OBJECTIVE: A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy. DESIGN: We conducted a multicentre, prospective, randomised, double-blind placebo-controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325 mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3 months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints. RESULTS: At 3 months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirin's pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=-0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention. CONCLUSIONS: We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice. TRIAL NUMBER: NCT00468910. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
RCT Entities:
OBJECTIVE: A major impediment to translating chemoprevention to clinical practice has been lack of intermediate biomarkers. We previously reported that rectal interrogation with low-coherence enhanced backscattering spectroscopy (LEBS) detected microarchitectural manifestations of field carcinogenesis. We now wanted to ascertain if reversion of two LEBS markers spectral slope (SPEC) and fractal dimension (FRAC) could serve as a marker for chemopreventive efficacy. DESIGN: We conducted a multicentre, prospective, randomised, double-blind placebo-controlled, clinical trial in subjects with a history of colonic neoplasia who manifested altered SPEC/FRAC in histologically normal colonic mucosa. Subjects (n=79) were randomised to 325 mg aspirin or placebo. The primary endpoint changed in FRAC and SPEC spectral markers after 3 months. Mucosal levels of prostaglandin E2 (PGE2) and UDP-glucuronosyltransferase (UGT)1A6 genotypes were planned secondary endpoints. RESULTS: At 3 months, the aspirin group manifested alterations in SPEC (48.9%, p=0.055) and FRAC (55.4%, p=0.200) with the direction towards non-neoplastic status. As a measure of aspirin's pharmacological efficacy, we assessed changes in rectal PGE2 levels and noted that it correlated with SPEC and FRAC alterations (R=-0.55, p=0.01 and R=0.57, p=0.009, respectively) whereas there was no significant correlation in placebo specimens. While UGT1A6 subgroup analysis did not achieve statistical significance, the changes in SPEC and FRAC to a less neoplastic direction occurred only in the variant consonant with epidemiological evidence of chemoprevention. CONCLUSIONS: We provide the first proof of concept, albeit somewhat underpowered, that spectral markers reversion mirrors antineoplastic efficacy providing a potential modality for titration of agent type/dose to optimise chemopreventive strategies in clinical practice. TRIAL NUMBER: NCT00468910. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: James D Lewis; Kimmie Ng; Kenneth E Hung; Warren B Bilker; Jesse A Berlin; Colleen Brensinger; Anil K Rustgi Journal: Arch Intern Med Date: 2003-02-24
Authors: Paul F Pinsky; James Fleshman; Matt Mutch; Christopher Rall; Aline Charabaty; David Seligson; Sarah Dry; Asad Umar; Robert E Schoen Journal: Cancer Prev Res (Phila) Date: 2010-06-22
Authors: Terryl J Hartman; Binbing Yu; Paul S Albert; Martha L Slattery; Electra Paskett; James Walter Kikendall; Frank Iber; Brenda K Brewer; Arthur Schatzkin; Elaine Lanza Journal: Cancer Epidemiol Biomarkers Prev Date: 2005-10 Impact factor: 4.254
Authors: Aasma Shaukat; Steven J Mongin; Mindy S Geisser; Frank A Lederle; John H Bond; Jack S Mandel; Timothy R Church Journal: N Engl J Med Date: 2013-09-19 Impact factor: 91.245
