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OBJECTIVE: The clinical significance of lymphocyte infiltration (LI) at the invasive front in endometrial carcinomas (EC) has not been determined. The aim of the current study was to evaluate the association between zone formation of LI at the invasive front of the tumor margin and prognoses of the patients with EC. METHODS: All available pathological slides of the enrolled cases were reviewed, and the degree of LI at the invasive front was categorized into 2 groups: strong LI and weak LI. Clinical significance of LI was evaluated retrospectively. RESULTS: A total of 333 cases with EC were enrolled in the study: 225 cases with weak LI and 108 cases with strong LI. Weak LI was more frequently observed in the patients with grade1/2 endometrioid EC. Multivariate analyses for progression-free survival (PFS) and overall survival (OS) revealed that weak LI was identified as an independent worse prognostic factor for OS (p = 0.004) in addition to PFS (p = 0.022). CONCLUSION: Weak LI at the invasive front of the tumor margin was associated with worse prognoses in EC. Although further studies are needed, it is suggested that LI could be a biomarker of prognoses in EC.
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Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Linfócitos do Interstício Tumoral/patologia , Biomarcadores Tumorais/imunologia , Carcinoma Endometrioide/imunologia , Neoplasias do Endométrio/imunologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos RetrospectivosRESUMO
OBJECTIVE: The pretreatment neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) have been reported to be useful as markers for prognostic factors and metastasis in several cancers. The aim of this study was to identify the predictor of lymph node (LN) metastasis by pretreatment NLR and PLR in patients with endometrial cancer. METHODS: Medical charts of the patients with endometrial cancers that received primary surgery at our hospital between 2007 and 2013 were retrospectively analyzed. The cutoff value was calculated from the receiver operating characteristics (ROC) curve. Clinicopathological parameters including inflammatory markers were evaluated for LN metastasis using multiple logistic regression analysis. RESULTS: Among 197 patients enrolled in the study, LN metastasis was observed in 25 patients (13%). ROC curves demonstrated that the best cutoff value of NLR for predicting LN metastasis was 2.18 and that of PLR was 206. In univariate analysis, several pathological factors, NLR, and PLR were identified as predictors of LN metastasis. In multiple logistic regression analysis, lymphovascular invasion and NLR were found to be significantly correlated with LN metastasis (p = 0.002, 0.039). CONCLUSION: A higher pretreatment NLR was identified as a predictor of LN metastasis in endometrial cancers. Although further study is needed to confirm the results, NLR could be a candidate clinical marker for detection of LN metastasis.
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Biomarcadores Tumorais/sangue , Neoplasias do Endométrio/sangue , Neutrófilos/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Endométrio/cirurgia , Feminino , Humanos , Modelos Logísticos , Metástase Linfática , Contagem de Linfócitos , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Retrospectivos , Análise de SobrevidaRESUMO
OBJECTIVE: Most of the endometrial carcinomas are detected in early stages and have a better prognosis; however, predictive factors for recurrence have not been determined. METHODS: Patients with grade 1 endometrioid carcinoma (EG1) according to the 2014 WHO criteria at FIGO 2009 stage IA that were identified through scanning medical charts were included, and we assessed whether the presence of uterine serous carcinoma (SC) component which comprised less than 5% of the total volume using the ovarian two-tiered grading system could be a recurrent risk factor in these patients. RESULTS: Among 126 cases which met inclusion criteria, 12 cases had SC. SC tumors were divided into 2 groups: SC resembling high-grade serous carcinoma (HGSC) and SC resembling low-grade serous carcinoma (LGSC). Five (3.9%) cases had HGSC and 7 (5.6%) cases had LGSC. Recurrence was observed in 3 of all cases (2.3%): 2 cases with HGSC, and 1 case with LGSC. Regarding several clinicopathological factors, only the presence of SC was associated with recurrence. The sensitivity and specificity to predict recurrence using this system were 100 and 93%, respectively. CONCLUSION: The identification of SC using the ovarian two-tiered grading system could be an accurate predictor of recurrence in stage IA EG1.
