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COMPLICATIONS OF CANCER

September 2nd, 2013

What are the causes of anemia in patients with cancer?
Anemia in cancer patients is often multifactorial. Anemia may result from blood loss due to bleeding from tumors or from gastritis due to the use of nonsteroidal anti-inflammatory agents (NSAIDs). It may also be caused by hemolysis (secondary to antibodies associated with the tumor), disseminated intravascular coagulation (DIC), sepsis, or a paraneoplastic syndrome. Anemia is frequently caused by bone marrow suppression by chemotherapy or by marrow involvement by the tumor.

Define anemia of chronic disease.
Anemia of chronic disease is common in cancer patients. The diagnosis is made when no other cause of anemia can be found and plasma iron is < 60 mg/dl, total iron-binding capacity is 100-250 mg/dl, and ferritin is > 60 ng/ml. The hematocrit is generally 25-30%. An inadequate erythropoietin response to anemia and a blunted response to treatment with recombinant human erythropoietin have been demonstrated in some patients.

What are the predisposing factors for infection in patients with cancer?
Predisposing factors for infection include defects in cellular and humoral immunity, organ compromise due to tumor-related obstruction, chemotherapy-related granulocytopenia, disruption of mucosal (e.g., respiratory and alimentary tract) and integumental surfaces, iatrogenic procedures or placement of prosthetic devices, central nervous system dysfunction, and hyposplenic or postsplenectomy states.

Discuss the sources of infection in patients with cancer.
The vast majority of infections originate from the patients’ own endogenous flora. Sources of infection in neutropenic patients include the lungs, urinary tract, skin, upper aerodigestive tract (mouth, skin, teeth), central nervous system, rectum, perirectum, biopsy sites, and GI tract (appendicitis, cholecystitis, perforations). In investigating the cause of an infection, cultures should include blood, urine, sputum, and, if appropriate to the patient’s clinical status, stool, pleural fluid, or peritoneal fluid.

Which tumors spread to bone most commonly?
Cancers of the lung, breast, kidney, prostate, and thyroid as well as multiple myeloma and malignant melanoma spread to bone most commonly.

Are metastatic bone lesions osteoblastic or osteolytic?
Renal cell carcinoma and multiple myeloma tend to be purely lytic, prostate carcinoma tends to be mainly blastic, and the others are mixed. Tumors that are lytic are most often associated with hypercalcemia, whereas blastic metastases are not generally associated with this complication.

To which bones does cancer most often metastasize?
The most frequently involved bones are the spine, ribs, pelvis, and long bones.
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Characterize the pain associated with bone metastases.
The pain of bone metastases is characterized by a dull, aching discomfort that is worse at night and may improve with physical activity.

Which tumors metastasize to the lungs?
Most types of tumors can metastasize to the lungs. Therefore, the more common the tumor, the more commonly it is found to have spread to the lung (e.g., breast cancers). Although they also can spread to the lungs, GI cancers tend to first metastasize locally and to the liver before pulmonary involvement is seen. Tumors that spread via the bloodstream, such as sarcomas, renal cell carcinoma, and colon cancer, tend to produce nodular lung lesions. Those that spread via lymphatic routes, such as cancers of the breast, pancreas, stomach, and liver, often manifest a pattern of lymphangitic spread.

Discuss the symptoms of intracranial metastases.
Headache occurs in up to 50% of patients with intracranial metastases. It is classically described as occurring early in the morning, disappearing or decreasing after arising, and may be associated with nausea and/or projectile vomiting. Other symptoms include focal signs such as unilateral weakness, numbness, seizures, or cranial nerve abnormalities. Nonfocal complaints such as mental status changes or ataxia may occur.

How are intracranial metastases diagnosed and treated?
The diagnosis is made by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the brain. Treatment consists of decreasing intracranial pressure with steroids, followed by radiotherapy. Surgery is recommended for patients with single intracranial lesions.

What are the signs and symptoms of malignant pericardial effusion?
The presentation of malignant pericardial effusion can resemble heart failure, with dyspnea, peripheral edema, and an enlarged heart on chest x-ray. However, the dyspnea is often out of proportion to the degree of pulmonary congestion seen on the x-ray. Kussmaul’s sign, or jugulovenous distention with inspiration, and pulsus paradoxus of > 10 mmHg with distant heart sounds are clues to the presence of a pericardial effusion.

