RESUMO
BACKGROUND AND AIMS: Self-renewal and differentiation of intestinal epithelium is a tightly regulated process, whose perturbations are implicated in human colorectal tumourigenesis. The insulin/insulin-like growth factor (IGF) signalling pathway may play an important role in intestinal epithelium homeostasis. Insulin receptor substrate 2 (IRS2) is a poorly characterised component in this pathway. METHODS: Using complementary in vitro and in vivo human and murine models, expression (mRNA and protein levels), localisation (immunohistochemistry) and regulation of IRS2 were investigated in the normal intestine and colorectal tumours. In silico analysis of the human IRS2 promoter was performed together with reporter and chromatin immunoprecipitation assays. RESULTS: Significant IRS2 expression was detected in the intestine, with specific protein localisation in the villus region of the ileum and in the surface epithelium of the colon. In human HT29 and Caco2 cells, IRS2 mRNA levels increased with spontaneous and induced differentiation, together with CDX2 (caudal-related homeobox protein 2), P21 and KLF4 (Krüppel-like factor 4). Adenoviral infection with human CDX2 induced IRS2 expression in APC- (adenomatous polyposis coli) and beta-catenin-mutated cells. On the other hand, IRS2 downregulation was observed in differentiated enterocytes after adenoviral infection with short hairpin CDX2 (shCDX2), in the intestine of CDX2 heterozygous mice and in colorectal tumours of Apc(Min/+) and patients with familial adenomatous polyposis (FAP). The human IRS2 promoter region presents several CDX2-binding sites where CDX2 immunoprecipitated in vivo. IRS2 reporters were functionally activated via CDX2 and blocked via a dominant-negative CDX2 protein. CONCLUSIONS: Combining gain- and loss-of-function approaches, an intriguing scenario is presented whereby IRS2 is significantly expressed in the apical intestinal compartment and is directly controlled by CDX2 in normal intestine and tumours.
Assuntos
Neoplasias Colorretais/química , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas Substratos do Receptor de Insulina/genética , Mucosa Intestinal/química , Neoplasia Endócrina Múltipla/metabolismo , Animais , Fator de Transcrição CDX2 , Diferenciação Celular , Linhagem Celular Tumoral , Colo , Células HT29 , Proteínas de Homeodomínio/análise , Proteínas de Homeodomínio/metabolismo , Humanos , Íleo , Imuno-Histoquímica , Proteínas Substratos do Receptor de Insulina/análise , Proteínas Substratos do Receptor de Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Mucosa Intestinal/metabolismo , Fator 4 Semelhante a Kruppel , Masculino , Camundongos , Regiões Promotoras Genéticas , Ligação Proteica , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
We analyzed the hMLH1 and hMSH2 genes in 30 unrelated hereditary nonpolyposis colorectal cancer (HNPCC) patients using mutational and immunohistochemical analyses combined whenever possible with primer extension assays, designed to estimate hMLH1 and hMSH2 transcript expression in peripheral blood lymphocytes. Single-strand conformational polymorphism screening and PCR-direct sequencing revealed seven hMLH1 and five hMSH2 sequence variants in 14 unrelated HNPCC patients, including three definite pathogenic mutations, four amino acid substitutions of uncertain pathogenic significance, and five polymorphisms. Immunohistochemistry indicated the lack of either hMLH1 or hMSH2 protein expression in tumors from 13 patients, and the absence of both hMLH1 and hMSH2 immunostaining was observed in the tumor from one additional case. The lack of hMLH1 or hMSH2 immunostaining was associated with the presence of microsatellite instability in the corresponding tumor and was also observed in tumors from patients negative for pathogenic mutations by mutational screening. There was a marked unbalance in the allelic expression of either hMLH1 or hMSH2 transcripts in three of eight unrelated HNPCC patients that could be analyzed, although a less marked unbalance was detected in two additional patients. Tumors from patients with germ-line unbalance in hMLH1 or hMSH2 transcript expression did not express the corresponding mismatch repair protein and displayed microsatellite instability. Our results indicate that constitutional alterations in hMLH1 and hMSH2 transcript expression may represent genetic markers for HNPCC carrier status also in cases in which mutational analysis did not detect a definite pathogenic variant. This suggests that transcript deregulation may represent a relevant mode of germ-line inactivation for mismatch repair genes.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Adaptadoras de Transdução de Sinal , Alelos , Proteínas de Transporte , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Análise Mutacional de DNA , Heterogeneidade Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Linfócitos/metabolismo , Repetições de Microssatélites , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/genética , Proteínas Nucleares , Mutação Puntual , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Deleção de Sequência , Transcrição GênicaRESUMO
