RESUMEN
We report the case of a female found to have mosaicism for mutation in the STK11 gene, with the mutant allele expressed in her gametes, evident by her affected offspring, and in her gastrointestinal tract demonstrated on an excised polyp analysed for diagnosis. Mosaicism for Peutz-Jeghers syndrome (PJS) has been reported in a small number of cases previously but a clinical presentation such as this has not previously been described. This finding of mosaicism was several years after initial investigations failed to identify the same STK11 mutation in this woman whose son was diagnosed with PJS at a young age. This case highlights the importance of considering mosaicism as an explanation for apparent de novo cases of PJS syndrome. It also has implications for genetic counselling, predictive testing and cancer screening.
Asunto(s)
Pólipos Intestinales/genética , Mosaicismo , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinasas/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Niño , Colonoscopía , Femenino , Pruebas Genéticas , Humanos , Íleon/diagnóstico por imagen , Íleon/patología , Pólipos Intestinales/diagnóstico , Pólipos Intestinales/patología , Masculino , Persona de Mediana Edad , Madres , Mutación , Síndrome de Peutz-Jeghers/diagnóstico , Síndrome de Peutz-Jeghers/patologíaRESUMEN
We report a familial adenomatous polyposis patient with a known truncating mutation on exon 15 of the APC gene who developed an invasive follicular thyroid cancer in addition to multiple intra-cranial and spinal desmoids. This combination of manifestations has not previously been recorded in the literature.
Asunto(s)
Poliposis Adenomatosa del Colon/complicaciones , Neoplasias del Sistema Nervioso Central/etiología , Fibromatosis Agresiva/etiología , Neoplasias Primarias Secundarias/etiología , Neoplasias de la Tiroides/etiología , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/patología , Proteína de la Poliposis Adenomatosa del Colon/genética , Neoplasias del Sistema Nervioso Central/patología , Niño , Exones/genética , Fibromatosis Agresiva/patología , Humanos , Masculino , Mutación/genética , Neoplasias Primarias Secundarias/patología , Pronóstico , Neoplasias de la Tiroides/patologíaRESUMEN
Familial gastrointestinal stromal tumours (GISTs) are rare but otherwise well-characterized tumour syndromes, most commonly occurring on a background of germline-activating mutations in the tyrosine kinase receptor c-KIT. The associated clinical spectrum reflects the constitutive activation of this gene product across a number of cell lines, generating gain-of-function phenotypes in interstitial cells of Cajal (GIST and dysphagia), mast cells (mastocytosis) and melanocytes (hyperpigmentation). We report a three-generation kindred harbouring a c-KIT germline-activating mutation resulting in multifocal GISTs, dysphagia and a complex melanocyte hyperpigmentation and hypopigmentation disorder, the latter with features typical of those observed in Waardenburg type 2 syndrome (WS2F). Sequencing of genes known to be causative for WS [microphthalmia transcription factor (MITF), Pax3, Sox10, SNAI2 ] failed to show any candidate mutations to explain this complex cutaneous depigmentation phenotype. Our case report conclusively expands the clinical spectrum of familial GISTs and shows a hitherto unrecognized link to WS. Possible mechanisms responsible for this novel cause of WS2F will be discussed.
