Medicine Grand Rounds March 9, 2005

1
Medicine Grand RoundsMarch 9, 2005

• Yoshi Makino, M.D.
• USC Department of Internal Medicine
• Andrew Stolz, M.D.
• Faculty Moderator

2
Case Presentation

• Patient F.B. is a 64 year old African-American
  male, referred from an outside M.D. for OB()
  stool and anemia. Patient was scheduled for
  colonoscopy based on the above indications.
• PSH none
• PMH
• HTN
• hyperlipidemia

3
Case Presentation

• SH
• EtOH 1-2 beers/day, 6-pack on weekends x 40
  years
• Tobacco ¾ ppd x 40 years
• Drugs Marijuana in youth without h/o IVDA
• ROS
• Denies h/o BRBPR, melena, stool caliber changes,
  nor weight loss. Without h/o GERD or other upper
  GI complaints.

4
Case Presentation

• Allergies NKDA
• Medications
• Pravachol 40 mg PO daily
• HCTZ 25 mg PO daily
• Atenolol/Chlorthalidone 50 mg / 25 mg PO daily
• Quinapril 40 mg PO daily
• Norvasc 10 mg PO daily
• Cardura 2 mg PO daily
• EC ASA 81 mg PO daily
• Darvocet or Tylenol 500 mg prn pain/HA

5
Laboratories
6
Colonoscopy

• Poor prep
• Anus small IH
• Sigmoid 2 cm flat polyp, s/p bx
• Transverse colon one diminutive polyp and a 1.5
  cm sessile polyp, s/p bx
• Ascending colon multiple 2-9mm sessile polyp,
  s/p bx

7
Biopsy Results

• 8 of 11 polyps biopsied showed tubular adenoma
• Of these 8 polyps, 2 also showed areas of focal
  increased glandular complexity and high grade
  dysplasia

8
Colonoscopy Images
9
Colonoscopy Images
10
Family History
Colon CA Age 70s
Colon CA Age 68
Colon CA dx age 46 Presently 66
Bone CA Age 64
Multiple adenomatous polyps _at_ age 42, now 46
11
Familial Colorectal Cancers
12
Objectives

• Overview
• Types of familial colorectal cancers
• Clinical Features
• Diagnostic Criteria
• Genetics
• Genetic Testing
• Surveillance
• Management/Treatment

13
Colon Cancer Overview

• Annual Statistics
• 150,000 new cases diagnosed
• 56,000 deaths
• Second leading cause of cancer deaths
• Lifetime incidence rate of 5
• Most cases occurring after age 50

14
Lifetime Risk of CRC

• General Population 3.5 - 6
• Prior History of CRC 15
• Family History 15
• Colorectal Adenomas 15-25
• HNPCC 80
• Ulcerative colitis 50-90
• FAP 100
• Pucciarelli. 21st ICLAM Congress. Venice, April
  2004.

15
Familial Colorectal Cancers

• Familial clustering studies suggest 20-30 of
  colon cancers may have a genetic cause
• Johns LE et al. Am J Gasteoenterol
  2001962992-3003.
• The causative genes have been identified in only
  lt5 of cases

Cao et al. AJG 200297(7)1822-1827
16
Familial Adenomatous Polyposis

• Familial Adenomatous Polyposis (FAP) was first
  described by Lockhart-Mummery in 1925 as a
  disease with clear dominant inheritance
• Adenomatous Polyposis Coli (APC 5q21) gene
  identified by Kinzer and Groden in 1991

Courtesy of Florida State University and
Pucciarelli 2004
17
Clinical Features of FAP

• Greater than 100 colonic adenomatous polyps,
  frequently exceeding 1000 polyps
• Polyps can develop throughout the colon and
  rectum
• 90 of patient will have duodenal and
  periampullary polyps
• 100 lifetime risk for colorectal carcinoma
• Polyps appear at a mean age of 16 years, and
  colon cancer develops at a mean of 39 years, and
  invariably by 50 years

18
Extracolonic Manifestations

• High association with gastric fundic polyps
• Extracolonic cancers include
• duodenal and periampullary tumors (5-10)
• pancreatic (2)
• thyroid (2)
• Gastric (0.5)
• Osteomas, desmoid tumors and soft tissue tumors
  of the skin
• Congenital hypertrophy of the retinal pigment
  epithelium (CHRPE)
• Hernegger et al. Dis Colon Rectum. 2002
  Jan45(1)127-136.

