RESUMEN
The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-2alpha protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n=90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1alpha and HIF-2alpha expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1alpha and HIF-2alpha, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (P<0.001) and associated with poor survival (hazard ratio (HR)=8.7, P<0.005) and decreased disease-free survival (HR=4.7, P<0.005). hypoxia-inducible factor-1alpha and -2alpha were expressed in >50% of rectal cancers (HIF-1alpha, 54%, 48/90; HIF-2alpha, 64%, 58/90). HIF-1alpha positivity was associated with both TNM stage (P<0.05) and vascular invasion (P<0.005). In contrast, no associations were demonstrated [corrected] between HIF-2alpha [corrected] and any pathological features or [corrected] outcome. The study showed an independent association between HIF-1alpha expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1alpha, but not HIF-2alpha, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management.
Asunto(s)
Adenocarcinoma/diagnóstico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias del Recto/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Pronóstico , Neoplasias del Recto/metabolismo , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Análisis de SupervivenciaRESUMEN
AIM: The mechanism by which neoplasias respond to hypoxia determines their biological behavior and prognosis. Understanding the biology of tumors under hypoxic conditions is crucial for the development of anti-angiogenic therapy. Using the largest cohort of rectal adenocarcinomas to date, this study aimed to assess microvessel density (MVD) and carbonic anhydrase-9 (CA-9) expression and to correlate the results with recurrence and cancer-specific survival. MATERIALS AND METHODS: Patients (n=101) who underwent surgery for rectal adenocarcinoma without previous neoadjuvant therapy or metastatic disease were selected. MVD and CA-9 expression were assessed immunohistologically by using the CD34 antibody and the MN/CA9 M75 antibody, respectively. In a multifactorial analysis, the results were correlated with tumor stage, recurrence rate, and long-term survival. RESULTS: MVD was higher with increased T- and N-stages (p<0.01) and associated positively with poor survival (hazard ratio (HR) 1.3 per 10 vessel increase, p<0.01). CA-9 was expressed in 73% of cancers. Negative lymph node status correlated with CA-9 positivity (p<0.05), reflected in a higher rate of CA-9 positivity in earlier Dukes' stages (p<0.05). CA-9 positivity across tumor node metastasis (TNM) stages approached significance (Stage I/II: 80% CA-9 positive vs. 20% CA-9 negative; Stage III: 63% CA-9 positive vs. 37% negative, p=0.051). A trend was seen towards better cancer-specific survival in patients with CA-9 positive carcinomas (HR 0.51, p=0.07) on univariate analysis. DISCUSSION: MVD was higher in more advanced T- and N-stages and may be used as a determinant of survival in patients with rectal adenocarcinomas. CA-9 expression was seen more often in earlier Dukes' stages, possibly representing an early tumor hypoxic response. CA-9 expression by adenocarcinoma cells may confer long-term survival advantage in surgically treated rectal cancer.
Asunto(s)
Adenocarcinoma/irrigación sanguínea , Adenocarcinoma/enzimología , Antígenos de Neoplasias/análisis , Biomarcadores de Tumor/análisis , Anhidrasas Carbónicas/análisis , Microvasos/patología , Neoplasias del Recto/irrigación sanguínea , Neoplasias del Recto/enzimología , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Anhidrasa Carbónica IX , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Recurrencia , Medición de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: The present study investigated the risk of lymph node metastasis according to the depth of tumour invasion in patients undergoing resection for rectal cancer. METHOD: The histology of patients undergoing oncological resection with regional lymphadenectomy for rectal cancer at St Marks Hospital from 1971 to 1996 was reviewed. Of the total number of 1549 patients, 303 patients with T(1) or T(2) rectal cancers were selected. The tumour type, grade, evidence of vascular invasion, depth of submucosal invasion (classed into 'sm1-3') were evaluated as potential predictors of lymph node positivity using univariate and multi-level logistic regression analysis. RESULTS: Tumour stage was classified as T(1) in 55 (18.2%) and T(2) in 248 (81.2%) patients. The incidence of lymph node metastasis in the T(1) group was 12.7% (7/55), compared to 19% (47/247) in the T(2) group. The node positive and negative groups were similar with regard to patient demographics, although the former contained a significantly higher number of poorly differentiated (P = 0.001) and extramural vascular invasion tumours (P = 0.002). There was no significant difference in the number of patients with sm1-3, or T(2) tumour depths within the lymph node positive and negative groups. On multivariate analysis the presence of extramural vascular invasion (odds ratio = 10.0) and tumour grade (odds ratio for poorly vs well-differentiated = 11.7) were independent predictors of lymph node metastasis. CONCLUSION: Whilst the degree of vascular invasion and poor differentiation of rectal tumours were significant risk factors for lymph node metastasis, depth of submucosal invasion was not. This has important implications for patients with superficial early rectal cancers in whom local excision is being considered.