BACKGROUND: Desmoid tumors (DTs), the result of an abnormal proliferation of connective tissue, occur frequently in familial adenomatous polyposis. Treatment of DT is difficult because of the high rate of recurrence after operation. Recently, antiestrogens and nonsteroidal antiinflammatory drugs have been used with good results as inhibitors of DT cell proliferation. METHODS: In this report we performed in vitro studies on cultured desmoid cells and skin fibroblasts of four patients who underwent surgical resection of DT and normal skin biopsy. We evaluated the expression of estrogen receptors and the mitogenic effect of 17 beta-estradiol and sulindac, a nonsteroidal antiinflammatory compound, on cell proliferation and collagen synthesis of desmoid cells. RESULTS: Proliferation and collagen synthesis of desmoid cells were stimulated by 17 beta-estradiol, and tamoxifen, an antiestrogenic compound, inhibited this effect. Desmoid cells also expressed estrogen receptors. Moreover, growth of desmoid cells from one of the patients was inhibited by sulindac. CONCLUSIONS: The in vitro evaluation of drug responsiveness in patients operated on for DT could be used as both a prognostic tool in the natural history of DT and in addressing pharmacologic therapy in this disorder.
Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Fibromatose Agressiva/tratamento farmacológico , Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/patologia , Adolescente , Adulto , Divisão Celular/efeitos dos fármacos , Criança , Colágeno/biossíntese , Estradiol/farmacologia , Fibromatose Agressiva/metabolismo , Fibromatose Agressiva/patologia , Humanos , Receptores de Estrogênio/metabolismo , Sulindaco/farmacologia , Células Tumorais CultivadasRESUMO
We reported previously that the expression of type 2 somatostatin receptor (sst2) was positively related to patient outcome in the childhood tumor neuroblastoma. To quantitate the expression of mRNA sst2 expression, we used a competitive RT-PCR assay. To improve the practicability of this measurement and its applicability to large groups of patients, we present here an original 'real-time' quantitative RT-PCR method, based on a dual-labeled fluorogenic probe and the TaqMan technology. By this method, we have measured sst2 mRNA expression in 24 breast cancer samples and 26 colon carcinomas as well as on the corresponding non-adjacent non-neoplastic tissue of the same patients. The proposed method has a dynamic range of 4 x 10(4) to 4 x 10(8) molecules of sst2 mRNA. The intra-assay precision of the test, evaluated as signal detection variability, was 2.4%. Accuracy, evaluated by the addition of standard RNA to unknown samples, provided a mean recovery of 98+/-2%. A significant correlation has been observed in a study performed in 24 neuroblastoma samples measured both with the proposed method and with a competitive RT-PCR assay (r=0.913, p<0.001). In our preliminary clinical study, no significant differences were observed in sst2 mRNA levels between normal and tumor specimens in both colorectal (normal tissue 5.1 x 10(7)+/-2.0 x 10(7) molecules/microg total RNA, cancer tissue 9.7 x 10(7)+/-4.2 x 10(7)) and breast tumors (normal tissue 5.5 x 10(8)+/-2.0 x 10(8), cancer tissue 4.4 x 10(8)+/-3,7 x 10(8)).However, in colorectal cancer, sst2 mRNA values of subjects with high circulating carcinoembryonic antigen (CEA) levels (>5 ng/ml) were statistically lower (2.3 x 10(7)+/-6.2 x 10(6) molecules/, microg total RNA; p<0.05) than those of subjects with low CEA concentration (1.4 x 10(8)+/-6.7 x 10(7)). Also, the sst2 mRNA ratio between normal and tumor tissue (N/T ratio) resulted significantly inversely related to CEA levels. In breast cancer, a significant difference was found between the mean N/T ratio of negative (below 10 fmol/mg protein) and positive estrogen receptor tumors (p<0.05). Analogous results were found selecting breast tumors on the basis of the progesterone receptor status (p<0.05). The proposed method is accurate, precise, sensitive and less labor-intensive than the competitive RT-PCR assay. For a correct evaluation of sst2 mRNA expression, it seems very important to measure the sst2 expression both in tumor and in the non-tumoral non-adjacent tumor specimens.
Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Corantes Fluorescentes/metabolismo , RNA Mensageiro/metabolismo , Receptores de Somatostatina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Neoplasias da Mama/química , Antígeno Carcinoembrionário/metabolismo , Neoplasias Colorretais/química , Feminino , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Neuroblastoma/genética , Neuroblastoma/patologia , Receptores de Somatostatina/metabolismo , Reprodutibilidade dos Testes , Coloração e Rotulagem , Taq Polimerase/metabolismo , Células Tumorais CultivadasRESUMO
Patients affected by inflammatory bowel disease (IBD) frequently suffer from thromboembolic events. Aims of this study were to investigate hemostatic system and the presence of antiphospholipid antibodies (aPL) in IBD patients. Forty-one patients affected by Crohn's disease (CD) and 19 by ulcerative colitis (UC) were studied, compared to 40 healthy control subjects. Platelet count (PLT), PT, aPTT, fibrinogen (Fib), prothrombin fragment F1+2, antithrombin (AT), protein C (PC), protein S (PS), factor XIII (FXIII), plasminogen (PLG), plasminogen activator inhibitor (PA1), spontaneous platelet aggregation in platelet-rich plasma (PRP-SPA) and in whole blood (WB-SPA), and antiphospholipid antibodies (aPL) were evaluated. PLT, Fib, F1+2 and WB-SPA were significantly increased in IBD patients (p at least <0.05) both in active and inactive phases; aPL positivity was more frequent (p<0.05) and FXIII was significantly decreased (p<0.05) in comparison to control subjects. The thrombophilic state of IBD patients is not related to the degree of activity of the disease or to previous thrombotic events; aPL express the immunological alterations connected with IBD and are not the main cause of thrombotic events.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Coagulação Sanguínea/imunologia , Colite Ulcerativa/sangue , Doença de Crohn/sangue , Hemostasia/fisiologia , Trombose/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Colite Ulcerativa/complicações , Colite Ulcerativa/imunologia , Doença de Crohn/complicações , Doença de Crohn/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In Crohn's disease (CD) a condition of hypercoagulability with increased risk for thrombotic events has been reported. In this study we have investigated hemostatic parameters in thirty-one patients affected by CD before, 3 and 12 months after bowel operation, and in thirty healthy controls. Before surgery platelet number (PLT), fibrinogen (Fbg), prothrombin fragment F1 + 2 (F1 + 2), PAI and whole blood-spontaneous platelet aggregation (WB-SPA) were significantly higher (p at least < 0.0005) in patients than in controls, while factor XIII (F XIII) was significantly lower (p at least < 0.005). Three and twelve months after surgery PLT, FBG and WB-SPA significantly decreased in comparison to pre-surgery values (respectively p at least < 0.05 and p < 0.01), but PLT and Fbg were still significantly higher than in controls at 3 and 12 months (p < 0.01). At three and 12 months after operation F XIII was significantly higher in comparison with pre-surgery values (p at least < 0.05). The presence of antiphospholipid antibodies (aPL) was not different between CD patients and controls before surgery, whereas it significantly increased 12 months after surgery (p < 0.05). Our results suggest that in CD hemostatic changes are only in part influenced by local flogistic processes and that an inflammatory systemic condition may provoke both the bowel and extraintestinal manifestations of CD.
