Clinical outcomes after double-balloon enteroscopy in patients with obscure GI bleeding and a positive capsule endoscopy

ORIGINAL ARTICLE: Clinical Endoscopy

Clinical outcomes after double-balloon enteroscopy in patients with obscure GI bleeding and a positive capsule endoscopy Arthur J. Kaffes, MBBS, FRACP, Chiang Siah, MBBS, Jenn H. Koo, MBBS Sydney, Australia

Background: Obscure GI bleeding (OGIB) accounts for about 5% of all patients with GI bleeding. There are limited data on double-balloon enteroscopy (DBE) after a positive finding on capsule endoscopy (CE) in this setting. Objective: To determine the clinical outcomes after DBE therapy. Design: Prospective single-center cohort study. Setting: Tertiary referral university hospital. Main Outcome Measurements: Recurrent bleeding and blood transfusion requirements. Patients and Methods: This prospective study of 60 consecutive patients with OGIB was conducted between July 2004 and March 2006. Patients underwent CE before DBE to target the lesion for either further diagnostic evaluation or therapeutic intervention. The mean (standard deviation [SD]) duration of follow-up was 10.0  5.2 months. Results: The mean (SD) age was 62  18 years, with 31 men. A total of 74 DBE procedures were performed. An abnormality was seen by DBE in 45 patients (75%). In 12 patients (20%), a diagnosis was clarified or a new diagnosis was made. Therapy at DBE was performed in 34 patients (57%): 30 diathermies and 4 polypectomies. Endoscopic tattooing for targeted surgical removal was made in 3 additional patients. Multiple logistic regression analysis identified previous blood transfusion (odds ratio 10.5, 95% confidence interval 3.1-35; P ! .001) to be the only independent predictor that required endoscopic therapy at DBE. Forty-eight patients (80%) had no further bleeding, and 46 patients (77%) had a normal Hb. Blood transfusion requirements fell from 34 patients to 10, P ! .001. One patient had a perforation after therapeutic diathermy. Limitations: Nonrandomized study. Conclusions: In patients with OGIB and a positive finding on CE, DBE provided a safe and ambulatory method to achieve an excellent clinical outcome with significant reductions in recurrent bleeding and blood-transfusion requirements. (Gastrointest Endosc 2007;66:304-9.)

Obscure GI bleeding (OGIB) accounts for approximately 5% of all patients with GI bleeding.1 This clinical scenario remains a difficult clinical problem, both in diagnosis and management of these patients. Often, patients undergo extensive investigations that are usually fruitless, with many if not most patients achieving no clear diagnosis. A clinical dilemma develops when a decision needs to be made whether to undertake an invasive definitive investigation, such as intraoperative enteroscopy, or to adopt a supportive ‘‘wait and see’’ approach, including multiple transfusions, prothrombotic agents, and hormonal agents.1 Copyright ª 2007 by the American Society for Gastrointestinal Endoscopy 0016-5107/$32.00 doi:10.1016/j.gie.2007.02.044

Since the introduction of capsule endoscopy (CE) (M2A; Given Imaging Ltd, Yoqneam, Israel) into clinical practice, the ability to diagnose small-bowel disease has improved greatly. This technique was shown to improve the diagnostic yield in cases of OGIB compared with traditional methods, eg, push enteroscopy (PE), small-bowel contrast studies, and CT.2-13 The Achilles’ heel of CE remains the inability of histologic assessment of a lesion and its lack of therapeutic capacity. Until recently, the only ambulatory endoscopic therapy available for OGIB was PE. This technique has been used with limited success and has limitations, with only a minority of the small bowel being seen.14,15 To date, the criterion standard for small-bowel examination remains intraoperative enteroscopy (IOE), where the total small

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bowel can be seen for diagnostic assessment and for therapy.16-20 Although IOE is successful, it is also associated with high morbidity and mortality.16-19 Since the introduction of the new double-balloon enteroscopy (DBE) technique by Yamamoto and Fujinon (Fuji Photo Optical Co, Ltd, Saitama, Japan), there is the promise for ambulatory endoscopic intervention for the entire small intestine.21-30 To date, there are limited data on the clinical utility of this technologic advance, particularly with regard to the relationship with wireless CE. With CE established as a small-bowel diagnostic imaging modality, the role for DBE appears to be emerging as a therapeutic tool for lesions found by CE. This prospective study reports the clinical outcomes in 60 consecutive patients who presented with OGIB, with positive findings on CE.