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Antígeno Ca-125/sangue , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/patologia , Recidiva Local de Neoplasia/sangue , Proteína Supressora de Tumor p53/sangue , Adulto , Idoso , Biomarcadores Tumorais/sangue , Cistadenocarcinoma Seroso/sangue , Neoplasias do Endométrio/sangue , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Valor Preditivo dos Testes , PrognósticoRESUMO
Development and homeostasis of multicellular organisms require interactions between neighbouring cells. We recently established an in vitro model of cell-cell interaction based on a collagen vitrigel membrane. We have now examined the role of neural cells in retinal homeostasis by coculture of human retinal pigment epithelial (RPE) cells and neural cells on opposite sides of such a membrane. The neural cells (differentiated PC12 cells) induced up-regulation of semaphorin 4A (Sema4A), a member of the semaphorin family of neural guidance proteins, in RPE (ARPE19) cells. This effect of the neural cells was mimicked by the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and was abolished by the PACAP antagonist PACAP(6-38). Coculture with neural cells or stimulation with PACAP also induced the phosphorylation of extracellular-signal-regulated kinase in ARPE19 cells, and this effect of the neural cells was inhibited by PACAP(6-38). Finally, among various cytokines examined, only the amount of interleukin-6 released by cocultures of ARPE19 and neural cells differed from that released by ARPE19 cells cultured alone. Interleukin-6 was not detected in culture supernatants of neural cells, and the reduction in the amount of interleukin-6 released by the cocultures compared with that released by ARPE19 cells alone was prevented by PACAP(6-38). Our findings suggest that PACAP released from retinal neural cells (photoreceptors or optic nerve cells) may regulate Sema4A expression in RPE cells and thereby contribute to the maintenance of retinal structure and function. Development and homeostasis of multicellular organisms require interactions between neighbouring cells. With the use of a coculture system based on a collagen vitrigel membrane, we have now shown that neural cells induce up-regulation of the neural guidance protein Sema4A in RPE cells. This effect of neural cells appears to be mediated by the neuropeptide PACAP. PACAP released from retinal neural cells (photoreceptors or optic nerve cells) may thus regulate Sema4A expression in RPE cells and thereby contribute to the maintenance of retinal structure and function.
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Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Retina/citologia , Semaforinas/genética , Regulação para Cima , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura/métodos , Citocinas/metabolismo , Regulação para Baixo , Células Epiteliais/efeitos dos fármacos , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Modelos Biológicos , Nervo Óptico/citologia , Nervo Óptico/metabolismo , Células Fotorreceptoras/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Ratos , Retina/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: The incidence of glaucoma increases with age, as does age-related macular degeneration (AMD), with the reported incidence of glaucoma among AMD subjects being 5.4 %. Optical coherence tomography (OCT) can detect glaucomatous changes in the inner retina with high sensitivity. The purpose of this study was to compare ganglion cell complex (GCC) parameters and the thickness of the peripapillary retinal nerve fiber layer (RNFL) in normal eyes to that observed in eyes with age-related macular degeneration (AMD) and eyes with both AMD and glaucoma. METHODS: The GCC components [GCC thickness, focal loss volume (FLV), and global loss volume (GLV)] and peripapillary RNFL thickness were measured using RTVue spectral-domain OCT (SD-OCT). The GCC and RNFL parameters of normal eyes, AMD eyes treated with different types of therapy, and AMD eyes with and without glaucoma were evaluated using nonparametric tests. Univariate and multivariate analyses were used to determine whether the GCC and RNFL parameters could be used to differentiate AMD eyes with glaucoma from those without glaucoma. RESULTS: Seventy-one normal eyes, 120 eyes with AMD, and 23 eyes with AMD and glaucoma were studied. The values of all GCC components were significantly different in the normal eyes from those observed in the eyes with AMD, except for the RNFL thicknesses. The GCC and RNFL parameters were not significantly different between the eyes receiving different types of therapy among the AMD groups. The RNFL thickness was significantly correlated with glaucoma diagnosis in AMD eyes. CONCLUSIONS: These findings indicate that there is damage to the inner retinal layers in eyes with AMD. The RNFL thickness can be a useful parameter for differentiating eyes with AMD from eyes with both AMD and glaucoma.