Assuntos
Colostomia , Doença de Crohn/fisiopatologia , Doença de Crohn/cirurgia , Hemostasia/fisiologia , Adolescente , Adulto , Anticorpos Antifosfolipídeos/sangue , Fator XIII/metabolismo , Feminino , Fibrinogênio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Inativadores de Plasminogênio/sangue , Agregação Plaquetária , Contagem de Plaquetas , Protrombina/metabolismo , Índice de Gravidade de DoençaRESUMO
The aim of this study was to evaluate the relationship between DNA ploidy, proliferative activity and other prognostic factors and the survival of patients with colorectal cancer. 45 patients were prospectively investigated for 6 years. Fresh multiple samples for flow cytometric analysis of DNA content were collected during surgical resection of primary tumor. A 42% frequency of aneuploidy was observed with a median DNA index value of 1.54. The proliferative activity (%S+G2M cells) was higher in the aneuploid cell sub-population (28.6%) compared to the diploid counterpart (22.7%)(p = 0.05). No significant relationship between DNA ploidy and tumor site, Dukes' stage, histological type, grading age or sex was observed. No correlation between DNA ploidy and survival was demonstrated, including in the analysis of patient subsets according to stage. No additive prognostic information was obtained from a breakdown analysis as a function of DI values, percentages of aneuploid cells and proliferative activity. This study suggests that flow cytometric content analysis lacks prognostic value in colorectal carcinoma.
Assuntos
Neoplasias Colorretais/patologia , DNA de Neoplasias/análise , Citometria de Fluxo , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Divisão Celular , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , PrognósticoRESUMO
The study of the antiproliferative action of somatostatin (ss) is important not only to understand the regulation of neuroendocrine tumours that express receptors (sst), but also non-endocrine tumours which express these receptors. We previously demonstrated the presence of sst2 in a wide panel of cell lines from human neuroblastoma. Although hypotheses have been put forward that treatment with ss or its analogs may be beneficial in oncological patients, this does not appear to be the case in neuroblastoma; patients with high sst2 levels (who are therefore sensitive to ss treatment) have per se a relatively positive outcome. Therefore, adjuvant treatment with ss is not necessary. Viceversa, patients with a poor prognosis are essentially characterized by a low expression of sst2 (and therefore are insensitive to a therapy with ss). In these patients adjuvant treatment with ss might be indicated, but would have little chance of success. Although the majority of neuroendocrine tumours expresses sst2, pancreas and prostate cancer express sst1 but not sst2, and are therefore insensitive to octreotide treatment which binds preferentially to sst2. Tumours like colorectal carcinoma and breast cancer also express sst2 in their more favourable forms. However, the concentration of sst2 in colorectal cancer is similar, if not lower than that in the surrounding normal tissue. Therefore, the probability of successful adjuvant therapy with ss is relatively low. In breast cancer, it is possible that sensitivity to estrogens may have a positive influence on the expression of sst2. This might justify clinical trials with ss in breast cancer.
Assuntos
Proteínas de Neoplasias/fisiologia , Neoplasias/metabolismo , Receptores de Somatostatina/fisiologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Masculino , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias/tratamento farmacológico , Neuroblastoma/genética , Neuroblastoma/metabolismo , Octreotida/uso terapêutico , Receptores de Somatostatina/biossíntese , Receptores de Somatostatina/genética , Somatostatina/fisiologia , Somatostatina/uso terapêuticoRESUMO
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomical dominant trasmitted disease phenotypically defined according to the "Amsterdam criteria" as follows: at least 3 affected relatives, one of whom first degree relative of other two, at least two successive generations affected. Important cardinal features are: 1) prevalent proximal location of cancers (above splenic flexure); 2) multiple synchronous or methachronous large bowel cancers; 3) early age of onset (<50 years); 4) presence of extracolonic cancers (endometrium, stomach, urinary tract, skin). The treatment is essentially surgical and total colectomy with ileo-rectum anastomosis is already proposed as standard procedure with annual endoscopic examination of retained rectum. The screening of individuals at risk, so determined by the analysis of pedigree or the results of molecular tests, must be performed every 1-2 years by colonoscopy starting around the age of 25 years. In this review are described and analysed the spectrum of the disease with particular attention to the frequency and characteristics of extracolonic cancers. Moreover, the guidelines of the surveillance and screening are reported following the data of the literature and as proposed by the International Collaborative Group (ICG-HNPCC).