Double-balloon enteroscopy in patients with obscure GI bleeding

Capsule Summary What is already known on this topic d

d

When compared with push enteroscopy, small-bowel contrast studies, and CT, capsule endoscopy (CE) improves diagnostic yield in cases of obscure GI bleeding, but it cannot provide a histologic assessment or deliver therapy. Double-balloon enteroscopy (DBE) offers a new way of examining and treating small-bowel diseases.

What this study adds to our knowledge d

In a prospective, single-center study of 60 patients with obscure GI bleeding who underwent DBE after CE, the diagnosis was clarified or a new diagnosis was made in 12 patients, endoscopic therapy was delivered in 34, and endoscopic tattooing was performed in 3.

PATIENTS AND METHODS Study protocol This prospective study was conducted in a single tertiary referral hospital in Sydney, Australia, from July 2004 to March 2006. One endoscopist with experience in DBE and in therapeutic endoscopy performed the DBEs, with trainee registrars assisting with the outer tube. DBE can be performed via the antegrade (oral) or retrograde (anal) route, and the intention was to perform a targeted approach with the DBE. The approach was determined by the endoscopist, based on the time a lesion was seen in relation to the total small-bowel transit time on the CE study. If the lesion was within the proximal two thirds of the small bowel, then an antegrade DBE was used. In some cases, the CE report showed a prolonged holdup in 1 area of the small bowel, and this was taken into account when predicting the likely site of pathology. The decision to perform DBE by using the alternate route after completing the initial procedure was made after considering several factors, including the results of the initial procedure, the clinical indication, and patient consent. The maximum duration of each procedure by either route was limited to a 1-hour insertion time (withdrawal and therapeutic time not included). The basis for this was our experience in that the instrument usually made poor progress through the small intestine after a 1-hour insertion, and the relevant pathology was found within this time frame in most cases. In addition, we attempted to limit the prolonged sedation time. If a second alternate approach was to be considered, then the distal-most insertion point was tattooed with a submucosal carbon particle injection (SPOT endoscopic marker; GI Supply, Camp Hill, Pa). If required, the patients were then rescheduled for the alternative examination, usually within 2 weeks, and identification of the tattoo indicated complete visualization of the small bowel. The DBE was performed with the patient under conscious sedation with a combination of intravenous mida-

zolam, fentanyl, and propofol administered by the attending anesthetist. Hyoscine butylbromide was not routinely given during the procedure unless required for therapeutic intervention. The preparation for the procedures included a fasting period of 8 hours before the oral procedure and a routine bowel preparation with a sodium picosulfate–based preparation (Picoprep; Pharmatel, Thornleigh, Australia), with a clear fluid diet the day before the procedure for the anal approach.

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Patients All patients had presented with OGIB as defined by the American Gastroenterological Association (AGA) criteria.1 Patients were referred after initial investigations had been performed by their referring gastroenterologist. There was no defined protocol for iron replacement or blood-transfusion requirements for these patients, because this was determined by the treating physician. Patient demographics, previous investigations (endoscopic and radiologic), findings and intervention with DBE, limitations of insertion, complication rates, and follow-up after therapy were all recorded. Biopsy specimens were taken, and therapy was instituted when indicated. The CE reports and images were reviewed before DBE to target the identified lesion and to determine the correct initial approach. Follow-up information was obtained from outpatient clinical reviews and telephone contacts with the patient, family members, or referring physicians. All patients had follow-up blood counts to determine the state of their GI bleeding. Ethics board approval was obtained before data collection, and all patients gave verbal and signed consent for the procedures.

The DBE system The double-balloon endoscope was designed specifically by Dr Hironori Yamamoto and Fujinon to evaluate

Double-balloon enteroscopy in patients with obscure GI bleeding

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TABLE 1. DBE findings and endoscopic therapy performed according to initial CE findings CE finding

No.

