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ABSTRACT: : Desmoid tumors associated with familial adenomatous polyposis show variable behavior; about 10% grow relentlessly, resulting in severe morbidity or mortality. Investigations that could identify the minority of desmoid tumors that behave aggressively would allow these tumors to be treated early and spare the majority of patients who have more benign disease from unnecessary intervention.
: The aim of this study was to investigate whether imaging the tumor metabolic-vascular phenotype by modern methods predicts growth.
: This is a prospective case series study.
: The study was conducted at a tertiary center specializing in familial adenomatous polyposis and desmoid disease.
: Nine patients with familial adenomatous polyposis (4 male, mean age 39 years) with desmoid tumor underwent F-FDG-PET and dynamic contrast-enhanced MRI. Standard MRI was repeated a year later to assess tumor growth.
: The primary outcome measured was the correlation between F-FDG-PET and dynamic contrast-enhanced MRI parameters and subsequent desmoid growth.
: Failed intravenous access precluded dynamic contrast-enhanced MRI in 1 female patient. Thirteen desmoid tumors (4 intra-abdominal, 2 extra-abdominal, 7 abdominal wall; mean area, 68 cm) were analyzed in the remaining 8 patients. Two patients died before follow-up MRI. Five tumors decreased in size, 3 increased in size, and 3 remained stable after a year. Significant correlation (Spearman rank correlation, significance at 5%) existed between maximum standardized uptake value and kep (r = -0.56, p = 0.04), but not with other vascular parameters (K (r = -0.47, p = 0.09); ve (r = -0.11, p = 0.72); integrated area under the gadolinium-time curve at 60 seconds (r = -0.47, p = 0.10)). There was no significant difference in the maximum standardized uptake value or dynamic contrast-enhanced MRI parameters (K, ve, kep, integrated area under the gadolinium-time curve at 60 seconds) between the tumors that grew or decreased in size or between the tumor sites. However, vascular metabolic ratio (maximum standardized uptake value/K) was significantly different for tumor site (p = 0.001) and size (p = 0.001, 1-way ANOVA).
: This investigation is limited because of its exploratory nature and small patient numbers.
: Although not predictive for tumor behavior, some correlations existed between dynamic contrast-enhanced MRI and F-FDG-PET parameters. Vascular metabolic ratio may provide further information on tumor behavior; however, this needs to be evaluated with further larger studies.
Diseases of the Colon & Rectum 10/2012; 55(10):1032-7. · 3.13 Impact Factor
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ABSTRACT: BACKGROUND: Treatment resistant chronic pouchitis causes significant morbidity. Elemental diet is effective treatment for Crohn's disease. Since pouchitis shares some similarities to Crohn's disease we hypothesised that elemental diet may be an effective treatment. METHOD: Seven pouchitis patients (with ulcerative colitis) were studied. All had active pouchitis with a pouch disease activity index (PDAI) ≥7. Exclusion criteria were recent NSAIDs, antibiotics or probiotics. Sufficient elemental diet to achieve energy requirements was provided. Flexible-pouchoscopy was performed, and the Cleveland Global Quality of Life score (CGQoL), Pouch Disease Activity Index (PDAI) and BMI were recorded at baseline and following 28days of elemental diet. Faecal samples were also collected at these time points and analysed for major bacterial groups using culture independent fluorescence in situ hybridisation. Data were analysed using Wilcoxon's signed-rank test. RESULTS: Following 28days of exclusive elemental diet, median stool frequency decreased from 12 to 6 per day (p=0.028), median clinical PDAI decreased from 4 to 1 (p=0.039). There was no significant difference in quality of life scores or PDAI before and following treatment. There was a trend towards an increase in the concentration of Clostridium coccoides-Eubacterium rectale (median 7.9 to 8.5log(10)/g, p=0.08) following exclusive elemental diet. CONCLUSION: Treatment with four weeks elemental diet appeared to improve the symptoms of chronic pouchitis in some patients but is not an effective strategy for inducing remission. Although a potential symptom modifier, elemental diet cannot be recommended for the routine treatment of active pouchitis.
