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Novel Diagnostic Strategies in Inflammatory Bowel Disease

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    1. Novel Diagnostic Strategies in Inflammatory Bowel Disease Mark H. Flasar, M.D. Assistant Professor of Medicine Division of Gastroenterology and Hepatology

    2. The Short List Laboratory testing Serologic markers Genetic testing Metabolite monitoring Markers of disease activity (serum, stool) Radiography Enterography (CT, MRI) Pelvic imaging (MRI) Ultrasound Endoscopy Chromoendoscopy Advanced endoscopic imaging Rectal EUS for fistulae

    3. All That in 30 Minutes???

    4. Serology: The Two Jakes ASCA: The Crohns Disease Ab + in 60% of CD1-3 IgA + IgG vs. cell wall of S. cerevisiae pANCA: The Ulcerative Colitis Ab + in 40-80% UC, 2-28% CD (UC-like CD)4 Newer assay more specific for UC Loss of perinuclear stain after DNAse ASCA: Sacch=brewers yeast Simple ELISA, standardized, easy to run Poor correlation with mucosal S. cerevesiae Mallant-Hent RC, et al. World J Gastroenterol 2006;12:292 ANCA: ANCA IgG, pANCA IIF, DNASE sens pANCA IIF Results variable based on assay, personnel experience. ELISA+IFE--?60%, IFE alone?0-40% ASCA: Sacch=brewers yeast Simple ELISA, standardized, easy to run Poor correlation with mucosal S. cerevesiae Mallant-Hent RC, et al. World J Gastroenterol 2006;12:292 ANCA: ANCA IgG, pANCA IIF, DNASE sens pANCA IIF Results variable based on assay, personnel experience. ELISA+IFE--?60%, IFE alone?0-40%

    5. Other CD Abs: OmpC and CBir1 Anti-OmpC* IgA + in 55% of CD5 Vs. E. coli outer membrane porin C protein Anti-Cbir1t IgA + in 50-55% CD6,7 40% Ab- CD pts are + for anti-CBir17 Anti-I2 + in 54% CD8-9 Vs. bacterial DNA in LP monocytes OmpC less + in peds (24% in pediatric-onset CD) Zholudev A, et al. Am J Gastroenterol 2004;99:2235 CBir1 Induces colitis in animal models 40% CD pts - for all other Abs are + for anti-CBir1 (suggesting possible unique CD phenotype) I2 assoc w/ Pseudomonas flouresciensOmpC less + in peds (24% in pediatric-onset CD) Zholudev A, et al. Am J Gastroenterol 2004;99:2235 CBir1 Induces colitis in animal models 40% CD pts - for all other Abs are + for anti-CBir1 (suggesting possible unique CD phenotype) I2 assoc w/ Pseudomonas flouresciens

    6. Other Abs: PAB and anti-Glycans Anti-Glycan Abs11,12 Vs. bacterial/fungal cell wall carbohydrates ALCA, ACCA, AMCA? + in 18-38% CD Anti pancreatic Ab (PAB) + in 30% CD10 unknown relevance in CD Low correlation between presence of AMCA, ACCA, ALCA suggests different microorganism targets for each Anti-laminaribocide Ab (ALCA) Anti-chitobioside (ACCA) Anti-mannobioside (AMCA)Low correlation between presence of AMCA, ACCA, ALCA suggests different microorganism targets for each Anti-laminaribocide Ab (ALCA) Anti-chitobioside (ACCA) Anti-mannobioside (AMCA)

    7. Serology: What is it Good For? Diagnosis IBD vs. Functional/Healthy CD vs. UC Pre-clinical marker Predict disease course or complications in IBD CD and UC phenotype CD and UC progression/aggression Risk of pouchitis after IPAA for UC Following disease activity/treatment response IBD vs. functional/healthy: Use when low index suspicion and want to avoid endoscopy/expensive testingIBD vs. functional/healthy: Use when low index suspicion and want to avoid endoscopy/expensive testing

    8. ASCA, pANCA for IBD vs. Healthy How about ASCA alone? Here, test characteristics examined as a secondary aim, looking at population with high prevalence CD (36%). Not a very good screening testHow about ASCA alone? Here, test characteristics examined as a secondary aim, looking at population with high prevalence CD (36%). Not a very good screening test

