RESUMO
Introduction: The optimal rectal cancer care is achieved by a multidisciplinary approach, with a high-quality surgical resection, with complete mesorectal excision and adequate margins. New approaches like the transanal total mesorectal excision (TaTME) aim to achieve these goals, maximizing the sphincter preservation ratio, with good oncologic and functional results. This report describes a way to implement TaTME without a proctor, presents the first case series of this approach in a center experienced in rectal cancer, and compares the results with those of the international literature. Methods: We performed a retrospective study of the first 10 consecutive patients submitted to TaTME for rectal cancer at our institution. The primary outcomes were postoperative complications, pathological specimen quality and local recurrence rate. The results and performance were compared with the outcomes of a known structured program with proctorship and with the largest meta-analysis on this topic. Results: All patients had locally advanced cancer; therefore, all underwent neoadjuvant therapy. A total of 30% had postoperative complications, without mortality or re-admissions. In comparison with the structured training program referred, no differences were found in postoperative complications and reintervention rates, resulting in a similar quality of resection. Comparing these results with those of the largest meta-analysis on the subject, no differences in the postoperative complication rates were found, and very similar outcomes regarding anastomotic leaks and oncological quality of resection were registered. Conclusion: The results of this study validate the safety and effectiveness of our pathway regarding the implementation of the TaTME approach, highlighting the fact that it should be done in a center with proficiency in minimally invasive rectal surgery. (AU)
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias Retais/cirurgia , Cirurgia Endoscópica Transanal/métodos , Período Pós-Operatório , Recidiva , Resultado do Tratamento , Duração da Cirurgia , Estadiamento de NeoplasiasRESUMO
In C4-HD murine mammary carcinomas and in human breast cancer T47D cells, we showed that medroxyprogesterone acetate (MPA) induces a nuclear physical association between estrogen receptor alpha (ERa) and progesterone receptors (PR). The blockade of ERa inhibits cell proliferation mediated by progestins. We hypothesized that this nuclear association between ERa/PR is necessary to trigger progestin-induced cell proliferation and tumor growth. We demonstrated that fulvestrant (FUL, ICI182.780) induced complete regression of C4-HD tumors growing with progestins. MPA treatment induced an early increase in both CCND1 and MYC expression in T47D cells. The blockade of ERa prevented the MPA-dependent transcription of both genes. Specific binding of PR/ERa was observed at the same MPA-sensitive regions at the CCND1 and MYC gene promoters after chromatin immunoprecipitation (ChIP) analysis. ICI inhibited binding of ERa to both gene regulatory sequences while PR binding was unaffected. The nuclear colocalization between both receptors in T47D cells was confirmed by: confocal microscopy, Duolink assays and co-immunoprecipitation assays. In breast cancer samples we also observed a nuclear interaction between both steroid receptors. Our results indicate that the presence of ERa interacting with activated PR at the CCND1 and MYC promoters is required to trigger progestin-induced gene transcription and cell proliferation in breast cancer cells.
Assuntos
Carcinoma/patologia , Estradiol/análogos & derivados , Receptor alfa de Estrogênio/fisiologia , Neoplasias Mamárias Experimentais/patologia , Receptores de Progesterona/fisiologia , Animais , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/genética , Carcinoma/induzido quimicamente , Carcinoma/tratamento farmacológico , Proliferação de Células , Imunoprecipitação da Cromatina , Ciclina D1/metabolismo , Estradiol/administração & dosagem , Receptor alfa de Estrogênio/efeitos dos fármacos , Feminino , Fulvestranto , Genes myc , Humanos , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/tratamento farmacológico , Acetato de Medroxiprogesterona/farmacologia , Murinae , Progestinas/metabolismo , Receptores de Progesterona/efeitos dos fármacos , Transcrição GênicaRESUMO
Synthetic progesterone used in contraception drugs (progestins) can promote breast cancer growth, but the mechanisms involved are unknown. Moreover, it remains unclear whether cytoplasmic interactions between the progesterone receptor (PR) and estrogen receptor alpha (ERα) are required for PR activation. In this study, we used a murine progestin-dependent tumor to investigate the role of ERα in progestin-induced tumor cell proliferation. We found that treatment with the progestin medroxyprogesterone acetate (MPA) induced the expression and activation of ERα, as well as rapid nuclear colocalization of activated ERα with PR. Treatment with the pure antiestrogen fulvestrant to block ERα disrupted the interaction of ERα and PR in vitro and induced the regression of MPA-dependent tumor growth in vivo. ERα blockade also prevented an MPA-induced increase in CYCLIN D1 (CCND1) and MYC expression. Chromatin immunoprecipitation studies showed that MPA triggered binding of ERα and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAi-mediated silencing of ERα inhibited ERα, but not PR binding to both regulatory sequences, indicating that an interaction between ERα and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ERα-PR association on target gene promoters is essential for progestin-induced cell proliferation.
