For Familial Adenomatous Polyposis Patients Research Articles

Abstract SY07-02: Cell competition vs cell cooperation: Unlocking oncogenic potential of mutant clones in the gut

Abstract The epithelial monolayer of the intestine is one of the fastest renewing tissues of the human body. Every week, the entire epithelium is replaced by intestinal stem cells (ISCs) that reside in crypt-like structures within the monolayer. Within these crypts, a small number of ISCs continuously divide to provide all specialized cell types necessary to maintain normal intestinal homeostasis, while simultaneously competing with each other for a position within the crypt bottom. This competition, characterized by neutral loss-and-replacement events, can be drastically disturbed when one of the ISCs acquires a mutation that confers a competitive advantage. As a result, mutant ISCs will replace all normal ISCs, colonize the intestinal crypt, and facilitate the initiation of colorectal cancer (CRC). CRC development is a stepwise process characterized by the accumulation of mutations in cancer driver genes over time. Almost 80% of all CRCs present with early mutations in the tumor suppressor gene APC, leading to constitutive activation of the Wnt pathway and the formation of pre-malignant adenomas. We have previously demonstrated that, within individual crypts, Apc-mutant ISCs have a competitive advantage over normal ISCs, although the mechanism underlying this unequal competition remained unclear. Recently, we revealed that Apc-mutant ISCs in fact act as "supercompetitors" by secreting Wnt antagonists such as NOTUM, WIF1 and DKK2, that actively disadvantage neighboring wild type ISCs by forcing them do differentiate. We demonstrated that boosting wild type fitness by downstream pharmacological activation of the Wnt signaling pathway by GSK3β-inhibitor lithium rendered wild type ISCs resistant to the Wnt antagonists, reduced the number of Apc-mutant crypts, and prevented adenoma formation. Together, this work highlights that modulating cell competition between normal and mutant cells within the crypt can provide a novel approach to prevent CRC development. Our findings are particularly relevant for familial adenomatous polyposis (FAP) patients, that carry germline mutations in APC and are predisposed to the development of CRC. Based on our fundamental discoveries, we are currently performing a clinical trial to assess the chemopreventive effect of lithium on the expansion of APC-mutant clones in FAP patients [ClinicalTrials.gov: NCT05402891]. Importantly, it is becoming increasingly evident that intestinal adenomas do not form from a single Apc-mutant crypt, but require fields of multiple mutant crypts to facilitate tumor initiation. Although field cancerization by enhanced crypt fission has been observed for several oncogenic mutants in the gut (e.g. KrasG12D, PIK3CAH1047R), Apc-mutant cells are often contained within individual crypts. This indicates that multiple independent mutant clones may act cooperatively to facilitate tumorigenesis, thereby pointing towards a polyclonal origin of intestinal adenomas. Our current work investigates how Apc-mutant clones interact by modifying their local environment through reciprocal signalling with stromal and epithelial cells to escape the anatomical constraints of the crypt, thereby unlocking their oncogenic potential in the gut. Ultimately, unravelling the molecular mechanisms underlying clonal cooperation will inform potential chemoprevention strategies for CRC. Citation Format: Sanne van Neerven. Cell competition vs cell cooperation: Unlocking oncogenic potential of mutant clones in the gut [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY07-02.

Complicaciones asociadas al reservorio ileal en colitis ulcerativa versus poliposis familiar adenomatosa: Impacto en la calidad de vida del paciente

BackgroundProctocolectomy with ileal reservoir is the surgical procedure of choice for patients with ulcerative colitis and familial adenomatous polyposis. ObjectivesTo evaluate long-term postoperative complications (1994-2019) in patients operated for familial adenomatous polyposis (FAP) and ulcerative colitis (UC) and the degree of satisfaction with the procedure. MethodsObservational study based on the analysis of a retrospective database with prospective follow-up in 115 consecutive patients: 79 with UC and 36 with FAP. A total of 88 patients were followed up, 60 with UC and 28 with PFA. Results48 males (54.4%) with a mean age of 44.8 ± 10.6 years were evaluated. Indications for surgery were intractable disease in 54 patients (47%), dysplasia/cancer in 43 (37%), severe bleeding in 4 (4%) and perforation in 3 (3%). A proctectomy and mucosectomy of the rectal stump was performed in 67 (76.1%), and a double stapling technique in 21. A protective ileostomy was performed in all patients with UC and FAP. No differences were found in early complications between the two groups. Late complications showed a higher rate of reservoritis in UC patients compared to FAP (44.9 vs. 14.3%, p = 0.001), with more refractory reservoritis in the UC group (13.3 vs. 0%, p = 0.04) with no differences in bowel obstruction, strictures, or anastomotic fistulas. Overall satisfaction and adaptation were considered good in 87% of UC patients and only 57% in the FAP group (p < 0.01). ConclusionsProctocolectomy with ileal reservoir has comparable morbidity and mortality, except for the higher rate of reservoritis in patients with a history of UC, despite this contingency there is a better quality of life and greater acceptance of surgery in UC patients than in FAP patients.