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Glaucoma/diagnóstico , Fibras Nervosas/patologia , Células Ganglionares da Retina/patologia , Degeneração Macular Exsudativa/diagnóstico , Idoso , Inibidores da Angiogênese/uso terapêutico , Exsudatos e Transudatos , Feminino , Angiofluoresceinografia , Humanos , Pressão Intraocular , Masculino , Fotoquimioterapia , Tomografia de Coerência Óptica , Tonometria Ocular , Acuidade Visual/fisiologia , Degeneração Macular Exsudativa/tratamento farmacológicoRESUMO
OBJECTIVE: Although treatment for recurrent epithelial ovarian, tubal, and peritoneal cancers is usually not curative and intends to be palliative, a certain significance of secondary cytoreductive surgery (SCS) for recurrent tumor has been reported; still, there are limitations in this strategy including difficulty in predicting successful complete resection and selecting good candidates. The purpose of this study was to explore the potential survival benefit of SCS in patients with recurrent epithelial ovarian, tubal, and peritoneal cancers. METHODS: Among all patients who underwent primary therapy for epithelial ovarian, tubal, and peritoneal cancers between 1994 and 2006 at our institute, medical records of patients who were submitted to SCS for recurrence following complete remission after primary therapy were retrospectively investigated. Kaplan-Meier method and log-rank test were used for survival analysis, and Cox proportional hazard regression model was used for quantifying the relations between survival and covariates. RESULTS: Thirty-four patients met the inclusion criteria. Complete resection of all visible tumors at SCS was achieved in 24 of patients (75%). Median postrecurrence survival was 60 months. On univariate analysis, solitary recurrence, disease-free interval, CA125 value at recurrence, and complete resection were significant prognostic factors on postrecurrence survival; whereas on multivariate analysis, CA125 value at recurrence and complete resection were independent prognostic factors. In addition, a comparison according to the initial method that detected recurrence revealed that patients whose recurrence was detected with CA125 elevations had significantly worse postrecurrence survival than those detected with routine examinations including image scans (P = 0.021). CONCLUSIONS: In the present study, the impact of SCS on the significant survival benefit was identified for patients with low CA125 value at recurrence as well as with complete resection. Although further analyses are needed, patients whose recurrence was diagnosed by routine examinations without CA125 elevation might be better candidates for SCS.
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Neoplasias das Tubas Uterinas/cirurgia , Recidiva Local de Neoplasia/cirurgia , Neoplasias Epiteliais e Glandulares/cirurgia , Neoplasias Ovarianas/cirurgia , Neoplasias Peritoneais/cirurgia , Idoso , Antígeno Ca-125/sangue , Neoplasias das Tubas Uterinas/sangue , Feminino , Humanos , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Ovarianas/sangue , Neoplasias Peritoneais/sangue , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Among the 161 cases of pT1 ovarian cancer treated at our hospital during the last 25 years, the impact of systematic lymphadenectomy was evaluated in 93 cases of the pT1N0M0 group(N0 group), 59 cases of the pT1NxM0(Nx group), and 9 cases of the pT1N1M0(N1 group). Significantly greater relapse-free survival(RFS)and overall survival(OS)were observed in 108 cases of the N0+N1 group compared to the Nx group(p=0. 006, p=0. 02). Multivariate analysis showed that systematic lymphadenectomy was a significant prognostic factor(hazard ratio 0. 473(95%CI, 0. 235-0. 951; p=0. 036). The present study suggested the systematic lymphadenectomy had a significant therapeutic effect on pT1 stage ovarian cancers.
