synergy 4&9
`
`November 2005
`
`Volume 100
`
`Number 11
`
`OFFICIAL PUBLICATION OF THE AMERICAN COLLEGE OF GASTROENTEROLOGY
`
`Editors: Joel E. Richter, MD, MACG NicholasJ. Talley, MD, PhD, FACG
`
`-
`
`ft
`
`7
`
`AJG Leading Articles of the Month
`
`The American
`
`Journal of
`Gastroenterology
`
`
`See Full Table of Contents Inside
`
`http://www.amjgastro.com
`Geneoscopy Exhibit 1005, Page 1
`
`Es. shageal
`
`par. Prolonged pH Monitoring Using the Bravo System
`|
`JM. Remes-Troche, J. lbarra-Palomino,
`R.I. Carmona-Sanchez,et al.
`
`rnFj
`
`Blomach
`
`(35° Randomized Trial of Esomeprazole- vs, Pantoprazole-based Triple
`e Therapy for H. pylori
`P-I, Hsu, K-H, Lai, C-K. Lin, et al.
`
`|
`
`See Accompanying Editorial
`
`Ls
`
`Envoscopy
`
`loi Urgent Colonoscopy for Acute Lower GI Hemorrhage
`3.7. Green, D.C. Rockey, G. Portwood,etal.
`See Accompanying Editorial
`[40°Meta-Analysis of Capsule Endoscopy In Obscure GI Bleeding
`».L. Triester J.A. Leighton, G.l Leontiadis, et al,
`241° Pandomized, Double-Blind, Placebo-Controlled Trial of Endoscopic
`——Sterolds for Recalcitrant Esophageal Peptic Strictures
`! Ramage, Jr, A. Rumailla, TH. Baron, et al
`
`biood Biliary Tract
`
`43)
`
`Journal Impact Factor as a Predictorof Trial Quality and Outcomes
`fo Gluud, TILA Sarensen, PC. Getzsche, etal.
`»e¢ Accompanying Editorial
`f_”- openseof Hepatitis C Genotype-4 Naive Patients to 24-Weeks
`_ *8g-Interferon-c2b/Ribavirin or Induction-Dose
`.teMferon-a2b/Ribavirin/Amantadine
`
`yy ®. El-Zayadi, M. Attia, E.M.F Barakat, etal.
`
`vil 'matory Bowel Disease
`
`'" Delayed-Release Oral Mesalamine at 4.8 g/day (800 mg tablet) for
`“‘aderately Active Colitis: ASCENDII Trial
`2 8, Hanauer WJ. Sandborn, A. Kornbluth, et al.
`
`
`
`
`
`
`
`
`
`FunctionalGI Disorders
`
`2510 Tumor Necrosis Factor-Alpha and Interleukin 10 Gene Polymorphisms
`in IBS
`PPJ. van der Veek, M. van den Berg, YE. de Kroon, etal.
`
`See Accompanying Editorial
`
`Colon
`
`2519 An Automated, Quantitative, Immunochemical, Fecal Occult Blood
`Screening Test
`A. Vilkin, P Rozen, Z. Levi, et al.
`
`2526
`
`Inappropriate Colorectal Cancer Screening
`D.A. Fisher, L. Judd, N.S. Sanford
`
`Pancreas
`
`2540
`
`Small Gallstones and Acute Pancreatitis: Potential Benefits of
`Prophylactic Cholecystectomy?
`N.G. Venneman, E, Buskens, M.G.H. Besselink, et al.
`
`Pathology
`
`2551 Expression of Fas Ligand by Hepatic Macrophages in Fulminant
`Hepatic Failure
`A, Mita, ¥ Hashikura, Y-I. Tagawa, etal.
`
`Reviews
`
`2560
`
`Interactions Between Commensal Bacteria and Gut Sensorimotor
`Function
`G. Barbara, V. Stanghellini, G. Brandi, et al.