    9. ASCA, pANCA for IBD vs. Healthy How about ASCA AND ANCA? The aim of this study was to see how well ACSA, ANCA and combination could tell IBD from controls. (n = 582: 407 CD, 147 UC, and 28 indeterminate colitis), patients with non-IBD diarrheal illnesses (n = 74), and healthy controls (n = 157). CONCLUSIONS: Specificity of serological markers for IBD is high, but low sensitivity makes them less useful as diagnostic tests. The combination of tests is probably more powerful, although, clinical subgroups still need to be defined. How about ASCA AND ANCA? The aim of this study was to see how well ACSA, ANCA and combination could tell IBD from controls. (n = 582: 407 CD, 147 UC, and 28 indeterminate colitis), patients with non-IBD diarrheal illnesses (n = 74), and healthy controls (n = 157). CONCLUSIONS: Specificity of serological markers for IBD is high, but low sensitivity makes them less useful as diagnostic tests. The combination of tests is probably more powerful, although, clinical subgroups still need to be defined.

    10. Utility of Serodiagnostics in Pediatric IBD: Use of a Two-Step Assay Used different algorithm, with more sensitive cutoffs, then traditional testing. Serial testing such as this supposed to increase specificity. Prev=45% Here, SENS=69% spec=95% ppv=90% npv=80% Sens not sig. better (81% overall). Allowed 81% reduction in FP, thus possibly avoiding unneeded testing in some. Other studies had conflicting results Khan K, et al. Inflamm Bowel Dis 2002;8:325 50% new CD pts had serology ASCA+ also often had + routine markers inflammation Accounting for rectal bleeding, markers of inflam and serology, Only 76% identified as possibly having IBD prior to an endoscopy Thus, - serology may not preclude an endoscopic examUsed different algorithm, with more sensitive cutoffs, then traditional testing. Serial testing such as this supposed to increase specificity. Prev=45% Here, SENS=69% spec=95% ppv=90% npv=80% Sens not sig. better (81% overall). Allowed 81% reduction in FP, thus possibly avoiding unneeded testing in some. Other studies had conflicting results Khan K, et al. Inflamm Bowel Dis 2002;8:325 50% new CD pts had serology ASCA+ also often had + routine markers inflammation Accounting for rectal bleeding, markers of inflam and serology, Only 76% identified as possibly having IBD prior to an endoscopy Thus, - serology may not preclude an endoscopic exam

    11. Summary: IBD vs. Functional/healthy pANCA and ASCA are specific for UC and CD respectively Can HELP rule in disease (if high PTP) The moderate sensitivity and low negative predictive value preclude them as a screening test Unable to rule out disease Potential application in pediatric disease to avoid invasive work up Not in recent algorithm North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America

    12. Serology: What is it Good For? Diagnosis IBD vs. Functional/Healthy CD vs. UC Pre-clinical marker Predict disease course or complications in IBD CD and UC phenotype CD and UC progression/aggression Risk of pouchitis after IPAA for UC Following disease activity/treatment response

    13. ASCA for CD vs. UC How did ASCA do? Secondary aim of study that looked at performance of different assays in a known population. Again, if ASCA+, especially in a high-prev population, it is CD. Otherwise, it offers little help. How did ASCA do? Secondary aim of study that looked at performance of different assays in a known population. Again, if ASCA+, especially in a high-prev population, it is CD. Otherwise, it offers little help.

    14. Diagnosis: CD vs. UC 97 IC pts v for ASCA/pANCA and followed17 31/97 (32%) Declared themselves 48% pts had all Abs 85% of these, dx remained IC Adding anti-OmpC and anti-I2 in did not help18 What about ASCA/ANCA? 97 pts w/u extensively for IC, still couldnt tell which. Serology applied, then followed to see if declared. over 9.9 year f/u 32% declared by about 6 years. No more into about 10 yrs f/u (longer IC, longer stay in IC). 1/3 ASCA+/ANCA-, ASCA-/ANCA+, small amount both+, 48% all - What about ASCA/ANCA? 97 pts w/u extensively for IC, still couldnt tell which. Serology applied, then followed to see if declared. over 9.9 year f/u 32% declared by about 6 years. No more into about 10 yrs f/u (longer IC, longer stay in IC). 1/3 ASCA+/ANCA-, ASCA-/ANCA+, small amount both+, 48% all -

    15. Diagnosis: CD vs. UC (IC) 238 UC pts for IPAA had preop serology19 anti-OmpC, anti CBir1, ASCA, pANCA 16 (7%) developed CD after IPAA MV analysis? ASCA+ 3-fold risk CD Glycan panel?gASCA, ALSA, ACCA11 1 Ab+: sens 77%, spec 90%, PPV 91%, NPV 77% 2+ Abs+ increased specificity/PPV At expense of sens/NPV.