Asunto(s)
Tumores del Estroma Gastrointestinal/genética , Síndromes Neoplásicos Hereditarios/genética , Síndrome de Waardenburg/genética , Alelos , Trastornos de Deglución/genética , Trastornos de Deglución/patología , Tumores del Estroma Gastrointestinal/patología , Mutación de Línea Germinal , Humanos , Hiperplasia , Células Intersticiales de Cajal/patología , Masculino , Persona de Mediana Edad , Mutación Missense , Plexo Mientérico/patología , Síndromes Neoplásicos Hereditarios/patología , Linaje , Fenotipo , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Análisis de Secuencia de ADN , Síndrome de Waardenburg/patologíaRESUMEN
The genetic predisposition Peutz-Jeghers Syndrome (PJS) has been shown to be associated with mutations in the serine threonine kinase 11 (STK11) gene but only a proportion of probands have been shown to harbour changes in the gene. The remaining patients were proposed to be either associated with a second PJS gene or they harboured more cryptic mutations within the STK11 gene itself. With the introduction of the multiplex ligation probe amplification (MLPA) assay, large sequence losses or gains can be more readily identified. In this report we have screened 33 PJS patients from unrelated families, employing a combination of denaturing high-performance liquid chromatography, direct DNA sequencing and the MLPA assay to identify deleterious changes in the STK11 gene. The results revealed that 24 (73%) of patients diagnosed with PJS-harboured pathogenic mutations in the STK11 gene, including 10 (36%) with exonic or whole-gene deletions. No phenotypic differences were identified in patients harbouring large deletions in the STK11 gene compared to patients harbouring missense or nonsense mutations. Mutation analysis in PJS should include techniques such as MLPA to identify large exonic or whole-gene deletions and rearrangements. The high proportion of families with identifiable mutations in the STK11 gene using this range of techniques suggests that most, if not all PJS, is attributable to mutations in the STK11 gene, perhaps including as yet undiscovered changes in promoter or enhancer sequences or other cryptic changes.
Asunto(s)
Mutación , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinasas/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Adolescente , Adulto , Australia , Niño , Preescolar , Análisis Mutacional de ADN , Exones , Femenino , Eliminación de Gen , Humanos , Masculino , Persona de Mediana Edad , Técnicas de Amplificación de Ácido Nucleico , Síndrome de Peutz-Jeghers/enzimología , Eliminación de SecuenciaRESUMEN
BACKGROUND: Peutz-Jeghers syndrome (PJS) is caused by germline STK11 mutations and characterised by gastrointestinal polyposis. Although small bowel intussusception is a recognised complication of PJS, risk varies between patients. OBJECTIVE: To analyse the time to onset of intussusception in a large series of PJS probands. METHODS: STK11 mutation status was evaluated in 225 PJS probands and medical histories of the patients reviewed. RESULTS: 135 (60%) of the probands possessed a germline STK11 mutation; 109 (48%) probands had a history of intussusception at a median age of 15.0 years but with wide variability (range 3.7 to 45.4 years). Median time to onset of intussusception was not significantly different between those with identified mutations and those with no mutation detected, at 14.7 years and 16.4 years, respectively (log-rank test of difference, chi(2) = 0.58, with 1df; p = 0.45). Similarly no differences were observed between patient groups on the basis of the type or site of STK11 mutation. CONCLUSIONS: The risk of intussusception in PJS is not influenced by STK11 mutation status.
Asunto(s)
Intususcepción/genética , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinasas/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
We assessed the efficacy of a comprehensive programme for stopping smoking in 210 smokers scheduled for surgery, before admission and 3 months after attending a pre-operative clinic. Participants were randomly allocated to receive an intervention incorporating nicotine replacement therapy for patients smoking more than 10 cigarettes per day ("dependent smokers"), or to a control group to receive usual care. Dependent smokers allocated to the intervention group were more likely to report abstinence before surgery than those allocated to receive usual-care (63 (73%) vs. 29 (56%), respectively; OR 2.2 (95% CI 1.0-4.8)), and 3 months after attendance (16 (18%) vs. 3 (5%), respectively; OR = 3.9 (95% CI 1.0-21.7).
Asunto(s)
Cuidados Preoperatorios/métodos , Cese del Hábito de Fumar/métodos , Prevención del Hábito de Fumar , Adulto , Anciano , Femenino , Costos de la Atención en Salud , Humanos , Masculino , Persona de Mediana Edad , Nicotina/uso terapéutico , Agonistas Nicotínicos/uso terapéutico , Cuidados Preoperatorios/economía , Evaluación de Programas y Proyectos de Salud , Cese del Hábito de Fumar/economía , Tabaquismo/rehabilitación , Resultado del TratamientoRESUMEN
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant, inherited condition that is characterized primarily by the development of early-onset colorectal cancer and a number of other epithelial malignancies. The underlying genetic basis of the disease is associated with a breakdown of DNA-mismatch repair. There are many genes involved in DNA-mismatch repair, and five of them have been implicated in HNPCC. Two of the genes (hMSH2 and hMLH1) account for the majority of HNPCC families (approximately 60%), and it is not known what the exact contributions of the remaining three genes (hPMS1, hPMS2, and hMSH6) are in relation to this condition. In addition, a sixth gene (hEXO1) has been associated with a disease phenotype that is consistent with HNPCC. Current estimates suggest that all four of these genes, combined, may account for up to 5% of families. In this report, we examine the contribution of hPMS2 and hEXO1 to a well-defined set of families that fulfill the diagnostic criteria for HNPCC. The genes, hPMS2 and hEXO1, were studied by denaturing high performance liquid chromatography (DHPLC) analysis in 21 families that have previously been determined not to have mutations in hMSH2 or hMLH1. hPMS2 accounts for a small proportion of HNPCC families, and none were deemed to be associated with hEXO1. Mutations in hPMS2 appear to account for a small proportion of families adhering to the Amsterdam II criteria, whereas hEXO1 does not appear to be associated with HNPCC.