19
Gastric Fundic Gland Polyps

• Fundic gland polyps account for 50 of all
  gastric polyps and are observed in 0.8-1.9 of
  all patients undergoing EGD
• Studies estimate 52-88 of FAP patients have
  gastric fundic glands polyps
• Lifetime risk of gastric cancer is estimated to
  be 0.6
• Burt. Gastro 20031251462-1469.

20
Gastric Fundic Gland Polyps
Burt. Gastro 20031251462-1469.
21
CHRPE
Edward S. Harkness Eye Institute, Columbia
University
22
Clinical Criteria for FAP

• Clinical diagnosis of FAP can be made if
• Presence of gt100 colon adenomas
• Multiple adenomas, with both of the following
  criteria
• a first-degree relative is diagnosed with FAP
• the patient is on the affected side of the family
• Groden et al. Cell 199166589600
• However, genetic testing is now standard of care
  for those meeting the above criteria
• Giardiello FM. JAMA 199727812781281

23
Attenuated FAP

• In 1990, Lynch et al described two families with
  right-sided colonic flat adenomas with more
  polyps than HNPCC but fewer than FAP
• Lynch also observed later age of onset of colon
  cancer, and a paucity of rectal adenomas
• Lynch et al. Cancer. 1990 Sep 166(5)909-15.
• Initially called hereditary flat adenoma
  syndrome, later called attenuated FAP

24
Clinical Features of AFAP

• Less than 100 adenomas, typically morphologically
  flat
• Polyps primarily located proximal to the splenic
  flexure, sparing the rectum
• Diagnosed at mean age of 44 years, and cancers at
  a mean of 56 years
• Extracolonic malignancies similar to FAP, but
  CHRPE, desmoid tumors and, osteomas are not seen
• Hernegger et al. Dis Colon Rectum. 2002
  Jan45(1)127-136.

25
Clinical Criteria for AFAP

• Leppert et al suggest a set of diagnostic
  criteria for the disease
• A positive family history of colorectal cancer
  withat least one of the following criteria
• CRC at any age
• gt 5 colorectal adenomas
• 2-4 adenomas and multiple gastric fundic polyps
• Leppert et al. N Engl J Med 1990 3229.
• Later studies suggest a fourth criteria
• Number of colorectal adenomas must be lt 100
• Knudsen et al. Familial Cancer. 2003243-55.

26
The Genetics of FAP and AFAP

• Primary defect is in the adenomatous polyposis
  coli (APC) gene, located on 5q21
• APC gene is a classic tumor suppressor gene,
  primarily down-regulating intercellular ß-catenin
  activity and ultimately slowing cell cycle entry
  and progression
• Dominant negative model suggests that the
  mutated gene product forms dimers with the
  wild-type protein, causing lowered or abolished
  tumor suppressor activity
• 30 of FAP/AFAP cases are due to de novo
  mutations of the APC gene Burt. Gastro.
  2000119837-853

27
APC, ß-catenin and E-cadherin
Fearnhead et al. Hum Mol Gen. 200110(7)721-733.
28
APC Gene Mutations
Fearnhead et al. Hum Mol Gen. 200110(7)721-733.
29
APC Mutation Phenotypes
Colored distinct protein domains / Boxed
areas of mutation Fearnhead et al. Hum Mol Gen.
200110(7)721-733.
30
Extreme Phenotypic Variability
Burt et al. Gastro. 2004127444-451.
31
HNPCC / Lynch Syndrome

• Hereditary Nonpolyposis Colorectal Cancer was
  first described in 1913 by Warthin, and formally
  characterized as an autosomal dominant condition
  by Lynch et al. in 1966
• Lynch et al. Arch Intern Med 1966117206212.
• Mismatch Repair (MMR) gene defects identified by
  3 independent groups in 1993
• Ionov et al. Nature 1993. / Thibodeau et al.
  Science 1993.Peltomaki et al. Science 1993

32
Clinical Features of HNPCC

• Sporadic colonic polyps (lt10 polyps)
• Despite the name non-polyposis, accelerated
  transformation of flat polyps ? carcinoma is
  suspected
• 70-80 lifetime risk for colorectal carcinoma, at
  a mean age of 44 years