Wild-type APC Influences the Severity of Familial Adenomatous Polyposis.

Germline mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP). FAP patients develop multiple colonic adenomas early in life. The number of polyps can vary considerably because of different mutations1 but also for family members carrying the same mutation.2 Several genes have been considered as modifiers for the intrafamilial severity differences.3

Ileal Pouch of Ulcerative Colitis Patients Exhibit Impaired Autophagy

BACKGROUND: Total rectocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgery of choice for patients with ulcerative colitis (UC) that are refractory to clinical treatment and for familial adenomatous polyposis (FAP) with many rectal polyps. The main complication after this procedure is the pouch inflammation (pouchitis) that can affect up to 45 percent of patients who are submitted to IPAA for UC, and only five percent of the FAP patients who undergo the same procedure. Previous studies have shown increased pro-inflammatory cytokines in the ileal pouch (IP) mucosa of UC patients, even in the absence of clinical, endoscopic and histological inflammation. Autophagy is an evolutionarily conserved catabolic pathway that consists of selective degradation of cellular components and a homeostatic mechanism that protects cells exposed to stress situations (toxins, starvation), and defects in this pathway have been reported in inflammatory bowel diseases. However, there are no studies on the IP. Therefore, we studied markers for autophagy in the IP mucosa of UC and FAP patients comparing them to controls with a normal distal ileum. METHODS: Sixteen patients with IP in "J" shape, asymptomatic and with endoscopically normal mucosa were evaluated. The control group consisted of eight patients with normal colonoscopy. Gene expression was analyzed by qPCR and protein levels by immunoblotting and immunofluorescence. This study was approved by the Ethics Committee of the University of Campinas and was performed in accordance with the Declaration of Helsinki. All results were reported as means ± SEM. Data were analyzed by non-parametric Test, comparing all groups. The level of significance was set at P<0.05. RESULTS: There was a significant decrease in the transcriptional levels of ATG5, MAP1LC3A and BAX in the FAP group (P<0.05). There was also a decrease in the protein level of Beclin-1 in the UC and FAP compared to the control group (P<0.05). Although the LC3II levels by immunoblot were higher in the UC group, total LC3 and LC3/p62 co-localization were lower in the immunofluorescence analysis in the UC and FAP compared to the control group (P<0.05). Corroborating to these results, there was an increase of p62 by immunoblot in the UC group, compared to controls (P<0.05). CONCLUSION(S): These results indicate impaired macroautophagy mechanism in the IP. In FAP, decreased autophagy may be related to impaired apoptosis, otherwise in UC, may be mainly due to increased Toll-Like Receptors (TLR) activation. These findings may explain the inflammation predisposition, mainly in the IP mucosa of UC patients. Acknowledgments: We thank FAPESP (São Paulo Research Foundation) for financial support. Negreiros LMV (co-author) received scholarship from FAPESP. We are grateful to Prof. Tristan Torriani for English grammar revision. We thank Francesca Ramos and José Diego Botezelli for technical assistance and the staff of the Life Sciences Core Facility (LaCTAD) from State University of Campinas (UNICAMP), for the Cell Biology analysis.

Longitudinal analysis of colon crypt stem cell dynamics in sulindac treated Familial Adenomatous Polyposis patients

The non-steroidal anti-inflammatory drug sulindac decreases size and number of adenomas after 4-6 months of treatment for familial adenomatous polyposis (FAP) patients. However, the underlying mechanism remains unknown. As stem cells are thought to be the tumor precursor cells, visualizing their behavior is crucial for monitoring tumor progression. Increased tag diversity in inactive genes is indicative of a protracted clonal evolution and consequently, increased risk for tumor formation. Therefore, the effect of sulindac on stem cell dynamics was studied. Normal appearing single crypts were laser microdissected in placebo- and sulindac- treated FAP patient tissue after which the methylation patterns were visualized by Next Generation Sequencing. A significant difference in tag diversity over time was found in the sulindac group compared to the placebo group (*p = 0.018), indicative of a shortened clonal evolution treated sulindac. The rate of change in tag diversity over time was correlated with polyp number change over time. No significant difference over time was observed in the percent methylation when comparing placebo vs sulindac. In conclusion, daily sulindac administration in FAP patients significantly altered colorectal stem cell dynamics, which might explain the chemopreventive action of this drug indicating that tag diversity may be used as a predictive biomarker.