Asunto(s)
Escisión del Ganglio Linfático/estadística & datos numéricos , Ganglios Linfáticos/patología , Invasividad Neoplásica/patología , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Biopsia con Aguja , Estudios de Cohortes , Colectomía/métodos , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Probabilidad , Pronóstico , Neoplasias del Recto/cirugía , Estudios Retrospectivos , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
OBJECTIVE: It is not common that, after diversion of the faecal stream by a colostomy, the defunctioned colon develops colitis. The pathogenesis of this colitis is still unclear and it has been proposed that ischaemia may play a major role. Our aim is to look for signs of ischaemia in a group of patients developing colitis after diversion colostomy for various causes. METHOD: Surgical specimens from 32 patients resected for colitis developed after diverting colostomy were examined with routine (haematoxylin-eosin) and Elastic-Van Gieson and Perls' stains. RESULTS: The histological features related to mucosal crypt architecture, crypt epithelium and inflammation were mild, non specific or related to the underlying disease. Fibrosis was present in 21 (65.6%) patients, superficial coagulative necrosis was found in 18 (56%) patients, splitting and/or thickening of muscularis mucosae was present in 20 (62%) patients. The vessels were substantially normal or ectasic without thrombi or alterations in the wall. Evident ischaemia with coagulative necrosis, submucosal oedema and focal fibrosis was detected in only two (6%) patients and an intermediate picture between acute and chronic ischaemia was present in 16 (50%) patients. CONCLUSION: It is possible that ischaemia plays some role in the pathogenesis of diversion colitis; however, further studies are needed to firmly establish its role.
Asunto(s)
Colitis/diagnóstico , Colitis/patología , Isquemia/diagnóstico , Isquemia/patología , Adolescente , Adulto , Anciano , Preescolar , Estudios de Cohortes , Colostomía/métodos , Femenino , Fibrosis/patología , Humanos , Recién Nacido , Inflamación , Masculino , Persona de Mediana Edad , Membrana Mucosa/patología , Estudios RetrospectivosRESUMEN
Patients with multiple (5-100) colorectal adenomas (MCRAs) often have no germline mutation in known predisposition genes, but probably have a genetic origin. We collected a set of 25 MCRA patients with no detectable germline mutation in APC, MYH/MUTYH or the mismatch repair genes. Extracolonic tumours were absent in these cases. No vertical transmission of the MCRA phenotype was found. Based on the precedent of MYH-associated polyposis (MAP), we searched for a mutational signature in 241 adenomatous polyps from our MCRA cases. Somatic mutation frequencies and spectra at APC, K-ras and BRAF were, however, similar to those in sporadic colorectal adenomas. Our data suggest that the genetic pathway of tumorigenesis in the MCRA patients' tumours is very similar to the classical pathway in sporadic adenomas. In sharp contrast to MAP tumours, we did not find evidence of a specific mutational signature in any individual patient or in the overall set of MCRA cases. These results suggest that hypermutation of APC does not cause our patients' disease and strongly suggests that MAP is not a paradigm for the remaining MCRA patients. Our MCRA patients' colons showed no evidence of microadenomas, unlike in MAP and familial adenomatous polyposis (FAP). However, nuclear beta-catenin expression was significantly greater in MCRA patients' tumours than in sporadic adenomas. We suggest that, at least in some cases, the MCRA phenotype results from germline variation that acts subsequent to tumour initiation, perhaps by causing more rapid or more likely progression from microadenoma to macroadenoma.