`2569 Management of Polycystic Liver Disease
`H.L, Arnold, S.A, Harrison
`
`2583 Milk Thistle for Alcoholic and/or Hepatitis B or C Liver Diseases
`A. Rambaldi, 8.P Jacobs, G. laquinto,et al.
`
`
`
`Geneoscopy Exhibit 1005, Page 1
`
`

`

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`Geneoscopy Exhibit 1005, Page 2
`
`Geneoscopy Exhibit 1005, Page 2
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`

`

`American Journal of Gastroenterology
`«2005 by Am. Coll, of Gastroenterology
`Published by Blackwell Publishing
`
`
`ISSN 0002-9270
`doi: 10.1111/).1572-024 1.2005.0023 L.x
`
`Performance Characteristics and Evaluation of an
`Automated-Developed and Quantitative, Immunochemical,
`Fecal Occult Blood Screening Test
`Alex Vilkin, M.D.,' Paul Rozen, MB., BS.,!:? Zohar Levi, M.D.,! Amal Waked, B.Sc.,! Eran Maoz, M.D.,?
`ShlomoBirkenfeld, M.D.,° and Yaron Niv, M.D,!2
`' Gastroenterology Department, Rabin Medical Center, Beilinson Hospital, Petach Tikva; *Tel Aviv University
`MedicalSchool, Tel Aviv, Israel; and * GastroenterologyUnits, Clalit Health Services, Tel Aviv, Israel
`
`
`
`OBJECTIVES:
`
`METHODS:
`
`RESULTS:
`
`Guaiacfecal occult blood colorectal cancer (CRC) screening tests (FOBT) are faulted for low
`sensitivity and nonspecificity for human hemoglobin (Hb). Automated-developed, immunochemical,
`human Hb FOBT(I-FOBT)is specific, eliminates diet restrictions, and Hb quantification allows
`selection of a threshold for colonoscopy. Aims were to determine 1) test reproducibility; 2) test
`stability; 3) intrapatient daily |-FOBT variation; 4) test sensitivity and specificity for neoplasia in 500
`symptomatic/high-risk patients undergoing colonoscopy; and 5) to correlate fecal Hb measurements
`with findings.
`
`The desktop instrument OC-Sensor(Eiken, Japan) automatically develops and quantitates 50
`tests/h for Hb. Patients prepared three tests, which were quantified and then 1) repeatedly
`re-examined; 2) stored at 4°C or 20°C or 28°C and repeatedly examined; and 3) fecal Hb levels were
`correlated with colonoscopic findings.
`
`Five |-FOBTs re-examinedfive times in 1 day had nosignificant measurement changes. Thirty tests
`stored for 21 or more days had a decay/day of 0.3% + 0.4 at 4°C (NS), 2.2% + 1.7 at 20°C (NS),
`and 3.7% + 1,8 at 28°C (p < 0.05). There were intrapatient variations between the three daily
`I-FOBTs (NS). At the recommended 100 ng Hb/mLthreshold, all six cases of CRCs and 20 outof 28
`cases of advanced adenomasweredetected; evaluated togethertheir sensitivity and specificity were
`76.5% and 95.3%.
`
`CONCLUSIONS: Desktop, automated-developed, quantitative I-FOBT is now available. Refrigerated OC-Sensor
`samples are stable for 21 days, easy to prepare and develop and, at the 100 ng Hb/mL threshold,
`have high sensitivity, specificity, and negative predictive values for significant neoplasia. Suitability
`for population CRC screening awaits further evaluation.
`
`(Am J Gastroenterol 2005;100:2519-2525)
`
`
`The standard guaiac fecal occult blood test (G-FOBT)is
`faulted for its low sensitivity for significant colorectal neo-
`plasia [colorectal cancer (CRC) and advanced adenomatous
`polyps (AAP)], and low specificity due to nonspecificity for
`human hemoglobin (Hb);see reference (1). It is also faulted
`by the possibility of inaccurate development and evaluation
`by inadequately trained personnel (2-4).