33
Extracolonic Manifestations

• Numerous extracolonic cancers including
• Endometrium (43)
• Stomach (19)
• Biliary tract (18)
• Urinary tract (10)
• Ovary (9)
• Brain (1)
• Small bowel (rare)
• Specific MMR mutations are associated with
  varying rates of the above cancers
• MSH2 mutations have higher incidences of cancer
  than MLH1 mutations
• MSH6 mutations have highest rate of endometrial
  cancers
• Grady. Gastro. 200312415741594

34
Clinical Criteria for HNPCC

• Amsterdam criteria (All criteria must be met)
• One member diagnosed with colorectal cancer
  before age 50 years
• Two affected generations
• Three affected relatives, one of them a
  first-degree relative of the other two
• FAP should be excluded
• Tumors should be verified by pathologic
  examination
• Amsterdam II and Bethesda criteria are more
  lenient, however there is no consensus on which
  criteria should be used for genetic testing
• Grady. Gastro. 200312415741594

35
The Genetics of HNPCC

• A defect in one of several MMR genes has been
  associated with HNPCC
• MLH1 (59)
• MSH2 (38)
• MSH6 (1.3), PMS2 (0.8), PMS1 (0.4), TGFBR2,
  EXO1, MLH3
• MMR genes are vital in the repair of
  microsatellites (short, repeated DNA sequences)
• Microsatellite instabilities (MSI) are expansion
  or contraction of these repeated sequences

36
MSI and MMR
Yangming et al. AJG. 200297(7)1822-1827.
37
Summary of Familial CRCs
Adapted from Grady. Gastro. 200312415741594
38
Overview of Genetic Testing

• Should be offered to patients
• With strong family history
• Where test results can be adequately interpreted
• If results would influence screening and
  management
• ASCO Statement. J Clin Onc 1996141730-1736.
• Patients should at least meet the clinical
  criteria for the disease in question
• A genetic counselor should be involved to provide
  both pretest and post-test counseling

39
Who to Test for FAP

• Clinical criteria for FAP met
• gt100 colon adenomas, or
• Multiple adenomas in first degree relative of a
  known FAP case, on the affected side of family
• First-degree relatives of a person with a known
  APC mutation, regardless of polyp status
• A person with multiple adenomas who is a relative
  of a person with a known APC mutation
• Grady. Gastro. 200312415741594.

40
Who to Test for AFAP

• Clinical criteria for AFAP met
• Greater than 5 to 10 and less than 100 colorectal
  adenomas
• 2-4 adenomas and multiple gastric fundic polyps
• First-degree relatives of a person with a known
  APC mutation, regardless of polyp status
• A person with multiple adenomas who is a relative
  of a person with a known APC mutation
• Grady. Gastro. 200312415741594.

41
Genetic Testing in AFAP/FAP

• Testing involves direct DNA sequencing of APC
  gene
• 95 mutation detection rate
• Most expensive (800/test)
• Other tests are less expensive but also less
  sensitive
• Confirmation strand electrophoresis with protein
  truncation (80-90)
• Protein truncation alone (80)
• Linkage analysis
• Detection rate dependent on accuracy of family
  tree
• Cannot be performed if only one member is
  affected (25 of FAP cases are de novo)
• Grady. Gastro. 200312415741594.

42
Who to Test for HNPCC

• Amsterdam criteria met
• Greater than 5 to 10 and less than 100 colorectal
  adenomas
• 2-4 adenomas and multiple gastric fundic polyps
• First-degree relatives of a person with a known
  MMR mutation
• Complex algorithm using Bethesda criteria and
  other predictors (e.g. CRC case at lt35 years of
  age) has also been proposed
• Grady. Gastro. 200312415741594.

43
Genetic Testing in HNPCC

• Direct DNA sequencing of MSH2, MLH1, /- MSH6 is
  highest yielding approach
• gt95 of HNPCC cases MSH2 and MLH1
• Extremely expensive (800-3000)

44
MSI Testing

• 95 of HNPCC tumors have MSI
• 13 of all CRC have MSI
• 1-6 of CRC are associated with HNPCC
• MSI testing can be conducted for 300-500
• Serves as a useful screening test prior to full
  MSH2, MLH1 testing
• Pucciarelli. 21st ICLAM Congress. Venice, April
  2004.

45
Summary of Costs

• FAP/AFAP
• APC Full Sequence 800
• Single site mutation analysis 200
• HNPCC
• MLH/MSH2 Full Sequence 800-3000
• MSI Testing 300-500
• Pricing from American Gastroenterology
  Association 2001.