DBE findings

Endoscopic intervention

AE

28

21 AE; 5 no abnormality detected; 1 polyp; 1 failed small bowel (multiple colon AE)

22 Diathermy; 1 polypectomy

Red spots

9

3 Red spots; 3 no abnormality detected; 1 ulcer; 1 polyp; 1 failed terminal ileal intubation

2 Diathermy; 1 tattooing

Blood

8

5 AE; 2 ulcers; 1 mucosal bleeding only

5 Diathermy; 1 tattooing

Polyps

7

4 Polyps; 2 ulcers; 1 failed

3 Polypectomy; 1 tattooing

Ulcer

4

1 Ulcers; 3 no abnormality detected

Nil

Possible submucosal mass

2

2 No abnormality detected

Nil

Radiation enteritis changes

1

1 Radiation enteritis

1 Diathermy

Abnormal mucosa distal ileum

1

1 Lymphoid hyperplasia

Nil

TABLE 2. New or clarified diagnosis made by DBE after the initial diagnosis made by CE

CE finding

No.

New or clarified diagnosis at DBE

AE

28

1 Polyp

Red spots

9

1 Ulcer; 1 polyp

Blood

8

5 AE; 2 ulcers

Polyps

7

2 Ulcers

Ulcer

4

No new diagnosis

Possible submucosal mass

2

No new diagnosis

Radiation enteritis changes

1

No new diagnosis

Abnormal mucosa distal ileum

1

No new diagnosis

the entire small bowel. After an initial experience with a diagnostic thinner instrument, a larger, therapeutic, instrument was used. It consists of a working enteroscope (length, 200 cm; outer diameter, 9.4 mm; and working channel, 2.8 mm) and an overtube (length, 145 cm; outer diameter, 13.2 mm). The overtube is filled with water to reduce the friction between the plastics and to allow the inner enteroscope to move easily. A soft latex balloon is placed on the end of the enteroscope once the overtube is positioned; the overtube comes fitted with a larger, soft, latex balloon. Both balloons can be inflated and/or deflated independently to a set pressure by using an external pump device. Unlike Dr Yamamoto, we did not have available the transparent cap that is placed on the tip of the endoscope. This device is used to ‘‘open’’ the small-bowel lumen by maneuvering the instrument tip, limiting the need for insufflation. 306 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 2 : 2007

The DBE technique used is as previously described by the innovators Yamamoto et al.21 Our standard practice is to perform DBE without the use of radiology assistance.

Statistics The statistical software package SPSS for Windows Version 14 (SPSS Inc, Chicago, Ill) was used to analyze the data. Mean (standard deviation [SD]) was used to summarize data for continuous variables, whereas percentages were used for categorical variables. The c2 test or the Fisher exact test was used to test for an association between categorical variables. Multiple logistic regression analysis with backward stepwise variable selection was used to identify the independent predictors of each outcome variable of interest. Odds ratios (OR) and their 95% confidence intervals (CI) were used to quantify associations of interest. The McNemar test was used to compare the pre- and post-DBE need for transfusion and for iron supplements. Two-sided tests with a significance level of 5% were used throughout.

RESULTS Patients The mean (SD) age of the cohort was 62  18 years; 31 men. The mean lowest Hb was 77 g/L (reference range, 10-125 g/L). Thirty-four patients (57%) had a previous blood transfusion, and 39 (65%) required ongoing oral or parenteral iron replacement. The majority of patients had a history of overt bleeding (n Z 34), with the remainder being occult. Previous investigations included upperGI endoscopy (mean, 2.4 procedures per patient), colonoscopy (mean, 1.7 procedures per patient), small-bowel contrast radiology (usually follow-through studies) in 14 patients, PE in 14, CT of the abdomen in 4, red-cell scan in 4, and angiography in 3. www.giejournal.org

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Double-balloon enteroscopy in patients with obscure GI bleeding

TABLE 3. Clinical outcomes presented as number of patients according to the therapy as directed by DBE No. pre-DBE

No. post-DBE

No.