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Idade de Início , Colectomia/métodos , Neoplasias Colorretais/complicações , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/genética , Diagnóstico Diferencial , Humanos , Transmissão Vertical de Doenças Infecciosas , Neoplasias Primárias Múltiplas , Segunda Neoplasia Primária , Vigilância da PopulaçãoRESUMO
Despite recent technical advances in diagnostic imaging (computerised tomography, magnetic resonance), intramuscular haemangiomas are relatively uncommon and often difficult to diagnose. Angiosarcomas are probably the most important tumour to be differentiated from hemangiomas, in order to define the optimal therapeutic approach. Only biopsy allows a proper preoperative diagnosis, although this diagnostic technique involves some risks. Total excision is the treatment of choice. Radiotherapy has been employed without substantial results. A review of the literature and a case report are presented here.
Assuntos
Hemangioma/diagnóstico , Hemangiossarcoma/diagnóstico , Doenças Musculares/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adulto , Diagnóstico Diferencial , Hemangioma/patologia , Hemangioma/terapia , Hemangiossarcoma/patologia , Hemangiossarcoma/terapia , Humanos , Imageamento por Ressonância Magnética , Masculino , Doenças Musculares/patologia , Doenças Musculares/terapia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia , Coxa da Perna , Tomografia Computadorizada por Raios XRESUMO
Only recently, in our laboratory of experimental surgery, we started with a protocol for orthotopic liver transplantation (OLT) in a pig model. This was felt as mandatory for experimental purposes as well as for future clinical applications at our center. We report herein our own experience with 41 OLTx. Intraoperative "lethal" complications occurred in up to 32% (14/41) whereas postoperative complications occurred in the remainders at different intervals of time with a maximum survival of 30 days. No attention was paid to prevent rejection-infection episodes. The main cause of death was the primary non-function (PNF) or dis-function (PDF) manifested either intra or postoperatively in 16 out the 41 OLTx (39%). Intraoperative technical errors accounted for up to 9% (4/41 OLTx). Acute hemorrhage gastritis and gastric perforations occurred postoperatively in 6 animals (14%) and represent one of the peculiar aspects of OLT in pig model.
Assuntos
Transplante de Fígado/métodos , Animais , Complicações Intraoperatórias/epidemiologia , Complicações Intraoperatórias/etiologia , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Taxa de Sobrevida , SuínosRESUMO
Much recent data have been published on the risk of local recurrence (LR) following curative surgery for rectal cancer and the impact of adjuvant therapy. On the other hand, improvements in surgical techniques, as the total mesorectal excision, have apparently reduced the risk of LR. Furthermore, in selected cases, neoadjuvant therapy seems to reduce much more the incidence of LR. A list of prognostic factors which affect the onset of LR, other than the different procedures, was considered. To investigate such evidences a retrospective analysis was undertaken in our series, focusing on examination of the employed techniques as potential predictors of local recurrence. Thus, in a 18-yr-period (1986-2003), two hundred and ninety-five patients who had undergone elective curative surgical resection of rectal cancer were included in the study. The demographic, operative and follow-up data were collected retrospectively. All patients underwent total mesorectal excision, whereas neoadjuvant therapy was performed in a selected series of patients, according to defined entry criteria patterns. Results evidenced LR in 7.1% of patients and occurred between 6 months to 8 year following surgery. Comparisons were made between patients who had different surgical procedures; indeed sphyncter saving procedures correlated with a higher incidence of LR rather than abdomino-perineal resection. Pelvic recurrences were observed more frequently compared to the anastomotic ones. A limited number of patients with LR underwent surgery due to the associated condition of metastatic lesions; the follow-up related to such series evidenced a mortality rate of 57% within 3 year from reoperation. A low local recurrence rate can be achieved after total mesorectal excision (TME) without preoperative radiotherapy. Our results suggest that preoperative radiotherapy may be employed only for those patients who are at a higher risk for local recurrence.