46
Surveillance for FAP

• Surveillance may initially be by sigmoidoscopy
• Annually, starting at age 10-12
• Annual colonoscopy from mid-teens until age 30
• Every 3-5 years past age 30
• EGD starting at 30 years, every 1-3 years,
  depending on polyp status in duodenum
• Consider AFP and liver imaging from infancy to
  age 5
• Grady. Gastro. 200312415741594.

47
Surveillance for AFAP

• Surveillance must be by colonoscopy
• Due to lesions proximal to splenic flexure
• Contrasts with screening by flexible
  sigmoidoscopy in classic FAP
• Colonoscopy starting at 1017 years, annually
• EGD starting at 30 years, every 13 years,
  depending on polyp status in duodenum
• Grady. Gastro. 200312415741594.

48
Surveillance for HNPCC

• Surveillance must be by colonoscopy, as lesions
  are usually located in ascending colon
• Colonoscopy starting at age 25
• May be conducted every 2-3 years
• Annual colonoscopy after age 40 until age 75
• EGD starting at 30 to 50 years, every 2 years,
  until age 75
• All above studies should be conducted 5 years
  earlier than youngest affected person in family
• Grady. Gastro. 200312415741594.

49
Distinguishing Flat Polyps
Eisen et al. Gastrointest Endosc 200255687-94.
50
High-resolution Chromoendoscopy
Adenomatous Polyp
Hyperplastic Polyp
Pit pattern
Grooves
Eisen et al. Gastrointest Endosc 200255687-94.
51
High-resolution Chromoendoscopy

• Conventional dyes (e.g. 0.9 indigo carmine) or
  florescent dyes used in conjunction with a
  high-resolution endoscope (410k 850k pixels vs
  standard scopes 100k 200k pixels)
• Hyperplastic polyps
• a characteristic pit pattern of orderly
  arranged circular dots, morphologically similar
  to surrounding normal mucosa.
• Adenomatous Polyps
• surface grooves occasionally with a sulcus-like
  appearance
• In a recent multicenter trial by Eisen et al.,
  chromoendoscopy had a sensitivity of 82 and
  specificity of 82 in distinguishing the above
  polyps

Eisen et al. Gastrointest Endosc 200255687-94.
52
2D Axial Image Acquisition
http//itswww.epfl.ch/cuisenai/endoscopy.shtml
53
3D Virtual Reconstruction
http//itswww.epfl.ch/cuisenai/endoscopy.shtml
54
FAP in Virtual Colonoscopy
Clinical Application of 3D Virtual
Colonoscopy myweb.hinet.net/ home7/r2207759/
55
Management of FAP/AFAP

• 100 lifetime risk of CRC in FAP
• Exact risk of CRC in AFAP remains unknown
  (general consensus is roughly 60-80)
• Disease progression from adenoma to carcinoma is
  not accelerated
• Colonoscopy
• In AFAP, there is a sufficiently low number of
  colonic polyps to make polypectomy practical
• Burt et all. Gastro. 2004127444-451.
• EGD
• Best treatment of gastric fundic gland polyps is
  presently unknown
• Burt. Gastro 20031251462-1469.

56
When to Perform Colectomy?

• In FAP patients, The American Society of Colon
  and Rectal Surgeons recommends colectomy between
  ages 15 to 18
• Church and Simmang. Dis Colon Rectum, August
  2003.
• No clear consensus exists for AFAP
• 15 year delay in onset of disease would suggest
  colectomy at age 30
• In a series of 120 patient with AFAP by Burt et
  al., first CRC was at a mean age of 58 years
  (range of ages 29 to 81), with 12 patients over
  the age of 60 with intact colons
• Burt et all. Gastro. 2004127444-451.

57
Type of Surgery

• Three main surgical options
• Colectomy and ileorectal anastomosis (IRA),
• Proctocolectomy with ileostomy (TPC)
• Proctocolectomy with ileal pouch-anal anastomosis
  (IPAA)
• As AFAP almost always spares the rectum, present
  consensus is for IRA, with subsequent
  surveillance by flexible sigmoidoscopy annually
• Bülow et al. Gastro. 200011914541460.
• Church and Simmang. Dis Colon Rectum, August 2003.

58
Pharmacologic Therapy

• Treatment with sulindac and celecoxib may also
  reduce polyp burden
• Giardiello et al. N Engl J Med 19933281313-1316.
  