Authors: Elizabeth L Barry; Leah B Sansbury; Maria V Grau; Iqbal U Ali; Shirley Tsang; David J Munroe; Dennis J Ahnen; Robert S Sandler; Fred Saibil; Jiang Gui; Robert S Bresalier; Gail E McKeown-Eyssen; Carol Burke; John A Baron Journal: Cancer Epidemiol Biomarkers Prev Date: 2009-09-15 Impact factor: 4.254
Authors: Frank A Sinicrope; Elizabeth Half; Jeffrey S Morris; Patrick M Lynch; Jason D Morrow; Bernard Levin; Ernest T Hawk; Deborah S Cohen; Gregory D Ayers; L Clifton Stephens Journal: Cancer Epidemiol Biomarkers Prev Date: 2004-06 Impact factor: 4.254
Authors: Yolanda Stypula-Cyrus; Nikhil N Mutyal; Mart Dela Cruz; Dhananjay P Kunte; Andrew J Radosevich; Ramesh Wali; Hemant K Roy; Vadim Backman Journal: FEBS Lett Date: 2014-02-01 Impact factor: 4.124
Authors: Hemant K Roy; Patrick Iversen; John Hart; Yang Liu; Jennifer L Koetsier; Young Kim; Dhanajay P Kunte; Madhavi Madugula; Vadim Backman; Ramesh K Wali Journal: Mol Cancer Ther Date: 2004-09 Impact factor: 6.261
Authors: Keisuke Kosumi; Yohei Masugi; Juhong Yang; Zhi Rong Qian; Sun A Kim; Wanwan Li; Yan Shi; Annacarolina da Silva; Tsuyoshi Hamada; Li Liu; Mancang Gu; Tyler S Twombly; Yin Cao; David A Barbie; Katsuhiko Nosho; Hideo Baba; Wendy S Garrett; Jeffery A Meyerhardt; Edward L Giovannucci; Andrew T Chan; Charles S Fuchs; Shuji Ogino; Reiko Nishihara Journal: Oncoimmunology Date: 2017-01-31 Impact factor: 8.110
Authors: Yin Cao; Reiko Nishihara; Zhi Rong Qian; Mingyang Song; Kosuke Mima; Kentaro Inamura; Jonathan A Nowak; David A Drew; Paul Lochhead; Katsuhiko Nosho; Teppei Morikawa; Xuehong Zhang; Kana Wu; Molin Wang; Wendy S Garrett; Edward L Giovannucci; Charles S Fuchs; Andrew T Chan; Shuji Ogino Journal: Gastroenterology Date: 2016-07-27 Impact factor: 22.682
Authors: Shuji Ogino; Jonathan A Nowak; Tsuyoshi Hamada; Amanda I Phipps; Ulrike Peters; Danny A Milner; Edward L Giovannucci; Reiko Nishihara; Marios Giannakis; Wendy S Garrett; Mingyang Song Journal: Gut Date: 2018-02-06 Impact factor: 23.059
Authors: Shuji Ogino; Jonathan A Nowak; Tsuyoshi Hamada; Danny A Milner; Reiko Nishihara Journal: Annu Rev Pathol Date: 2018-08-20 Impact factor: 23.472
Authors: Yohei Masugi; Reiko Nishihara; Juhong Yang; Kosuke Mima; Annacarolina da Silva; Yan Shi; Kentaro Inamura; Yin Cao; Mingyang Song; Jonathan A Nowak; Xiaoyun Liao; Katsuhiko Nosho; Andrew T Chan; Marios Giannakis; Adam J Bass; F Stephen Hodi; Gordon J Freeman; Scott Rodig; Charles S Fuchs; Zhi Rong Qian; Shuji Ogino Journal: Gut Date: 2016-05-05 Impact factor: 23.059
Authors: David A Drew; Samantha M Chin; Katherine K Gilpin; Melanie Parziale; Emily Pond; Madeline M Schuck; Kathleen Stewart; Meaghan Flagg; Crystal A Rawlings; Vadim Backman; Peter J Carolan; Daniel C Chung; Francis P Colizzo; Matthew Freedman; Manish Gala; John J Garber; Curtis Huttenhower; Dmitriy Kedrin; Hamed Khalili; Douglas S Kwon; Sanford D Markowitz; Ginger L Milne; Norman S Nishioka; James M Richter; Hemant K Roy; Kyle Staller; Molin Wang; Andrew T Chan Journal: Trials Date: 2017-02-01 Impact factor: 2.279
Authors: Scott Gladstein; Dhwanil Damania; Luay M Almassalha; Lauren T Smith; Varun Gupta; Hariharan Subramanian; Douglas K Rex; Hemant K Roy; Vadim Backman Journal: Cancer Med Date: 2018-03-23 Impact factor: 4.452
Authors: Parambir S Dulai; Siddharth Singh; Evelyn Marquez; Rohan Khera; Larry J Prokop; Paul J Limburg; Samir Gupta; Mohammad Hassan Murad Journal: BMJ Date: 2016-12-05
Authors: Shuji Ogino; Iny Jhun; Douglas A Mata; Thing Rinda Soong; Tsuyoshi Hamada; Li Liu; Reiko Nishihara; Marios Giannakis; Yin Cao; JoAnn E Manson; Jonathan A Nowak; Andrew T Chan Journal: NPJ Precis Oncol Date: 2017-12-06