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1.
Hum Cell ; 37(2): 491-501, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38184488

RESUMO

Neoadjuvant chemotherapy (NAC) followed by surgery is a standard approach for management of locally advanced esophageal squamous cell carcinoma (ESCC). Patients who do not respond well to NAC have a poor prognosis. Despite extensive research, the mechanisms of chemoresistance in ESCC remain largely unknown. Here, we established paired tumor organoids-designated as PreNAC-O and PostNAC-O-from one ESCC patient before and after NAC, respectively. Although the two organoids did not exhibit significant differences in proliferation, morphology or drug sensitivity in vitro, the tumorigenicity of PostNAC-O in vivo was significantly higher than that of PreNAC-O. Xenografts from PreNAC-O tended to exhibit keratinization, while those from PostNAC-O displayed conspicuous necrotic areas. The tumorigenicity of PostNAC-O xenografts during the chemotherapy was comparable to that of PreNAC-O without treatment. Furthermore, the gene expression profiles of the xenografts suggested that expression of genes involved in the EMT and/or hypoxia response might be related to the tumorigenicity of PostNAC-O. Our data suggested that the tumorigenicity of residual cancer had been enhanced, outweighing the effects of chemotherapy, rather than being attributable to intrinsic chemoresistance. Further studies are required to clarify the extent to which residual cancers share a common mechanism similar to that revealed here.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasia Residual , Terapia Neoadjuvante , Organoides/patologia
2.
Cancer Sci ; 114(11): 4459-4474, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37715346

RESUMO

Neoadjuvant chemotherapy (NAC) followed by surgery is one of the standard therapeutic approaches in Japan for patients with locally advanced esophageal carcinoma. Recently, the JCOG1109 study revealed that NAC with docetaxel, cisplatin and 5-fluorouracil (5-FU) (DCF-NAC) is superior to NAC with cisplatin and 5-FU, and has now become the standard preoperative chemotherapy. Using a microarray system, we have previously investigated the expression profiles of endoscopic biopsy samples from patients with esophageal squamous cell carcinoma (ESCC) before DCF-NAC (preNAC) and identified 17 molecules as biomarkers predictive of a pathologically complete response to DCF-NAC. Here, we re-grouped our previous dataset based on the histopathological response grade with the addition of several microarray profiles and conducted a re-analysis using bioinformatic web tools including DAVID, GSEA, UALCAN, and CIBERSORTx. We identified 204 genes that were differentially expressed between the highly resistant and sensitive groups. Some of these differentially expressed genes (DEGs) were related to the immune response and showed higher expression in the sensitive group. UALCAN showed that high expression of 28 of the top 50 DEGs was associated with a favorable prognosis (p < 0.25), and that this reached a significant (p < 0.05) level for 18 of them, suggesting that patients with high expression of these genes might have benefited from chemotherapy and thus had a better outcome. In preNAC biopsy tissues from a DCF-sensitive case, we demonstrated the presence of cells expressing mRNA for CXCL9, one of the prognosis-related DEGs. Our results highlight the association of immune-related expression profile in preNAC ESCC with the DCF-NAC efficacy.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Cisplatino/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Resultado do Tratamento , Taxoides/uso terapêutico , Fluoruracila/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Neoadjuvante/métodos
3.
Cancers (Basel) ; 15(16)2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37627132

RESUMO

Prediction of therapeutic outcomes is important for cancer patients in order to reduce side effects and improve the efficacy of anti-cancer drugs. Currently, the most widely accepted method for predicting the efficacy of anti-cancer drugs is gene panel testing based on next-generation sequencing. However, gene panel testing has several limitations. For example, only 10% of cancer patients are estimated to have druggable mutations, even if whole-exome sequencing is applied. Additionally, even if optimal drugs are selected, a significant proportion of patients derive no benefit from the indicated drug treatment. Furthermore, most of the anti-cancer drugs selected by gene panel testing are molecularly targeted drugs, and the efficacies of cytotoxic drugs remain difficult to predict. Apart from gene panel testing, attempts to predict chemotherapeutic efficacy using ex vivo cultures from cancer patients have been increasing. Several groups have retrospectively demonstrated correlations between ex vivo drug sensitivity and clinical outcome. For ex vivo culture, surgically resected tumor tissue is the most abundant source. However, patients with recurrent or metastatic tumors do not usually undergo surgery, and chemotherapy may be the only option for those with inoperable tumors. Therefore, predictive methods using small amounts of cancer tissue from diagnostic materials such as endoscopic, fine-needle aspirates, needle cores and liquid biopsies are needed. To achieve this, various types of ex vivo culture and endpoint assays using effective surrogate biomarkers of drug sensitivity have recently been developed. Here, we review the variety of ex vivo cultures and endpoint assays currently available.