Prevalence of laparoscopic surgical treatment and its clinical outcomes in patients with familial adenomatous polyposis in Japan.

Laparoscopic surgery is becoming the preferred technique for most colorectal interventions. This study aimed to clarify the time trend of surgical treatment for familial adenomatous polyposis (FAP) and its relevance to clinical outcomes in Japan over a 13-year period. This was a multicenter retrospective cohort study comprising 23 specialist institutions for colorectal disease and a cohort of 282 FAP patients who underwent total colectomy or proctocolectomy during 2000-2012. Patient clinical backgrounds and surgical outcomes were compared between the first and second halves of the study period. The proportion of surgical types adopted over the entire study period was 46, 21, 30, and 3% for ileoanal anastomosis (IAA), ileoanal canal anastomosis, ileorectal anastomosis, and permanent ileostomy, respectively. FAP patients undergoing laparoscopic surgery have increased since 2008 and reached 74% in the past 3years. In particular, the number of patients undergoing laparoscopic proctocolectomy with IAA increased approximately four-fold from the first to the second half of the study period. A laparoscopic approach was increasingly used in patients with coexisting colorectal malignancies. Despite this trend, surgical results of the laparoscopic approach between the two study periods showed similar morbidity, pouch operation and stoma closure completion rates. No postoperative mortality was observed in this series, and laparoscopic surgery was comparable to open surgery in terms of stoma closure rate, incidence of intra-abdominal/abdominal desmoid tumors, and postoperative survival rate in both study periods. Laparoscopic approach is increasingly being adopted for prophylactic FAP surgery in Japan and may provide clinically acceptable practical outcomes.

Laparoscopic-assisted Proctocolectomy With Prolapsing Technique for Familial Adenomatous Polyposis

The role of laparoscopic total proctocolectomy (TPC) and ileal pouch-anal anastomosis (IPAA) for familial adenomatous polyposis (FAP) has been controversial, given its technical difficulty of selecting the appropriate distal transection line and achieving safe anastomosis. We herein describe our initial experience with the prolapsing technique for laparoscopic-assisted TPC and IPAA (J-pouch) in the treatment of FAP. A consecutive series of patients with FAP undergoing laparoscopic-assisted TPC with IPAA were identified from a prospectively collected database between June 2004 and February 2012. Medical records were reviewed for patient demographics, operative outcomes, and follow-up. The surgery was successfully completed in all 6 patients without any conversion to open surgery. The median operating time was 279 minutes (range, 240 to 386 min) and the median blood loss was 17.5 mL (range, 5 to 161 mL). No patient required blood transfusion. The median length of diet resumption and postoperative hospital stay were 7 days (range, 6 to 10 d) and 15 days (range, 13 to 21 d), respectively. A postoperative complication, wound infection, occurred in 1 patient. No anastomotic leakages or small bowel obstructions occurred. At a median follow-up of 59 months (range, 14.2 to 107.5 mo), no carcinoma had developed at the pouch or at the anastomotic site. Sexual function and fertility were unchanged as compared with preoperatively in 2 male patients. None of the patients experienced night-time incontinence or had to use a pad. Our limited experience suggests that this prolapsing technique helps prevent problems with laparoscopic-assisted TPC and IPAA for FAP patients.

Efforts to advance surgical treatments for patients with familial adenomatous polyposis for 40 years in a cancer hospital.

There have been numerous studies on surgical procedures for familial adenomatous polyposis (FAP), but the evolution in surgical treatments as they pertain to the major perioperative item, i.e., complications, as well as advantages and disadvantages of surgery, in only one institution have not been reported. We examined this surgical treatment evolution in FAP patients. We enrolled 67 FAP patients who had undergone surgery and classified them into three groups, i.e., early phase (1965 to 1977), intermediate phase (1978 to 1987), and late phase (1988 to 2004). We assessed clinicopathological findings and outcomes in these three groups. With the passage of time, surgical techniques and therapeutic benefits improved, but the overall survival rates of early and late phase patients were significantly better than that of intermediate phase patients. As the surgical techniques improved, patient stress diminished but outcomes in the late period were not always better than in the early period. Surveillance has been enhanced by the increased prevalence of colonoscopy and genetic research has also contributed to better disease management. It is necessary to research the prognosis of FAP patients in the future.