Journal of Crohn s and Colitis 08/2012; · 2.57 Impact Factor
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ABSTRACT: Present quality of life instruments for inflammatory bowel disease do not evaluate many social aspects of patients' lives that are potentially important in clinical decision making. We have developed a new Social Impact of Chronic Conditions - Inflammatory Bowel Disease (SICC-IBD) questionnaire to assess these areas.
A 34-item questionnaire was piloted to determine quality of life relating to education, personal relationships, employment, independence and finance. It was compared with the Short Form 36-Item version 2 (SF-36v2) and the Inflammatory Bowel Disease Questionnaire (IBDQ) in 150 patients with chronic ulcerative colitis on an endoscopic surveillance register who had never had surgery.
Reliability and validity testing enabled the questionnaire to be shortened to only eight items. There was a high level of reliability (Cronbach's α=0.72). The questionnaire correlated well with the social functioning domain of the SF-36 (rs=0.56) and was able to distinguish clinical severity of disease.
The SICC-IBD is a new tool for assessment of patients with ulcerative colitis, which has identified new aspects of social disability for further study and for potential use as an additional tool in therapy decisions.
Colorectal Disease 05/2012; 14(5):e250-7. · 2.93 Impact Factor
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ABSTRACT: The aim was to investigate quality of life, sexual, fecal, and urinary function in females undergoing restorative proctocolectomy (RPC).
A prospective case-control study was performed in two tertiary centers. Controls were females with ulcerative colitis, without a stoma or RPC. Validated questionnaires (SF-36, Female sexual function index, King's questionnaire, and the Wexner scale) were administered in the outpatient setting. Pearson chi(2), t-test, and Mann-Whitney U-tests were used to assess significance.
A total of 255 females were identified and 49% (n = 124) recruited. In all, 109 patients fulfilled the inclusion criteria: 55 (50.5%) inflammatory bowel disease (IBD); 54 (49.5%) RPC. The mean age of RPC patients was 41.8 years (± 12.7 SD) vs. 43.8 years (± 15.8) for IBD (P = 0.491). RPC females with urinary symptoms (urgency, frequency, or incontinence) were 10 years younger than IBD (RPC mean age 37.6 ± 7.3 years vs. IBD 47.4 ± 13.5; P = 0.044). Urgency in fecal function was experienced by more IBD patients (IBD 75.0% vs. RPC 47.9%; P = 0.006), although RPC patients had increased day (P < 0.001) and night bowel frequency (P < 0.001) and were more likely to experience night seepage (P = 0.001). RPC females who had a vaginal delivery (VD) were more likely to have day seepage (P = 0.046) and require pads (P = 0.026) than RPC females who had not undergone VD. There was no significant difference in sexual function.
RPC may adversely impact urinary function in female patients over time. Bowel frequency, seepage, and pad usage are increased following RPC and function may be worse following VD. RPC does not adversely affect overall sexual function.
Inflammatory Bowel Diseases 01/2012; 18(9):1601-7. · 4.86 Impact Factor
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ABSTRACT: Desmoid tumour is a common extraintestinal manifestation of patients with familial adenomatous polyposis (FAP) who have undergone prophylactic colectomy. We aimed to determine whether MRI provides equivalent or better assessment of desmoid tumours than CT, the current first-line investigation.
Following ethics approval and informed consent, FAP patients with known desmoid tumour underwent contrast-enhanced 64-slice multidetector CT (MDCT) and 1.5 T MRI (incorporating T(1) weighted, T(2) weighted, short tau inversion-recovery and T(1) weighted with contrast, axial, sagittal and coronal sequences). The number, site, size, local extent, tumour signal intensity and desmoid-to-aorta enhancement ratio were analysed.
MRI identified 23 desmoid tumours in 9 patients: 9 intra-abdominal desmoid (IAD) tumours, 10 abdominal wall desmoid (AWD) tumours and 4 extra-abdominal desmoid (EAD) tumours. CT identified only 21 desmoids; 1 EAD and 1 AWD were not identified. The two modalities were equivalent in terms of defining local extent of desmoid. Five IAD tumours involved the bowel, six caused ureteric compression and none compromised the proximal superior mesenteric artery. There was no difference in median desmoid size: 56.7 cm(2) (range 2-215 cm(2)) on MDCT and 56.3 cm(2) (3-215 cm(2)) on MRI (p=0.985). The mean MRI enhancement ratio, at 1.12 (standard deviation 0.43), was greater than the CT enhancement ratio, which was 0.48 (0.16) (p<0.0001). High signal intensity on T(2) MRI was associated with increased MRI enhancement ratio (p=0.006).