4.
Lab Invest ; 102(12): 1355-1366, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35922477

RESUMO

Despite recent advances in sequencing technology and large-scale drug screenings employing hundreds of cell lines, the predictive accuracy of mutation-based biomarkers is still insufficient as a guide for cancer therapy. Therefore, novel types of diagnostic methods using alternative biomarkers would be highly desirable. We have hypothesized that sensitivity-specific changes in the phosphorylation of signaling molecules could be useful in this respect. Here, with the aim of developing a method for predicting the response of cancers to cisplatin using a combination of specific biomarker(s) and patient-derived tumor organoids (PDOs), we found that cisplatin-sensitive cell lines or PDOs showed enhanced phosphorylation of c-Jun (p-c-Jun) within 24 h after cisplatin treatment. We also compared the responses of 6 PDOs to cisplatin with the therapeutic effect of neoadjuvant chemotherapy (docetaxel/cisplatin/5-fluorouracil) in 6 matched patients. Mechanistically, the c-Jun induction was partly related to TNF signaling induced by cisplatin. Our data suggest that enhanced phosphorylation of c-Jun in response to cisplatin treatment could be a predictive biomarker for the efficacy of cisplatin in selected cancer patients.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Organoides/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Fosforilação , Docetaxel/farmacologia , Neoplasias/patologia , Biomarcadores
5.
World J Clin Oncol ; 12(4): 249-261, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33959478

RESUMO

BACKGROUND: 18F-fluorodeoxyglucose-positron emission tomography (PET)/computed tomography is useful in diagnosing lymph node and distant metastases of esophageal cancer. However, its value for predicting survival is controversial. AIM: To evaluate the value of PET complete metabolic response (CMR) as a prognostic predictor for esophageal cancer. METHODS: Between June 2013 and December 2017, 58 patients with squamous cell esophageal cancer who underwent neoadjuvant chemotherapy (NAC) in Oita University were enrolled in this retrospective cohort study. Tumors were clinically staged using fluorodeoxyglucose-PET/computed tomography before and after NAC. After NAC, maximal standardized uptake value ≤ 2.5 was defined as PET-CMR, and maximal standardized uptake value > 2.5 was defined as non-PET-CMR. We compared short-term outcomes between the PET-CMR group and non-PET-CMR group and evaluated prognostic factors by univariate and multivariate analyses. RESULTS: The PET-CMR group included 22 patients, and the non-PET-CMR group included 36 patients. There were no significant differences in intraoperative and postoperative complications between the two groups. Five-year relapse-free survival and overall survival in the PET-CMR group were significantly more favorable than those in the non-PET-CMR group (38.6 mo vs 20.8 mo, P = 0.021; 42.8 mo vs 25.1 mo, P = 0.011, respectively). PET-CMR was a significant prognostic factor in terms of relapse-free survival by univariate analysis (hazard ratio: 2.523; 95% confidence interval: 1.034-7.063; P < 0.041). Particularly, PET-computed tomography negative N was an independent prognostic factor of relapse-free survival and overall survival by multivariate analysis. CONCLUSION: PET-CMR after NAC is considered a favorable prognostic factor for esophageal cancer. Evaluation by PET-computed tomography could be useful in clinical decision making for esophageal cancer.