Assuntos
Recidiva Local de Neoplasia/epidemiologia , Neoplasias Retais/cirurgia , Terapia Combinada , Humanos , Neoplasias Retais/terapia , Estudos RetrospectivosRESUMO
Familial adenomatous polyposis (FAP) is characterized by multiple adenomatous colorectal polyps, some of which progress to adenocarcinoma in the absence of surgery. Colectomy with ileorectal anastomosis still remains much in use, although strict surveillance of the rectal stump is necessary to prevent rectal cancer. After 1983, sulindac has been used to control rectal polyps in about 90 FAP patients, at doses of 150-400 mg/day. The treatment was well tolerated, and regression of the polyps was frequently observed. However, recurrence of polyps was sometimes observed, and the onset of rectal cancer during sulindac therapy was also reported. A review of the literature and the personal experience of the authors are here presented, discussing the pharmacological profile and possible mechanisms of action of sulindac.
Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Sulindaco/uso terapêutico , Adulto , Animais , Ensaios Clínicos como Assunto , Neoplasias Colorretais/prevenção & controle , Humanos , Camundongos , Sulindaco/farmacologiaRESUMO
BACKGROUND AND OBJECTIVES: Ileorectal anastomosis (IRA) is still used in the treatment of familial adenomatous polyposis (FAP). Sulindac appears to induce regression of colorectal adenomas; however, its effects in long-term therapy and in preventing carcinoma remain unclear. METHODS: Fifteen FAP patients treated by IRA received sulindac (200 mg/day) for a mean period of 48.6 +/- 28.7 (range 12-124) months. Number, size, and type of rectal polyps were assessed by endoscopic and histological evaluation every 6 months. RESULTS: Significant regression of polyps was observed in all patients after 6 months (P < 0.02). However, after a mean of 48.6 +/- 28.7 months, both number and size of polyps increased again, showing no statistical difference with baseline values. Minute polyps appeared reddish, while the largest lesions were flat or slightly elevated. Endoscopic polypectomy was necessary in 9 patients and transanal surgical excision in 3. Two patients were submitted to restorative proctectomy because of a large polyp with severe dysplasia and a rectal cancer, respectively. CONCLUSIONS: Sulindac appears to influence the morphological appearance of polyps in FAP patients, inducing apparent regression. However, at a dose of 200 mg, it does not influence the progression of polyps toward a malignant pattern.
Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Neoplasias Retais/prevenção & controle , Sulindaco/uso terapêutico , Polipose Adenomatosa do Colo/patologia , Polipose Adenomatosa do Colo/cirurgia , Adolescente , Adulto , Neoplasias Colorretais/patologia , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proctocolectomia Restauradora , Neoplasias Retais/patologiaRESUMO
Recently a few cases of pigment epithelium hypertrophy associated with Gardner's syndrome and familial polyposis have been described. The authors report the results of an ophthalmoscopic investigation on patients affected by Gardner's syndrome and familial polyposis. The importance of the ophthalmoscopic finding associated with this type of intestinal pathology is discussed.