MRI is at least equivalent (and may be superior) to MDCT for the detection of desmoid tumours in FAP. Coupled with the advantage of avoiding radiation, it should be considered as the primary imaging modality for young FAP patients.
The British journal of radiology 01/2012; 85(1015):e254-61. · 2.11 Impact Factor
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ABSTRACT: Peutz-Jeghers syndrome is characterized by GI polyps and mucocutaneous pigmentation and carries an increased risk of GI cancer. GI polyps may bleed or cause intussusception. Luminal GI surveillance is recommended, but there are few data detailing outcomes from GI surveillance in Peutz-Jeghers syndrome.
This study aimed to assess outcomes from GI surveillance in patients with Peutz-Jeghers syndrome.
This study is a retrospective review, using hospital and registry notes and endoscopy and histology reports.
The investigation was conducted at a tertiary referral center.
All patients with Peutz-Jeghers syndrome who were followed up at St Mark's hospital were included.
The primary outcomes measured were surveillance procedures performed, complications, and long-term outcomes.
Sixty-three patients from 48 pedigrees were included; the median age when patients were first seen was 20 years (range, 3-59). Only baseline investigations were performed in 12 patients. The remaining patients were followed up for 683 patient years, a median of 10 years (range, 2-41). Seven hundred seventy-six procedures were performed to assess the GI tract. These led to 5 double-balloon enteroscopies, 1 push enteroscopy, and 71 surgical procedures. Of the surgical procedures, 20 were performed as a result of baseline investigations, 12 arose from investigations of symptoms, and 39 were due to surveillance of asymptomatic patients. No emergency surgical interventions were performed. No luminal GI cancers were diagnosed. Of the 2461 polypectomies performed, 6 polyps contained atypia or dysplasia. Six complications arose from endoscopy or surgical intervention, requiring 5 laparotomies to manage these complications.
GI surveillance in Peutz-Jeghers syndrome is relatively safe and avoids the need for emergency surgery for small-bowel polyps. The lack of GI cancers may reflect that surveillance and polypectomy have prevented cancer from developing, although the detection of neoplasia or dysplasia is uncommon.
Diseases of the Colon & Rectum 12/2011; 54(12):1547-51. · 3.13 Impact Factor
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ABSTRACT: Desmoid tumours (DT) are myofibroblastic proliferations occurring in 15% of patients with familial adenomatous polyposis (FAP). Several small series have analysed the incidence of DT and predisposing risk factors. Using meta-analytical techniques, this study aimed to identify risk factors for DT development in patients with FAP.
Studies of sporadic DT were excluded. The study end-points were the incidence of DT in FAP and DT development by gender, adenomatous polyposis coli (APC) mutation, family history of DT and previous abdominal surgery. A random effect Mantel-Haenszel model was used to calculate odds ratios for each risk factor and age group.
Ten studies of 4625 patients with FAP fulfilled our inclusion criteria. A total of 559 (12%) patients developed DT. Cumulative analysis demonstrated that 80% of DT developed by age 40, the peak incidence rate being in the second and third decades. A positive family history of DT was the most significant risk factor (OR 7.02, 95% CI 4.15-11.9, P < 0.001). An APC mutation 3' to codon 1399 (OR 4.37, 95% CI 2.14-8.91, P < 0.001) and previous abdominal surgery (OR 3.35, 95% CI 1.33-8.41, P = 0.01) were also implicated. Women were more likely to develop DT (OR 1.57, 95% CI 1.13-2.18, P = 0.007).
There is consistency amongst polyposis registries in documenting the incidence and risk factors for DT development. Having a positive family history for DT is of greater significance than a 3' mutation, suggesting the existence of modifier genes, independent of the APC genotype-phenotype correlation. Few of these risk factors are modifiable. Delaying prophylactic surgery could be appropriate in female patients with a 3' APC mutation and attenuated polyposis.