`The
`introduction of central
`laboratory and office-
`developed,
`immunochemical,
`fecal occult blood tests (I-
`FOBT)specific for human Hb improved specificity (5—1 1).
`However, for the office-developed tests, the I-FOBT man-
`ufacturers have predetermined the degree of sensitivity for
`Hb,andthe occasional experience with more complex office-
`development was not conducivefor large-scale screening and
`maintaining quality control (1-4, 8, 11).
`
`The automated-developed and quantitative I-FOBTis hu-
`man Hb specific, eliminatesthe need fordietrestrictions, and
`the Hb quantification allows selection of a suitable threshold
`level for follow-up colonoscopy (5—7, 9-12).
`The introduction of such methodology, for large-scale
`screening, requires evaluation ofthe instrumentandits per-
`formance characteristics. In addition, we need to evaluate
`its true sensitivity and specificity for colorectal neoplasia
`versus colonoscopy in different clinical settings and de-
`termine which level of fecal Hb should trigger follow-up
`colonoscopy.
`Specific aims were to determine1) test-developmentrepro-
`ducibility; 2) effect of temperature and duration of storage
`on fecal sample stability; 3) intrapatient daily I-FOBTtest
`variation; 4) sensitivity and specificity for neoplasia found
`
`This material may be protected by Copyright law (Title 17 U.S. Code)|2519
`Geneoscopy Exhibit 1005, Page 3
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`Geneoscopy Exhibit 1005, Page 3
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`

`

`2520
`
`Vilkin et al.
`
`Sample cup part
`
`Scraper.
`
`Figure 1. Left: Stool probe and fecal sample storage tube. The closed tube is 8 cm long, 2 cm wide. On each tube there is a unique bar code
`and space to write name and date. Right: Desktop instrument and accessories. The instrumentis 32 cm wide, 53 cm deep, and 42 cm high.
`
`in persons also undergoing colonoscopy; and 5)to correlate
`fecal Hb levels with clinical findings.
`
`METHODS
`
`Patients
`These were ambulatory persons who were symptomatic and
`scheduledfor colonoscopy, or asymptomatic personsat high-
`risk for CRC andinvited for colonoscopy. Thelatter included
`surveillance postpolypectomyand those having a family his-
`tory of colorectal neoplasia. Exclusionsincludedvisible rec-
`tal bleeding, knowndiagnosisof inflammatory bowel disease,
`hematuria, menstruation, and noncooperation with preparing
`a fecaltest.
`All participants received an oral and/or telephone expla-
`nation of the tests and written instructions on preparing the
`I-FOBTs.
`Colonoscopy was to the cecum orup to an obstructing
`carcinomaif present. Otherwise, an incomplete examination
`was repeated or excluded from analysis. All lesions were
`noted, biopsied, or removed. Patients’ electronic data files
`were available from the three participating endoscopy units
`belonging to the same medical organization.
`Numbersof polyps were noted as were theirsites. Pathol-
`ogy reports were available and pathology specimens re-
`viewed when necessary. Polyps were classified as non-
`adenomas or adenomas. Adenomas were grouped bysize:
`<5 mm, 5-9 mm, >10 mm; and also by their histology:
`tubular, tubulo-villous, villous; dysplasia was classified as
`low-grade dysplasia (LGD)or high-grade dysplasia (HGD).
`“Significant” neoplasia included CRC or advanced adeno-
`matous polyps (AAP); this latter category included adeno-
`mas >10 mm, or having more than 20% of villous his-
`tology or any amount of HGD independentofsize. All
`AAPs <10 mm were re-examinedto confirm their histology
`diagnosis.
`
`Patients with symptomsor having a positive |-FOBT unex-
`plained by their colonoscopyfindings continued their inves-
`tigations. These included upper-gastrointestinal endoscopy
`and smal] bowelinvestigation when appropriate.
`The study was approved by the Ethics Committee of the
`Rabin Medical Center in 2004. All participants gave an in-
`formed, signed consentfor the I-FOBT and colonoscopy ex-
`amination.