Asunto(s)
Adenoma/genética , Neoplasias Colorrectales/genética , ADN Glicosilasas/genética , Genes APC , Mutación de Línea Germinal , Poliposis Adenomatosa del Colon/genética , Adulto , Anciano , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Pérdida de Heterocigocidad , Persona de Mediana Edad , beta Catenina/genéticaAsunto(s)
Colitis/diagnóstico , Colon/irrigación sanguínea , Diverticulitis del Colon/diagnóstico , Isquemia/diagnóstico , Anciano de 80 o más Años , Colitis/etiología , Colitis/patología , Colon/patología , Constricción Patológica/patología , Diagnóstico Diferencial , Diverticulitis del Colon/complicaciones , Diverticulitis del Colon/patología , Femenino , Hemorragia Gastrointestinal/etiología , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/patología , Obstrucción Intestinal/complicaciones , Obstrucción Intestinal/etiología , Isquemia/complicaciones , Isquemia/patologíaRESUMEN
Indeterminate colitis is only a partial diagnosis, which is provisional until sufficient information becomes available for a more precise diagnosis of either ulcerative colitis or Crohn's disease. As originally defined, i.e. based only on the pathological features in the colon resected for fulminant colitis, a few patients eventually developed Crohn's disease. If the term is used only after all available clinical and investigative evidence is considered, 'indeterminate colitis' behaves clinically like ulcerative colitis. This has important implications for pouch surgery.
Asunto(s)
Colitis/diagnóstico , Colon/patología , Colitis/cirugía , Colitis Ulcerosa/diagnóstico , Reservorios Cólicos/normas , Enfermedad de Crohn/diagnóstico , Diagnóstico Precoz , Humanos , Proctocolectomía Restauradora , PronósticoRESUMEN
OBJECTIVE: To analyse somatic molecular changes, clinicopathological features, family history, and germline mutations in families with colorectal cancer (CRC). METHODS: Molecular changes (K-ras and beta-catenin mutations, chromosome 18q allele loss (LOH), APC LOH, microsatellite instability (MSI), and expression of beta-catenin and p53) were examined in four series of CRC patients with proven or probable hereditary disease: hereditary non-polyposis colon cancer (HNPCC); MYH associated polyposis (MAP); multiple (>5) colorectal adenomas without familial adenomatous polyposis (FAP); and other families/cases referred to family cancer clinics (FCC series). HNPCC was diagnosed using a combination of germline mutation screening and tumour studies. A series of unselected CRC patients was also studied. RESULTS: There was overlap between genetic pathways followed by each type of CRC, but significant differences included: increased frequency of K-ras mutation and reduced frequency of APC LOH in cancers from MAP, but not from multiple adenoma patients; reduced frequency of LOH in HNPCC CRCs; and increased MSI in CRCs from HNPCC, but not from FCC or multiple adenoma patients. HNPCC was apparently detected efficiently by combined germline and somatic analysis. Cancers from the FCC, unselected, and multiple adenoma series shared similar molecular characteristics. In the FCC and multiple adenoma series, hierarchical cluster analysis using the molecular features of the cancers consistently identified two distinct groups, distinguished by presence or absence of K-ras mutation. CONCLUSIONS: While K-ras mutation status is known to differentiate hereditary bowel cancer syndromes such as MAP and FAP, it may also distinguish groups of non-HNPCC, FCC patients whose disease has different, as yet unknown, genetic origins.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Adulto , Alelos , Análisis por Conglomerados , Análisis Mutacional de ADN , Genes ras , Humanos , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Persona de Mediana Edad , Modelos Genéticos , MutaciónRESUMEN
