GASTROINTESTINAL UPDATE
| UPDATE ON H PYLORI PEPTIC ULCER DISEASE AND GASTROINTESTINAL REFLUX —David C. Metz, MD,
Professor of Medicine, Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia
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| Gastrointestinal (GI) disease associated with Helicobacter pylori: established associations—peptic ulcer disease;
every infected patient gets gastritis (H pylori almost only cause); main cause of gastric cancer worldwide; gastric lymphoma
or mucosa-associated lymphoid tissue (MALT)oma (rare condition); controversial associations—nonulcer
dyspepsia (NUD); gastroesophageal reflux disease (GERD; H pylori potentially protective)
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| Pathway to disease: H pylori exposure leads to acute infection that becomes chronic superficial gastritis (CSG); CSG
then develops into 1) antral-predominant infection, in which patient becomes hypersecretory, leading to hypergastrinemia
and duodenal ulcers, or 2) chronic pangastritis, in which inflammatory effects travel up into body of stomach, and patient
becomes hyposecretory with inflammation that predisposes patient to atrophy, gastric ulceration, gastric cancer, and, if
lymphocyte-dominant, MALToma
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| Ulcer dyspepsia: rare; perform structural study to locate ulcer and treat; study—treating H pylori-associated ulcers
with antibiotics heals ulcer and reduces recurrence rate; treating with antisecretory therapy does not cure ulcer, and recurrence
rate remains high
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 | Potential causes: acid peptic—acid hypersensitivity; undiagnosed GERD (15% of cases); motility abnormalities—
problems with compliance and accommodation of proximal stomach; gastric arrhythmias; neuromuscular disease; visceral
hyperalgesia—chemoreceptor or mechanoreceptor abnormalities
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| Management: therapy based on primary symptoms; antisecretory agents; prokinetic drugs; anticholinergic agents; speaker
uses amitriptyline (Elavil) as first-line therapy for visceral perception blockade; placebo response high; response variable
and unpredictable
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| Treating H pylori infection in undifferentiated dyspepsia: advantages—cures patients with ulcers; may prevent
cancer; may improve symptoms in some patients with NUD; relatively inexpensive; modeling studies demonstrate
cost-effectiveness; disadvantages—cause undiagnosed; may not be cost-effective in practice; not reassuring to
anxious patients (studies show endoscopy associated with greater quality of life [QOL])
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| Moayyedi et al: 2324 patients 40 to 49 yr of age from 36 primary care centers in United Kingdom; validated dyspepsia
and QOL instruments used; H pylori status determined by urea breath test; patients randomized to therapy or no therapy;
2-yr follow-up; results—treatment resulted in statistically significant improvement in percentage of patients with
foregut symptoms (however, speaker believes result not clinical success); no difference in QOL scores
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| Scandinavian study: 500 patients with dyspepsia randomized to test-and-treat with antibiotics or prompt endoscopy, and
reevaluated over 3-mo period 7 yr later (66% of patients participated); primary endpoint—proportion of asymptomatic
days (using diary); results—test-and-treat no more beneficial than prompt endoscopy
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| Treating H pylori infection in NUD: Cochrane Systematic Review Update—of many studies, only 1 has positive
outcome; H pylori eradication has small but statistically significant effect on reduction of NUD symptoms; Talley et
al—no difference between antibiotics and placebo
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| Treating H pylori-associated dyspepsia: undifferentiated dyspepsia—acceptable to test and treat, may reduce resources;
NUD—probably not beneficial; ulcer dyspepsia—treatment of H pylori indicated
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| H pylori and GERD: inversely related; case-controlled studies have shown predominant inverse association
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| GERD and esophageal cancer risk: Barrett’s syndrome likely intermediate step; Lagergren et al—8-fold increase in
esophageal cancer risk in patients with once-weekly heartburn, 11-fold increase in patients with nighttime heartburn, and 44-
fold increase in patients with long-standing reflux symptoms
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| Patterns of foregut cancer in United States: adenocarcinoma of distal esophagus—epidemic; fastest growing
cancer in white and black men; squamous carcinoma—declining; distal gastric cancer—declining; H pylori main
cause; cardia cancer—mirrors adenocarcinoma of distal esophagus; note—eradicating H pylori potentially reduces
incidence of distal gastric cancer but increases incidence of adenocarcinoma of distal esophagus and cardia cancer
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| H pylori and proton pump inhibitors (PPIs): curing H pylori may reduce efficacy of PPIs; pH levels less inhibited
by PPIs in cured patients than noncured patients
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| Precipitation of GERD by eradication of H pylori: unmasks established disease; associated with obesity (patients
feel better and eat more)