How is the diagnosis of malignant pericardial effusion confirmed?
Confirmation of the clinical diagnosis is made by echocardiogram or CT scan. Malignant effusions are usually exudates and are often hemorrhagic. Cytology is helpful if positive but does not exclude cancer if negative.

Discuss the treatment of malignant pericardial effusion.
Treatment depends on the patient’s condition but should include drainage of the fluid for diagnostic as well as therapeutic reasons. A nonsurgical approach is preferred, with catheter drainage followed by sclerosis of the pericardium, sometimes with a sclerosing agent such as doxycycline. Other approaches include subxiphoid pericardiectomy, balloon pericardiectomy, pericardial window, and pericardial stripping for patients with prolonged life expectancy.

What are the presenting symptoms and signs of spinal cord compression?
Ninety-five percent of cancer patients with spinal cord compression present with back pain. Other symptoms include lower extremity weakness, bowel or bladder incontinence, or increased deep tendon reflexes in the lower extremities.

How is spinal cord compression diagnosed?
The diagnosis is made by MRI or by myelography with CT, which will demonstrate blockage of the spinal canal.

How is spinal cord compression treated?
Treatment is directed first at relieving spinal cord swelling and pain, using high-dose steroids and adequate pain medication. However, definitive treatment must be carried out emergently to prevent further neurologic deterioration, which may be irreversible. Radiotherapy and/or surgery should be initiated immediately. Preservation of neurologic function is generally better with surgery.

Which tumors most commonly cause spinal cord compression?
The most common tumors causing cord compression are lung cancer, breast cancer, prostate cancer, carcinoma of unknown primary, lymphoma, and multiple myeloma. The most common site of cord compression is the thoracic spine, followed by the lumbosacral spine and the cervical spine.

Which tumors are associated with nonbacterial thrombotic endocarditis?
Also known as marantic endocarditis, this paraneoplastic syndrome is associated with mucinous adenocarcinomas, most commonly of the lung, stomach, or ovary, but has been described in other types of cancers as well.

How does nonbacterial thrombotic endocarditis present?
It is manifested by the appearance of embolic peripheral or cerebral vascular events causing arterial insufficiency, encephalopathy, or focal neurologic defects. Heart murmurs are often not present.

How is nonbacterial thrombotic endocarditis diagnosed and treated?
Echocardiograms may be negative, and the diagnosis is usually made post mortem. Treatment with anticoagulants or antiplatelet drugs has been tried with little success.

What are the tumor-related causes of hypercalcemia?

  • Lytic bone metastases, which release calcium into the bloodstream. This is the most common cause in solid tumors with bony metastases.
  • Humoral hypercalcemia of malignancy (HHM) occurs in patients without bony metastases. Cancers associated with this syndrome secrete a non-PTH substance with activity similar to parathyroid hormone. HHM is associated most commonly with squamous cell cancers of the lung, esophagus, or head and neck but can also be found in renal cell carcinoma, transitional cell carcinoma of the bladder, and ovarian carcinoma.
  • Formerly known as osteoclast-activating factor, osteolytic substances such as interleukin 1 (IL-1), IL-6, and TNF-alpha (lymphotoxin) may cause hypercalcemia in plasma cell dyscrasias.
  • Vitamin D metabolites produced by some lymphomas may promote intestinal calcium absorption.

What is tumor lysis syndrome?
When rapidly growing tumors are effectively treated with chemotherapy, breakdown products of tumor lysis are released into the bloodstream in large amounts. This process may cause hyperkalemia, hyperuricemia, hyperphosphatemia, and hypocalcemia. Renal failure can result from the hyperuricemia. This complication is seen within hours to days after treatment of tumors such as acute leukemia, Burkitt’s lymphoma, and other rapidly proliferating lymphomas. It is rarely, if ever, seen with solid tumors, but has been described in small cell carcinoma of the lung.