Chemoprevention of familial adenomatous polyposis by bromo‐noscapine (EM011) in the ApcMin/+ mouse model

Germline mutation of the tumor suppressor gene, adenomatous polyposis coli (APC), is responsible for familial adenomatous polyposis (FAP) with nearly 100% risk for colon cancer at an early age. Although FAP is involved in only 1% of all colon cancer cases, over 80% of sporadic cancers harbor somatic mutations of APC. We show here that bromo-noscapine (EM011), a rationally designed synthetic derivative of a natural nontoxic tubulin-binding alkaloid-noscapine, that reduces the dynamics of microtubules, causes a reversible G(2) /M arrest in wild type murine embryonic fibroblasts (MEFs), but an aberrant exit from a brief mitotic block, followed by apoptosis in MEFs after APC deletion with small interfering RNA. Furthermore, both β-catenin levels and activity fell to half the original levels with a concomitant reduction of cell proliferation-inducing cyclin D1, c-Myc, and induction of cytostatic protein p21 before caspase-3 activation. Additionally, we show a statistically significant reduction in the number of newly emerging intestinal polyps (to 35% compared with untreated mice) as well as the mean size of polyps (to 42% compared with untreated mice) in EM011-treated Apc(Min/+) mice as compared to their sham-treated control littermates. The remaining polyps in the EM011 treated group of Apc(Min/+) mice showed evidence of elevated apoptosis as revealed by immunohistochemistry. We failed to detect any evidence of histopathological and hematological toxicities following EM011 treatment. Taken together, our data are persuasive that a clinical trial of EM011 is possible for the prevention/amelioration of polyposis in FAP patients.

Abstract 939: Chemoprevention of familial adenomatous polyposis by EM011 in the ApcMin/+ mouse model

Abstract Abstract Germline mutation of the tumor suppressor gene, adenomatous polyposis coli (APC), is responsible for familial adenomatous polyposis (FAP) with nearly 100% risk for colon cancer at an early age. Although FAP is involved in only 1% of all colon cancer cases, over 80% of sporadic cancers harbor somatic mutations of APC. We show here that 9-bro-noscapine (EM011), a rationally-designed synthetic derivative of a natural non-toxic tubulin-binding alkaloid−noscapine, that reduces the dynamics of microtubules, causes a reversible G2/M arrest in wild type mouse embryonic fibroblasts (MEFs), but an aberrant exit from a brief mitotic block, followed by apoptosis in MEFs isolated from ApcMin/+ mice. Furthermore, both β-catenin levels and activity fell to half the original levels with a concomitant reduction of cell proliferation-inducing cyclin D1, c-Myc, and induction of cytostatic protein p21 prior to caspase-3 activation. Additionally, we show a statistically significant reduction in the number of newly emerging intestinal polyps (to 35% compared with untreated mice) as well as the mean size of polyps (to 42% compared with untreated mice) in EM011-treated ApcMin/+ mice as compared to their sham-treated control littermates. The remaining polyps in the EM011 treated group of ApcMin/+ mice showed evidence of elevated apoptosis as revealed by immunohistochemistry. We failed to detect any evidence of histopathological and hematological toxicities following EM011 treatment. Taken together, our data are persuasive that a clinical trial of EM011 is possible for the prevention/amelioration of polyposis in FAP patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 939.

Detection of epithelial apoptosis in pelvic ileal pouches for ulcerative colitis and familial adenomatous polyposis