Asunto(s)
Adenosina Trifosfatasas/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Exodesoxirribonucleasas/genética , Mutación/fisiología , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Proteínas Portadoras , Cromatografía Líquida de Alta Presión , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Análisis Mutacional de ADN , Cartilla de ADN , Reparación del ADN/genética , Salud de la Familia , Predisposición Genética a la Enfermedad/genética , Humanos , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Epidemiología Molecular , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/genética , Proteínas Nucleares , Proteínas Proto-Oncogénicas/genéticaRESUMEN
OBJECTIVE: The consumption of cruciferous vegetables has a protective effect on the development of colorectal cancer. The phytochemical Sulforaphane is an isothiocyanate found almost exclusively in cruciferous vegetables. We have studied the effect of Sulforaphane on cell proliferation of an HT-29 colon cancer cell line. MATERIALS AND METHODS: HT-29 colon cancer cells were cultured in 96-well microtitre plates. Sulforaphane (in concentrations ranging from 0.01 to 0.1 mmol) were added to the wells. Cell proliferation was measured using the colourimetric assay technique. RESULTS: The proliferation of colon cancer cells was significantly reduced by Sulforaphane at concentrations of >/=0.02 mmol. CONCLUSION: These findings may help explain the epidemiologically proven protective effect of vegetables against colon cancer.
Asunto(s)
Anticarcinógenos/uso terapéutico , Neoplasias del Colon/prevención & control , Células HT29/efectos de los fármacos , Tiocianatos/uso terapéutico , Anticarcinógenos/farmacología , División Celular/efectos de los fármacos , Neoplasias del Colon/patología , Relación Dosis-Respuesta a Droga , Humanos , Isotiocianatos , Sulfóxidos , Tiocianatos/farmacologíaRESUMEN
The occurrence of duodenal polyposis is well recognized in familial adenomatous polyposis. Lymphoid hyperplasia in association with familial adenomatous polyposis usually occurs in the terminal ileum, but it can occur in the duodenum and may be endoscopically difficult to distinguish from an adenoma. A case report is presented in which a 54-year-old male with familial adenomatous polyposis, who 20 years earlier had a subtotal colectomy and ileorectal anastomosis, presented with a large rectal villous tumor and was found to have a duodenal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The role of lymphoid hyperplasia in the development of mucosa-associated lymphoid tissue lymphoma is discussed, as well as the issue of mucosa-associated lymphoid tissue lymphoma in familial adenomatous polyposis. In cases in which biopsies of polypoid lesions in patients with familial adenomatous polyposis show dense lymphoid aggregates, flow cytometry may assist in the diagnosis.