Assuntos
Polipose Adenomatosa do Colo/complicações , Síndrome de Gardner/complicações , Epitélio Pigmentado Ocular/patologia , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Hipertrofia/complicações , Masculino , Pessoa de Meia-IdadeRESUMO
Surgical treatment of familial adenomatous polyposis (FAP) is still controversial. From 1984 we carried out a prospective evaluation of total colectomy with ileorectal anastomosis (IRA) and restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) to determine differences in postoperative complications, functional results, occurrence of desmoids, and recurrence of polyps in the rectal stump. IRA was performed below the peritoneal reflection and was indicated in the absence of rectal cancer and in the presence of fewer than 10 polyps or minute polyposis in the last 10 cm of the rectal mucosa. IRA patients underwent a regular endoscopic follow-up and prolonged sulindac administration (100 mg twice daily). When criteria for IRA were absent, IPAA was performed adopting a manual anastomosis at the pectinate line. Fourteen patients were operated with IRA and 24 with IPAA. There was no difference in sex and age between the two groups of patients. The number of rectal polyps was significantly different in the two groups. Immediate postoperative complications were observed in only five IPAA patients, three of whom (12%) required reoperation. Late postoperative complications occurred more frequently in IRA patients (14%) than in IPAA patients (4%). Desmoids developed in both groups (five in the IRA group and four in IPAA group). The number of bowel movements was similar in both groups, but 25% of IPAA patients complained of nocturnal fecal soiling. Fulguration or polypectomy for recurrent polyps was necessary in all but two IRA patients at follow-up. The rectal stump was easily eradicated by polyps in all but four patients with minute polyps at surgery. In the latter patients a diffuse or carpeting rectal polyposis occurred. IPAA can give optimum control of colorectal polyposis in FAP patients with an acceptable incidence of postoperative complications and satisfactory functional results. This type of surgical procedure is indicated in most FAP patients, and IRA should be reserved for patients without polyps or with fewer than 10 polyps in the rectal stump; otherwise growth of polyps cannot be adequately controlled.
Assuntos
Polipose Adenomatosa do Colo/cirurgia , Proctocolectomia Restauradora , Reto/cirurgia , Adolescente , Adulto , Anastomose Cirúrgica , Criança , Colectomia , Feminino , Humanos , Íleo/cirurgia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos ProspectivosRESUMO
The proliferative activity and polyamine levels of the rectal epithelium in unoperated ulcerative colitis patients and in ulcerative colitis patients after total colectomy and ileorectal anastomosis were determined and compared with control subjects. Cell proliferation was evaluated in rectal biopsies by in vitro 3H thymidine incorporation by measuring the labeling index and the position of labeled cells along the crypt; polyamines were determined with a chromatographic method. In ulcerative colitis patients the labeling index was significantly increased, and labeled cells were shifted toward the upper part of the crypt when compared with controls. Ileorectal anastomosis patients showed a normalization of the labeling index and a distribution of labeled cells similar to controls. Polyamine levels were also increased in ulcerative colitis patients; in ileorectal anastomosis patients, the level of polyamines was decreased in respect to unoperated patients and return to normal values except for spermine. Because the increased proliferation and higher polyamine levels are related to increased colon cancer risk, our results confirm that ulcerative colitis is a risk factor for the development of carcinoma. Ileorectal anastomosis may reduce this risk through a normalization of mucosal cell proliferative activity and of some polyamine levels.
Assuntos
Colite Ulcerativa/patologia , Íleo/cirurgia , Mucosa Intestinal/patologia , Reto/patologia , Reto/cirurgia , Adolescente , Adulto , Análise de Variância , Anastomose Cirúrgica , Autorradiografia , Divisão Celular , Colite Ulcerativa/cirurgia , Feminino , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Poliaminas/metabolismo , TimidinaRESUMO
The accurate staging of rectal carcinoma is very important for treatment planning. The histological data obtained from the surgical specimens of 22 patients with rectal carcinoma were compared with pre- and postoperative endorectal US findings and with preoperative CT results. According to an adapted version of the Astler and Coller classification, the different degrees of tumor spread into the rectal wall were represented as follows: stage A: 1 patient; stage B1: 5 patients; stage B2: 6 patients; stage C1: 1 patient; stage C2: 8 patients and stage D: 1 patient. Preoperative staging, based on the overall results of CT and US, was in agreement with histology in 19 of 22 cases. Individual analysis of US and CT results, in comparison with histological data, showed US staging accuracy to be 77.3% (17/22 patients). US accuracy in demonstrating tumor spread into the rectal wall (stages A, B1, C1) was 100% (7/7 patients); US was 70% accurate in lymph node detection (7/10 patients) and 93.3% accurate in demonstrating perirectal infiltration (14/15 patients). CT diagnostic accuracy was 66.7% (10/15 patients) in the evaluation of perirectal lymph nodes, but tumor spread into the rectal wall (stages A and B1) could not be evaluated. While admitting the primary role of US in the staging of rectal carcinoma, according to our results a combination of US and CT yields a more accurate preoperative diagnostic picture.