Colorectal Disease 11/2011; 13(11):1222-9. · 2.93 Impact Factor
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ABSTRACT: Restorative proctocolectomy with ileal-pouch anal anastomosis (RPC) is the operation of choice for ulcerative colitis (UC) patients requiring surgery. It is also used for patients with familial adenomatous polyposis (FAP). Pouchitis accounts for 10% of pouch failures. It is an idiopathic inflammatory condition that may occur in up to 50% of patients after RPC for UC. It is rarely seen in FAP patients after RPC. The etiology of pouchitis remains unclear. An overlap with UC is suggested by the frequency with which pouchitis affects patients with UC compared with FAP patients. There is significant clinical evidence implicating bacteria in the pathogenesis of pouchitis. Studies using culture and molecular methods demonstrate a dysbiosis of the pouch microbiota in pouchitis. Risk factors, genetic associations, and serological markers of pouchitis suggest that the interactions between the host immune responses and the pouch microbiota underlie the etiology of this idiopathic inflammatory condition. Here we present a detailed review of the data focusing on the pouch microbiota and the immune responses that support this hypothesis. We also discuss the contribution of luminal metabolic factors and the epithelial membrane in the etiology of this inflammatory process. The ileoanal pouch offers a unique opportunity to study the inter-relationships between the gut microbiota and host immune responses from before the onset of disease. For this reason the study of pouchitis could serve as a human model that significantly enhances our understanding of inflammatory bowel diseases in general.
Inflammatory Bowel Diseases 10/2011; 18(6):1146-55. · 4.86 Impact Factor
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ABSTRACT: This study was primarily aimed to quantify perioperative mortality risk in elderly patients undergoing elective colonic resectional surgery. In addition, the safety of minimally invasive colonic surgery in this patient group was evaluated.
All patients aged > 75 undergoing elective colonic resection for colorectal malignancy between 1996 and 2007 in English NHS hospitals were included from the Hospital Episode Statistics (HES) dataset.
Between the study dates, 28,746 patients > 75 years underwent elective colonic resection. The national annual number of colonic excisions carried out amongst elderly patients increased from 2188 patients in 1996/7 to 3240 patients in 2006/7. Following adjustment for gender, comorbidity and surgical approach, advancing age was an independent predictor for 30-day mortality (OR 2.47 for patients aged 85-89 vs 75-79, P < 0.001). Use of laparoscopy was a significant predictor of reduced perioperative mortality (OR 0.56, P = 0.003) once adjusted for advancing age, gender and comorbidity. Comparison of 30-day and 1-year postoperative mortality following elective colonic resection in patients aged 90 revealed a large excess of patients dying outside of the immediate perioperative period (10.1% and 26.2% for proximal cancers, respectively; 12.9% and 36.1% for distal colonic resections, respectively).
Advancing age is an independent risk factor for postoperative death in elderly patients undergoing elective colonic resection for cancer. The risk of death in the elderly is extremely high and surgical decision-making should incorporate the mortality risk that occurs outside the immediate perioperative period. In this national series, patients selected for a laparoscopic procedure were at lower risk of perioperative death than those undergoing the conventional approach.
Colorectal Disease 07/2011; 13(7):779-85. · 2.93 Impact Factor
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ABSTRACT: Evidence is emerging regarding the relationship between a dysbiosis of the human gut microbiota and a number of gastrointestinal diseases as well as diseases beyond the gut. Probiotics have been investigated in many gastrointestinal disease states, with variable and often modest outcomes. Faecal transplantation is an alternative approach to manipulate the gut microbiota.
To review the use of faecal transplantation therapy for the management of gastrointestinal disorders.
Available articles on faecal transplantation in the management of gastrointestinal disorders were identified using a Pubmed search and bibliographies of review articles on the subject were collated.
A total of 239 patients who had undergone faecal transplantation were reported. Seventeen of 22 studies of faecal transplantation were in fulminant or refractory Clostridium difficile. Studies of faecal transplantation are heterogeneous regarding the patients, donors, screening, methods of administration and definition of response. Faecal transplantation for C. difficile has been demonstrated to be effective in 145/166 (87%) patients. Small numbers of patients are reported to have undergone successful faecal transplantation for irritable bowel syndrome and inflammatory bowel disease.