6.
PLoS One ; 12(11): e0188098, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29136005

RESUMO

BACKGROUND: Recently, neoadjuvant chemotherapy with docetaxel/cisplatin/5-fluorouracil (NAC-DCF) was identified as a novel strong regimen with a high rate of pathological complete response (pCR) in advanced esophageal cancer in Japan. Predicting pCR will contribute to the therapeutic strategy and the prevention of surgical invasion. However, a predictor of pCR after NAC-DCF has not yet been developed. The aim of this study was to identify a novel predictor of pCR in locally advanced esophageal cancer treated with NAC-DCF. PATIENTS AND METHODS: A total of 32 patients who received NAC-DCF followed by esophagectomy between June 2013 and March 2016 were enrolled in this study. We divided the patients into the following 2 groups: pCR group (9 cases) and non-pCR group (23 cases), and compared gene expressions between these groups using DNA microarray data and KeyMolnet. Subsequently, a validation study of candidate molecular expression was performed in 7 additional cases. RESULTS: Seventeen molecules, including transcription factor E2F, T-cell-specific transcription factor, Src (known as "proto-oncogene tyrosine-protein kinase of sarcoma"), interferon regulatory factor 1, thymidylate synthase, cyclin B, cyclin-dependent kinase (CDK) 4, CDK, caspase-1, vitamin D receptor, histone deacetylase, MAPK/ERK kinase, bcl-2-associated X protein, runt-related transcription factor 1, PR domain zinc finger protein 1, platelet-derived growth factor receptor, and interleukin 1, were identified as candidate molecules. The molecules were mainly associated with pathways, such as transcriptional regulation by SMAD, RB/E2F, and STAT. The validation study indicated that 12 of the 17 molecules (71%) matched the trends of molecular expression. CONCLUSIONS: A 17-molecule set that predicts pCR after NAC-DCF for locally advanced esophageal cancer was identified.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Cisplatino/administração & dosagem , Estudos de Coortes , Docetaxel , Neoplasias Esofágicas/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Proto-Oncogene Mas , Taxoides/administração & dosagem , Resultado do Tratamento
7.
Cancer Sci ; 107(12): 1919-1928, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27699948

RESUMO

Gastric cancer (GC) is characterized by amplifications of receptor tyrosine kinases (RTK) and KRAS, therefore, targeting of the RTK/KRAS downstream pathways could help to broaden the applicability of molecular targeted therapy for GC. We assembled a panel of 48 GC cell lines and screened predictors of responsiveness to inhibition of the RAF/MEK/ERK pathway, one of the RTK/KRAS downstream pathways. We found that GC cells with MET amplification or KRAS mutation, but not amplification, tended to be sensitive to MEK inhibition. However, several cell lines without RTK/KRAS alterations also showed high sensitivity to MEK inhibition. We then focused on the phosphorylation of RTK/KRAS downstream molecules to screen for predictors' sensitivity to MEK inhibition. We found that the phosphorylation level of mammalian target of rapamycin complex 1 (mTORC1) downstream molecules, including p70S6K, 4EBP1, and S6, was significantly associated with sensitivity to MEK inhibition in GC cells (P < 0.05), suggesting that mTORC1 activity is related to the sensitivity to MEK inhibition. Furthermore, the change in mTORC1 activity after MEK inhibition was also significantly associated with this sensitivity (P < 0.001). Among the mTORC1 downstream molecules, the change in S6 phosphorylation (pS6) showed the most significant correlation with sensitivity. Using xenograft models derived from highly sensitive and resistant cell lines, we found specific reduction of pS6 in xenografts from highly sensitive cell lines after 6 h of treatment with an MEK inhibitor. Thus, our data suggest the potential clinical applicability of an MEK inhibitor for a proportion of GC patients who could be selected on the basis of pS6 change after MEK inhibition.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteína S6 Ribossômica/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Expressão Gênica , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos/metabolismo , Fosforilação , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Am J Cancer Res ; 5(10): 2998-3014, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26693055

RESUMO

Previously, we have reported that gain at chromosome 20q13 is the most common genomic copy number aberration in gastric cancer (GC) (29/30 cases), and that among the genes located in this region, we have identified DDX27, whose expression level shows the highest correlation with genomic copy number, as a candidate therapeutic target for GC. Here, we analyzed the clinicopathological significance of DDX27 using immunohistochemistry and studied its functions using knockdown assays. We found that DDX27 was frequently upregulated in GC tissues (98 of 140 cases, 70%), and significantly associated with venous invasion and liver metastasis. Furthermore, multivariate analysis of GC patients showed that high expression of DDX27 was independently associated with poorer prognosis. In functional assays, knockdown of DDX27 reduced the ability of GC cells to form colonies both on conventional plates and soft agar, but had little effect on their invasiveness. We also found that knockdown of DDX27 reduced the viability of GC cells through inhibition of cell cycle progression independently of apoptosis. Interestingly, DDX27 depletion induced accumulation of TP53 in a TP53 wild-type cell line, AGS, but not in a TP53-deleted cell line, 44As3, although DDX27 knockdown commonly reduced the viability of both, indicating the TP53-dependent and independent cell cycle control of DDX27. Thus, our results suggest that expression of DDX27 contributes to colony formation by GC cells through cell cycle control and may be a potential therapeutic target for GC patients with chromosome gain at 20q13.