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| H pylori antibiotic resistance: amoxicillin resistance rare; metronidazole resistance significant; clarithromycin resistance
12%; in future, may need to culture and test for sensitivity; no good antibiotics available
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| H pylori treatment recommendations: first-line therapy—PPI-based triple therapy (PPI, amoxicillin 1 g, and
clarithromycin 500 mg bid) for 10 to 14 days; if patient allergic to penicillin, replace with metronidazole; do not replace
clarithromycin (reduces efficacy); salvage regimen—standard triple therapy with PPI (PPI overcomes metronidazole resistance);
no response—if other regimens fail, culture and sensitivity test required; speaker uses rifabutin and norfloxacin
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| CURRENT STATUS OF GASTRIC LYMPHOMA —E. Christopher Ellison, MD, Robert M. Zollinger Professor and
Chair of Surgery, Ohio State University College of Medicine and Public Health, Columbus
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| Introduction: gastric lymphomas considered non-Hodgkin’s type; GI tract most common site of extranodal non-
Hodgkin’s lymphoma
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| Risk factors: primary—H pylori infection; others—HIV infection; immunosuppression after solid organ transplantation;
celiac disease; inflammatory bowel disease
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| Primary gastric lymphoma according to grade: 60% of gastric lymphomas derived from MALToma; 41% of patients
have low-grade MALToma, 18% have high-grade tumor with evidence of low-grade MALToma, and rest have no MALToma
involvement
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| Histologic classification: low-grade MALToma—infiltration of cells and destruction of gastric glands; high-grade
lymphoma—replacement of interstitium with sheets of transformed blast cells
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| Mucosa associated lymphoid tissue: represents specialized lymphoid tissue associated with certain epithelia, eg,
Peyer’s patches in ileum, Waldeyer’s ring in nasopharyngeal area; gastric mucosa normally devoid of lymphocytes;
pathogenesis—arises from chronic H pylori infection; specific antigens generate unique inflammatory response in gastric
tissue, leading to development of T-cell infiltration, production of interleukin-2, and proliferation of B-cells within
stomach mucosa; gradual transformation then occurs from oligoclonal to monoclonal population of lymphocytes and, via
malignant transformation, to low-grade MALToma
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| Modified Ann Arbor Staging System: stage IE—single extralymphatic site; stage IE1 —mucosa or submucosa;
stage IE2 —penetrates submucosa; stage IIE—2 lymph node regions on same side of diaphragm; stage IIE1 —regional
lymph node metastasis; stage IIE2 —distant lymph node metastasis; stage IIIE—both sides of diaphragm or spleen
(IIIS); stage IVE—extranodal, liver, or bone involvement
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| Symptoms: epigastric pain; early satiety; fatigue; weight loss; night sweats and pruritus occur in 12% of patients, and
50% experience anemia (most common symptom; overt bleeding uncommon); average time from onset to diagnosis 3 mo
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| Work-up: palpate lymph nodes, liver, and spleen; endoscopy and biopsy for H pylori; endoscopic ultrasonography
(EUS) to evaluate E1 vs E2 early lymphomas; computed tomography (CT); bone marrow biopsy; positron emission tomography
(PET) helpful and superior to gallium scanning
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| Eradication of H pylori in MALToma: Fischbach et al (2004)—90 patients treated for 7 days with omeprazole,
clarithromycin, metronidazole, or amoxicillin; patients underwent esophagogastroduodenoscopy (EDG) and EUS every 3
mo for 2 yr, then every 6 mo; complete H pylori eradication occurred in 88 of 90 patients; 62% of patients had complete
remission of MALToma, 18% had minimal residual disease (relapse rate 7% at 6, 8, and 15 mo), 12% had partial remission,
4% had no change, and 2% had progressive disease; study—23 of 42 patients with stage IE1 MALToma had complete
remission, and 10 had minimal residual disease; EUS may predict response to H pylori eradication if MALToma
staged as E1 ; note—general consensus that MALToma can be treated with H pylori eradication
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| Diffuse large cell gastric lymphoma: Aviles et al (2004)—548 patients randomized to surgery alone, surgery plus
chemotherapy, surgery plus radiation therapy, or chemotherapy alone; chemotherapy alone had highest rate of disease-free survival;
chemotherapy alone and surgery plus chemotherapy had highest rates of overall survival; chemotherapy alone preferred
management
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| Low-grade MALT: Yoon et al—patients with MALT confined to gastric wall had lymphoma regression when treated
with H pylori eradication; patients with t(11:18) translocation had propensity for lymphoma persistence and required
subsequent therapy; patients with more advanced disease (stage III or IV) failed H pylori eradication treatment and went
on to chemotherapy and radiation therapy
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| SURGICAL THERAPY FOR GASTRIC CANCER —D. Scott Lind, MD, Cecil F. Whittaker Professor and Chief of Surgical
Oncology, Medical College of Georgia, Augusta