BACKGROUND AND AIMS: The risk of colorectal cancer is increased in ulcerative colitis (UC). Patients with UC have diverse colonoscopic appearances. Determining colonoscopic markers for cancer risk could allow patient risk stratification. PATIENTS AND METHODS: Following on from an earlier study which demonstrated a correlation between inflammation severity and neoplasia risk, a case control study was performed to look for colonoscopic markers of colorectal neoplasia risk in UC. Each patient with neoplasia detected between 1988 and 2002 was matched with two non-dysplastic colitic controls. Data were collected on post-inflammatory polyps, scarring, strictures, backwash ileitis, a shortened, tubular, or featureless colon, severe inflammation, and normal looking surveillance colonoscopies. RESULTS: Cases (n = 68) and controls (n = 136) were well matched. On univariate analysis, cases were significantly more likely to have post-inflammatory polyps (odds ratio (OR) 2.14 (95% confidence interval 1.24-3.70)), strictures (OR 4.22; 1.08-15.54), shortened colons (OR 10.0; 1.17-85.6), tubular colons (OR 2.03; 1.00-4.08), or segments of severe inflammation (OR 3.38; 1.41-10.13), and less likely to have had a macroscopically normal looking colonoscopy (OR 0.40; 0.21-0.74). After multivariate analysis, a macroscopically normal looking colonoscopy (OR 0.38; 0.19-0.73), post-inflammatory polyps (2.29; 1.28-4.11), and strictures (4.62; 1.03-20.8) remained significant. The five year risk of colorectal cancer following a normal looking colonoscopy was no different from that of matched general population controls. CONCLUSIONS: Macroscopic colonoscopic features help predict neoplasia risk in UC. Features of previous/ongoing inflammation signify an increased risk. A macroscopically normal looking colonoscopy returns the cancer risk to that of the general population: it should be possible to reduce surveillance frequency to five years in this cohort.
Asunto(s)
Colitis Ulcerosa/complicaciones , Colonoscopía/métodos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/etiología , Adolescente , Adulto , Anciano , Análisis de Varianza , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vigilancia de la Población/métodos , Medición de Riesgo/métodosRESUMEN
BACKGROUND AND AIMS: Based on conflicting reports regarding the role of the fibrotic stromal response in cancer development--namely, that a desmoplastic reaction can favour either the host or the tumour--it is clear that the role of the stromal response is varied. We have classified the fibrotic stroma of rectal adenocarcinoma penetrating the muscularis propria, based on histologically identified stromal components. METHODS: Three categories of stroma were used: mature-when the stroma was composed of mature collagen fibres (fine and elongated fibres into multiple layers); intermediate-when keloid-like collagen was intermingled with mature fibres; and immature-consisting of a myxoid stroma in which no mature fibres were included. RESULTS: In a data set of 862 patients, 53% of patients had mature fibrotic cancer stroma, 33% had intermediate stroma, and 15% had immature stroma. Five year survival rates decreased as follows: mature stroma (80%), intermediate stroma (55%), and immature stroma (27%). The adverse tumour phenotype, tumour cell budding (conspicuous isolated cells or small clusters of cancer cells), was observed in the cancer fronts in tumours with unfavourable fibrotic stroma (p<0.0001). Based on multivariate analysis, categorised fibrotic stroma was selected as an independent prognostic parameter (hazard ratio 1.39; 95% confidence interval 1.17-1.64) together with tumour differentiation. By immunohistochemical examination, as maturation of the fibrotic stroma decreased, stromal T cells became significantly sparser. Furthermore, myofibroblasts were distributed extensively in immature fibrotic stroma compared with mature and intermediate fibrotic stroma. CONCLUSION: The morphological categorisation of fibrotic cancer stroma highlights the role of the stromal response in relation to the behaviour and host immune reactions of rectal adenocarcinoma and would be a useful tool for predicting patient prognostic outcome.