Assuntos
Neoplasias da Mama/patologia , Ciclina D1/genética , Receptor alfa de Estrogênio/metabolismo , Genes myc , Neoplasias Mamárias Experimentais/patologia , Receptores de Progesterona/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Processos de Crescimento Celular/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Estradiol/análogos & derivados , Estradiol/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/genética , Feminino , Fulvestranto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Acetato de Medroxiprogesterona/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Hormônio-Dependentes/patologia , Regiões Promotoras Genéticas , Receptores de Progesterona/genéticaRESUMO
Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors which have been implicated in breast cancer. The aim of this study was to evaluate FGFR-1, -2, -3, and -4 protein expressions in normal murine mammary gland development, and in murine and human breast carcinomas. Using immunohistochemistry and Western blot, we report a hormonal regulation of FGFR during postnatal mammary gland development. Progestin treatment of adult virgin mammary glands resulted in changes in localization of FGFR-3 from the cytoplasm to the nucleus, while treatment with 17-ß-estradiol induced changes in the expressions and/or localizations of FGFR-2 and -3. In murine mammary carcinomas showing different degrees of hormone dependence, we found progestin-induced increased expressions, mainly of FGFR-2 and -3. These receptors were constitutively activated in hormone-independent variants. We studied three luminal human breast cancer cell lines growing as xenografts, which particularly expressed FGFR-2 and -3, suggesting a correlation between hormonal status and FGFR expression. Most importantly, in breast cancer samples from 58 patients, we found a strong association (P < 0.01; Spearman correlation) between FGFR-2 and -3 expressions and a weaker correlation of each receptor with estrogen receptor expression. FGFR-4 correlated with c-erbB2 over expression. We conclude that FGFR-2 and -3 may be mechanistically linked and can be potential targets for treatment of estrogen receptor-positive breast cancer patients.
Assuntos
Neoplasias da Mama/metabolismo , Glândulas Mamárias Animais/fisiologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Adulto , Idoso , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Pessoa de Meia-Idade , Gravidez , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Transplante HeterólogoRESUMO
Fibroblast growth factor (FGF) receptor 2 (FGFR-2) polymorphisms have been associated with an increase in estrogen receptor and progesterone receptor (PR)-positive breast cancer risk; however, a clear mechanistic association between FGFR-2 and steroid hormone receptors remains elusive. In previous works, we have shown a cross talk between FGF2 and progestins in mouse mammary carcinomas. To investigate the mechanisms underlying these interactions and to validate our findings in a human setting, we have used T47D human breast cancer cells and human cancer tissue samples. We showed that medroxyprogesterone acetate (MPA) and FGF2 induced cell proliferation and activation of ERK, AKT, and STAT5 in T47D and in murine C4-HI cells. Nuclear interaction between PR, FGFR-2, and STAT5 after MPA and FGF2 treatment was also showed by confocal microscopy and immunoprecipitation. This effect was associated with increased transcription of PRE and/or GAS reporter genes, and of PR/STAT5-regulated genes and proteins. Two antiprogestins and the FGFR inhibitor PD173074, specifically blocked the effects induced by FGF2 or MPA respectively. The presence of PR/FGFR-2/STAT5 complexes bound to the PRE probe was corroborated by using NoShift transcription and chromatin immunoprecipitation of the MYC promoter. Additionally, we showed that T47D cells stably transfected with constitutively active FGFR-2 gave rise to invasive carcinomas when transplanted into NOD/SCID mice. Nuclear colocalization between PR and FGFR-2/STAT5 was also observed in human breast cancer tissues. This study represents the first demonstration of a nuclear interaction between FGFR-2 and STAT5, as PR coactivators at the DNA progesterone responsive elements, suggesting that FGFRs are valid therapeutic targets for human breast cancer treatment.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Progesterona/metabolismo , Fator de Transcrição STAT5/metabolismo , Animais , Antineoplásicos Hormonais/farmacologia , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Acetato de Medroxiprogesterona/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de NeoplasiasRESUMO