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| Minimally invasive techniques: sentinel lymph node biopsy (SLNB)—standard of care for melanoma and breast
cancer; laparoscopic gastrectomy—widely used in Japan due to endemic gastric cancer; laparoscopic staging—trial
data show no benefit from more aggressive dissection; endoscopic mucosal resection—pioneered in Japan for early
gastric cancer; EUS—better at determining T stage than CT; shows size and appearance of nodes; can guide fine needle
aspiration
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| Neoadjuvant chemotherapy: favored by speaker for T3 and T4 lesions or node-positive disease; some data support
improved overall survival and local regional control
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| Laparoscopic staging: goal to detect occult M1 disease (typically missed by CT); gastric cancer has high tendency to
spread peritoneally, and peritoneal disease not picked up well by CT; laparoscopic staging can lead to revised and more
accurate staging in 20% to 30% of patients, and may prevent unnecessary laparotomy
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| Gastric resection: extent of gastric resection controversial; Italian Gastrointestinal Tumor Study Group randomized
>600 patients with distal gastric cancer to total or subtotal gastrectomy and found no difference in overall survival; patients
with part of stomach preserved had better nutritional outcomes; for proximal tumors (insidious proximal spread in
submucosal lymphatics), speaker favors total gastrectomy with 4- to 6-cm proximal margin; because pylorus good deterrent
to spread into duodenum, subtotal gastrectomy favored for distal tumors (facilitates reconstruction); tumors of cardia
and gastroesophageal (GE) junction—in United States, increasing in incidence, particularly in white men; not
associated with Barrett’s syndrome; aggressive biologic behavior; procedure difficult technically; gastrectomy with transhiatal
exposure of esophagus usually allows adequate margin without entering chest for anastomosis; with more proximal
tumors, thoracotomy sometimes required; transhiatal esophagectomy with abdominal and left neck incision required
occasionally
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| Roux-en-Y gastric bypass: standard reconstruction after total gastrectomy; Roux limb should be 45 to 60 cm long to
avoid alkaline reflux esophagitis; not done for less than total gastrectomy due to delayed gastric emptying in Roux syndrome
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| Braun enteroenterostomy: bile diverted away from stomach as in Roux-en-Y; Vogel studied ≈100 patients undergoing
Braun enteroenterostomy with dual scanning (looking at gastric emptying and bile reflux into stomach) and had good
results; clinical outcome correlation remains to be proven
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| Gastric reservoir: goal to improve nutritional status; however, literature shows no significant difference in weight,
anastomotic leak, Visick score, or mortality
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| D2 resection: in United States, resectability rate of gastric cancer ≈70%; most US surgeons not trained in procedure
(standard of care in Japan); mortality higher in United States despite less extensive resection, likely due to inexperience
with procedure and early diagnosis in Japan
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| Biologic differences in gastric cancer: stage migration plays role (better staging leads to better outcomes); Western
patients usually older, heavier, and have more comorbidities, leading to worse outcomes; in United States, medical therapy
has reduced number of gastric resections
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| Lymphatic drainage of stomach: meticulously studied by Japanese; lymph nodes categorized into 16 stations correlating
to D resections (most US surgeons trained in D1 resection); need ≥15 nodes to accurately stage patient using tumor,
node, metastasis (TNM) staging system (Japanese use 25)
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| Extent of lymphadenectomy: British Medical Research Council trial and Dutch Gastric Cancer Trial—
randomized prospective trials comparing D1 to D2 resections; with more extensive dissections, morbidity and mortality
statistically higher; no difference in overall survival; led to more accurate staging and improved local control
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| Sentinel node biopsy: based on fact that sentinel or principal node first node of tumor spread; if node tumor-free, likelihood
remaining nodes also tumor-free 95%; can spare patients with negative SLNB morbidity of lymphatic dissection;
enables more accurate staging and mapping of lymphatics, so only nodes involved with tumor removed; studies show
high false-negative rate
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| Laparoscopic resection: option for colorectal cancer; advantages apply to gastric resection, ie, shorter hospital stay,
less pain, improved pulmonary and immune function; disadvantages include longer surgery, cost, and steeper learning
curve
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Educational Objectives
| The goal of this program is to educate the listener on peptic ulcer disease, gastrointestinal (GI) reflux, gastric lymphoma,
and gastric cancer. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Discuss the relationship between Helicobacter pylori infection and GI disease.