Asunto(s)
Adenocarcinoma/patología , Neoplasias del Recto/patología , Células del Estroma/patología , Adenocarcinoma/inmunología , Fibroblastos/patología , Fibrosis , Humanos , Recuento de Linfocitos , Análisis Multivariante , Pronóstico , Neoplasias del Recto/inmunología , Análisis de Supervivencia , Subgrupos de Linfocitos T/patologíaRESUMEN
BACKGROUND AND AIMS: Colonoscopic surveillance for cancer in longstanding extensive ulcerative colitis relies heavily on non-targeted mucosal biopsies. Chromoendoscopy can aid detection of subtle mucosal abnormalities. We hypothesised that routine pancolonic indigo carmine dye spraying would improve the macroscopic detection of dysplasia and reduce the dependence on non-targeted biopsies. PATIENTS AND METHODS: One hundred patients with longstanding extensive ulcerative colitis attending for colonoscopic surveillance underwent "back to back" colonoscopies. During the first examination, visible abnormalities were biopsied, and quadrantic non-targeted biopsies were taken every 10 cm. Pancolonic indigo carmine (0.1%) was used during the second colonoscopic examination, and any additional visible abnormalities were biopsied. RESULTS: Median extubation times for the first and second colonoscopies were 11 and 10 minutes, respectively. The non-targeted biopsy protocol detected no dysplasia in 2904 biopsies. Forty three mucosal abnormalities (20 patients) were detected during the pre-dye spray colonoscopy of which two (two patients) were dysplastic: both were considered to be dysplasia associated lesions/masses. A total of 114 additional abnormalities (55 patients) were detected following dye spraying, of which seven (five patients) were dysplastic: all were considered to be adenomas. There was a strong trend towards statistically increased dysplasia detection following dye spraying (p = 0.06, paired exact test). The targeted biopsy protocol detected dysplasia in significantly more patients than the non-targeted protocol (p = 0.02, paired exact test). CONCLUSIONS: No dysplasia was detected in 2904 non-targeted biopsies. In comparison, a targeted biopsy protocol with pancolonic chromoendoscopy required fewer biopsies (157) yet detected nine dysplastic lesions, seven of which were only visible after indigo carmine application. Careful mucosal examination aided by pancolonic chromoendoscopy and targeted biopsies of suspicious lesions may be a more effective surveillance methodology than taking multiple non-targeted biopsies.
Asunto(s)
Colitis Ulcerosa/patología , Colon/patología , Colorantes/uso terapéutico , Carmin de Índigo , Mucosa Intestinal/patología , Adulto , Anciano , Biopsia , Colonoscopía , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Ten to 15% of patients with pouchitis experience refractory or recurrent disease. The aim of this study was to evaluate the effectiveness of a single daily high dose probiotic preparation (VSL#3) in maintaining antibiotic induced remission, and quality of life (QOL), for one year in such patients. METHODS: Patients with pouchitis at least twice in the previous year or requiring continuous antibiotics, associated with a pouchitis disease activity index (PDAI) > or =7 (0 = perfect; 18 = worst), in whom remission was induced by four weeks of combined metronidazole and ciprofloxacin, were randomised to receive VSL#3 6 g or placebo once daily for one year or until relapse. Symptomatic, endoscopic, and histological evaluations were made before, and two and 12 months after randomisation or at the time of relapse. Remission was defined as a clinical PDAI < or =2 and endoscopic PDAI < or =1. Relapse was defined as an increased clinical PDAI score > or =2 and increased endoscopic PDAI score > or =3. QOL was assessed using the inflammatory bowel disease questionnaire (IBDQ). RESULTS: Thirty six patients were randomised: 20 to VSL#3 and 16 to placebo. Remission was maintained at one year in 17 patients (85%) on VSL#3 and in one patient (6%) on placebo (p<0.0001). The IBDQ score remained high in the VSL#3 group (p = 0.3) but deteriorated in the placebo group (p = 0.0005). CONCLUSION: The once daily high dose probiotic VSL#3 is effective in maintaining antibiotic introduced remission for at least a year in patients with recurrent or refractory pouchitis. This is associated with a high level of quality of life.