Este trabajo consta de cinco etapas de investigación: I- Primera etapa: estuvo destinada a mostrar tres objetivos; 1) cómo medir exactamente el conducto raquídeo lumbar; 2) si existe estenosis o estrechez real del conducto y 3) si existe, si es capaz de provocar sintomatología. Aquí se realizó un estudio sobre piezas anatómicas de esqueleto sin y con lesiones degenerativas severas y de cadáver, en cuanto a su morfología y a la amplitud del conducto raquídeo, sometiéndolas luego a exploración con los métodos modernos de diagnóstico que disponíamos en ese momento, terminándose en hacer una correlación entre las imágenes obtenidas y los hallazgos quirúrgicos en 57 pacientes. II- Segunda etapa: con los datos obtenidos en la etapa anterior, se buscó una explicación fisiopatológica para el cuadro de Claudicación Intermitente No Vascular [CINV], por la discordancia existente entre la clínica y las imágenes de los estudios complementarios y para ello también se recurrió al análisis de piezas anatómicas relacionándolas con dichas imágenes y la observación minuciosa del conducto raquídeo en 119 columnas operadas. III- Tercera etapa: se buscó ver que utilidad reportaban la RMN y la flebografía espinal, para un mejor conocimiento del conducto raquídeo y su contenido, a fin de lograr una interpretación fidedigna frente a una patología del segmento espinal lumbar. IV- Cuarta etapa: consistió en la investigación morfológica y comprendió tres protocolos: 1) Anatómico: su propósito consistió en el estudio de las estructuras ligamentarias contenidas en los forámenes intervertebrales [ligamentos ductoconjugales o foraminales] y en el conducto raquídeo [ligamentos durales]. 2) Embriológico: su propósito consistió en el estudio de la embriogénesis de los ligamentos durales. La investigación de la anatomía del desarrollo de los mismos, tuvo como objetivo determinar su origen embriológico y modalidad inervatoria. 3) Histomorfológico: su propósito consistió en el estudio de la histomorfología de la fibrosis en las revisiones lumbosacras. V- Quinta etapa: consistió en la investigación terapéutica centrada básicamente en el análisis de las opciones quirúrgicas existentes y su evolución en el tiempo, hasta llegar a los conceptos actuales, sobre una casuística de 187 pacientes operados... (TRUNCADO)
Assuntos
Humanos , Escoliose , Estenose Espinal/cirurgia , Hipertrofia , Mielografia , Tomografia Computadorizada por Raios X , Vértebras Lombares/anatomia & histologia , Vértebras Lombares/lesõesRESUMO
Este trabajo consta de cinco etapas de investigación: I- Primera etapa: estuvo destinada a mostrar tres objetivos; 1) cómo medir exactamente el conducto raquídeo lumbar; 2) si existe estenosis o estrechez real del conducto y 3) si existe, si es capaz de provocar sintomatología. Aquí se realizó un estudio sobre piezas anatómicas de esqueleto sin y con lesiones degenerativas severas y de cadáver, en cuanto a su morfología y a la amplitud del conducto raquídeo, sometiéndolas luego a exploración con los métodos modernos de diagnóstico que disponíamos en ese momento, terminándose en hacer una correlación entre las imágenes obtenidas y los hallazgos quirúrgicos en 57 pacientes. II- Segunda etapa: con los datos obtenidos en la etapa anterior, se buscó una explicación fisiopatológica para el cuadro de Claudicación Intermitente No Vascular [CINV], por la discordancia existente entre la clínica y las imágenes de los estudios complementarios y para ello también se recurrió al análisis de piezas anatómicas relacionándolas con dichas imágenes y la observación minuciosa del conducto raquídeo en 119 columnas operadas. III- Tercera etapa: se buscó ver que utilidad reportaban la RMN y la flebografía espinal, para un mejor conocimiento del conducto raquídeo y su contenido, a fin de lograr una interpretación fidedigna frente a una patología del segmento espinal lumbar. IV- Cuarta etapa: consistió en la investigación morfológica y comprendió tres protocolos: 1) Anatómico: su propósito consistió en el estudio de las estructuras ligamentarias contenidas en los forámenes intervertebrales [ligamentos ductoconjugales o foraminales] y en el conducto raquídeo [ligamentos durales]. 2) Embriológico: su propósito consistió en el estudio de la embriogénesis de los ligamentos durales. La investigación de la anatomía del desarrollo de los mismos, tuvo como objetivo determinar su origen embriológico y modalidad inervatoria. 3) Histomorfológico: su propósito consistió en el estudio de la histomorfología de la fibrosis en las revisiones lumbosacras. V- Quinta etapa: consistió en la investigación terapéutica centrada básicamente en el análisis de las opciones quirúrgicas existentes y su evolución en el tiempo, hasta llegar a los conceptos actuales, sobre una casuística de 187 pacientes operados... (TRUNCADO)(AU)
Assuntos
Humanos , Hipertrofia , Mielografia , Tomografia Computadorizada por Raios X , Escoliose , Estenose Espinal/cirurgia , Vértebras Lombares/anatomia & histologia , Vértebras Lombares/lesõesRESUMO
Se presenta el cuarto caso mundial y el primero nacional de leiomioma del duodeno. Se trata de un hombre de 78 años de edad cuyo síntoma fundamental fue una hemorragia digestiva alta. Se describen los métodos diagnósticos y terapéuticos utilizados, enfatizando el papel decisivo de la biopsia por inclusión
Assuntos
Idoso , Humanos , Masculino , Neoplasias Duodenais/cirurgia , Leiomioma/cirurgia , Neoplasias Duodenais/complicações , Hemorragia Gastrointestinal/etiologia , Leiomioma/complicaçõesRESUMO
Se presenta el cuarto caso mundial y el primero nacional de leiomioma del duodeno. Se trata de un hombre de 78 años de edad cuyo síntoma fundamental fue una hemorragia digestiva alta. Se describen los métodos diagnósticos y terapéuticos utilizados, enfatizando el papel decisivo de la biopsia por inclusión (AU)