    16. Summary: CD vs. UC (IC) Most specific test is combining ASCA/ANCA20, 21 PPV ranges 77-96% in several studies22-24 IC is likely a distinct clinical entity Serology as adjunct Newer markers may help (CBir1) 44% pANCA+ CD. vs 4% of pANCA+ UC pts25 differentiate ANCA+ UC-like CD (CBir1+) from ANCA+ UC (CBir1-) differentiate ANCA+ UC-like CD (CBir1+) from ANCA+ UC (CBir1-)

    17. Prevalence effects on PPV, NPV

    18. Serology Panel: Effects of Prevalence

    19. Serology: What is it Good For? Diagnosis IBD vs. Functional/Healthy CD vs. UC Pre-clinical marker Predict disease course or complications in IBD CD and UC phenotype CD and UC progression/aggression Risk of pouchitis after IPAA for UC Following disease activity/treatment response

    20. Diagnosis: Pre-clinical markers pANCA variably present in UC relatives26-29 ASCA+ in CD relatives 5x more than controls30,31 Study of 40 IBD patients banked sera32 31% of CD pts were ASCA+ prior to dx No ASCA+ controls 25% UC pts were pANCA+ No pANCA+ controls No UC pts were ASCA+ Mean interval from serology to detection was 38 monthsMean interval from serology to detection was 38 months

    21. Serology: What is it Good For? Diagnosis IBD vs. Functional/Healthy CD vs. UC Pre-clinical marker Predict disease course or complications in IBD CD and UC phenotype CD and UC progression/aggression Risk of pouchitis after IPAA for UC Following disease activity/treatment response

    22. Relationship Between Marker Antibodies and CD Cohort Analyzed immune response heterogeneity in 330 pts33 Found ASCA 56%, OmpC 55%, I2 50%, and pANCA 23% Described 4 distinct immune response phenotype clusters ASCA+, OmpC and I2 +, pANCA+, All negative 15-20% had all neg Abs Eighty-five percent responded to at least 1 antigen only 4% responded to all 4 Among microbial antigens, 78% responded to at least 1, and 57% were double positive, but only 26% responded to all 3. The level of response was stable over time and with change in disease activity. Among patients with the same qualitative antigen-response profiles, quantitative response differed. Cluster analysis of these antibody responses yielded 4 groups CONCLUSIONS: Rather than global loss of tolerance, there seem to be patient subsets with differing responses to selected microbial and autoantigens Eighty-five percent responded to at least 1 antigen only 4% responded to all 4 Among microbial antigens, 78% responded to at least 1, and 57% were double positive, but only 26% responded to all 3. The level of response was stable over time and with change in disease activity. Among patients with the same qualitative antigen-response profiles, quantitative response differed. Cluster analysis of these antibody responses yielded 4 groups CONCLUSIONS: Rather than global loss of tolerance, there seem to be patient subsets with differing responses to selected microbial and autoantigens

    23. Antibody Expression Correlates with Clinical Characteristics This study looked at Sera from 156 consecutive CD patients and compared to clinical profiles. higher ASCA levels were shown to be independently associated with early age of disease onset as well as both fibrostenosing and internal penetrating disease behaviours. Higher ANCA levels were associated with later age of onset and ulcerative colitis-like behaviour. This study looked at Sera from 156 consecutive CD patients and compared to clinical profiles. higher ASCA levels were shown to be independently associated with early age of disease onset as well as both fibrostenosing and internal penetrating disease behaviours. Higher ANCA levels were associated with later age of onset and ulcerative colitis-like behaviour.