Faecal transplantation has been reported with good outcomes for fulminant and refractory C. difficile. No adverse effects of faecal transplantation have been reported. However, there are no level 1 data of faecal transplantation and reports to date may suffer from reporting bias of positive outcomes and under-reporting of adverse effects. This therapy holds great promise, where a dysbiosis of the gut microbiota is responsible for disease and further studies are necessary to explore this potential.
Alimentary Pharmacology & Therapeutics 06/2011; 34(4):409-15. · 3.77 Impact Factor
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ABSTRACT: About 5% of restorative proctocolectomy (RPC) patients develop chronic antibiotic-dependent pouchitis. These require antibiotic maintenance therapy. We report our experience in managing this patient group.
Patients with RPC that was treated with antibiotic maintenance therapy were identified from the hospital pouch database. Data including faecal antibiotic sensitivity, functional outcome, side effects and Cleveland Global Quality of Life (CGQOL) score were recorded.
Twenty-five patients were identified. The median length of treatment was 15.8 (range 3-62) months. Ten (40%) patients had pouchitis with co-existing prepouch ileitis. The median frequency of defecation was 7 (range 4-11)/24 h, the median clinical Pouch Disease Activity Index (PDAI) was 0 (range 0-1) and the CQGOL score was 0.7 (range 0.5-1.0). Of those who relapsed, three (50%) patients had achieved mucosal healing following the induction of remission. Failure of mucosal healing did not predict a reduced time to relapse (P = 0.18). Prepouch ileitis was associated with an increased risk of developing antibiotic resistance (P = 0.023). Treatment of this with alternating antibiotic combination therapy was successful in all cases.
Antibiotic maintenance therapy appears safe, well-tolerated and effective for the treatment of chronic antibiotic-dependent pouchitis. It results in an improved quality of life and function. Prepouch ileitis, but not failure of mucosal healing, is associated with an increased risk of developing antibiotic resistance.
Colorectal Disease 04/2011; 13(4):438-44. · 2.93 Impact Factor
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ABSTRACT: This observational study aimed to determine national provision and outcome following pouch surgery (restorative proctocolectomy, RPC) and to examine the effect of institutional and surgeon caseload on outcome.
All patients undergoing primary RPC between April 1996 and March 2008 in England were identified from the administrative database Hospital Episode Statistics. Institutions and surgeons were categorized according to the total RPC caseload performed over the study interval.
Some 5771 primary elective pouch procedures were undertaken at 154 National Health Service hospital trusts. Median follow-up was 65 (interquartile range (i.q.r.) 28-106) months. The 30-day in-hospital mortality rate was 0·5 per cent and the 1-year overall mortality rate 1·5 per cent. Some 30·5 per cent of trusts performed fewer than two procedures per year, and 91·4 per cent of surgical teams (456 of 499) carried out 20 or fewer RPCs over 8 years. Median surgeon volume was 4 (i.q.r. 1-9) cases. Failure occurred in 6·4 per cent of cases. Low-volume surgeons operated on more patients at the extremes of age (P < 0·001) and a lower proportion with ulcerative colitis (P < 0·001). Older age, increasing co-morbidity, increasing social deprivation, and both lower provider and surgeon caseload were independent predictors of longer length of stay. Older patient age and low institutional volume status were independent predictors of failure.
Many English institutions and surgeons carry out extremely low volumes of RPC surgery. Case selection differed significantly between high- and low-volume surgeons. Institutional volume and older age were positively associated with increased pouch failure.
British Journal of Surgery 03/2011; 98(3):408-17. · 4.61 Impact Factor
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British Journal of Cancer 03/2011; 104(7):1236; author reply 1237. · 5.04 Impact Factor
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ABSTRACT: Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis is the operation of choice for patients with ulcerative colitis. Pouchitis is the most common cause of pouch dysfunction. Although the pathogenesis of this disease is not well understood, bacteria have been implicated in the disease process. Numerous bacterial studies have been reported over the last 25 years with few unifying findings. In addition, many different treatments for pouchitis have been reported with varying results. Antibiotic treatment remains the most studied and is the mainstay of treatment. In this article we review the aetiology of pouchitis and the evidenced-based treatment options.