BackgroundIleal pouch-anal anastomosis (IPAA) is the surgical procedure of choice for patients with refractory ulcerative colitis (UC) and for familial adenomatous polyposis (FAP) with many rectal polyps. Pouchitis is one of the more frequent complications after IPAA in UC patients; however, it is rare in FAP.ObjectiveEvaluate pro-apoptotic activity in endoscopically and histological normal mucosa of the ileal pouch in patients with UC and FAP.MethodsEighteen patients (nine with UC and nine with FAP) with J pouch after total rectocolectomy were studied. Biopsies were obtained from the mucosa of the pouch and from normal ileum. The specimens were snap-frozen and the expressions of Bax and Bcl-2 were determined by immunoblot of protein extracts and by immunohistochemistry analysis. FADD, Caspase-8, APAF-1 and Caspase-9 were evaluated by immunoprecipitation and immunoblot.ResultsPatients with UC had significantly higher protein levels of Bax and APAF-1, Caspase-9 than patients with FAP, but were similar to controls. The expressions of Bcl-2 and FADD, Caspase-8 were similar in the groups. Immunohistochemistry for Bax showed less intensity of immunoreactions in FAP than in UC and Controls. Bcl-2 immunostaining was similar among the groups.ConclusionPatients with FAP present lower levels of pro-apoptotic proteins in all methods applied, even in the absence of clinical and endoscopic pouchitis and dysplasia in the histological analysis. These findings may explain a tendency of up-regulation of apoptosis in UC patients, resulting in higher rates of progression to pouchitis in these patients, which could correlate with mucosal atrophy that occurs in inflamed tissue. However, FAP patients had low pro-apoptotic activity in the mucosa, and it could explain the tendency to low cell turn over and presence of adenomas in this syndrome.

Attitudes toward genetic testing in childhood and reproductive decision-making for familial adenomatous polyposis

Childhood DNA testing, prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) are available for familial adenomatous polyposis (FAP). However, the use of PND and PGD is controversial. The purpose of this study was to investigate attitudes toward, and experiences with, childhood DNA testing, PND and PGD among members of families at high risk for FAP. In this nationwide, cross-sectional study, questionnaires were sent to individuals from families at high risk for FAP assessing attitudes toward and experiences with childhood testing, PND and PGD, as well as several sociodemographic, clinical and psychosocial variables. Of the individuals from FAP families invited to participate in the study, 525 members participated (response rate=64%). Most parents who had children who were minors (n=93) (82%) were satisfied with the DNA testing procedure. One-third of all individuals wanted DNA testing for their children before age 12. Forty percent of FAP patients indicated that the disease influenced their desire to have children. Only 15% considered termination of pregnancy for FAP acceptable. Approximately 30% of individuals with a FAP diagnosis and their partners considered PND and PGD as acceptable for themselves. A positive attitude was associated with higher levels of guilt and a positive attitude toward termination of pregnancy. Importantly, of those with FAP at childbearing age, 84% had had no previous information at all about either PND or PGD. Future efforts should be aimed at educating FAP family members about reproductive options, allowing them to make an informed choice about family planning. Routine discussion of all reproductive options with a medical specialist should be encouraged.

Restorative proctocolectomy and ileal pouch-anal anastomosis for familial adenomatous polyposis revisited

Since restorative proctocolectomy (RPC) with ileal-pouch anal anastomosis (IPAA) removes the entire diseased mucosa, it has become firmly established as the standard operative procedure of choice for familial adenomatous polyposis (FAP). Many technical controversies still persist, such as mesenteric lengthening techniques, close rectal wall proctectomy, endoanal mucosectomy vs. double stapled anastomosis, loop ileostomy omission and a laparoscopic approach. Despite the complexity of the operation, IPAA is safe (mortality: 0.5-1%), it carries an acceptable risk of non-life-threatening complications (10-25%), and it achieves good long-term functional outcome with excellent patient satisfaction (over 95%). In contrast to the high incidence in patients operated for ulcerative colitis (UC) (15-20%), the occurrence of pouchitis after IPAA seems to be rare in FAP patients (0-11%). Even after IPAA, FAP patients are still at risk of developing adenomas (and occasional adenocarcinomas), either in the anal canal (10-31%) or in the ileal pouch itself (8-62%), thus requiring lifelong endoscopic monitoring. IPAA operation does not jeopardise pregnancy and childbirth, but it does impair female fecundity and has a low risk of impairment of erection and ejaculation in young males. The latter can almost completely be avoided by a careful "close rectal wall" proctectomy technique. Some argue that low risk patients (e.g. <5 rectal polyps) can be identified where ileorectal anastomosis (IRA) might be reasonable. We feel that the risk of rectal cancer after IRA means that IPAA should be recommended for the vast majority of FAP patients. We accept that in some very selected cases, based on clinical and genetics data (and perhaps influenced by patient choice regarding female fecundity), a stepwise surgical strategy with a primary IPA followed at a later age by a secondary proctectomy with IPAA could be proposed.