• Steinbach et al. N Engl J Med 2000342194652.
• In 1999, FDA approves celecoxib as a treatment
  for patients with FAP
• Dosage celecoxib 400 mg PO BID
• To reduce the number of adenomatous colorectal
  polyps in familial adenomatous polyposis (FAP),
  as an adjunct to usual care (e.g., endoscopic
  surveillance, surgery).
• FDA Application NDA 21-156 20-998/S007

59
Celecoxib and FAP
Steinbach et al. N Engl J Med 2000342194652.
60
Management of HNPCC

• Life time risk of colon cancer is gt80
• Disease progression from adenoma to carcinoma is
  accelerated
• Burt. Gastro 20031251462-1469.
• Given high prevalence of extracolonic
  malignancies, consider
• Pap smears, transvaginal ultrasound, endometrial
  aspiration biopsy every 1-2 years
• Urinalysis, urine cytology, and if abnormal,
  ultrasound /- cystoscopy every 1-2 years

61
Surgical Management of HNPCC

• If colorectal cancer found, subtotal colectomy
  with ileorectal anastamosis is recommended, as
  metachronous lesions are common
• Prophylactic colectomy is recommended, but no
  consensus exists on timing
• Procotocolectomy should be considered in MSH2
  mutation, given higher rates of rectal
  involvement
• Kouraklis et al. Dig Dis Sci. 2005
  Feb50(2)336-44.

62
CRC Survival Rates in HNPCC

• 5 year survival rates for patients with HNPCC CRC
  is significantly better than for sporadic cases
  of CRC
• Sankila et al. in 1996 followed 175 patients with
  genetically proven HNPCC CRC, compared to 14,086
  patients with sporadic CRC
• 5 year survival rate in HNPCC 65 versus
  sporadic 44
• Sankila et al. Gastro. 110682-687, 1997.

63
Conclusions

• Genetic and familiar factors may account for up
  to 30 of colorectal cancers
• While specific genetic defects are rarely
  identified (5 of cases), given the high
  malignant potential (80-100 lifetime risk of
  CRC), early recognition is vital
• Many polyps ? think FAP
• Few polyps ? think HNPCC (more common), but do
  not discount AFAP
• Involve a genetic counselor early, and use
  genetic testing judiciously

64
Patient Follow-up

• Patient had an EGD on 9/20/2004 to evaluate for
  gastric fundic gland polyps and periampullary
  disease
• No significant lesions found
• Patient underwent genetic counseling at Norris
  Comprehensive Cancer Center on 9/24/2004
• Ultimately, the proband (the sister) underwent
  genetic testing via the Kaiser Permanente system
• MLH1 mutation found

65
Acknowledgements

• Dr. Andrew Stolz
• Rebecca Zemetra
• Roche Pharmaceuticals
• This presentation is available at
• http//www.makino.net/gastro

66
Questions?
I have two questions.
67
Genetic Testing and Counseling

• Dr. Andrew Stolz
• Associate Professor of Medicine
• USC Department of Internal Medicine
• Division of Gastrointestinal and Liver Diseases

68
Risk - Benefits for Genetic Testing
69
Genetic Testing Strategy for BRC1/2
Pre-Test counseling session
Pt declines BRCA 1/2
Reinforce medical management Counsel as needed.

• Post genetic testing session
• Discuss option for medical management
• Coping strategy for family members

Nature Cancer Rev 4153, 2004
70
Potential Outcomes of Genetic Testing
71
Screening Recommendation for APC Patients

• Annual screening for hepatoblastoma up to age 5
• Sigmoidoscopy every one to two years after age 10
• Colonoscopy once polyps are detected.
• Annual colonoscopy if colectomy is delayed more
  than a year after polyps emerge.
• Esophagogastroduodenoscopy (EGD) beginning when
  colonic polyposis is detected or by age 25.
• Small bowel X-ray (small bowel enteroclysis or
  abdominal and pelvic CT with orally administered
  contrast) when duodenal adenomas are detected or
  prior to colectomy,
• Attention to extraintestinal manifestations,
  usually for cosmetic concerns.
• Annual physical examination including palpation
  of the thyroid.