Asunto(s)
Reservoritis/tratamiento farmacológico , Probióticos/uso terapéutico , Adulto , Ciprofloxacina/uso terapéutico , Quimioterapia Combinada , Heces/microbiología , Femenino , Humanos , Masculino , Metronidazol/uso terapéutico , Persona de Mediana Edad , Satisfacción del Paciente , Reservoritis/rehabilitación , Probióticos/efectos adversos , Calidad de Vida , Recurrencia , Inducción de Remisión , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Small, flat colorectal cancers have been widely reported in the Japanese literature but are thought to occur rarely outside Japan. The aim of this retrospective cohort study was to clarify the prevalence of flat colorectal cancer in a Western population. METHODS: One thousand and twenty-six consecutive colonoscopies performed by a single experienced endoscopist were retrospectively analysed over a two-year period. The morphology, site and histological appearance of all documented colorectal cancers (CRC) were recorded. RESULTS: Forty-seven cases of CRC were detected, five of which (10%) demonstrated flat configuration. Flat cancers varied between 8 and 15 mm in diameter (mean 11 mm). Histologically, all flat lesions were moderately differentiated Dukes A adenocarcinomas. Two of these cancers contained no adenomatous component. CONCLUSION: This study confirms that small, flat colorectal cancers are not an uncommon finding at colonoscopy in Western patients. Compared to polypoid neoplastic lesions, flat cancers appear to undergo malignant change at a smaller size.
Asunto(s)
Adenocarcinoma/epidemiología , Neoplasias Colorrectales/epidemiología , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Anciano de 80 o más Años , Colectomía/métodos , Colonoscopía , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Reino Unido/epidemiologíaRESUMEN
Chemoradiotherapy is the standard treatment for most patients with epidermoid anal cancer. Pre-treatment staging is based on size for T1-T3 lesions and clinical and radiological assessment of adjacent organ invasion for T4 lesions. For patients with residual or recurrent carcinoma, anorectal excision offers the best chance of oncological salvage. Pathological staging systems for anorectal excision specimens were validated at the time when surgical treatment was first line therapy. A validated staging system is necessary for salvage surgical excision specimens following an attempt to cure by radiotherapy and chemotherapy for the purpose of prognosis and further treatment planning.
Asunto(s)
Neoplasias del Ano/patología , Carcinoma de Células Escamosas/patología , Estadificación de Neoplasias/normas , Neoplasias del Ano/cirugía , Carcinoma de Células Escamosas/cirugía , Humanos , Reproducibilidad de los ResultadosRESUMEN
The putative locus for hereditary mixed polyposis syndrome (HMPS) in a large family of Ashkenazi descent (SM96) was previously reported to map to chromosome sub-bands 6q16-q21. However, new clinical data, together with molecular data from additional family members, have shown 6q linkage to be incorrect. A high-density genomewide screen for the HMPS gene was therefore performed on SM96, using stringent criteria for assignment of affection status to minimize phenocopy rates. Significant evidence of linkage was found only on a region on chromosome 15q13-q14. Since this region encompassed CRAC1, a locus involved in inherited susceptibility to colorectal adenomas and carcinomas in another Ashkenazi family (SM1311), we determined whether HMPS and CRAC1 might be the same. We found that affected individuals from both families shared a haplotype between D15S1031 and D15S118; the haplotype was rare in the general Ashkenazi population. A third informative family, SM2952, showed linkage of disease to HMPS/CRAC1 and shared the putative ancestral haplotype, as did a further two families, SMU and RF. Although there are probably multiple causes of the multiple colorectal adenoma and cancer phenotype in Ashkenazim, an important one is the HMPS/CRAC1 locus on 15q13-q14.