How is tumor lysis syndrome treated?
Treatment is the same as for renal failure, with vigorous hydration, dialysis if necessary, and appropriate treatment of electrolyte disorders. Prophylactic treatment with aggressive hydration and allopurinol prior to administering chemotherapy in susceptible patients can prevent this serious complication.

Which medications are commonly used for cancer pain?
As elucidated in the World Health Organization guidelines, pain medications are to be administered in a three-step ladder according to the intensity and pathophysiology of symptoms and individual requirements. For mild pain, the recommended baseline drugs are NSAIDs. Patients with moderate-to-severe pain generally require an opioid agent such as codeine or oxycodone; severe pain requires a stronger opioid such as morphine.

What are the neuromuscular complications of cancer?
Complication_cancer

References
WEB SITES

  1. National Cancer Database: http://www.facs.org/cancer/ncdb/index.html
  2. National Guideline Clearinghouse: http://www.guideline.gov/
  3. PDQ Cancer Information Summaries: http://www.cancer.gov/
  4. SEER Cancer Statistics Review, 1975-2000: http://seer.cancer.gov/csr/1975_2000/

BIBLIOGRAPHY

  • American Joint Committee on Cancer: Cancer Staging Manual, 6th ed. New York, Springer-Verlag, 2002.
  • Calabresi P, Schein PS (eds): Basic Principles and Clinical Management of Cancer, 2nd ed. New York, Macmillan, 1993.
  • Casciato DA, Lowitz BB (eds): Manual of Clinical Oncology, 5th ed. Boston, Little, Brown, 2000.
  • DeVita T Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2001.
  • Haskell CM: Cancer Treatment, 4th ed. Philadelphia, W.B. Saunders, 1995.
  • Holland JF, Frei E, et al (eds): Cancer Medicine, 6th ed. New York, BC Decker, 2003.
  • Tannock IF, Hill RP (eds): The Basic Science of Oncology, 3rd ed. New York, McGraw-Hill, 1998.

Posted in Oncology | 2 Comments »


Irritable Bowel Syndrome (IBS)

April 30th, 2013

What is irritable bowel syndrome (IBS)?
Irritable bowel syndrome comprises a group of functional bowel disorders in which abdominal discomfort or pain is associated with defecation or a change in bowel habits, and with features of disordered defecation.

How does one diagnose IBS?
The diagnosis of IBS is based on identifying positive symptoms consistent with the disorder, as described in the Rome Criteria and with the exclusion of other conditions (either organic or functional) with similar clinical presentation.

ROME II DIAGNOSTIC CRITERIA FOR IRRITABLE BOWEL SYNDROME
>At least 12 weeks or more, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two out of three features:
Relieved with defecation; and/or
Onset associated with change in frequency of stool; and/or
Onset associated with a change in form (appearance) of stool.

>Symptoms that cumulatively support the diagnosis of irritable bowel syndrome:
Abnormal stool frequency (> 3 bowel movements/day or < 3 bowel movements/week);
Abnormal stool form (lumpy/hard or loose/watery stool);
Abnormal stool passage (straining; urgency; feeling of incomplete evacuation)
Passage of mucus
Bloating or feeling of abdominal distension

What is the Rome Committee?
The Rome Committee consists of a group of multinational experts in functional bowel disorders. The working team first met in Rome in 1988 to develop criteria for the diagnosis of functional gastrointestinal disorders (Rome Criteria). In 1998 the working team proposed changes and modifications, which were published in 1999 and are known as Rome II Criteria. A further update, Rome III Criteria, is expected in 2006.

Is there any specific biologic and pathophysiologic marker to diagnose IBS?
No. There is no specific discriminatory finding or diagnostic test for IBS.

Describe the supporting symptoms of IBS.

  • Fewer than three bowel movements a week
  • More than three bowel movements a day
  • Hard or lumpy stools
  • Loose (mushy) or watery stools
  • Straining during a bowel movement
  • Urgency (having to rush to have a bowel movement)
  • Feeling of incomplete evacuation
  • Passing mucus (white material) during a bowel movement
  • Abdominal fullness, bloating, or swelling

What is the importance of the supportive symptoms of IBS?
The supportive symptoms help in the classification of IBS as either diarrhea predominant or constipation predominant.