9.
Expert Opin Ther Targets ; 13(7): 811-22, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19466912

RESUMO

BACKGROUND: Epithelial membrane protein 3 (EMP3), was recently reported to be a tumor suppressor gene for several solid tumors, and is drawing attention as a novel prognostic marker, since its expression level or hypermethylation of the promoter region is associated with clinical prognosis in neuroblastoma and esophageal cancer. However, some controversial data were also observed in gliomas and breast cancers, and there seems to be more than deletion/hypermethylation to its silencing mechanisms. OBJECTIVE: To clarify the discrepancies in the biological behavior of EMP3 among the different organ-derived malignancies or histologies and validate the potential of EMP3 as a tumor suppressor for solid tumors. METHODS: Literature dealing with EMP3 in the PubMed database was reviewed. RESULTS/CONCLUSIONS: EMP3 is a novel tumor suppressor gene in some kinds of malignancies, but not all, at the step of cellular immortalization rather than carcinogenesis. It may become a potent prognostic marker and a therapeutic target in such tumors.


Assuntos
Genes Supressores de Tumor , Glicoproteínas de Membrana/genética , Neoplasias/genética , Animais , Biomarcadores Tumorais/genética , Sistemas de Liberação de Medicamentos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/diagnóstico , Prognóstico
10.
Gan To Kagaku Ryoho ; 36(3): 417-24, 2009 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-19295265

RESUMO

BACKGROUND: We conducted this study to evaluate the efficacy of S-1 combination chemotherapy as second-line treatment for advanced/recurrent gastric cancer that was resistant to S-1 based chemotherapy as first-line treatment. PATIENTS AND METHODS: We evaluated patients included in phase II.III clinical trials, that is SPIRITS trial(S-1 vs CDDP +S-1), GC0301/TOP-002(S-1 vs CPT-11+S-1), OGSG0002(S-1+CPT-11)and OGSG0105(S-1+paclitaxel). Eligibility criteria at first-line included; pathologically proven gastric cancer, adequate bone marrow, hepatic, and renal functions, PS 0-2, no prior therapy, life expectancy estimated > or =12 weeks, age 20-75 years and written informed consent. Endpoints were as follows; )PFS in first-line and second-line, )Time to Second Progression(TSP), 3) OS. RESULTS: Sixty-six patients were evaluable in this study. We classified these patients into 4 groups according to the protocol. A)S-1 alone in first-line and S-1 combination in second-line(n=7), B)S-1 alone in first-line and other drugs in second-line(n=13), C)S-1 combination in first-line and another S-1 combination in second-line(n=33), D) S-1 combination in first-line and other drugs in second-line(n=13). We compared S-1 combination group(A+C)to other drugs group(B+D)in second-line. In first-line, PFS was 157.5 days in group(A+C)and 130 days in group(B +D)(p=0.2749). In second-line, PFS, TSP and OS were as follows; 72.5, 256.5, 473 days in group(A+C)and 56, 201.5, 398.5 days(PFS; p=0.0806, TSP: p=0.0718, OS: p=0.0204)in group(B+D), respectively. With regards to adverse events, group(A+C)in first-line showed higher frequency in grade 3/4 leukopenia(10%), febrile neutropenia(5%)and grade 3 diarrhea(10%)than group(B+D). In second-line, group(B+D)showed grade 3/4 leukopenia (12%)and neutropenia(8%)than group(A+C). There were no treatment-related deaths. CONCLUSION: These results indicate that S-1 combination chemotherapy is efficient as second-line for advanced/recurrent gastric cancer that got resistant to S-1 based chemotherapy as first-line.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácido Oxônico/uso terapêutico , Terapia de Salvação , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Tegafur/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/efeitos adversos , Recidiva , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Tegafur/efeitos adversos
11.
Cancer Lett ; 274(1): 25-32, 2009 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-18823699