Therapeutic Advances in Gastroenterology 11/2010; 3(6):335-48.
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ABSTRACT: Colectomy and ileorectal anastomosis (IRA) or restorative proctocolectomy are performed for prophylaxis in familial adenomatous polyposis (FAP). After IRA patients may require secondary proctectomy for worsening polyposis or rectal cancer. Outcomes after IRA were evaluated and risk factors predictive of progressive rectal disease identified.
Parametric survival analysis was used to identify predictors of progressive rectal disease in all patients undergoing an IRA for FAP at a single centre. Hazard ratios (HRs) were calculated for phenotype, genotype, sex, age at surgery and presence of colonic cancer.
Of 427 patients who underwent IRA, 48 (11.2 per cent) developed rectal cancer and 77 (18.0 per cent) required proctectomy for worsening polyposis over a median follow-up of 15 (range 7-25) years. By the age of 60 years half of the patients retained their rectum. Rectal polyp count exceeding 20 (HR 30.99, 95 per cent confidence interval 9.57 to 100.32; P < 0.001), APC mutation codon 1250-1450 (HR 3.91, 1.45 to 10.51; P = 0.007), colonic polyp count 500 or more (HR 2.18, 1.24 to 3.82; P = 0.006) and age less than 25 years at the time of surgery (HR 1.99, 1.17 to 3.37; P = 0.011) were independent predictors of progressive rectal disease.
The risk of proctectomy after IRA for FAP is based on patient genotype, phenotype and age at surgery.
British Journal of Surgery 11/2010; 97(11):1710-5. · 4.61 Impact Factor
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ABSTRACT: Treatment with fluoroquinolones is associated with the development of Clostridium difficile and extended spectrum beta-lactamase-producing bacteria (ESBL). Clostridium difficile and ESBL are resistant to many antibiotics and each may cause pouchitis after restorative proctocolectomy (RPC) refractory to empirical antibiotic therapy.
To assess the prevalence and establish risk factors for the development of ESBL and Clostridium difficile toxins (CDT) in RPC patients with recurrent or refractory pouchitis under follow-up at our institution over a 1-year period.
An enzyme-linked immunosorbent assay was used to detect CDT and a culture technique was used to identity ESBL in faecal samples. All patients had previously received fluoroquinolone treatment.
Forty-eight patients (35 (74%) men; median age 42 years) underwent testing at a median interval from RPC of 8 (range 1-25) years. No patient had a positive CDT result, but ESBL bacteria were identified in 16 (33%) samples. ESBL positivity was significantly related to prepouch ileitis (P = 0.035) and maintenance antibiotic therapy (P = 0.039).
Extended spectrum beta-lactamase, but not CDT, is a common finding in faecal samples from patients with recurrent or refractory pouchitis. Treatment with maintenance antibiotics and prepouch ileitis are risk factors for developing ESBL-producing bacteria.
Alimentary Pharmacology & Therapeutics 09/2010; 32(5):664-9. · 3.77 Impact Factor
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A D Beggs,
A R Latchford,
H F A Vasen,
G Moslein,
A Alonso,
S Aretz,
L Bertario,
I Blanco,
S Bülow,
J Burn, [......],
W Hyer,
M Ponz de Leon,
L Renkonen-Sinisalo,
J R Sampson,
A Stormorken,
S Tejpar,
H J W Thomas,
J T Wijnen, S K Clark,
S V Hodgson
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ABSTRACT: Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.
Gut 07/2010; 59(7):975-86. · 10.11 Impact Factor
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ABSTRACT: Desmoids are myofibroblastic proliferations occurring in 15% of patients with familial adenomatous polyposis (FAP), 70% being intra-abdominal desmoids (IAD). Since the morbidity and mortality due to desmoids is almost entirely attributable to IAD, we aimed to identify specifically risk factors predicting IAD development in FAP.
We undertook a retrospective review of our institutional database. Multivariate analysis was performed, and hazard ratios (HR) calculated for variables including female gender, 3' APC mutation, surgical intervention for FAP (colectomy with ileo-rectal anastomosis or restorative proctocolectomy), age at surgery and family history (FH) of desmoids.