Asunto(s)
Poliposis Adenomatosa del Colon/complicaciones , Poliposis Adenomatosa del Colon/cirugía , Neoplasias Duodenales/etiología , Neoplasias Duodenales/patología , Íleon/cirugía , Linfoma de Células B de la Zona Marginal/etiología , Linfoma de Células B de la Zona Marginal/patología , Recto/cirugía , Poliposis Adenomatosa del Colon/patología , Anastomosis Quirúrgica , Colectomía , Humanos , Mucosa Intestinal/patología , Masculino , Persona de Mediana EdadRESUMEN
AIM: An audit was undertaken to assess whether surgeons were informed of the readmission of their patients with postoperative deep venous thrombosis (DVT), or pulmonary embolus (PE). METHODS: A retrospective medical record review was conducted to detect patients who had an unplanned readmission in which DVT or PE formed part of the diagnosis and the first admission included a surgical procedure. The readmission was to John Hunter Hospital, Newcastle, Australia, a major tertiary referral teaching hospital, and the first admission was to any acute care hospital. The main outcome measures were: (i) hospital and specialty of the admitting doctor, (ii) the type of surgery performed, (iii) the length of time between admissions and (iv) the patient's previous medical history. The medical record was reviewed for documented evidence that the surgeon who performed the procedure was aware of the readmission. RESULTS: Of the 215 patient reviewed, 34 were classified as unplanned readmissions following a surgical procedure. Twenty-four patients (70.6%) were readmitted under a different specialty, three (8.8%) patients were readmitted under the same specialty but under a different surgeon, and seven (20.6%) patients were readmitted under the same surgeon. Of the 27 patients admitted under a different consultant, only 12 (44.4%) had documented evidence that the previous surgeon was aware of the readmission. CONCLUSION: The rate of DVT/PE complications following surgery is underestimated. This may lead to a reduced emphasis in DVT/PE prophylaxis in the mistaken belief that DVT/PE frequency is rarer than it is. Improved communication between teams is necessary to improve care.
Asunto(s)
Cirugía General , Relaciones Interprofesionales , Readmisión del Paciente , Complicaciones Posoperatorias , Embolia Pulmonar/etiología , Trombosis de la Vena/etiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/uso terapéutico , Comunicación , Femenino , Humanos , Tiempo de Internación , Masculino , Auditoría Médica , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Embolia Pulmonar/tratamiento farmacológico , Procedimientos Quirúrgicos Operativos , Trombosis de la Vena/tratamiento farmacológico , Warfarina/uso terapéuticoRESUMEN
OBJECTIVE: Naringenin, a naturally occurring flavonoid found in citrus fruits, is known to have anticarcinogenic properties. We have examined the effect of Naringenin on cell proliferation of an HT-29 colon cancer cell line. METHODS: HT-29 colon cancer cells were cultured in 96-well tissue culture plates. Naringenin concentrations ranging from 0.02 to 2.85 mmol were added to the wells of the Test group. The Control group contained all the elements present in the Test group with the exception of Naringenin. Cell proliferation was measured by colourimetric assay using the 2% WST-1 cell proliferation kit. RESULTS: Significant inhibition of cell proliferation was observed in HT29 colon cancer cells exposed to Naringenin at doses greater than 0.71 mmol. CONCLUSIONS: These results suggest a potential role for citrus fruits as a source of chemoprotective agents for colon cancer.
Asunto(s)
Adenocarcinoma/patología , Antineoplásicos/farmacología , Neoplasias del Colon/patología , Flavanonas , Flavonoides/farmacología , División Celular/efectos de los fármacos , Citrus/química , Células HT29/efectos de los fármacos , Células HT29/patología , HumanosRESUMEN
Peutz-Jeghers syndrome (PJS) is a rare cancer predisposition, which is characterized by the presence of hamartomatous polyposis and mucocutaneous pigmentation. A significant proportion of both familial and sporadic forms of this disorder are associated with mutations in the STK11 (serine/threonine kinase 11)/LKB1 gene. In this report we present a series of Australian PJS cases, which suggest that mutations in the STK11 gene do not account for many families or patients without a family history. The most likely explanation is either the presence of another susceptibility gene or genetic mosaicism in the non-familial patients.
