor than in those with a G1 or G2 tumor in both assessments. CONCLUSIONS: The present study suggests that gross assessment may be useful to determine MI of less than 50%, although patients with a G3 tumor were more frequently underestimated.
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Neoplasias Endometriales/patología , Miometrio/patología , Adenocarcinoma de Células Claras/patología , Adenocarcinoma de Células Claras/cirugía , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Adenoescamoso/patología , Carcinoma Adenoescamoso/cirugía , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/cirugía , Neoplasias Endometriales/cirugía , Femenino , Humanos , Histerectomía , Cuidados Intraoperatorios , Imagen por Resonancia Magnética , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Cuidados Preoperatorios , PronósticoRESUMEN
Resistance of ovarian mucinous adenocarcinoma to standard chemotherapy with paclitaxel and carboplatin is associated with poor prognosis, and an effective treatment is needed. The present study aimed to identify an effective chemotherapy for ovarian mucinous adenocarcinoma. Five human ovarian mucinous adenocarcinoma cell lines (MN-1, OMC-1, RMUG-L, RMUG-S, TU-OM-1) were used in this study. Sensitivity of the cells to the anticancer agents was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and we assessed drug sensitivity by calculating the assay area under the curve for each agent. Protein expression was confirmed by Western blot analysis. We also examined the efficacy of combination chemotherapy on survival in a xenograft model of nude mice. The IC(50) to anticancer agents ranged widely. The assay area under the curve indicated that two of five cell lines (MN-1, TU-OM-1) were sensitive to oxaliplatin, 5-fluorouracil and etoposide, and only one (TU-OM-1) was sensitive to 7-ethyl-10-hydroxycamptothecin, which is an active metabolite of camptothecin. All cell lines were resistant to cisplatin and paclitaxel. The combination of oxaliplatin and 5-fluorouracil resulted in additive or synergistic effects on all cell lines. The combination of oxaliplatin and 5-fluorouracil significantly prolonged survival in a ovarian mucinous adenocarcinoma xenograft model of nude mice. Protein expression levels of the excision repair cross-complementation group 1 were lower in oxaliplatin sensitive cell lines. Exposure to 5-fluorouracil down-regulated cross-complementation group 1 expression in ovarian mucinous adenocarcinoma cells. We conclude that combination chemotherapy consisting of oxaliplatin and 5-fluorouracil was an effective treatment for ovarian mucinous adenocarcinoma and may be a pivotal candidate for a novel treatment strategy.