Asunto(s)
Poliposis Adenomatosa del Colon/genética , Cromosomas Humanos Par 15/genética , Ligamiento Genético , Haplotipos/genética , Judíos/genética , Mapeo Cromosómico , Cromosomas Humanos Par 6/genética , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Escala de Lod , Masculino , LinajeRESUMEN
BACKGROUND: Food antigens may contribute to gut inflammation in Crohn's disease. AIM: To assess in vivo sensitization to food antigens, ascertain whether sensitivity is gut specific, assess food sensitization in vitro, and correlate in vivo changes with histological and blood changes. METHODS: Skin testing and rectal exposure to six food antigens (cereal, cabbage, citrus, milk, yeast and peanut) and control saline were assessed double-blind by immediate and 3.5-h laser Doppler blood flowmetry, and rectal biopsies were taken. Peripheral blood lymphocyte proliferation was measured in response to the same antigens. RESULTS: Ten patients with Crohn's disease and 10 healthy controls were studied. Blood flow increased in 24 of 60 antigen sites in Crohn's disease patients and six of 60 antigen sites in controls (P < 0.0001) after 3.5 h. The Crohn's disease group demonstrated higher rectal blood flow than controls in response to all food antigens, and this was significantly different for the responses to yeast (P = 0.036) and citrus fruits (P = 0.038). Lymphocyte proliferation occurred in 32 of 60 tests in Crohn's disease patients and eight of 60 tests in controls (P < 0.0001). There were no skin responses. Submucosal oedema corresponded to increased mucosal flow. CONCLUSIONS: Crohn's disease patients demonstrate in vivo and in vitro sensitization to food antigens, which is gut specific. Mucosal flowmetry allows the identification of sensitization to gut antigens.
Asunto(s)
Alérgenos/inmunología , Enfermedad de Crohn/inmunología , Hipersensibilidad a los Alimentos/complicaciones , Mucosa Intestinal/inmunología , Adulto , Técnicas de Cultivo de Célula , División Celular/inmunología , Enfermedad de Crohn/patología , Método Doble Ciego , Femenino , Humanos , Flujometría por Láser-Doppler , Activación de Linfocitos , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Recto/irrigación sanguínea , Recto/inmunología , Flujo Sanguíneo Regional , Piel/irrigación sanguínea , Piel/inmunología , Pruebas Cutáneas/métodosRESUMEN
BACKGROUND: Serrated adenomas (SAs) of the colorectum combine architectural features of hyperplastic polyps and cytological features of classical adenomas. Molecular studies comparing SAs and classical adenomas suggest that each may be a distinct entity; in particular, it has been proposed that microsatellite instability (MSI) distinguishes SAs from classical adenomas and that SAs and the colorectal cancers arising from them develop along a pathway driven by low level microsatellite instability (MSI-L). AIMS: To define the molecular characteristics of SAs of the colorectum. MATERIALS AND METHODS: We analysed 39 SAs from 27 patients, including eight SAs from patients with familial adenomatous polyposis (FAP). We screened these polyps for selected molecular changes, including loss of heterozygosity (LOH) close to APC (5q21) and CRAC1 (15q13-q22), MSI, and mutations of K-ras, APC, p53, and beta-catenin. Expression patterns of beta-catenin, p53, MLH1, MSH2, E-cadherin, and O(6)-methylguanine DNA methyltransferase (MGMT) were assessed by immunohistochemistry. Comparative genomic hybridisation was performed on several polyps. RESULTS: MSI was rare (<5% cases) and there was no loss of expression of mismatch repair proteins. Wnt pathway abnormalities (APC mutation/LOH, beta-catenin mutation/nuclear expression) occurred in 11 SAs, including 6/31 (19%) non-FAP tumours. CRAC1 LOH occurred in 23% of tumours. K-ras mutations and p53 mutations/overexpression were found in 15% and 8% of SAs, respectively. Loss of MGMT expression occurred in 18% of polyps and showed a borderline association with K-ras mutations. Aberrant E-cadherin expression was found in seven polyps. Comparative genomic hybridisation detected no gains or deletions of chromosomal material. CONCLUSIONS: The serrated pathway of colorectal tumorigenesis appears to be heterogeneous. In common with classical adenomas, some SAs develop along pathways involving changes in APC/beta-catenin. SAs rarely show MSI or any evidence of chromosomal-scale genetic instability. K-ras mutations may however be less common in SAs than in classical adenomas. Some SAs may harbour changes in the CRAC1 gene. Changes in known genes do not account for the growth of the majority of SAs.