Blood transfusion

Iron replacement

Blood transfusion

Iron replacement

34

24

25

7

9

Surgery

5

6

1

0

0

Medical therapy

3

0

1

0

0

No therapy

18

4

12

3

6

Total

60

34

39

10

15

Endoscopic therapy

CE findings included angiectasia (AE) (28), red spots (9), blood only (8), polyps (7), ulcers (4), suspected submucosal tumor (2), radiation enteritis (1), and abnormal ileal mucosa (1). A total of 74 DBE procedures were performed (range, 1-4): 34 patients underwent antegrade DBE only (2 patients had 2 antegrade procedures), 16 patients underwent retrograde only, 10 patients underwent both antegrade and retrograde (1 patient had 3 retrograde procedures). Fifty four of the 60 patients underwent DBE as an ambulatory outpatient procedure (6 as hospital inpatients), with all but 2 being discharged the same day. The 1 patient admitted was at the request of the anesthetist for observation; the other patient was observed overnight for abdominal distention to exclude perforation. Both were discharged the following morning without any complication. The mean (SD) duration of follow-up was 10.0  5.2 months).

spot (histology revealed a dilated submucosal venous complex).

Clinical outcomes

DBE found an abnormality in 45 patients (75%). The findings at DBE in relation to the CE findings are outlined in Table 1. DBE clarified or made a new diagnosis in 12 patients (20%) (outlined in Table 2). In 3 patients, a new diagnosis of Crohn’s disease was made, and they underwent standard medical therapy, all with a good response. Endoscopic therapy was performed in 34 patients (57%) and included diathermy in 30 and polypectomy in 4 (2 Peutz-Jeghers polyps, 1 lipoma, and 1 juvenile polyp). The only significant pre-DBE predictor of undergoing endoscopic therapy at DBE was previous blood transfusion: 82% with a previous blood transfusion underwent endoscopic therapy versus 31% with no previous blood transfusion (OR 10.5, 95% CI 3.1-35; P ! .001). Age, sex, type of bleeding, DBE approach, antiplatelet agent use, and CE findings were all not significant predictors of undergoing endoscopic therapy. Three additional patients had endoscopic tattooing of lesions for surgical resection: 2 large polyps (1 lipoma and 1 Peutz-Jeghers polyp), and 1 patient with bleeding mucosa with no definite bleeding

Forty-seven patients had no further bleeding (80%) and had a normal Hb. Ten patients required a blood transfusion during the follow-up period of 10.0 months (17%) compared with 34 (57%) before DBE, P ! .001. In these 10 patients, 5 clearly demonstrated a reduction in bloodtransfusion requirements after DBE intervention. Thirtynine patients required iron replacement before DBE, with only 15 after DBE, P!.001. The clinical outcomes according to the treatment performed as a result of the DBE are outlined in Table 3. Of the 5 patients who underwent surgery, 3 were guided by SPOT marking, with the other 2 being hemorrhoidectomies for large internal bleeding hemorrhoids after negative small-bowel examinations. Four patients underwent further endoscopic investigation for ongoing bleeding. One patient had an IOE that was normal and did not affect her bleeding frequency. There were no significant predictors of further bleeding on univariate or multivariate analysis. Total enteroscopy and complications. Of the 10 patients who underwent both antegrade and retrograde procedures with the intention to perform total enteroscopy, none had successful total small-bowel examination. One patient developed a major complication. A smallbowel perforation was identified at the site of diathermy for an actively bleeding AE, and the segment was resected successfully, with no subsequent transfusion requirement. Minor complications, such as bloating, sore throat, and nausea were common. Only 1 patient required an erect abdominal radiograph to exclude perforation when she complained of abdominal distention after an oral DBE. Lesions missed by DBE or CE. Because total enteroscopy was not attempted or achieved in the any of our patients and the study was not designed to examine for accuracy, the missed lesion rate for DBE cannot be determined.

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DBE findings and intervention

Double-balloon enteroscopy in patients with obscure GI bleeding

Lesions missed by CE were seen in 5 patients (8%): 3 patients with small-bowel ulcers (2 were diagnosed with inflammatory bowel disease, 1 with aspirin-induced ulceration) and 2 large 3-cm polyps (1 in the ileum and 1 in the proximal jejunum). The proximal lesion was removed endoscopically with the assistance of an Endoloop device (Olympus Optical Co, Ltd, Tokyo, Japan) and subsequent resolution of anemia. The other lesion was tattooed, with subsequent successful laparoscopic resection and resolution of anemia.