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Excisão de Linfonodo , Neoplasias Epiteliais e Glandulares/cirurgia , Neoplasias Ovarianas/cirurgia , Adolescente , Adulto , Idoso , Carcinoma Epitelial do Ovário , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
The aim of this study is to investigate p16INK4a expression by immunocytochemistry for ascites in advanced ovarian cancer and explore the possibility to predict chemotherapeutic response and prognosis. The immunocytochemical study was performed on cytology of ascites obtained from 37 Stage III or Stage IV ovarian cancer patients with measurable disease before platinum/taxane-based first-line chemotherapy following primary cytoreductive surgery or as neoadjuvant chemotherapy. Twenty-one of 21 (100%) responders and 6 of 16 (44%) nonresponders showed p16INK4a immunopositivity (p < 0.001). Immunopositivity was frequently observed in serous adenocarciomas (17 of 18, 94%). Overall survival was significantly better in immunopositive cases compared with immunonegative cases (p = 0.0006). For subcellular localization, cytoplasm was diffusely positive in immunopositive cases (n = 27), 12 of which showed stronger nuclear immunostaining and demonstrated superior overall survival. In vitro expression of p16INK4a protein was also examined for both parent chemosensitive and acquired chemoresistant ovarian cancer cell lines. Chemosensitive KF28 parent cells showed stronger nuclear staining compared with chemoresistant KFr13Tx cells showing stronger cytoplasmic staining by immunocytochemistry, which were also confirmed by western blotting. Our data suggest that p16INK4a expression in cytology of ascites is a candidate marker in prediction of the primary response to chemotherapy and prognosis.
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Antineoplásicos/uso terapêutico , Ascite/patologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , PrognósticoRESUMO
BACKGROUND: To investigate the effects of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28, *6 and *27 in patients with gynecologic cancer who received chemotherapy with irinotecan and cisplatin. METHODS: Patients eligible for this study had cervical or ovarian cancer treated with chemotherapy; a course of the regimen consisted of 60 mg/m(2) of irinotecan on days 1, 8 and 15, and 60 mg/m(2) of cisplatin on day 1 every 4 weeks. UGT1A1 polymorphisms and toxicities were analyzed. RESULTS: From March 2007 to December 2007, 30 Japanese patients were enrolled; 24 ovarian carcinoma patients and 6 cervical cancer patients. The following genotypes of UGT1A1 were found: wild type in 17 patients (57%), *28 in 4 patients (13%), *6 in 8 patients (27%), *28*6 in 1 case (3%) and no case of *27 (0%). Grade 3/4 neutropenia, thrombocytopenia and diarrhea were significantly more frequent in *6 patients compared with wild-type patients. Also, in *6 patients irinotecan administration on days 8 or 15 was significantly more often omitted due to toxicities. In patients with *28 or *28*6, side effects were similar to those in patients with *6. CONCLUSION: In addition to UGT1A1*28, UGT1A1*6 might also be a key candidate to determine the dose of combination chemotherapy with irinotecan and cisplatin.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glucuronosiltransferase/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cisplatino/administração & dosagem , Feminino , Genótipo , Humanos , Irinotecano , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Polimorfismo Genético , Prognóstico , Estudos Prospectivos , Fatores de Risco , Resultado do Tratamento , Neoplasias do Colo do Útero/patologia , Adulto JovemRESUMO
Pure-type clear cell carcinoma (CCC) has been recognized as a distinct subtype of ovarian cancer, showing a resistance to chemotherapy and resulting in poor prognosis. Our aim was to evaluate the effects of complete surgical procedures followed by adjuvant chemotherapy for CCC patients whose tumors were confined to the ovary (pT1M0). During the period of 1987-2005, 56 patients with stage I CCC were identified and two cases were excluded due to retroperitoneal lymph node metastasis. A total of 54 patients were enrolled in the study and divided into two groups: Group A (n=38, 1993-2005) underwent complete surgical staging including pelvic and para-aortic lymphadenectomy. Group B (n=16, 1987-1992) underwent a hysterectomy, bilateral salpingo-oopherectomy, omentectomy without comprehensive lymphadenectomy. Every patient received six courses of adjuvant chemotherapy using a platinum agent. Survival analysis was estimated by the Kaplan-Meier method and prognostic factors were evaluated using a Cox regression model. The clinical characteristics of the two groups were similar, except for the rate of conventional platinum-based chemotherapy (p=0.02). Multiple regression survival analysis revealed that the completion of a comprehensive staging operation was the only independent factor for progression-free survival of stage I CCC patients (p=0.03) and that the chemotherapeutic regimen was not a prognostic factor (p=0.43). The present study indicates that we should accomplish complete surgical staging procedures for CCC confined to the ovary.