`
`Fecal Sampling
`The fecal test sampling device is shaped like a small test
`tube with the fecal probe inserted into it and sealing it. The
`probe hasa serrated tip, which is poked into the stool and
`then pushed back into the tube, past a scrapper, and through
`a membraneinto the sample cup. These remove mostofthe
`excess feces and leavethe stool collected (about 10 mg)into
`the serrations (Fig. 1). The tip is then put in a closed amount
`of Hbstabilizing buffer. Each sample tube has a unique bar
`code and before preparing the sample the patient writes his
`name and date on the tube, The examineeis requested to pre-
`pare three consecutive daily samples during the week before
`colonoscopy examination. Samples are double-closedin zip-
`lock bags and keptin the refrigerator until returned to the
`developing laboratory where they are also kept at 4°C until
`development.
`
`Instrument and Testing and I-FOBT Analysis and Control
`The instrumentused for developing and quantification ofthe
`I-FOBTis OC-Sensor, Eiken, Japan. This is a desktop instru-
`ment weighing 26 kg, and is 32 cm wide, 53 cm deep, and
`42 cm high.It is self-contained with reagent, buffer, washing
`and fluid-disposal bottles, and requires access to a standard
`powersupply (Fig. 1). Ten of the patient-prepared fecal sam-
`ple tubes are loaded into the sample rack, and in parallel
`there is another rack with disposable reaction cells. The in-
`strument automatically mixes the fecal buffer solution with
`the latex—antihuman HbA antibody reagent. Following the
`developmentcycle, there is automatic flushing of the system.
`
`Geneoscopy Exhibit 1005, Page 4
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`Geneoscopy Exhibit 1005, Page 4
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`

`

`
`
`Automated FOBT Evaluation
`
`2521
`
` 20°C (N=10)
`
`
`Dweekt Biweek2 Bweeks)
`
`28°C (N=9)
`
`
`
`
`
` Ss8Cumulativedecrease(%)
`
`o
`
`4°C (N=12} -20
`
`
`-40
`
`—
`
`Figure 2. Progressive changes in fecal Hb measurementsat endofthefirst, second, and third weeks’ storage at 4°C, 20°C, and 28-30°C.
`The cumulative changes (decay) at 28°C were significantly different (p < 0.05) from the initial measurements.
`
`Theflocculationis read as an optical change and compared to
`a standard calibration curve. Calibration is prepared for each
`day’s analysis, using the provided known high- and low-value
`contro]test fluids. The range of measurements is 50-2000 ng
`Hb/mL, approximately equivalent to 40-400 zg Hb/g feces,
`
`RESULTS
`
`Test Reproducibility
`Five prepared I-FOBT samples were quantified and repeat-
`edly examinedfive more timesin 1 day. They hadnosignifi-
`cant variation in measurements,F(s,20) = 0.24, p = 0.66.
`
`Evaluations Performed
`Five I-FOBT samples were each repeatedly re-examinedfive
`more times in | day. Thirty I-FOBT samples, having > 100
`jug Hb/mL initial measurements, were stored at 4° or 20° C or
`at ambient summer room temperature (28-30°C). They were
`repeatedly re-examined every second day for 3 wk. Further
`12 samples, having low butelevated initial Hb levels between
`100 and 200 ng/mL, were stored at 4°C and re-examined as
`above.
`
`Analysis and Statistical Methods
`AJstatistical analyses were performed using the SAS system
`for Windows,version 8.01. Results are given as mean + stan-
`dard deviation (SD). Stability of the test measurements and
`effects of duration of storage and temperature were analyzed
`by analysis of variance with repeated measurements. Weekly
`changesin the stored I-FOBTs were determined by compar-
`ing the lowest value measured in week 1, 2, and 3 with the
`initial values measured.
`For clinical correlation to I-FOBTlevels, the most severe
`pathology finding (histology and polyp size) recorded was
`used for each examinee.