Asunto(s)
Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinasas/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Australia , Mapeo Cromosómico , Análisis Mutacional de ADN , Femenino , Heterogeneidad Genética , Humanos , Masculino , Mutación , Análisis de SecuenciaRESUMEN
OBJECTIVE: To determine the adverse event (AE) rate for surgical patients in Australia. DESIGN: A two-stage retrospective medical record review was conducted to determine the occurrence of AEs in hospital admissions. Medical records were screened for 18 criteria and positive records were reviewed by two medical officers using a structured questionnaire. SETTING: Admissions in 1992 to 28 randomly selected hospitals in Australia. STUDY PARTICIPANTS: Five hundred and twenty eligible admissions were randomly selected from in-patient database in each hospital. A total of 14,179 medical records were reviewed, with 8747 medical and 5432 surgical admissions. MAIN OUTCOME MEASURES: Measures included the rate of AEs in surgical and medical admissions, the proportion resulting in permanent disability and death, the proportion determined to be highly preventable, and the identification of risk factors associated with AEs. RESULTS: The AE rate for surgical admissions was 21.9%. Disability that was resolved within 12 months occurred in 83%, 13% had permanent disability, and 4% resulted in death. Reviewers found that 48% of AEs were highly preventable. The risk of an AE depended on the procedure and increased with age and length of stay. CONCLUSION: The high AE rate for surgical procedures supports the need for monitoring and intervention strategies. The 18 screening criteria provide a tool to identify admissions with a greater risk of a surgical AE. Risk factors for an AE were age and procedure, and these should be assessed prior to surgery. Prophylactic interventions for infection and deep vein thrombosis could reduce the occurrence of AEs in hospitals.
Asunto(s)
Hospitales/estadística & datos numéricos , Enfermedad Iatrogénica/epidemiología , Admisión del Paciente/estadística & datos numéricos , Procedimientos Quirúrgicos Operativos/efectos adversos , Adolescente , Adulto , Factores de Edad , Anciano , Australia/epidemiología , Niño , Preescolar , Evaluación de la Discapacidad , Encuestas de Atención de la Salud , Hospitales/normas , Humanos , Incidencia , Lactante , Recién Nacido , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Reoperación/estadística & datos numéricos , Factores de Riesgo , Infección de la Herida Quirúrgica/epidemiología , Encuestas y CuestionariosRESUMEN
Up to 20% of colorectal cancers are thought to have a genetic component. Several familial syndromes are known to confer an increased risk for colorectal cancer. Advances in our understanding of these syndromes has improved the care delivered to, and the overall survival of, these patients. Genetic testing has great potential to further improve detection and direct subsequent preventative measures. The diagnosis, management and surveillance issues relating to some of the more commonly encountered syndromes - in particular Familial Adenomatous Polyposis and Hereditary Non-Polyposis Colorectal Cancer - are reviewed.
Asunto(s)
Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Poliposis Adenomatosa del Colon/genética , Australia/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Asesoramiento Genético , Humanos , Anamnesis , Sistema de Registros , Factores de RiesgoRESUMEN
BACKGROUND: Duodenal cancer is one of the leading causes of death in familial adenomatous polyposis (FAP) patients. An endoscopic surveillance programme was therefore initiated in 1988, the outcome of which is described in this paper. METHODS: We report the 10 year follow up of 114 patients with FAP who were prospectively screened for the presence and severity of duodenal adenomas. RESULTS: Six of 114 patients (median age 67 years) developed duodenal adenocarcinoma. Four of these were from 11 patients who originally had Spigelman stage IV disease (advanced duodenal polyposis), which gives a 36% risk within this group of developing cancer. One case of duodenal cancer arose from 41 patients who originally had stage III disease (2%) and one cancer arose from 44 patients with original stage II disease (2%). All six patients have died: five were inoperable and one had recurrence three years after a pancreaticoduodenectomy. There was no association between duodenal cancer and site of germline mutation of the APC gene. CONCLUSIONS: Surveillance for duodenal adenocarcinoma and subsequent early referral for curative surgery has not been effective. Selection of patients with advanced but benign (Spigelman stage IV) duodenal polyposis for prophylactic pancreaticoduodenectomy should therefore be considered and can now be justified on the basis of these results. More comprehensive endoscopic surveillance of high risk (stage III and IV) patients is needed in an attempt to avoid underestimating the severity of duodenal polyposis, and to evaluate the role of endoscopic therapy in preventing advanced disease.