RESUMO

EMP3, epithelial membrane protein 3, was recently reported to be a tumor suppressor gene in neuroblastomas and gliomas. We found that EMP3 was commonly repressed in esophageal squamous cell carcinoma (ESCC) cell lines by oligonucleotide microarrays. Its overexpression in ESCC cell lines caused growth inhibition with morphological changes and TERT repression. In addition to promoter hypermethylation, TSA caused repression of EMP3, indicating the involvement of histone deacetylase-regulated repressors. The post-recurrent survival after radical surgery was poorer in ESCC patients with lower EMP3 expression. We propose that EMP3 may be a tumor suppressor gene at the late step of ESCC carcinogenesis.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Genes Supressores de Tumor/fisiologia , Glicoproteínas de Membrana/genética , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Metilação de DNA , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Perfilação da Expressão Gênica , Histona Desacetilases/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Telomerase/metabolismo , Células Tumorais Cultivadas
12.
Int J Oncol ; 32(2): 413-23, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18202764

RESUMO

Prior laboratory prediction of individual drug response is of key importance in esophageal squamous cell carcinoma (ESCC), because of the extremely narrow therapeutic index of chemotherapy. However, very few critical markers have been validated to date for ESCC. We previously demonstrated that simultaneous performance of two different types of comprehensive gene expression analysis might provide a way to identify potent marker genes for drug sensitivity from the expression-sensitivity correlation analysis alone, but the screening method appeared not to be always effective. Therefore, we attempted to identify novel potent marker genes using a new statistical analysis of oligonucleotide microarray expression data, based on a two-dimensional mixed normal model, and selected 3 and 7 novel candidates for 5-fluorouracil (5-FU) and cis-platinum (CDDP), respectively. Interferon induced transmembrane protein 1 (IFITM1) gene alone, being suggested as a key gene of Wnt pathway, was commonly selected in both screening methods. The transfection analyses and siRNA-mediated knock-down experiments revealed that expression of IFITM1 closely related to cellular sensitivity to CDDP. Considering the fact that drug sensitivity is determined by multiple genes, we established the best linear model using quantified expression data of a set of all the selected marker genes including IFITM1, which converted the quantified expression data of ESCC cell lines into an IC50 value of each drug. In the same way, using the representative genes selected in vitro, we developed highly predictive formulae for disease-free survival (DFS) of the CDDP/5-FU combination after curative operation in esophageal cancer patients (R=0.917). A two-dimensional mixed normal model can be a powerful tool to identify novel drug-response determinants, and the IFITM1 gene selected by the statistical method a novel critical biomarker of CDDP response in ESCC.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/biossíntese , Cisplatino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/biossíntese , Antígenos de Diferenciação , Química Farmacêutica/métodos , Intervalo Livre de Doença , Fluoruracila/uso terapêutico , Humanos , Concentração Inibidora 50 , Análise de Sequência com Séries de Oligonucleotídeos , RNA Interferente Pequeno/metabolismo
13.
Gan To Kagaku Ryoho ; 34(7): 1119-21, 2007 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-17637553

RESUMO

A 70-year-old woman, who had undergone esophagectomy for cervical esophageal squamous cell carcinoma (pT3pN2M0, Stage III) 9 months earlier, was diagnosed as mediastinal lymph node recurrence by CT and endoscope. Patients underwent radiochemotherapy with 5 cycles of docetaxel 10 mg/m(2) on day 1 and 5-FU 250 mg/m(2) on day 1 to day 5, together with concurrent radiation (50 Gy/25 Fr) for mediastinum. After this treatment, a complete response (CR) was achieved, and there was no recurrence 9 months after the treatment. No severe adverse effects were observed. Concurrent radiochemotherapy with docetaxel and 5-FU is considered effective without serious side effects for postoperative recurrence in esophageal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Linfonodos/patologia , Idoso , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/cirurgia , Terapia Combinada , Docetaxel , Esquema de Medicação , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Esofagectomia , Feminino , Fluoruracila/administração & dosagem , Humanos , Metástase Linfática , Mediastino , Indução de Remissão , Taxoides/administração & dosagem
14.
Ann Surg Oncol ; 14(4): 1431-8, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17260107