`Persons having only hyperplastic polyps were included in
`the group not having neoplasia. For analysis of adenomas,
`the analysis included AAP and was then repeated without
`them. Forthe category of “significant” colorectal neoplasia,
`the analyses included only CRC or AAPorboth together.
`I-FOBTanalysis was based on the 100 ng Hb/mLthresh-
`old. These analyses were then repeated at increments of25 ng
`Hb/mL down to 50 ng and up to 200 ng Hb/mL for analyses
`correlating I-FOBTresults and presence ofneoplasia.
`
`Test Stability
`Thirty I-FOBT samples, positive for Hb and stored at 4°C,
`20°C, or 28-30°C, were repeatedly re-examined. Their ini-
`tial values ranged from 1032 + 783 to 787 + 393 ng Hb/mL.
`The decay/day was 0.3% + 0.4 at 4°C (NS), 2.2% + 1.7 at
`20°C (NS), and 3.7% + 1.8 at 28°C (p < 0.05), Their cumu-
`lative weekly change in I-FOBT measurements is shownin
`Figure 2. At 4°C, all these I-FOBT samples maintained their
`elevated fecal Hb levels for 21 or more days.
`Werepeated the study with a further 12 I-FOBT samples,
`stored at 4°C, having low butelevatedinitial measurements
`ranging from 104 to 233 ng Hb/mL. In two samples, with
`the lowest initial values, the repeated measurements were
`<100 ng Hb/mL by 3 wk from the time ofpreparation by the
`patient.
`
`Patient and Colonoscopy Results
`I-FOBTswereprepared by 521 patients. However 21, having
`a negative FOBT but incomplete colonoscopy examination,
`were excludedfrom this analysis. They confirmedtheir neg-
`ative colonic examination by radiology.
`The complete data from the initial 500 examinees were
`analyzed. They include 53.2% males, with a mean age of62.1
`+ 12.6 yr. The symptomatic patients coming for colonoscopy
`were of average risk in 57.5% while 32.7% had a family
`history of CRC and 53.4% of the latter were asymptomatic.
`Colonoscopy
`detected
`non-neoplastic
`(hyperplastic)
`polyps in 12.8% and adenomas in 22.4% of the examinees.
`They included tubular adenomasin 18.8%, tubulo-villous in
`3.2%, and villous adenomas in 0.4%. It was observed that
`58.8% of the adenomatous polyps were <5 mm, 21.1% were
`
`Geneoscopy Exhibit 1005, Page 5
`
`Geneoscopy Exhibit 1005, Page 5
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`

`

`2522
`
`Vilkin et al.
`
`Table 1. Fecal Occult Blood Levels Detected According to
`Colonoscopy and Pathology Findings
`
`No.
`381
`
`Fecal Hb (ng/mL)
`(Mean + SD)
`29.1 + 103.8
`
`Significance”
`
`Diagnosis
`Normal!
`Adenomas
`All
`Non-AAP
`AAP
`Cancer
`
`
`NS
`231.9 + 567.5
`113
`NS
`$8.0 + 156.5
`85
`P <0.01
`759.8 + 935.7
`28
`p<0.01
`1154.3 + 793.0
`6
`CRC + AAP p<0.01 34 829.4+ 913.8
`
`
`
`AAP = advanced adenomatous polyps; CRC = colorectal cancer.
`* As compared to the normal group.
`‘Includes 64 patients with only hyperplastic polyps.
`
`6-9 mm, and 20.2% were >10 mm; 11.4% of the patients
`had single adenomas, 11.6% had multiple adenomas. LGD
`was reported in 13.4% examinees, and HGD or cancer in
`3.2%of the examinees.
`Significant neoplasia was found in 34 patients (6.8%).
`These included 6 with CRC and 28 with AAP and weresig-
`nificantly more males (p = 0.01) and older than 65 yr of age
`(p < 0.01).