Asunto(s)
Adenocarcinoma/genética , Poliposis Adenomatosa del Colon/complicaciones , Neoplasias Duodenales/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/cirugía , Poliposis Adenomatosa del Colon/patología , Adolescente , Adulto , Anciano , Progresión de la Enfermedad , Neoplasias Duodenales/diagnóstico , Neoplasias Duodenales/cirugía , Duodenoscopía , Femenino , Estudios de Seguimiento , Humanos , Cuidados a Largo Plazo/métodos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Selección de Paciente , Pronóstico , Estudios ProspectivosRESUMEN
OBJECTIVE: To observe the effect of Indole-3-carbinol (I3C), a naturally occurring component of cruciferous vegetables, on cell proliferation of a colon cancer cell line. METHODS: Cell proliferation was measured using three different methods; 3H-thymidine incorporation, cell count and colourimetric assay. RESULTS: Each method of measurement revealed that I3C significantly reduced cell proliferation at concentrations of > 0.1 mM. CONCLUSION: The present study demonstrates for the first time the capacity of indole-3-carbinol to inhibit cell proliferation of a colon cancer cell line.
RESUMEN
PURPOSE: Bile has been implicated in the pathogenesis of duodenal polyps in patients with familial adenomatous polyposis. In vitro experiments have shown that familial adenomatous polyposis bile is capable of producing DNA adducts. This effect can be ameliorated by increasing the pH of the incubate. The aim of this double-blind randomized placebo-controlled trial was to examine the effect of oral ranitidine on duodenal polyposis in a group of patients with familial adenomatous polyposis. METHODS: Twenty-six patients with familial adenomatous polyposis were randomly assigned to ranitidine 300 mg daily or placebo for six months after baseline endoscopy. Polyp counts were performed and biopsy specimens taken to detect DNA adducts by 32P-postlabeling. RESULTS: No difference was seen in polyp numbers (P = 0.9) or relative adduct labeling (P = 0.7) after treatment with ranitidine or placebo. DISCUSSION: Acid suppression therapy does not seem to improve duodenal polyposis despite in vitro findings. On the other hand, ranitidine does not exacerbate actual (or markers of) neoplasia in this highly tumor-prone condition.
Asunto(s)
Poliposis Adenomatosa del Colon/tratamiento farmacológico , Antiulcerosos/farmacología , Aductos de ADN , Neoplasias Duodenales/tratamiento farmacológico , Pólipos Intestinales/tratamiento farmacológico , Ranitidina/farmacología , Poliposis Adenomatosa del Colon/genética , Administración Oral , Adulto , Bilis/química , Método Doble Ciego , Neoplasias Duodenales/genética , Endoscopía , Femenino , Ácido Gástrico , Humanos , Pólipos Intestinales/genética , Masculino , Resultado del TratamientoRESUMEN
PURPOSE: Familial adenomatous polyposis is an inherited colorectal cancer syndrome characterized by the presence of multiple adenomatous colorectal polyps. Molecular studies have revealed that germline mutations in the APC gene are the underlying cause of the disease. The nonsteroidal anti-inflammatory agent sulindac has been shown to reduce the number of colorectal adenomas. Most sulindac trials in the large bowel have focused on the distal colon and relatively little is known about its effect on the proximal colon. Moreover, it is unknown whether the site of the APC mutation affects the efficacy of sulindac. METHODS: This study investigated whether there were regional differences in the effect of sulindac on the colon and whether response to sulindac was dependent on the site of mutation in the APC gene. In an open prospective study 17 patients with familial adenomatous polyposis were treated with 300 mg oral sulindac daily for four months followed by a washout phase of six months. Ten of the patients had an intact colon and seven had rectal stumps only. The number, size, and the degree of dysplasia of the adenomas were evaluated by colonoscopy at entry, end of treatment and end of the study. RESULTS: Overall, a statistically significant decrease in the number of adenomas was observed (120 +/- 112 to 28 +/- 64, P = 0.007). After cessation of sulindac treatment the number of adenomas increased to 48 +/- 44.5, but remained significantly lower than the values observed at baseline. In the ten patients with intact colons, adenomas decreased by sevenfold in the proximal colon (103 +/- 73 to 15.1 +/- 47.4, P = 0.011) and twofold in the distal colon (80 +/- 52 to 29.6 +/- 37.2, P = 0.005). The size of adenomas and the grade of dysplasia also decreased. No correlation could be seen between the APC mutation site and the response to treatment. CONCLUSION: These data indicate that sulindac reduces the number of adenomas in the entire colon and that the effect seems to be more pronounced in the proximal colon.