Spectral biomarkers for chemoprevention of colonic neoplasia: a placebo-controlled double-blinded trial with aspirin.

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.

Giant Omphalocele Complicated by 9P Minus Syndrome.

Omphalocele is characterized as a ventral wall defect in which there exists a midline herniation of abdominal viscera into the base of the umbilical cord. Fetuses with a diagnosis of this entity are at a significantly increased risk of having an aneuploidy, additional anomalies, or associations with other syndromes such as Beckwith Wiederman. Secondary to these interconnections, there is an elevated risk of fetal loss in affected pregnancies. Detection of concordant abnormalities, appropriate genetic counseling, and involvement of pediatric subspecialties are paramount in affording a prognosis, and providing optimal perinatal management of omphalocele.

Optical measurement of rectal microvasculature as an adjunct to flexible sigmoidosocopy: gender-specific implications.

Flexible sigmoidoscopy is a robust, clinically validated, and widely available colorectal cancer screening technique that is currently sanctioned by major guideline organizations. Given that endoscopic visualization is generally limited to the distal third of the colon and women tend to have a proclivity for proximal lesions, the flexible sigmoidoscopy performance is markedly inferior in women than in men. Our group has shown that by using a novel light-scattering approach, we were able to detect an early increase in blood supply (EIBS) in the distal colonic mucosa, which served as a marker of field carcinogenesis and, hence, proximal neoplasia. Therefore, we sought to ascertain whether rectal EIBS would improve flexible sigmoidoscopy, especially in women. A polarization-gated spectroscopy fiber-optic probe was used to assess EIBS in the endoscopically normal rectum (n = 366). When compared with gender-matched neoplasia-free controls, females with advanced proximal neoplasia (n = 10) had a robust (60%; P = 0.002) increase in rectal mucosal oxyhemoglobin content whereas the effect size in males was less marked (33%; P = 0.052). In women, addition of rectal oxyhemoglobin tripled the sensitivity for advanced neoplasia over flexible sigmoidoscopy alone. Indeed, the performance characteristics seemed to be excellent (sensitivity, 100%; specificity, 76.8%; positive predictive value, 32.6%; and negative predictive value, 100%). A variety of nonneoplastic factors were assessed and did not confound the relationship between rectal EIBS and advanced neoplasia. Therefore, using rectal EIBS in combination with flexible sigmoidoscopy mitigated the gender gap and may allow flexible sigmoidoscopy to be considered as a viable colorectal cancer screening test in women.

Optical detection of buccal epithelial nanoarchitectural alterations in patients harboring lung cancer: implications for screening.

We have recently developed a novel optical technology, partial wave spectroscopic (PWS) microscopy, which is exquisitely sensitive to the nanoarchitectural manifestation of the genetic/epigenetic alterations of field carcinogenesis. Our approach was to screen for lung cancer by assessing the cheek cells based on emerging genetic/epigenetic data which suggests that the buccal epithelium is altered in lung field carcinogenesis. We performed PWS analysis from microscopically normal buccal epithelial brushings from smokers with and without lung cancer (n = 135). The PWS parameter, disorder strength of cell nanoarchitecture (L(d)), was markedly (>50%) elevated in patients harboring lung cancer compared with neoplasia-free smokers. The performance characteristic was excellent with an area under the receiver operator characteristic curve of >0.80 and was equivalent for both disease stage (early versus late) and histologies (small cell versus non-small cell lung cancers). An independent data set validated the findings with only a minimal degradation of performance characteristics. Our results offer proof of concept that buccal PWS may potentially herald a minimally intrusive prescreening test that could be integral to the success of lung cancer population screening programs.

Nanoscale cellular changes in field carcinogenesis detected by partial wave spectroscopy.

Understanding alteration of cell morphology in disease has been hampered by the diffraction-limited resolution of optical microscopy (>200 nm). We recently developed an optical microscopy technique, partial wave spectroscopy (PWS), which is capable of quantifying statistical properties of cell structure at the nanoscale. Here we use PWS to show for the first time the increase in the disorder strength of the nanoscale architecture not only in tumor cells but also in the microscopically normal-appearing cells outside of the tumor. Although genetic and epigenetic alterations have been previously observed in the field of carcinogenesis, these cells were considered morphologically normal. Our data show organ-wide alteration in cell nanoarchitecture. This seems to be a general event in carcinogenesis, which is supported by our data in three types of cancer: colon, pancreatic, and lung. These results have important implications in that PWS can be used as a new method to identify patients harboring malignant or premalignant tumors by interrogating easily accessible tissue sites distant from the location of the lesion.