Define diarrhea-predominant and constipation-predominant IBS.
Based on supporting symptoms, these disorders are defined as follows:

  1. Diarrhea-predominant (>three bowel movements per day): One or more of supporting systems 2, 4, or 6 and none of 1, 3, or 5; or two or more of 2, 4, or 6 and one of 1 or 5 (3, hard lumpy stools do not qualify).
  2. Constipation-predominant ( Subclassification of IBS into constipation-predominant or diarrhea-predominant and mixed patterns has limited value in understanding the pathophysiology of IBS.

Discuss the epidemiology of irritable bowel syndrome.
Most estimates indicate that the prevalence is approximately 10%, and this estimate is consistent with multiple non-U.S. studies. Constipation-predominant IBS is more common in women. Functional dyspepsia and IBS appear to overlap in this population.

What is the economic impact of IBS in the United States?
IBS is a distressing condition that impairs the quality of life and therefore requires treatment. Most persons with IBS do not consult physicians. Fewer than one quarter of individuals with IBS symptoms present for the evaluation and treatment of their symptoms. Patients with IBS are more likely to undergo surgical procedures, including hysterectomy and appendectomy.

The cost to society in terms of direct medical expenses and indirect costs, such as absenteeism, is considerable. There are between 2.4 and 3.5 million physician visits annually for IBS in the United States, during which 2.2 million prescriptions are written. IBS is associated with more than $8 billion (U.S.) a year in direct healthcare costs.

Describe the pathophysiology of IBS.
Initial observations suggest that abnormal motility underlies IBS symptoms. Accelerated small bowel and colon transit has been demonstrated in patients with diarrhea predominant IBS. More than 50% of IBS patients report exacerbation of symptoms after eating, suggesting a prominent gastrocolonic response. Furthermore, high amplitude-propagated contractions in the postprandial period are seen in diarrhea-predominant IBS and a lack of these contractions are seen in severe constipation.

Later observations showed that visceral hypersensitivity is important in explaining the clinical manifestations of IBS. IBS patients have lower visceral pain thresholds than healthy patients. As knowledge increased about the interrelatedness of the brain and gut, it was recognized that the abnormal motility and visceral hypersensitivity in IBS are determined by reciprocal interactions between brain and gut. 5-HT is a neurotransmitter in both the central and enteric nervous systems and is a key mediator of visceral hypersensitivity and heightened bowel motility in patients with IBS.

What is postinfectious irritable bowel syndrome?
Patients who report an acute onset of IBS symptoms after a bout of gastroenteritis are defined as postinfectious IBS (PI-IBS). These patients have previously normal bowel habits. Up to 30% of IBS patients describe an acute onset of bowel disturbances following an acute infective enteritis. PI-IBS is associated with a modest increase in mucosal T-lymphocytes and serotonin containing enteroendocrine cells. Patients with PI-IBS have the same prognosis as noninfective IBS, with fewer than half recovering after 6 years.

What symptoms are not typical of IBS and should prompt an evaluation for organic disease?

  1. Acute onset of symptoms
  2. Fever
  3. Rectal bleeding or anemia
  4. Weight loss
  5. Persistent diarrhea
  6. Severe constipation
  7. Nocturnal symptoms
  8. New onset of symptoms in patients >age 50.
  9. Abnormal colonoscopy/sigmoidoscopy
  10. Family history of GI cancer, inflammatory bowel disease (IBD), or celiac disease

What diagnostic tests are appropriate in a patient suspected of IBS?
To rule out anatomic disorders, the following screening tests are normally recommended: complete blood count, sedimentation rate, serum chemistries, thyroid stimulating hormone (TSH), stool, occult blood, stool for ova and parasites, and flexible sigmoidoscopy or colonoscopy (with mucosal biopsy), depending upon age and other associated symptoms (e.g., diarrhea). Serologic testing for celiac disease (tissue transglutaminase) should be performed on all patients suspected to have IBS-diarrhea predominant.