    24. CD progression/phenotype ASCA+ ? more aggressive, complicated disease Higher levels ? earlier disease onset35,36 In adult CD? FS, IP, SB resection, early surgery34,37-41,45 Higher long-term health care costs46 In peds CD 3x odds relapse in children42 early onset, fistula/abscess recurrence, repeat surgery, SB dz43,44 ASCA+/pANCA- SB involved more often than colon alone34

    25. CD progression/phenotype pANCA+ identifies34,35,47,48 UC-like subgroup, good therapy response , later onset anti-OmpC Levels assoc w/disease progression (non-FS/IP?FS?IP)39,49 Assoc w/FS, IP and SB surgery3, 34,38,47,49 Assoc w/FS, IP in pediatrics44 Anti-I2 assoc w/ FS and SB surgery34,47-8 Anti-CBir1 assoc w/FS, IP dz and SB surgery6,7

    26. Dose response of + Ab in CD Number and level of + Abs correlate w/severity ? immune reactivity may = ? immune tolerance ASCA+/anti-OmpC+anti-I2+ assoc w/? risk vs. all -Abs FS, IP and surgery (3-8x)38 196 pt prospective peds cohort had similar results44 ASCA+/anti-OmpC+/anti-I2+/anti-CBir1+ 11x risk IP or FS w/subsequent surgery if all 4+ vs. all 4- Time to complication significantly less if ANY + Ab Retrospective evaluation of 303 pts Retrospective evaluation of 303 pts

    27. Dose response of + Ab in CD

    28. Dose response of + Ab in CD CD behavior from presence AND level of markers38 Quartile sum (dose-response) of I2, ASCA, OmpC Higher quartiles?higher FS, SB dz, SB surg, IP and lower UC-like

    29. CD progression/phenotype Aggressive pediatric CD predicted by Abs50 If Anti-CBir1+/anti-OmpC+/ASCA+: 6x odds FS, 9x odds IP and 3x odds SB dz Same pattern seen for higher Ab response levels MV analysis Anti-CBir1, anti-OmpC assoc w/IP ASCA, anti-CBir1 assoc. w/FS 797 pt. prospective pediatric CD cohort; assessed for: CARD15 mutations Anti-CBir1, anti-OmpC, ASCA 797 pt. prospective pediatric CD cohort; assessed for: CARD15 mutations Anti-CBir1, anti-OmpC, ASCA

    30. UC progression/phenotype pANCA+ higher probability of severe L-sided dz treatment-resistance aggressive course with earlier surgery51 pouchitis after IPAA35,52 Appears to be dose dependent for cumulative incidence pouchitisAppears to be dose dependent for cumulative incidence pouchitis

    31. Follow-up/treatment response no corr. pANCA+, titer and UC activity49 Titer same after colectomy32 ASCA stable/independent of CD activity32,35,48 ACCA, ALCA stable as well11 No corr. ASCA to anti-TNF response52 Trend to poorer response to ASCA-/pANCA+ pts CD w/anti-OmpC+/I2+ better response to budesonide + Cipro/Flagyl while abs better to budesonide alone54 No ASCA/ANCA relation to TNF in in 279 Belgian CD pts52 Subanalysis of RCT in moderate ileal +/- R colon CD for budesonide/FLagyl No ASCA/ANCA relation to TNF in in 279 Belgian CD pts52 Subanalysis of RCT in moderate ileal +/- R colon CD for budesonide/FLagyl

    32. Summary: progression/phenotype Antibody profiles can predict CD behavior Stratify to therapy regimens Multiple antibodies associated with higher risks pANCA+ associated with pouchitis after IPAA in UC

    33. Conclusion: Serology Helpful if positive in correct population Can help Rule IN disease if high PTP Can help Rule OUT disease if low PTP Diagnostic ADJUNCT Possible alternative in certain populations Future hope for UC vs. CD Pre-clinical? Associated with phenotype/complications

    35. Thiopurine ADRs Dose dependent (usually 2/2 toxic metabolites) Hemotoxicity Leukopenia: 3.8-11.5% Pancytopenia: 0.4-2% Thrombocytopenia: 1.2% Hepatotoxicity: 0.3-9.9% 4.6% of 173 adult IBD patients69 Infections: 7.4-14.1% Malaise, nausea: 11%