Assuntos
Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma de Células Claras/mortalidade , Estadiamento de Neoplasias , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Análise de Regressão , Análise de SobrevidaRESUMO
The activation of JAK2/STAT3 pathway has been reported to have critical roles in several solid tumors. The present study aimed to evaluate the correlation between JAK2/STAT3 activation and clinicopathological parameters in ovarian cancer types. Tissue microarrays made from the patients treated at the National Defense Medical College Hospital between 1984 and 2008 were evaluated using immunohistochemical (IHC) stainings. Medical charts of these patients including IHC results were retrospectively analyzed, and prognostic factors for progression-free survival and overall survival were evaluated. Among 341 enrolled patients, positive expression of p-STAT3 was observed in 95 cases (28%). Positive p-STAT3 was an independent worse prognostic factor for overall survival in all the cases. Additionally, p-STAT3 expression was related with overall survival in patients with clear-cell histology, but not in serous histology. The effect of an inhibitor of STAT3, niclosamide, was evaluated in ovarian clear-cell cancer cells, and niclosamide treatment decreased expression of p-STAT3, leading to increased apoptosis in a dose-dependent manner in vitro. The activation of JAK2/STAT3 pathway had significant impact on survival of ovarian cancers, especially for the cases with clear-cell histology. Although further analyses are needed, suppression of this pathway could be a candidate for the treatment of ovarian cancers.
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The aim of the present study was to identify clinicopathological factors in long-term survivors following ovarian cancer recurrence. The patients who achieved longer survival after recurrence (n=18) and those who succumbed to the disease earlier (n=47) were identified and analyzed. There were no significant differences in age, performance status, stage distribution or histology between the two groups. Additionally, no significant difference was observed in progression-free survival after primary therapy. Multivariate analyses revealed that the predictive factors for long-term survival were i) secondary debulking surgery (OR=13.3; 95% CI: 1.39-226.7), ii) favourable response rate of second-line chemotherapy (OR=46.5; 95% CI: 1.84-313-4), and iii) ≥3 regimens after first recurrence (OR=9.01; 95% CI: 1.28-117.7). This study revealed that prolonged post-progression survival was associated with post-recurrence treatment. Therefore, appropriate selection of secondary debulking surgery and better chemotherapeutic response may lead to prolonged post-progression survival in recurrent ovarian cancer patients.
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Non-platinum single agents are usually used for patients with platinum-resistant recurrent ovarian cancers (ROC). However, the efficacy of these drugs is limited. The aim of the present study was to evaluate the efficacy and adverse events (AE) of combination therapy with irinotecan and platinum (CPT-Pt) for ROC. A total of 28 platinum-resistant or refractory patients with ROC treated with CPT-Pt at the National Defense Medical College Hospital institution between 2002 and 2012 were identified. All patients received taxane and carboplatin (TC) as a first-line treatment and relapsed within 6 months after completion of TC, or progressed during TC therapy. The median age was 59 years (range, 16-78), and median number of CPT-Pt therapy cycles was 5.5 (range, 2-16). The overall response rate was 14%, with a complete response (CR) in 2 patients and partial response (PR) in 2 patients. Stable disease (SD) for >3 months was observed in 15 patients (54%), resulting in a clinical benefit rate (CBR = CR + PR + SD) of 68%. The median progression-free survival and overall survival were 8 and 15 months, respectively. Fifteen cases (68%) developed grade 3/4 hematological AE and 3 cases (11%) developed non-hematological grade 3/4 AE, which were resolved by conservative management or dose reduction. Platinum re-treatment with irinotecan for platinum refractory or resistant ROC may be a candidate in such clinical settings.