Additional studies should be based on presenting symptoms (diarrhea, constipation, or abdominal pain). The use of diagnostic studies to exclude organic disease should be prudent and cost-effective and made in the context of the entire clinical history, including psychological issues

What is the role of stress and psychological factors in IBS?
Stress is widely believed to play a major role in the pathophysiology and clinical presentation of IBS. The effect of stress on gut function is universal, and patients with IBS appear to have greater reactivity to stress compared with healthy individuals.
Psychological factors include anxiety disorders, depression, somatization, a history of sexual or physical abuse, stressful lifetime events, chronic social stress, or maladaptive coping styles. Psychological symptoms are more prevalent in patients who have severe symptoms and who are seen in tertiary care centers. Furthermore, stress is associated with symptom onset, exacerbations, and severity.

What are essential elements in the management of a patient with IBS?
Treatment of IBS patients is indicated when the patient and physician believe that the IBS symptoms diminish the quality of life of the patient. The algorithm for management of IBS based on symptom predominance.
It is important to emphasize to the patient the negative results of tests to exclude organic disease and to reassure the patient. Patients should be asked about psychological factors, stress, and history of physical and sexual abuse because these factors may require specific treatment.
There is evidence to suggest that the outcomes in IBS patients can be improved when physicians: (1) actively listen to patient concerns; (2) provide an adequate explanation of disorder; (3) set realistic goals; (4) establish a long-term relationship; (5) respond to patient concerns and expectations; and (6) identify behavior stressors that exacerbate symptoms.

What is the role of fiber in management of IBS?
As a group, patients with IBS do not consume less fiber than control subjects. Fiber has a role in treating constipation; its value for IBS, pain, and diarrhea is controversial.
Many patients with IBS complain of bloating with higher doses of natural fiber. Short chain fatty acids are produced by bacterial fermentation of dietary fiber, resulting in gas formation. Short chain fatty acids can also stimulate rectal contractions and produce pain.

Are anticholinergic and antispasmodic agents useful in IBS?
The evidence-based position statement on the management of IBS produced by the American College of Gastroenterology states that there is insufficient evidence to make any recommendation about the effectiveness of antispasmodic agents available in the United States. Antispasmodic and anticholinergic agents are sometimes used on an as-needed basis for acute attacks of pain, distention, and bloating.

Discuss the role of psychotropic agents in treating patients with IBS.
Antidepressants have utility in IBS because many patients present with associated psychological symptoms. Antidepressants have neuromodulatory and analgesic properties, and there is also potential benefit even in the absence of psychiatric comorbidity. Neuromodulatory effects may occur sooner and with lower doses in IBS patients than the dose used in the treatment of depression (e.g., 10-25 mg amitriptyline or 50 mg desipramine). Recent studies suggest that selective serotonin reuptake inhibitors (SSRIs) may offer benefit in some patients with IBS. Tricyclic antidepressants (TCAs), offer benefit for abdominal pain and diarrhea; SSRIs cause diarrhea and may be helpful in patients with constipation-predominant IBS.

IRRITABLE BOWEL SYNDROME TREATMENT STRATEGIES

  1. Educate and reassure the patient.
  2. In diarrhea-predominant IBS, tricyclic antidepressants relieve diarrhea and associated pain.
  3. Opioids are useful in relief of diarrhea but may precipitate constipation.
  4. Smooth muscle relaxants are indicated in patients with predominant pain/bloating. Their effectiveness is controversial.
  5. 5-HT4-agonists are effective in treating constipation-predominant IBS.

Describe various types of psychological treatments used in patients with IBS.

  1. Cognitive behavioral therapy: this attempts to change the way patients perceive and react to their symptoms; uses diaries and exercises to reframe maladaptive thoughts and increase control over symptoms.
  2. Interpersonal psychotherapy: identifies and addresses difficulties in relationships. Several studies suggest benefit compared with standard medical therapy.
  3. Hypnosis: suggestions are used to reduce gut sensation. This is the best-evaluated psychological treatment. Improvements noted 1 year later.
  4. Relaxation training: uses imagery and relaxation techniques to reduce autonomic arousal and stimulate muscular relaxation; improves gut motility.

What is the association between serotonin (5-HT) and IBS?
A fundamental observation in IBS is the presence of enhanced visceral perception. Serotonin has a role in mediating visceral hypersensitivity and the peristaltic reflex. Ninety-five percent of serotonin is found in the gut, with 90% localized within enterochromaffin cells and 10% in the enteric neurons. Of the various types of serotonin, 5-HT3 and 5-HT4 are involved in sensory and motor functions of the gut and are targets for pharmacotherapy in IBS.