DISCUSSION There are few advances that revolutionize the way in which we manage our patients. CE can boast to be one of these.2-13 This technology has had a major impact on our diagnostic capabilities for patients with small-bowel diseases, particularly OGIB. Part of the impact has been in the ambulatory nature of this investigation and the ease for the patient undergoing it. Multiple studies now strongly support this modality for patients with small-bowel disease, especially in the case of OGIB, showing superiority to traditional investigations.2-8 With regard to detection rates, a recent publication by Hartmann et al19 confirmed CE to be as accurate as IOE in terms of detecting small-bowel lesions in patients with OGIB and supports CE as a small-bowel diagnostic criterion standard. One weakness of CE remains histologic sampling, along with the therapeutic abilities that we usually have available in the endoscopic setting. The latest advancement in small-bowel endoscopy that has tremendous potential is DBE and was first described by its innovator in 2001.21 The simple addition of 2 balloons to essentially traditional endoscopic equipment (the endoscope and the overtube) provides a vast improvement in access to the deeper segments of the small bowel. There are promising preliminary data that support the use of this new tool, provided mostly from Japan and Europe.21-30 These data are impressive with regard to improving the diagnostic ability in small-bowel disease and providing traditional endoscopic interventions in previously inaccessible areas. Recent publications provide good evidence for the use of DBE in OGIB, with an excellent diagnostic input and therapeutic rate. Therapy can be performed in the majority of these patients, depending on the management algorithm and the type of patient undergoing DBE. In addition, DBE can change or improve the diagnosis in a small but significant number of patients when CE is performed before DBE.22,29 IOE is considered the criterion standard for diagnosis and therapy, yet, at best, it can only achieve a resolution of bleeding in 45% to 70% of patients.16-18 In this study, the addition of DBE to CE for the diagnostic and treatment protocol for OGIB had a major impact. Overall, the diagnosis was clarified or a new diagnosis was made in 12 patients 308 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 2 : 2007

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(20%). Some form of endoscopic intervention was performed in 37 patients (62%): 34 underwent endoscopic therapy, and 3 patients had endoscopic tattooing. Importantly, the outcome data are very favorable, with more than three fourths of the patients having no further bleeding or anemia. The reduction in transfusion rate and iron requirements was also significant (P!.001 for each outcome). One shortfall of DBE is in not achieving total enteroscopy in all patients. Yamamoto et al21 had an 86% (24/ 28) success rate (2 cases with a single approach), whereas May et al25 reported a 45% rate (25/55), with the European multicenter study quoting 16%.25 We attempted total enteroscopy in 10 cases, with none achieving this goal. This is most likely because of the limited time we spend performing DBE compared with other groups.21-28 Additional contributing factors include the differing patient characteristics in Australia and the lack of availability of the clear cap used by Yamamoto et al,21 which reduces the need for air insufflation and improves the small-bowel maneuverability of the instrument. With the very high accuracy of CE in identifying small-bowel lesions, use of DBE in a targeted fashion, as was done in this study, is likely to diminish the need for total enteroscopy in the majority of patients. Gay et al28 suggested the same, showing a very high positive predictive value for CE to successfully predict the DBE approach. We found DBE to be a safe procedure that was easily performed in an ambulatory fashion. Only 2 of 54 patients required overnight observation but were discharged the following day without any problems. We only experienced 1 major complication related to diathermy treatment of a bleeding AE. This may have been avoided if a saline solution submucosal injection was performed first to decrease the depth of the injury.31 Major complications with DBE have been reported. Yamamoto et al23 reported 2 perforations, and there have been reports of postprocedure pancreatitis.27 Even though this study was not designed to determine the detection rates of CE and DBE, there were 2 missed lesions that required some attention. These were 2 large polyps missed by CE. A recent GIVEN database study suggests that missed lesions may be more common than previously reported.32 Missed lesions were seen in 10% of patients, which was highest in neoplastic disease, at 18.9%.32 In conclusion, in patients with OGIB and a positive finding on CE, DBE provided a safe and effective modality to treat and diagnose the cause. This targeted approach to OGIB appeared to have very favorable clinical outcomes over a medium- to long-term follow-up period.