72
Screening Recommendation for HNPCC Patients

• Colon cancer. Colonoscopy every one to two
  years beginning between age 20-25 years or ten
  years before the earliest age of diagnosis in the
  family.
• Gynecological cancer.  Endometrial cancer and
  ovarian cancer surveillance is less well
  established than that for colon cancer. In
  addition to an annual Pap smear and pelvic
  examination, annual transvaginal ultrasound
  examination, endometrial biopsy, and CA-125 blood
  test beginning between 25-30 years of age can be
  considered.
• Stomach and duodenum.  Upper endoscopy
  surveillance is available to for gastric and
  duodenal cancers. However, one study suggested no
  benefit from this because of the lack of
  identifiable precursor lesions.

73
References

• Al Tassan et al. Inherited variants of MYH
  associated with somatic GC--gtTA mutations in
  colorectal tumors. Nat Genet. 2002
  Feb30(2)227-32.
• Bülow et al. Ileorectal anastomosis is
  appropriate for a subset of patients with
  familial adenomatous polyposis. Gastroenterology.
  2000 Dec119(6)1454-60.
• Burt et al. Genetic testing and phenotype in a
  large kindred with attenuated familial
  adenomatous polyposis. Gastroenterology. 2004
  Aug127(2)444-51.
• Burt. Gastric fundic gland polyps.
  Gastroenterology. 2003 Nov125(5)1462-9.
• Cao et al. Challenge in the differentiation
  between attenuated familial adenomatous polyposis
  and hereditary nonpolyposis colorectal cancer
  case report with review of the literature. Am J
  Gastroenterol. 2002 Jul97(7)1822-7.
• Church and Simmang. Practice parameters for the
  treatment of patients with dominantly inherited
  colorectal cancer (familial adenomatous polyposis
  and hereditary nonpolyposis colorectal cancer).
  Dis Colon Rectum. 2003 Aug46(8)1001-12.

74
References

• Eisen et al. High-resolution chromoendoscopy for
  classifying colonic polyps a multicenter study.
  Gastrointest Endosc. 2002 May55(6)687-94.
• Fearnhead et al. The ABC of APC. Hum Mol Genet.
  2001 Apr10(7)721-33.
• Giardiello et al. Primary chemoprevention of
  familial adenomatous polyposis with sulindac. N
  Engl J Med. 2002 Apr 4346(14)1054-9.
• Giardiello et al. Treatment of colonic and rectal
  adenomas with sulindac in familial adenomatous
  polyposis. N Engl J Med. 1993 May
  6328(18)1313-6.
• Grady. Genetic testing for high-risk colon cancer
  patients. Gastroenterology. 2003
  May124(6)1574-94.
• Hawk et al. Colorectal cancer chemoprevention--an
  overview of the science. Gastroenterology. 2004
  May126(5)1423-47.
• Hernegger et al. Attenuated familial adenomatous
  polyposis an evolving and poorly understood
  entity. Dis Colon Rectum. 2002 Jan45(1)127-34
  discussion 134-6.
• Jones et al. Biallelic germline mutations in MYH
  predispose to multiple colorectal adenoma and
  somatic GC--gtTA mutations. Hum Mol Genet. 2002
  Nov 111(23)2961-7.

75
References

• Knudsen et al. Attenuated familial adenomatous
  polyposis (AFAP). A review of the literature. Fam
  Cancer. 20032(1)43-55.
• Kouraklis G, Misiakos EP. Hereditary nonpolyposis
  colorectal cancer (Lynch syndrome) criteria for
  identification and management.
• Dig Dis Sci. 2005 Feb50(2)336-44.
• Leppert et al. Genetic analysis of an inherited
  predisposition to colon cancer in a family with a
  variable number of adenomatous polyps. N Engl J
  Med. 1990 Mar 29322(13)904-8.
• Lynch et al. Phenotypic variation in colorectal
  adenoma/cancer expression in two families.
  Hereditary flat adenoma syndrome. Cancer. 1990
  Sep 166(5)909-15.
• Spirio et al. Alleles of the APC gene an
  attenuated form of familial polyposis. Cell. 1993
  Dec 375(5)951-7.
• Steinbach et al. The effect of celecoxib, a
  cyclooxygenase-2 inhibitor, in familial
  adenomatous polyposis. N Engl J Med. 2000 Jun
  29342(26)1946-52.
• Wang et al. MYH mutations in patients with
  attenuated and classic polyposis and with
  young-onset colorectal cancer without polyps.
  Gastroenterology. 2004 Jul127(1)9-16.

76
Acknowledgements

• Dr. Andrew Stolz
• Rebecca Zemetra
• Roche Pharmaceuticals
• This presentation is available at
• http//www.makino.net/gastro