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PURPOSE: Low skeletal muscle mass (sarcopenia) has been reported to have an influence on survival and toxicities of chemotherapy in several solid tumors. The impact of sarcopenia on the treatment of ovarian cancers has not been determined. The present study aimed to evaluate correlation between sarcopenia and toxicities of chemotherapy in ovarian cancers. METHODS: Medical charts of the ovarian cancer patients that received chemotherapy with paclitaxel and carboplatin at our hospital between 2010 and 2015 were retrospectively reviewed. Muscle areas of bilateral psoas major muscles at the fifth lumbar vertebra were measured using images obtained by computed tomography. The volume of muscle and clinicopathological factors were evaluated for toxicities of chemotherapy. The protocol of the present study was approved by the institutional review board of our institution. RESULTS: A total of 76 patients with ovarian cancers were identified, and enrolled in the present study. Median psoas index (PI, the psoas muscle major cross-sectional area divided by the height squared) was 583 mm2/m2 (range 326-999). The patients with low PI developed peripheral neuropathy more frequently compared with those with high PI (32 vs. 11%; P = 0.047). PI value was not associated with other toxicities such as neutropenia and thrombocytopenia. PI value was associated with grade 2 or higher peripheral neuropathy in univariate analysis (OR = 3.92; 95% CI 1.21-15.32; P = 0.02) and multivariate analysis (OR = 3.93; 95% CI 1.17-15.87; P = 0.03). CONCLUSIONS: PI value was significantly associated with peripheral neuropathy induced by combination therapy with paclitaxel and carboplatin in ovarian cancer patients. Although further studies are needed to confirm the results, the volume of skeletal muscle mass could be a potential biomarker to predict toxicities in ovarian cancer patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Músculos PsoasRESUMO
In the current study, we identified paclitaxel-resistant related genes by comparing gene expression profiles of paclitaxel-resistant and parent ovarian cancer cell lines. Gene expression profiles of the human ovarian cancer cell line (KF28), cisplatin-resistant cell line (KFr13) induced from KF28, and paclitaxel-resistant cell lines (KF28TX and KFr13TX) induced by exposing KF28 and KFr13 to dose-escalating paclitaxel were compared and analyzed using cDNA microarray. Of 557 human cancer-related cDNA transcripts compared, 5 genes were found to be underexpressed and 5 genes overexpressed in the paclitaxel-resistant KF28TX, while another paclitaxel-resistant KFr13TX had 5 underexpressed and 8 overexpressed genes. Among these genes, overexpression of the ATP-binding cassette subfamily (MDR-1), Rho guanine dinucleotide phosphate dissociation inhibitor beta (RhoGDI) and insulin-like growth factor binding protein 3 (IGFBP-3) was observed in both paclitaxel-resistant cell lines. Using real-time quantitative PCR, we confirmed the array results. We therefore conclude that IGFBP-3, RhoGDI and MDR-1 were correlated with paclitaxel resistance. Moreover, immunohistochemical staining was analyzed in 22 serous ovarian cancer tissues from patients who received paclitaxel-based chemotherapy, and RhoGDI overexpression was observed more frequently in non-responsers than in responders (p=0.004). RhoGDI expression proved to be a predictive marker of paclitaxel resistance not only in paclitaxel-resistant cell lines, but also in clinical samples.