ACKNOWLEDGMENTS We are indebted to Associate Professor Warwick Selby for his review and invaluable suggestions for this manuscript. www.giejournal.org

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DISCLOSURE No author has a conflict of interest to disclose regarding the work involved in this study.

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Double-balloon enteroscopy in patients with obscure GI bleeding 17. Douard R, Wind P, Panis Y, et al. Intraoperative enteroscopy for diagnosis and management of unexplained gastrointestinal bleeding. Am J Surg 2000;180:181-4. 18. Desa LA, Ohri SK, Hutton KA, et al. Role of intraoperative enteroscopy in obscure gastrointestinal bleeding of small bowel origin. Br J Surg 1991;78:192-5. 19. Hartmann D, Schmidt H, Bolz G, et al. A prospective two-center study comparing wireless capsule endoscopy with intraoperative enteroscopy in patients with obscure GI bleeding. Gastrointest Endosc 2005;61:826-32. 20. Jakobs R, Hartmann D, Benz C, et al. Diagnosis of obscure gastrointestinal bleeding by intra-operative enteroscopy in 81 consecutive patients. World J Gastroenterol 2006;12:313-6. 21. Yamamoto H, Sekine Y, Sato Y, et al. Total enteroscopy with a nonsurgical steerable double-balloon method. Gastrointest Endosc 2001;53: 216-20. 22. May A, Nachbar L, Wardak A, et al. Double-balloon enteroscopy: preliminary experience in patients with obscure gastrointestinal bleeding or chronic abdominal pain. Endoscopy 2003;35:985-91. 23. Yamamoto H, Kita H, Sunada K, et al. Clinical outcomes of double-balloon endoscopy for the diagnosis and treatment of small intestinal diseases. Clin Gastroenterol Hepatol 2004;11:1010-6. 24. Sunada K, Yamamoto H, Kita H, et al. Clinical outcomes of enteroscopy using double-balloon method for strictures of the small intestine. World J Gastroenterol 2005;11:1087-9. 25. May A, Nachbar L, Ell C. Double-balloon enteroscopy (push-and-pull enteroscopy) of the small bowel: feasibility and diagnostic and therapeutic yield in patients with suspected small bowel disease. Gastrointest Endosc 2005;62:62-70. 26. Ell C, May A, Nachbar L, et al. Push-and-pull enteroscopy in the small bowel using the double-balloon technique: results of a prospective European multicenter study. Endoscopy 2005;37:613-6. 27. Heine G, Hadithi M, Groenen M, et al. Double-balloon enteroscopy: indications, diagnostic yield, and complications in a series of 275 patients with suspected small-bowel disease. Endoscopy 2006;38:42-8. 28. Gay G, Delvaux M, Fassler I. Outcomes of capsule endoscopy in determining indication and route for push-and-pull enteroscopy. Endoscopy 2006;38:49-58. 29. Nakamura M, Niwa Y, Ohmiya N, et al. Preliminary comparison of capsule endoscopy and double-balloon enteroscopy in patients with suspected small-bowel bleeding. Endoscopy 2006;38:59-66. 30. Monkemuller K, Weigt J, Treiber G, et al. Diagnostic and therapeutic impact of double-balloon enteroscopy. Endoscopy 2006;38:67-72. 31. Norton ID, Wang L, Levine SA, et al. Efficacy of colonic submucosal saline solution injection for the reduction of iatrogenic thermal injury. Gastrointest Endosc 2002;56:95-9. 32. Lewis BS, Eisen GM, Friedman S. A pooled analysis to evaluate results of capsule endoscopy trials. Endoscopy 2005;37:960-5.

Received August 27, 2006. Accepted February 14, 2007. Current affiliations: AW Morrow Department of Gastroenterology and Hepatology (A.J.K.), Royal Prince Alfred Hospital, Camperdown, Royal Perth Hospital (C.W.S.), Perth, Liverpool Hospital (J.H.K.), Sydney, Australia. Reprint requests: Arthur J. Kaffes, MBBS, Ste 604, 35 Spring St, Bondi Junction, NSW 2022, Australia.

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