Assuntos
Cuidados Pré-Operatórios/métodos , Neoplasias Retais/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Retais/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Ultrassonografia/métodosRESUMO
BACKGROUND/AIMS: Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), decreases the occurrence of polyps in patients with familial adenomatous polyposis (FAP). The effects of colectomy with ileorectal anastomosis (IRA) and sulindac treatment on rectal mucosa proliferation and polyp occurrence were examined in patients with FAP. METHODS: The number and size of rectal polyps were measured with colonoscopy. The labeling index, the percentage of labeled cells per crypt compartment, was assessed in rectal biopsy specimens with [3H]thymidine incorporation and autoradiography in 6 non-IRA and 14 IRA patients before and after treatment with 200 mg of sulindac/day for 60 days. RESULTS: The IRA patients had a lower labeling index and a decrease in the percentage of labeled cells in the upper compartment of the crypt (P < 0.01) relative to non-IRA subjects. Sulindac did not influence the labeling index and the distribution of labeled cells along the crypt. On the contrary, a dramatic decrease in the size and number of polyps was observed after sulindac treatment (P < 0.001). CONCLUSIONS: The persistence of a abnormal mucosal proliferation after sulindac therapy, in spite of the reduction of polyp number, suggests caution in assuming a lower risk of rectal cancer in patients with FAP.
Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Pólipos Intestinais/prevenção & controle , Neoplasias Retais/prevenção & controle , Reto/patologia , Sulindaco/uso terapêutico , Polipose Adenomatosa do Colo/patologia , Polipose Adenomatosa do Colo/cirurgia , Adolescente , Adulto , Anastomose Cirúrgica , Divisão Celular/efeitos dos fármacos , Criança , Feminino , Humanos , Íleo/cirurgia , Masculino , Pessoa de Meia-Idade , Reto/cirurgiaRESUMO
BACKGROUND: Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is the most common extracolonic manifestation of familial adenomatous polyposis (FAP) and is an early clinical marker of the disease. It seems to be correlated with the position of constitutional mutations of the adenomatous polyposis coli (APC) gene. METHODS: The authors investigated the expression of CHRPE and its correlation with the position of the APC gene in FAP patients and in "at risk" relatives from 31 FAP kindreds. To obtain comparable data on CHRPE expression, the authors developed a novel scoring system based on morphologic and dimensional criteria. RESULTS: A positive CHRPE score was obtained in 29 of 39 FAP patients (74%) and in 16 of 53 relatives who showed no clinical evidence of FAP (30%). Colonoscopy revealed polyps in 20 of the 47 relatives who could be examined. The cumulative sensitivity and specificity of CHRPE were 72.88% and 96.29%, respectively. APC gene mutations were characterized in 34 subjects from 17 kindreds. In 28 of the subjects, mutations were detected in exon 15, between codons 876 and 1324. Mutations were found in exon 9 in 6 subjects. In 3 of the 6 subjects, they were found at the site where both forms of alternative splicing of the exon occur (codon 437). In the other 3 subjects (another kindred), mutations were found in the portion of exon 9 in which alternative splicing occurs (codon 367). Only 1 of the 6 subjects (16.6%) with mutations in exon 9 had a positive CHRPE score, compared with 28 of 28 subjects (100%) with mutations in exon 15. None of the 3 subjects with mutations in codon 437 had a positive CHRPE score. The CHRPE scores of exon 15 mutation carriers varied markedly both within and among kindreds, irrespective of the mutation site. CONCLUSIONS: The results of this study indicate that the site of APC gene mutation influences CHRPE expression but is not the only factor responsible for the presence and level of retinal lesions in FAP patients.