    36. Thiopurine ADRs Dose-independent (hypersensitivity) Flu-like symptoms (including fever):2-6.5% GI distress: 4.6% Pancreatitis:1.2-4.9% NRH, HVOD, AIN, pneumonitis: rare/case reports Malignancy:? Purported 4x lymphoma risk in IBD70 Benefits outweigh risks in decision analysis71

    37. Metabolite Monitoring 6-TG corresponds with clinical efficacy while 6-MMP corresponds with hepatotoxicity72-3 Peds clinical efficacy related to 6-TGN > 235 pmol/8x10e8 RBC Hepatotoxicity corr w/6-MMP> 5700 pmol/8x10e8 RBC (3x risk)

    38. Metabolite Monitoring Monitoring of 6-TG + 6-MMP levels may allow prediction of toxicity and guide dose titration Mixed results from studies73,77-8

    39. Metabolite Monitoring: CON No diff in 6-TGN between responders and NR79-82 No diff in 6-TGN between remission and NR78, 81, 83-85

    40. Metabolite Monitoring: PRO Correlation between 6-TG and remission72-3, 86-91 Higher 6-TGN levels assoc. with greater clinical response73, 90, 92-3 Meta-analysis showed higher 6-TG assoc w/sig higher levels remission94 6-TGN >230-260 pmol/8x10e8 RBC more likely to be in remission (OR 3.27, 95% CI 1.71-6.27) Cost-effective analysis suggested MM may decrease costs and improve outcomes vs. usual care95

    41. Metabolite Monitoring Controversy whether monitoring good for predicting toxicity Recent retrospective study reports poor test characteristics of 6-MMP levels in predicting hepatotoxicity at 5,300 and 9,800 cutoffs69

    42. Summary: Metabolite Monitoring Useful in pts not achieving expected results despite appropriate dose and time intervals Very low 6-TG and 6-MMP?noncompliance Very rarely poor absorption form short gut 6-MMP:6-TG>10-11 suggests preferential shunting to 6-MMP Suggests unfavorable metabolism, unlikely to be clinically effective89,96 Suboptimal 6-TG levels (<230-260 pmol/8x10e8 RBC and no shunting to 6-MMP), doses could be pushed to get optimal levels Likely not useful for toxicity

    43. CT Enterography Allows visualization of lumen, mucosa, bowel wall and extraluminal pathology Traditional oral contrast has similar attenuation to enhancing mucosa Multidetector CT scanner 1-2L of Low Houndsfield-unit oral contrast (<30 HU) Water +/- methylcellulose, lactulose, PEG barium/sorbitol (improves distension) Traditional IV contrast

    44. CT Enterography problematic in cases of suspected infection or perforation Fluid collections/abscesses appear similar to bowel Mucosal enhancement on CTE correlates with endoscopically and histologically active mucosal disease97-8

    45. CT Enterography

    46. CT Enterography

    47. CT Enterography

    48. CT Enterography Crohns With Neo-TI & Colonic Disease Better evaluation of colon than with SIFTCrohns With Neo-TI & Colonic Disease Better evaluation of colon than with SIFT

    49. CT Enterography Enteroclysis 100% agreement with surgical findings of fistula and stricture99-100 SBFT Reported 85-95% sensitivity/specificity for identification of stricture, fistula and mucosal abnormalities101 Incorrectly identified stricture number in 31% vs. operative findings102

    51. CT Enterography CTE compared to operative findings in 36 CD patients103 CTE correctly identified 100% strictures (83% accuracy) 100% abscesses 94% fistulae (86% accuracy for # fistulae) 97% inflammatory mass Overestimated or underestimated disease extent in 31% Stricture, fistula, inflammatory mass, abscess counts

    52. Chromoendoscopy (CE) Conventional Colonoscopy (CC) surveillance 2-4 bx every 10cm in colon, q5cm in rectum Known miss rates for even for visible exophytic lesions Tandem endoscopy studies? 15-24% adenomas <1 cm missed55-6 Similar results for colectomy specimens vs. preop colonoscopy57

    53. Chromoendoscopy (CE) Flat and depressed lesions have premalignant importance58 Can look like normal mucosa endoscopically (easy miss) Depressed can become invasive early on Only 20-50% intraepithelial neoplasia detected with CC59 Even miss rate for CRC 4% CRC colectomy pts had normal colonoscopy in preop 6-36mo60