`
`Fecal Occult Blood Results
`For the entire population undergoing colonoscopy, the mean
`I-FOBT measurement was 49.0 + 216.5 ng Hb/mL for sam-
`ple 1, 41.0 + 207.1 for sample 2, and 51.3 + 237.6 for sample
`3 (p = 0.5). At the Hbthreshold of 100 ng Hb/mL,the over-
`all positivity was 9.6%,rising to 15.0% at the 50 ng Hb/mL
`threshold. Conversely, positivity fell to 7.8% at the 200 ng
`Hb/mL threshold.
`
`The I-FOBTresults according to endoscopy and pathology
`diagnosis are given in Table |. The mean I-FOBTvalues from
`patients having significant colorectal neoplasia were signif-
`icantly different from those having a normal colonoscopy
`examination; p < 0.01 (Figures3 and4).
`
`Correlations ofI-FOBT with Diagnosis
`CANCER.Six patients with CRC were identified by
`colonoscopy. They were identified by utilizing all three I-
`FOBTSs. Five were identified by sample 1, four by sample 2,
`and all six by sample 3.
`
`ADVANCED ADENOMATOUS POLYPS. Twenty-eight
`patients were identified by endoscopy and 20 of them by
`utilizing the measurementsofall three I-FOBTs.
`
`SIGNIFICANT NEOPLASIA. These include the six pa-
`tients of CRC and 28 patients of AAP, and of these 34, 26
`were identified by utilizing the measurements ofall three I-
`FOBTs. Eighteen patients were identified by both samples
`1 and 2, 21 by sample 3. The sensitivity and specificity re-
`sults ofthe I-FOBTsat the standard 100 ng Hb/mL threshold
`were 76.5% and 95.3%, respectively (Figs. 3 and 4). Simi-
`lar analyses at lower and higher I-FOBT Hbthresholds and
`identification by the three I-FOBTsis given in Table 2.
`
`INTRAPATIENT I-FOBT VARIATION. Therelative sensi-
`tivity ofeach ofthe three -FOBTs for CRC or CRC and AAP,
`at the 100 ng Hb threshold, and their additive valuesare given
`in Table 3. The best results were obtained whenall three tests
`were performed andutilized for analysis.
`
`POLYPS.This refers to the most significant polypoid le-
`sion identified in the screenee. [n 175 of the 500 examinees,
`
`
`
`
`
`(CRC (N58)
`
`AAP*CRC (e344)
`
`0
`
`
`+—
`—
`Normal,MonAd (N=381)
`Non-AAP [N=86)
`
`AAP (N=2a)
`
`
`
`Diagnosis
`
`Figure 3, Box plots of fecal Hb values for each diagnostic category. Dark line indicates median Hb value, colored block covers the upper
`and adjacent two lower quartiles, bars are the maximum and minimum levels measured. CRC and/or AAP measurementsare significantly
`elevated as compared to the normal-hyperplastic polyp group, p < 0.01.
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`
`Automated FOBT Evaluation
`
`2523
`
`
`
`
`—?-— CAC (N=)
`a AAP (N=28)
`
`
`fo All Acerorien (M2113)
`
`100%
`
`80%
`
`Sensitivity 40%
`
`20%
`
`0%
`
`0%
`
`10%
`
`20%
`
`30%
`
`40%
`
`50%
`
`60%
`
`70%
`
`80%
`
`90%
`
`100%
`
`Figure 4. Receiver—operator characteristic curve for sensitivity and specificity for each diagnostic category at the 100 ng Hb/mL threshold
`for fecal blood measured.There is high sensitivity for CRC and also AAP, with low sensitivity for adenomas as a category.
`
`1 - Specificity
`
`a polypoid lesion wasidentified. In 64, the polyp was not
`an adenoma but a hyperplastic polyp. In 93 screenees, the
`polyp was a tubular adenoma, whereas 16 had tubulo-villous
`and 2 had villous adenomas; the remaining 7 had not been
`recovered forfull histological examination.