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Antineoplásicos Fitogênicos/uso terapêutico , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Inibidores de Dissociação do Nucleotídeo Guanina/genética , Neoplasias Ovarianas/genética , Paclitaxel/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Células Tumorais Cultivadas , Inibidor alfa de Dissociação do Nucleotídeo Guanina rho , Inibidores da Dissociação do Nucleotídeo Guanina rho-EspecíficoRESUMO
Bisphosphonates are now well established as successful agents for the prevention and treatment of postmenopausal osteoporosis and corticosteroid-induced bone loss. Bisphosphonates have also recently become important in the management of cancer-induced bone disease, and they now have a widely recognized role for patients with multiple myeloma and bone metastases secondary to breast cancer and prostate cancer. Recent studies suggest that, besides the strong antiosteoclastic activity, the efficacy of such compounds in the oncological setting could also be due to direct anti-tumor effect. However, the effect of bisphosphonates to ovarian and endometrial cancers has not been elucidated. Thus, we examined the direct effect of bisphosphonates on the various ovarian cancer cell lines. Except for etidronate, all of bisphosphonates examined had the direct inhibitory effects on proliferation of all ovarian cancer cell lines used. Especially, pamidronate had the most marked inhibitory effect and inhibited dose-dependently the proliferation of ovarian cancer cell lines. KFr 13 cells among ovarian cancer cell lines used was the most sensitive to pamidronate and the caspase 3 activity was markedly stimulated by treatment with pamidronate, suggesting induction of apoptosis.
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Proliferação de Células/efeitos dos fármacos , Difosfonatos/farmacologia , Neoplasias Ovarianas/patologia , Caspase 3 , Caspases/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , Feminino , Humanos , Neoplasias Ovarianas/enzimologiaRESUMO
Frequent mutation of the ARID1A gene has been recently identified in ovarian clear-cell adenocarcinoma (CCA); however, the clinical significance of BAF250a expression encoded by the ARID1A gene remains to be determined. The aim of the present study was to assess whether BAF250a expression had an impact on the clinical features of CCA. A total of 97 cases of CCA treated at a single institution were enrolled in the present study. The tissue samples were evaluated by immunohistochemical staining. BAF250a-deficient expression was observed in 30% (29/97) of all CCA cases. Of this, 19% of non-atypical endometriosis, 26% of atypical endometriosis, 39% of endometriosis-related CCA, 5% of benign clear-cell adenofibroma (CCAF), 5% of borderline CCAF and 10% of CCAF-related CCA. BAF250a-deficient expression was significantly more frequent in endometriosis-related CCA compared with that in CCAF-related CCA (P=0.02). No significant difference was observed in the response rate of primary chemotherapy according to BAF250a expression status (P=0.48). Additionally, BAF250a expression status was not significantly correlated with progression-free and overall survival in patients with CCA. Although loss of BAF250a expression was associated with early tumorigenesis in endometriosis-related CCA, this alteration was not significantly correlated with chemosensitivity and prognoses of CCA. Further biomarker analyses, including BAF250a expression, are required to improve the prognoses of CCA.
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Liquid chromatography (LC) was coupled on-line to a homogeneous continuous-flow protease assay using fluorescence resonance energy transfer (FRET) as a readout for the screening of inhibitors of an enzyme (e.g., Subtilisin Carlsberg). The inhibitors aprotinin (a protein of approximately 6500 g/mol) and 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF, 240 g/mol) were mixed with other, non-active compounds and separated on a size-exclusion chromatography column. After the separation, the analytes were eluted to the postcolumn reactor unit where the enzyme solution and subsequently the FRET peptide substrate were added; by measuring the fluorescence intensity the degree of inhibition was monitored on-line. As expected, only the two inhibitors caused a change in the FRET response. Detection limits for aprotinin were 5.8 microM in the flow injection analysis (FIA) mode and 12 microM in the on-line LC mode. System validation was performed by determining IC50 values for aprotinin for the FIA mode (19 microM) and the on-line mode (22 microM). These IC50 values were in line with the value determined in batch experiments (25 microM). With this system, chemical information (i.e., chromatographic retention time) and biological information (i.e., enzyme inhibition) can be combined to characterize mixtures.