Asunto(s)
Adenoma/genética , Neoplasias Colorrectales/genética , Perfilación de la Expresión Génica , Adenoma/química , Neoplasias Colorrectales/química , Proteínas del Citoesqueleto/análisis , Proteínas del Citoesqueleto/genética , Genes APC , Genes p53 , Genes ras , Humanos , Inmunohistoquímica , Pérdida de Heterocigocidad , Mutación , Transactivadores/análisis , Transactivadores/genética , beta CateninaRESUMEN
BACKGROUND: p53 mutations are frequently observed in colorectal carcinomas but they have also been found in colorectal adenomas, although considerably less frequently. AIMS: To explore p53 mutations in benign tumours, we have screened 70 colorectal adenomas for allelic loss at, and point mutations in, TP53 by analysis of selected microdissected cell populations. RESULTS: Sixteen (22.8%) adenomas were found to have allelic loss, of which 11 (15.7%) had p53 mutations. In adenomas with mild, moderate, or severe dysplasia, mutation or allelic loss occurred in 4.8%, 16.7%, and 52.6%, respectively (p<0.001). Seven different mutations were found, all missense changes or inframe deletions: one (Thr150Arg) has not been found before while three (Gln144His, Gly245Arg, and Glu285Gln) have not been described previously in colorectal tumours. The other three mutations (Arg175Gly, DeltaPro190, and Gly245Ser) have been found in colorectal carcinomas, the last commonly. Adenomas harboured a spectrum of p53 mutations which was significantly different from cancers as regards the position in the gene and a higher frequency of G-->C/C-->G changes. CONCLUSIONS: Combining our data on adenomas with data already published and in comparison with the spectrum of mutations in colorectal carcinomas, it is suggested that some p53 mutations have a weaker effect than others and are therefore more likely to be found in adenomas which have not progressed to carcinomas.
Asunto(s)
Adenoma/genética , Neoplasias Colorrectales/genética , Genes p53 , Mutación Puntual/genética , Distribución de Chi-Cuadrado , Femenino , Humanos , Inmunohistoquímica , Pérdida de Heterocigocidad , Masculino , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
AIM: To establish the histological categorization of fibrotic stroma which reflects the biological behaviour of advanced rectal cancer. METHODS AND RESULTS: Six hundred and twenty-seven surgically resected cases of advanced rectal carcinoma were examined. We histologically categorized fibrotic stroma in the invasive frontal region into three groups: type A, multiple fine and mature fibres were stratified into layers; type B, broad bands of eosinophilic hyalinized collagen ('keloid-like' collagen) were intermingled; type C, myxoid stroma. Type A stroma was observed in 63% of patients, type B stroma in 25%, type C stroma in 12%. The incidence of type A stroma decreased in accordance with Dukes stage (98% in Dukes A; 73% in B; 41% in C1; 29% in C2) and conversely, there was an increase of C type (0% in Dukes A; 4% in B; 20% in C1; 54% in C2). Stroma type had a significant correlation with long-term survival (80% of 5-year survival in type A stroma; 54% in type B; 26% in type C). Based on multivariate analysis, it was found that the stromal pattern had independent prognostic value, together with nodal involvement, growth pattern, and lymphocyte infiltration. CONCLUSIONS: Tumour fibrotic stroma may play an important role as a regulator of neoplastic behaviour. Pathological categorization of the fibrotic stroma is helpful for predicting the prognostic outcome of patients with rectal carcinoma.