`The sensitivity of the I-FOBT for identifying an ade-
`nomatous polyp is shown in Figures 3 and 4. There was
`a low sensitivity for adenomatous polyps sized <10 mm.
`Utilizing the results of all
`three I-FOBTs, at the 100 ng
`Hb/mLthreshold, the sensitivity for adenomas > 10 mm was
`82.6%, 6~9 mm was 20.8%, and <5 mm was 9.0%. There
`was no significant difference in the mean I-FOBT mea-
`surements, whether the adenomas were single or multiple
`(p = 0.4).
`
`107 to a high of 3050 ng Hb/mL (mean 1056 ng). The other
`eight, with low I-FOBT values, had only a mean of 19 ng
`Hb/mL.
`Conversely, 21 screenees, without significant colorectal
`neoplasia, had an I-FOBT measurement >100 ng Hb/mL,
`while the entire normal group had mean measurement of
`47.2 ng Hb/mL. These 21 patients are being evaluated and
`followed upclinically. Five had knowniron-deficiency ane-
`mia; 10 had adenomas <10 mm in diameter, 1—6 in number.
`All 21 screenees had had a gastroscopy examination, and in
`15 there were significant findings (including multiple find-
`ings): esophagitis (2), hiatus hernia (1), gastritis (8), status
`postgastric surgery (3), gastric carcinoid (1), and duodenitis
`(4).
`
`Screenees with False-Negative or False-Positive
`I-FOBT Results
`This group refers to the eight screenees with AAP who had
`I-FOBTlevels <100 ng Hb/mL. Of the 28 screenees found
`by colonoscopy to have an AAP, 20 had I-FOBT measure-
`ments >100 ng Hb/mL, The values ranged from a low of
`
`Table 2. Sensitivity and Specificity for Significant Colorectal Neo-
`plasia, (N = 34) at Differing Fecal Hb Levels (N = 500)!
`
`Specificity
`Sensitivity
`Fecal] Hb
`(%)
`(%)
`(ng/mL)
`89.7
`79.4
`50
`93.3
`76.5
`75
`95.3
`76.5
`100
`95.7
`70.6
`125
`95.9
`70.6
`150
`
`200 96.3 64.7
`
`
`*Six colorectal cancers and 28 advanced adenomitous polyps.
`' Utilizing the highest of the three I-FOBT measurementin eachpatient.
`
`DISCUSSION
`
`This colonoscopy-controlled study allowed for a detailed
`evaluation of an automated desktop instrument for quanti-
`tative, immunochemical determination of fecal occult blood.
`The clinical evaluation demonstrated a high sensitivity of
`76.5% forall significant colorectal neoplasia and acceptable
`specificity of 95.3%.
`The technical evaluation included studies of reproducibil-
`ity of the instrument in developing and evaluating thetests
`
`Table 3. Sensitivity for Significant Colorectal Neoplasia (N = 34)"
`for Each I-FOBT! Prepared
`
`Cancer + AAP (%)
`Cancer(%)
`I-FOBTPositive
`52.9
`83.3
`Sample |
`52.9
`66.7
`Sample 2
`61.8
`100
`Sample 3
`64.7
`83.3
`Samples | and 2
`
`Samples 1, 2, and 3 76.5 100
`
`*Six colorectal cancers (CRC) and 28 advanced adenomatous polyps (AAP).
`1 At the 100 ng Hb/mL threshold.
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`2524
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`Vilkin et al,
`
`old chosen were different from those in Italy, namely 2 an-
`and stability ofthe prepared fecal occult bloodtests. Because
`nual samples and 150 ng/mL fecal Hb threshold in Japan
`of our high ambient temperature this latter point was care-
`versus | biennial sample and 100 ng/mL threshold in Italy
`fully evaluated, and we showed that the prepared I-FOBT
`(19, 20, 21).