Of the 558 patients analysed, 49 (9%) developed IAD; 22 (4%) diagnosed intra-operatively and 27 (5%) developing over a median post-operative period of 34 (7-120) months. 75% of IAD had developed before age 40. A 3' APC mutation (HR 5.2, 95% CI 2.1-13.3, P = 0.001), positive FH (HR 2.5, 95% CI 1.4-4.6, P = 0.003) and female gender (HR 1.9, 95% CI 1.0-3.5, P = 0.04) were found to be predictive of IAD development. No significant difference in IAD risk was detected between the type of surgical intervention (P = 0.37) or age at surgery (P = 0.29).
Our analysis confirms 3' APC mutation to be the most significant risk factor for IAD development. The independent association between positive FH and IAD risk suggests the existence of modifier genes, independent of the APC genotype-phenotype correlation. Few of these risk factors can be meaningfully modified. Delaying prophylactic surgery may be appropriate in female patients with a 3' APC mutation and attenuated polyposis.
Techniques in Coloproctology 03/2010; 14(2):141-6. · 1.29 Impact Factor
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ABSTRACT: The right colon differs from the left, in embryological origin, luminal environment, and function. In both sporadic colorectal cancer and Familial Adenomatous Polyposis (FAP), polyp density and cancer susceptibility vary markedly by colonic site. Adenomas in FAP have a different mutational spectrum in small intestine versus colon. This study aimed to investigate whether colonic location also influences the APC mutation spectrum in FAP. 127 1-2 mm mildly dysplastic adenomas from 5 patients with a codon 1309 germline mutation, and 41 from 3 patients with mutations proximal to codon 1265, were analysed to assess the frequency of loss of heterozygosity (LOH). We chose polyps from different locations in the colon. Immunohistochemistry for beta-catenin, caspase-3 and Ki-67 was performed to assess Wnt pathway activation, apoptosis and proliferation. In polyps from patients with a 1309 mutation, the frequency of LOH showed a gradient from rectum (highest) to caecum/ascending colon (lowest), but this was not present in patients with proximal germline APC mutations. Crypt-by-crypt analysis confirmed the LOH findings from whole polyps. Beta-catenin and caspase-3 expression showed no significant variation by colonic region, but Ki-67 expression decreased from ascending colon to rectum in tumours and normal tissue. Colonic site alters the mutational spectrum of APC, and crypt cell proliferation. The higher frequency of LOH in rectal polyps from patients with codon 1309 mutations may help to explain their increased polyp burden at this site compared with patients who have other germline APC mutations.
Familial Cancer 03/2010; 9(3):389-93. · 1.30 Impact Factor
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ABSTRACT: In patients with familial adenomatous polyposis (FAP), ileoanal pouch cancer is rare whereas rectal cancer is common, despite polyp initiation at the two sites being similar at the molecular level. This study investigated whether the disparity in adenoma aggressiveness reflects underlying differences in histogenesis.
Normal mucosal biopsies and 2-3 mm adenomas from patients with FAP were dissected into individual crypts. Crypt area, morphology, fission and mitoses were analysed for crypts from pouch, rectum and supra-anastomotic ileum. Immunohistochemistry of similar archival samples was performed for lysozyme, β-catenin and TP53 expression.
The morphology of normal crypts was similar at each site, although crypt area differed. The area of normal pouch crypts was intermediate between rectum and ileum. The area of adenomatous crypts of rectum and pouch was similar, but the latter had increased asymmetrical fission. Crypt mitoses were proportional to area in all tissues, but crypt fission was reduced in adenomatous crypts from the rectum compared with the pouch. Pouch adenomas retained lysozyme expression as seen in normal ileum. Nuclear β-catenin accumulation was similar, but TP53 expression was increased in rectal adenomas.
Diminutive polyps from rectum and pouch differ in morphology and proliferation. Aggressiveness in rectal polyps is not conferred by increased crypt proliferation, fission, or activation of the Wnt signalling pathway. Increased TP53 expression suggests other molecular mechanisms may be responsible. While crypt mitoses are proportional to crypt area, the threshold for fission may be site specific, indicating that tissue origin may influence histogenesis and thus malignant potential.
Colorectal Disease 12/2009; 13(4):387-92. · 2.93 Impact Factor