    54. Chromoendoscopy (CE) Chromo= dyes applied to mucosa during endoscopy highlight and better characterize specific mucosal changes Allows visualization of otherwise invisible mucosal changes enhancing detection and accuracy Absorptive, reactive, and contrast staining dyes Indigo carmine: nonabsorbed; collects in mucosal depressions Methylene blue: absorbed in normal cytoplasm; irregularities pale Cresyl violet: taken up in crypts of Leibeukuhn; appears as dots/pits. Pit patterns have histologic correlates. Can be used with the above 2 stains

    55. Chromoendoscopy (CE) CC poorly detects flat/depressed lesions Requires more meticulous training and examination Chromo +/- mag. ? detection of flat/raised neoplasia In R colon and in pts w/multiple adenomas61 In non-IBD pts with hx adenomas62 In screening population adenomas randomized to CC vs. CE63 Better detection of adenomas with pan-CE (espec. diminutive lesions) 259 pts randomized to CC vs CE (indigo carmine) 995 consecutive patients evaluated with CC vs indigo-carmine CE+mag. 260 pts randomized to pan-CE vs. targeted CE 259 pts randomized to CC vs CE (indigo carmine) 995 consecutive patients evaluated with CC vs indigo-carmine CE+mag. 260 pts randomized to pan-CE vs. targeted CE

    56. Chromoendoscopy in IBD HRCE? better detection (esp. flat) in 85 UC patients64 165 UC pts randomized to CC vs CE65 CE better an defining degree/extent inflammation CE better at dysplasia detection than CC (32 v 10 lesions) 100 UC surveillance pts got sequential CC and CE65 Pan-CE with target bx after standard CC bx protocol CC: ALL 2,904 random bx neg; 2/43 target bx?dysplasia CE: 7/114 target bx?dysplasia 165 UC pts: methylene blue165 UC pts: methylene blue

    57. Chromoendoscopy in IBD 350 UC pts had HMCE matched to UC controls w/CC66 Target bx AND 4-quadrant randoms HMCE Detected sig. more lesions Alone detected 79% of dysplasia 0.16% random bx + 8% targeted bx + CC 0.14% random bx + 1.6% target bx + Suggests random bx not very efficient Suggests random bx not very efficient

    58. Chromoendoscopy in IBD Dye spraying adds about 10 minutes to colonoscopy67 Abandoning random bx will shorten procedure Should be pretty even in terms of time after learning curve Recent CCFA committee on IBD CRC/dysplasia surveillance endorses CE in appropriately trained endoscopists68

    59. Rectal EUS 20-30% CD develop perianal disease103 Diagnostics include MRI, fistolography (radiating, inaccurate vs surgery, painful, cannot delineate relation to perianal structures), CT (radiating, limited for fistula), EUA EUS has emerging role Accurate imaging of perianal region preoperatively Road-mapping; theoretically reduce risk incontinence Therapeutic (abscess drainage) Safe Can assess response to therapy Superficial fistula closure may not herald deep tract closure No radiation

    60. Rectal EUS Can accurately delineate EAS, IAS, and pathologic defects Identified 82% fistula c/w EUA in unblinded series Better performance than fistulography105 EUS detected 82% fistula vs 24% by CT c/w EUA+fistulography No difference in abscess detection106 Anal endosonography (AES) 100% sensitive vs. 55% for MRI in detecting perianal abscesses found at EUA AES 89% sensitive vs. 48% for MRI in fistula detection107

    61. Rectal EUS Prospective, blinded study of EUS, MRI, EUA vs. consensus gold standard Accuracy EUS 91%, MRI 87%, EUA 91% Combination of any 2 modalities increased accuracy to 100%108 To assess medical response: IFX trial: AES at entry and 10 weeks in 30 perianal CD pts109 54% had week 10 clinical closure; only 18% closed by AES Those with week 10 closure on AES had sig. lower relapse rates 21 perianal CD pts with baseline, serial EUS during surgical/medical rx110 52% showed no persistent fistula activity; 64% of these able to stop rx

    62. Rectal EUS Future: Contrast-enhanced EUS: 3% Hydrogen peroxide 3D-EUS Both methods likely comparable111

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