RESUMO

BACKGROUND: The aim of this study was to assess the clinical outcome in patients with esophageal squamous cell carcinoma (ESCC) by using molecular biological classification based on immunohistochemical analysis in addition to tumor, node, metastasis system (TNM) classification. METHODS: Samples from 71 patients with ESCC who underwent surgery were analyzed immunohistochemically. Cyclin B1, E-cadherin, Bag-1, and heat-shock protein 70 were selected as the molecular biological parameters. The utility of molecular biological classification on clinical impact was examined and compared with TNM classification. RESULTS: Three patients were diagnosed as stage 0, 14 as stage I, 20 as stage II, 19 as stage III, and 15 as stage IV by TNM classification. Thirteen patients were classified as stage 0, 17 as stage I, 21 as stage II, 18 as stage III, and 2 as stage IV by molecular biological classification. Molecular biological stage (P < .0001) and TNM stage (P < .0001) were statistically significant prognostic parameters in univariate analysis. Twenty (28.2%) of 71 patients were assigned to the same stage by both classifications, and a significant correlation was identified between the two classifications (P = .0002). Molecular biological classification (P < .01) and TNM classification (P < .0001) were independent prognostic parameters in multivariate analysis. Combined TNM and molecular biological classification accurately reflected clinical outcome (P < .0001). CONCLUSIONS: Molecular biological classification combined with TNM classification is useful for assessing the prognosis of patients with ESCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/classificação , Neoplasias Esofágicas/classificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Caderinas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Ciclina B/metabolismo , Ciclina B1 , Proteínas de Ligação a DNA/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Fatores de Transcrição/metabolismo
15.
Oncol Rep ; 13(2): 235-9, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15643504

RESUMO

Expression of galectin-3, a member of the beta-galactosidase binding lectin family, is reported to correlate with cell adhesion. The present immunohistochemical study was performed to clarify the impact of galectin-3 expression on patients with esophageal squamous cell carcinoma. Galectin-3 expression was examined immunohistochemically in 154 patients with esophageal squamous carcinoma, who had undergone surgery without preoperative supplemental therapy at the Department of Surgery II in the Hospital of the Faculty of Medicine, Oita University, between 1990 and 2000. The cases with > or =30% nuclear-stained cancer cells were considered high nuclear expression cases. In contrast, the cases with > or =45% cytoplasm-stained cancer cells were considered high cytoplasm expression cases. Twenty-three of 154 ESCC cases were regarded as high nuclear expression (14.9%) and 72 of 154 cases were regarded as high cytoplasm-expression (46.5%). High expression of galectin-3 in the nuclei inversely correlated with vascular invasion (p=0.030) and histological differentiation (p=0.0064). In contrast, cytoplasmic expression of galectin-3 revealed no significant impact on clinicopathological factors. Neither nuclear nor cytoplasmic expression of galectin-3 was a prognostic indicator in ESCC. Elevated expression of galectin-3 in the nuclei but not the cytoplasm may be an important biological parameter related to histological differentiation and vascular invasion in patients with ESCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Galectina 3/metabolismo , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Diferenciação Celular , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica
16.
Am J Clin Pathol ; 122(1): 78-84, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15272533

RESUMO

Hypermethylation in the E-cadherin promoter region and expression of the transcription factor Snail were analyzed in 41 cases of esophageal squamous cell carcinoma (ESCC) and paired normal squamous epithelium by methylation-specific polymerase chain reaction (PCR) and reverse transcription-polymerase chain reaction (RT-PCR) to clarify the mechanism regulating E-cadherin deletion; 93 cases of ESCC were analyzed immunohistochemically to determine the clinicopathologic impact of E-cadherin deletion. Hypermethylation of the E-cadherin promoter and Snail overexpression were detected in 25 cases (61%) by methylation-specific PCR and 34 cases (83%) by RT-PCR, respectively. Reduced E-cadherin expression, observed immunohistochemically in 55 cases (59%), correlated with hypermethylation (P = .0011) but not Snail overexpression (P = .685). Hypermethylation and Snail overexpression correlated significantly with E-cadherin deletion (P = .0018). Snail overexpression was unrelated to clinicopathologic factors. Reduced E-cadherin expression correlated with tumor invasion (P = .019) and vascular invasion (P = .052) but not other factors. E-cadherin deletion had prognostic impact in univariate (P = .023) and multivariate (P = .034) analyses. E-cadherin deletion was regulated by hypermethylation and Snail expression. Examination of reduced E-cadherin expression is important for assessing biologic behavior, including clinical outcome, in patients with ESCC.