`could be kept up to 3 weeks in refrigeration without sig-
`We will now extend this screening study to include
`nificant degradation of the test antigen. As we have seen,
`asymptomatic but high-risk persons undergoing surveillance
`for low-elevated levels, the measurement could drop be-
`colonoscopy, at set intervals, because of a family history
`low the 100 ng Hb/mL threshold by 3 weeks even when
`of colorectal cancer or follow-up of past colorectal neo-
`refrigerated.
`It
`is important to emphasize,
`to the patient
`plasia (22). The results might influence future screening
`and to the medical service, the correct storage and dura-
`and follow-up policy and obviously reduce costs, patient in-
`tion of storage. The time period of 2 weeks from prepara-
`convenience, as well as demands on medical priorities and
`tion is adequate for batch processing of accumulatedtest
`services.
`samples.
`Thegoal will be to extend this automated-developed, quan-
`For many years, office-developed I-FOBTshave beenavai-
`titative, I-FOBT to colorectal neoplasia screening in the
`lable in Japan; because of their high peroxidase-containing
`asymptomatic average-risk population. This has been done
`diet, these tests were foundto be more suitable than G-FOBTs
`with the InSure (Enterix, United States, and Australia) test
`(7, 13). For the same reason this wasalso found to be true in
`in pilot studies in Australia and also in the United States (9,
`Hong Kong(10). In a population eating a Western-typediet,
`11). Another automated test is Magstream (Fujirebio, Japan)
`the problems with dietary peroxidases can be overcome by
`developed in Japan and also being evaluated in Australia,
`dietary restrictions and adaptations to the G-FOBT develop-
`France, and Hong Kong (23). Outside Japan, the automated
`ment protocol (1, 14).
`version of OC-Sensoris being used in a large-population,bi-
`The I-FOBTcard, laboratory or office-developed, is com-
`ennial, single sample study in NorthernItaly (18, 19). It has
`monly used in Japan and has becomeavailable in the United
`been usedin a population study in Uruguay (Dr, E. Fenocchi,
`States, Israel, Italy, and Australia (1, 3, 8, 9, 11, 15-17).
`personal communication). It will also be used inalarge Span-
`However, even though it is more specific than the G-FOBT,
`ish asymptomatic population screeningtrial (Dr. E. Carballo,
`because ofits manufacturer’s-determinedfixed sensitivity we
`personal communication).
`did not find it more sensitive than a cheaper G-FOBTofsim-
`The participation rate of preparingafecaltestis critical
`ilar sensitivity (8).
`for the success of a FOBT screening program. To facili-
`The introduction of the instrument-developed, quantita-
`tate average-risk compliance, there are two issues that are
`tive, fecal occult bloodtesting allowsthe physician to choose
`needed to be addressed. The provision of a toilet-disposable
`the optimal fecal Hb threshold levelthat triggers a follow-
`paper stool-collecting device facilitates preparing the test
`up colonoscopy. To validate this premise, we performed
`(3). The storage of the prepared I-FOBT inarefrigera-
`this study in high-risk and symptomatic patients undergoing
`tor, until development, is important for maintaining the test
`colonoscopy. From this study, we confirmedthat the I-FOBT
`stability. This is critical
`in countries with high ambient
`threshold of 100 ng Hb/mL allowedusto detectall the can-
`temperatures, even when homesare air-conditioned. The dou-
`cers and the majority of advanced adenomas,giving together
`ble zip-lock bags we provided answered someofthe scree-
`a sensitivity of 76.5%. Conversely, it provided an acceptable
`nees’ hesitancy about keeping the prepared test transiently
`specificity of 95.3% (1). This means that in this group of
`in their home refrigerator. This packaging could be further
`high-risk and symptomatic patients, all cases of cancer and
`most advanced adenomas would be detected and a negative
`improved.
`In conclusion, we have found this desktop, automated-
`test would provide a very high degree of certainty that there
`developed and quantified Hb version ofthe immunochemical
`wasnoclinically significant colorectal neoplasiaat this round
`fecal occult blood test to provide a highly sensitive test for
`of screening.
`detecting significant colorectal neoplasia with an acceptable
`At present, we will continue with co