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| 2. Treat H pylori-associated dyspepsia.
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| 3. Review the current status of gastric lymphoma treatment.
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| 4. Review developments in the management of gastric cancer.
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| 5. Discuss the potential role for sentinel lymph node biopsy in the treatment of gastric cancer.
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Discussed on This Program
Amitriptyline HCl [Elavil]
Amoxicillin [Amoxil, Amoxil Pediatric Drops, Trimox, Trimox Pediatric Drops]
Clarithromycin [Biaxin, Biaxin XL]
Metronidazole (several trade names)
Norfloxacin [Noroxin]
Rifabutin [Mycobutin]
www.audiodigest.org
To locate lectures of related interest, or to see a complete listing of Audio-Digest CME Programs, including written
summaries.
Suggested Reading
Aviles A et al: Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach: results of a controlled clinical
trial. Med Oncol 22:57, 2005; Aviles A et al: The role of surgery in primary gastric lymphoma: results of a controlled
clinical trial. Ann Surg 240(1):44, 2004; Carboni F et al: Gastrointestinal stromal tumors of the stomach. A
ten-year surgical experience. J Exp Clin Cancer Res 22:379, 2003; Fischbach W et al: Helicobacter pylori and
Gastric Malignancy. Helicobacter 10 Suppl 1:34, 2005; Fischbach W et al: Long term outcome of patients with
gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter
pylori eradication therapy: experience from a large prospective series. Gut 53:34, 2004; Ford A et al: Eradication
therapy for peptic ulcer disease in Helicobacter pylori positive patients. Cochrane Database Syst Rev
CD003840, 2006; Hellmig S et al: IL-1 gene cluster polymorphisms and development of primary gastric B-cell
lymphoma in Helicobacter pylori infection. Blood 104:2994, 2004; Ichikura T et al: Individualized surgery for
early gastric cancer guided by sentinel node biopsy. Surgery 139:501, 2006; Ishizaki M et al: Evaluation of sentinel
node identification with isosulfan blue in gastric cancer. Eur J Surg Oncol 32:191, 2006; Lassen AT et al: Helicobacter
pylori test and eradicate versus prompt endoscopy for management of dyspeptic patient s: 6.7 year follow up
of a randomised trial. Gut 53:1758, 2004; Mackay S et al: Management of gastric cancer. Aust Fam Physician
35:208, 2006; Malfertheiner P et al: Helicobacter pylori eradication has the potential to prevent gastric cancer: a
state-of-the-art critique. Am J Gastroenterol 100:2100, 2005; Moayyedi P et al: Eradication of Helicobacter pylori
for non-ulcer dyspepsia. Cochrane Database Syst Rev CD002096, 2006; Waisberg J et al: The role of surgery in
the treatment of primary gastric lymphoma. Int Surg 85:219, 2000; Wayne JD et al: Limited gastric resection. Surg
Clin North Am 85:1009, 2005; Yoon SS, Hochberg EP: Chemotherapy is an effective first line treatment for early
stage gastric mucosa-associated lymphoid tissue lymphoma. Cancer Treat Rev 32:139, 2006; Yoon SS et al: The
diminishing role of surgery in the treatment of gastric lymphoma. Ann Surg 240:28, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
the following has been disclosed: Dr. Metz receives grant support and honoraria from, is on the Speakers’ Bureau for,
and is a consultant for AstraZeneca, Wyeth, Santarus, and Tap. Dr. Lind is on the Speakers’ Bureau for Schering
Pharmaceuticals.
Drs. Metz and Ellison spoke at the 69th Annual Surgery Course: Advances in Gastrointestinal and GI Laparoscopic
Surgery, presented June 15-18, 2005, by the University of Minnesota Medical School and held in Minneapolis, MN.
Dr. Lind spoke at the Medical and Surgical Approaches to GI Disorders, presented July 25-29, 2005, by the Medical
College of Georgia and held in Amelia Island, FL. The Audio-Digest Foundation thanks the speakers and the sponsors
for their cooperation in the production of this program.
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