Assuntos
Biomarcadores Tumorais/análise , Caderinas/biossíntese , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Neoplasias Esofágicas/metabolismo , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição da Família Snail , Fatores de Transcrição/metabolismo , Regulação para Cima
17.
Oncol Rep ; 10(3): 623-7, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12684634

RESUMO

In the present study, micrometastasis in the rib marrow of 24 patients with esophageal cancer was examined using RT-PCR. RT-PCR was done using primers corresponding to cytokeratin 18 (CK18), squamous cell carcinoma antigen (SCC), and carcinoembryonic antigen (CEA). In 18 cases, CK18 was also detected in the rib marrow. Only one patient exhibited CEA amplification in the rib marrow. No cases demonstrated SCC amplification as a marker of micrometastasis in the rib marrow. The information from micrometastasis detected in the rib marrow using RT-PCR is useful in deciding whether or not adjuvant therapy is necessary after surgery. However, combined analysis using plural markers should be required since sensitivity or specificity of each marker may vary. Further follow-up of the patients is necessary to clarify the clinical impact of micrometastasis in rib marrow.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Medula Óssea/secundário , Carcinoma de Células Escamosas/secundário , Neoplasias Esofágicas/patologia , Células Neoplásicas Circulantes/química , Serpinas , Idoso , Antígenos de Neoplasias/análise , Neoplasias da Medula Óssea/química , Neoplasias da Medula Óssea/patologia , Antígeno Carcinoembrionário/análise , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/genética , Primers do DNA/química , Neoplasias Esofágicas/química , Neoplasias Esofágicas/genética , Feminino , Humanos , Queratinas/análise , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , RNA Neoplásico/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Costelas/metabolismo , Costelas/patologia
18.
Ann Surg Oncol ; 9(10): 1017-22, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12464596

RESUMO

BACKGROUND: It would be of considerable benefit to patients with esophageal cancer to be able to predict the effect of CRT before therapy, because critical side effects could be avoided and the therapeutic cost of CRT-resistant cases could be reduced. One of the biological parameters with the potential to indicate radioresponse is the DNA double-strand break repair enzyme DNA-PKcs. This study aims to clarify the correlation between DNA-PKcs expression and CRT effect. METHODS: Sixty-seven patients with progressive esophageal cancer treated with CRT were included in this study. The relationship between the expression of DNA-PKcs and the effect of CRT was examined by using immunohistochemistry. The relationships between DNA-PKcs expression, clinicopathologic parameters, and CRT effect were investigated statistically. RESULTS: A significant correlation was found between the expression of DNA-PKcs and the effect of CRT (P =.0149). The high-DNA-PKcs expression group showed greater therapeutic sensitivity than the low-expression group. Clinicopathologic factors had no relationship with DNA-PKcs expression or CRT effect. CONCLUSIONS: This study suggests that high expression of DNA-PKcs correlates with CRT effect. DNA-PKcs expression could, therefore, be useful for predicting the effect of CRT. In addition, these results may make it possible to plan therapy taking patients' quality of life into consideration.


Assuntos
Proteínas de Ligação a DNA , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/radioterapia , Proteínas Serina-Treonina Quinases/metabolismo , Tolerância a Radiação , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Cisplatino/administração & dosagem , Terapia Combinada , Proteína Quinase Ativada por DNA , Fracionamento da Dose de Radiação , Neoplasias Esofágicas/tratamento farmacológico , Feminino , Fluoruracila/administração & dosagem , Humanos , Imuno-Histoquímica , Masculino , Proteínas Nucleares , Estatísticas não Paramétricas , Resultado do Tratamento
19.
Jpn J Thorac Cardiovasc Surg ; 50(12): 537-40, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12561099

RESUMO

Primary adenocarcinoma of the esophagus is rare in Japan and, in most cases, arises from Barrett's esophagus epithelium. A 72-year-old man reporting heartburn and dysphagia and preoperatively diagnosed with adenosquamous carcinoma arising from Barrett's esophagus underwent thoracic esophagectomy and lymph node dissection in curative resection. Pathological diagnosis of the resected specimen showed adenosquamous carcinoma (coexistent adenocarcinoma and squamous cell carcinoma) invasive to the submucosal layer; metastasis was found in regional lymph nodes. Pathological staging was pT1bN1M0, stage II. Unfortunately, the man died of liver and lung metastasis 17 months postoperatively. To our knowledge, this rare case is only the fifth reported in the English literature on adenosquamous carcinoma arising from Barrett's esophagus.


Assuntos
Esôfago de Barrett/complicações , Carcinoma Adenoescamoso/etiologia , Neoplasias Esofágicas/etiologia , Idoso , Esôfago de Barrett/patologia , Esôfago de Barrett/cirurgia , Carcinoma Adenoescamoso/secundário , Carcinoma Adenoescamoso/cirurgia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Esofagectomia , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino
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