Assuntos
Cromatografia em Gel/métodos , Oligopeptídeos/metabolismo , Subtilisinas/análise , Aprotinina/farmacologia , Bioensaio/métodos , Transferência Ressonante de Energia de Fluorescência , Concentração Inibidora 50 , Sistemas On-Line , Subtilisinas/antagonistas & inibidores , Subtilisinas/isolamento & purificação , Sulfonas/farmacologiaRESUMO
Spermatozoa bind to the vitelline coat in the ascidians and many other animals. The binding of sperm in Halocynthia roretzi is mediated by a sperm alpha-L-fucosidase and complementary-L-fucosyl residues of glycoproteins in the vitelline coat. cDNA clones for alpha-L-fucosidase were isolated from growing testis mRNA. It contained a 1398 bp full-length cDNA insert (HrFuc'ase) that encoded the 466 amino acid residues of H. roretzi sperm alpha-L-fucosidase. A putative signal peptide of 21 amino acid residues proceeded the sequence for the mature protein (M.W. 52.4 kDa). The coding sequence for HrFuc'ase showed 47.7% sequence identity to the human liver fucosidase sequence. The polyclonal antibody was prepared against a lacZ-HrFuc'ase fusion protein expressed in E. coli. The antibody crossed to a 54 kDa protein in sperm on western blotting and inhibited fertilization in a dose dependent manner. These data suggest that sperm-egg binding is mediated by the sperm alpha-L-fucosidase, HrFuc'ase in the ascidian, H. roretzi.
Assuntos
Interações Espermatozoide-Óvulo/fisiologia , Espermatozoides/enzimologia , Urocordados/enzimologia , alfa-L-Fucosidase/metabolismo , Sequência de Aminoácidos , Animais , Western Blotting , Catálise , Clonagem Molecular , Soros Imunes/imunologia , Masculino , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Urocordados/genética , alfa-L-Fucosidase/química , alfa-L-Fucosidase/imunologiaRESUMO
The aim of this study was to evaluate the outcomes of patients with a gynecological malignancy who received palliative care with and without surgical procedures for malignant bowel obstruction (MBO) and to explore prognostic factors to aid the selection of patients who would benefit from palliative surgery. Medical records of patients with MBO due to a gynecological malignancy treated at our institute between 2005 and 2010 were reviewed. Successful palliation following surgery was defined as the ability to tolerate solid food for at least 60 days. Clinical variables were analyzed using Chi-square or Fisher's exact tests. Survival was evaluated using the Kaplan-Meier method and log-rank test. A total of 53 cases were identified; 20 had bowel surgery for MBO as a palliative procedure and 33 did not. Colostomy was performed in 11 (55%) of 20 patients and ileostomy was performed in 7 (35%). The postoperative morbidity was 35% and mortality within 30 days was 5%. Successful palliation following surgery was achieved in 14 (70%) of 20 cases with a median period of 146 days (range, 61-294). Survival following the diagnosis of MBO was longer in cases with surgery than those without (median survival time, 146 versus 69 days; P<0.0001). Although age, presence of ascites, laboratory values and types of prior anticancer therapy were not significantly different, a longer interval from last anticancer therapy to diagnosis of MBO was observed in patients who underwent surgery compared with those who did not (median, 57 versus 30 days; P<0.05), as well as superior performance status. Among the patients with surgery, the interval was also longer in patients with successful palliation compared with those without (median, 83 versus 32 days; P<0.05). The palliative benefit of surgery for MBO in selected patients with gynecological malignancy was observed. The interval from last anticancer therapy to diagnosis of MBO may serve as a prognostic factor when considering surgical intervention.