What are the roles for 5-HT3 antagonist and 5-HT4 agonist in management of IBS?
The indications, mechanism of actions, and major side effects of common 5-HT4 agonist and 5-HT3-receptor antagonist. Alosetron is effective in inducing adequate relief of abdominal pain and discomfort, improvement in bowel frequency, consistency, and urgency in women with diarrhea-predominant IBS. A significant adverse effect is acute ischemic colitis. Because of adverse effects, alosetron was withdrawn from the market in November 2000. As a consequence of vigorous public outcry following withdrawal, the Food and Drug Administration (FDA) approved the restricted use of alosetron in June 2002. Another medication in this class, cilansetron, is undergoing phase III studies for treatment of diarrhea-predominant IBS.
Tegaserod is partial 5-HT4 agonist, which is indicated in women with constipation-predominant IBS. It is the only FDA-approved agent for the short-term treatment of IBS patients with constipation. It improves global assessment and individual symptoms of IBS, including abdominal pain, stool frequency, and bloating.

References
WEBSITES
http://www.digestive.niddk.nih.gov/Open this link in a new window
(Search “IBS”)
http://www.aboutibs.org/Open this link in a new window

BIBLIOGRAPHY

  • American College of Gastroenterology Functional Gastrointestinal Disorders Task Force: Evidence-based position statement on the management of irritable bowel syndrome in North America. Am J Gastroenterol 97(11 Suppl):S1-S5, 2002.
  • Camilleri M, Chey WY, Mayer EA, et al: A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med 161:1733-1740, 2001.
  • Cash BD, Schoenfeld P, Chey WD: The utility of diagnostic tests in irritable bowel syndrome patients: A systematic review. Am J Gastroenterol 97:2812-2819, 2002.
  • Creed F, Fernandes L, Guthrie E, et al: The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology 124:303-317, 2003.
  • Drossman DA, Camilleri M, Mayer EA, Whitehead WE: AGA technical review on irritable bowel syndrome. Gastroenterology 123:2108-2131, 2002.
  • Drossman DA, Toner BB, Whitehead WE, et al: Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology 125:19-31, 2003.
  • Hamm LR, Sorrells SC, Harding JP, et al: Additional investigations fail to alter the diagnosis of irritable bowel syndrome in subjects fulfilling the Rome criteria. Am J Gastroenterol 94:1279-1282, 1999.
  • Mayer EA, Raybould HE: Role of visceral afferent mechanisms in functional bowel disorders. Gastroenterology 99:1688-1704, 1990.
  • Mertz H, Naliboff B, Munakata J, et al: Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology 109:40-52, 1995.
  • Muller-Lissner SA, Fumagalli I, Bardhan KD, et al: Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther 15:1655-1666, 2001.
  • Rogers J, Henry MM, Misiewicz JJ: Increased segmental activity and intraluminal pressures in the sigmoid colon of patients with the irritable bowel syndrome. Gut 30:634-641, 1989.
  • Saito YA, Schoenfeld P, Locke GR III: The epidemiology of irritable bowel syndrome in North America: A systematic review. Am J Gastroenterol 97:1910-1915, 2002.
  • Sanders DS, Carter MJ, Hurlstone DP, et al: Association of adult coeliac disease with irritable bowel syndrome: A case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 358:1504-1508, 2001.
  • Spiller RC: Postinfectious irritable bowel syndrome. Gastroenterology 124:1662-1671, 2003.
  • Talley NJ, Gabriel SE, Harmsen WS, et al: Medical costs in community subjects with irritable bowel syndrome. Gastroenterology 109:1736-1741, 1995.
  • Thompson WG, Longstreth G, Drossman DA, et al: Functional bowel disorders. In Drossman DA, Corazziari E, Talley NJ, et al (eds): Rome II The Functional Gastrointestinal Disorders. McLean, VA, Degnon Associates, 2000, pp 351-432.

Posted in SMALL AND LARGE BOWEL DISORDERS | 2 Comments »


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