Chemoprevention of intestinal polyposis in the APCDelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor

Mutations in the human adenomatous polyposis (APC) gene are causative for familial adenomatous polyposis (FAP), a rare condition in which numerous colonic polyps arise during puberty and, if left untreated, lead to colon cancer. The APC gene is a tumor suppressor that has been termed the "gatekeeper gene" for colon cancer. In addition to the 100% mutation rate in FAP patients, the APC gene is mutated in >80% of sporadic colon and intestinal cancers. The Apc gene in mice has been mutated either by chemical carcinogenesis, resulting in the Min mouse Apcdelta850, or by heterologous recombination, resulting in the Apcdelta716 or Apedelta1368 mice (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482-4486, 1995). Although homozygote Apc-/- mice are embryonically lethal, the heterozygotes are viable but develop numerous intestinal polyps with loss of Apc heterozygosity within the polyps (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482-4486, 1995). The proinflammatory, prooncogenic protein cyclooxygenase (COX)-2 has been shown to be markedly induced in the Apcdelta716 polyps at an early stage of polyp development (M. Oshima et al., Cell, 87: 803-809, 1996). We demonstrate here that treatment with the specific COX-2 inhibitor rofecoxib results in a dose-dependent reduction in the number and size of intestinal and colonic polyps in the Apcdelta716 mouse. The plasma concentration of rofecoxib that resulted in a 55% inhibition of polyp number and an 80% inhibition of polyps > 1 mm in size is comparable with the human clinical steady-state concentration of 25 mg rofecoxib (Vioxx) taken once daily (A. Porras et al., Clin. Pharm. Ther., 67: 137, 2000). Polyps from both untreated and rofecoxib- or sulindac-treated Apcdelta716 mice expressed COX-1 and -2, whereas normal epithelium from all mice expressed COX-1 but minimal amounts of COX-2. Polyps from either rofecoxib- or sulindac-treated mice had lower rates of DNA replication, expressed less proangiogenic vascular endothelial-derived growth factor and more membrane-bound beta-catenin, but showed unchanged nuclear localization of this transcription factor. This study showing the inhibition of polyposis in the Apcdelta716 mouse suggests that the specific COX-2 inhibitor rofecoxib (Vioxx) has potential as a chemopreventive agent in human intestinal and colon cancer.

Ocular findings in familial adenomatous polyposis.

Retinal pigment epithelium (RPE) lesions are predictive congenital phenotypic markers for familial adenomatous polyposis (FAP). This prospective screening study aims at assessing the incidence and significance of these lesions in FAP patients and their family members. Sixty-two members from three families including five patients with the diagnosis of FAP have been ophthalmologically surveyed. All RPE lesions were documented with fundus photography and fluorescein angiography was performed in 13 subjects. Sigmoidoscopy and/or radiological examination were performed annually in 9 family members with typical RPE lesions during 4 years to allow early diagnosis of FAP. Typical RPE lesions were present in five FAP patients and 15 family members. Telangiectatic dilatations in the retinal periphery with small dot-like hemorrhages were detected in 6 subjects from 3 families These lesions were particularly evident on fluorescein angiography. Annual colon analysis showed polyps in 3 out of 9 subjects who were positive for RPE lesions. RPE lesions are valuable as a clinical marker in predicting FAP. The co-existing peripheral vascular alterations which have not been reported before, are probably related to FAP.

Factors affecting the risk of rectal cancer following rectum-preserving surgery in patients with familial adenomatous polyposis

Rectum-preserving surgery is one of the most common surgeries for familial adenomatous polyposis (FAP). It is appropriate to analyze factors influencing risk of rectal cancer after rectum-preserving surgery in FAP patients. Three hundred twenty-two patients with FAP (169 males, 153 females) who had undergone rectum-preserving surgery and were part of 1050 FAP patients registered at our FAP registry were included in the study. Postoperative survival was investigated and cause of death was elucidated from the death certificate or by inquiry to the hospitals that registered the patients. For risk analysis, log-rank tests were used. Forty-four cases developed invasive cancer within a mean interval of 119 months after surgery. Cumulative risk of rectal cancer was 24.2 +/- 7 percent (mean +/- limit of 95 percent confidence interval) at 15 years. Influencing risk factors for rectal cancer were a postoperative period over ten years or age over 44 years, a rectum longer than 7 cm, and dense polyposis. Other factors such as sex and cancer in the colon at initial surgery were not correlated with risk. The rectum may be reasonably preserved in patients with FAP when polyps in the rectum are sparse, ileorectal anastomosis is made on or below the peritoneal reflection, and patients continue having rectal examinations for life.