Nahla Hasabou

Spectroscopic Microvascular Blood Detection From the Endoscopically Normal Colonic Mucosa: Biomarker for Neoplasia Risk

BACKGROUND & AIMS We previously used a novel biomedical optics technology, 4-dimensional elastically scattered light fingerprinting, to show that in experimental colon carcinogenesis the predysplastic epithelial microvascular blood content is increased markedly. To assess the potential clinical translatability of this putative field effect marker, we characterized the early increase in blood supply (EIBS) in human beings in vivo. METHODS We developed a novel, endoscopically compatible, polarization-gated, spectroscopic probe that was capable of measuring oxygenated and deoxygenated (Dhb) hemoglobin specifically in the mucosal microcirculation through polarization gating. Microvascular blood content was measured in 222 patients from the endoscopically normal cecum, midtransverse colon, and rectum. If a polyp was present, readings were taken from the polyp tissue along with the normal mucosa 10-cm and 30-cm proximal and distal to the lesion. RESULTS Tissue phantom studies showed that the probe had outstanding accuracy for hemoglobin determination (r(2) = 0.99). Augmentation of microvasculature blood content was most pronounced within the most superficial ( approximately 100 microm) layer and dissipated in deeper layers (ie, submucosa). EIBS was detectable within 30 cm from the lesion and the magnitude mirrored adenoma proximity. This occurred for both oxygenated hemoglobin and DHb, with the effect size being slightly greater for DHb. EIBS correlated with adenoma size and was not engendered by nonneoplastic (hyperplastic) polyps. CONCLUSIONS We show, herein, that in vivo microvascular blood content can be measured and provides an accurate marker of field carcinogenesis. This technological/biological advance has numerous potential applications in colorectal cancer screening such as improved polyp detection and risk stratification.

Optical Markers in Duodenal Mucosa Predict the Presence of Pancreatic Cancer

Purpose: Pancreatic cancer remains one of the most deadly cancers and carries a dismal 5-year survival rate of <5%. Therefore, there is urgent need to develop a highly accurate and minimally invasive (e.g., without instrumentation of the pancreatic duct given high rate of complications) method of detection. Our group has developed a collection of novel light-scattering technologies that provide unprecedented quantitative assessment of the nanoscale architecture of the epithelium. We propose a novel approach to predict pancreatic cancer through the assessment of the adjacent periampullary duodenal mucosa without any interrogation of the pancreatic duct or imaging of the pancreas. Experimental Design: Endoscopically and histologically normal-appearing periampullary duodenal biopsies obtained from 19 pancreatic cancer patients were compared with those obtained at endoscopy from 32 controls. Biopsies were analyzed using our newly developed optical technologies, four-dimensional elastic light-scattering fingerprinting (4D-ELF) and low-coherence enhanced backscattering (LEBS) spectroscopy. Results: 4D-ELF– and LEBS-derived optical markers from normal-appearing periampullary duodenal mucosa can discriminate between pancreatic cancer patients and normal controls with 95% sensitivity and 91% specificity. Moreover, the diagnostic performance of these optical markers was not compromised by confounding factors such as tumor location and stage. Conclusions: Here, we showed, for the first time, that optical analysis of histologically normal duodenal mucosa can predict the presence of pancreatic cancer without direct visualization of the pancreas.

Investigating population risk factors of pancreatic cancer by evaluation of optical markers in the duodenal mucosa

Pancreatic cancer screening has been hampered by the high rate of complications associated with interrogating the pancreas. The closest non-invasively accessible mucosa available for pancreatic cancer screening is the periampullary duodenal tissue. Our earlier report has shown the potential of using optical markers to interrogate this tissue for the presence of pancreatic cancer. In this study, we report a larger data set of low-coherence enhanced backscattering (LEBS) and elastic light scattering fingerprinting (ELF) optical markers from the periampullary duodenal mucosa. Optical measurements from biopsy samples were acquired from a total of 203 patients with varying clinical classification including healthy controls, a family history of pancreatic cancer, pancreatitis, mucinous cystic precursor lesions, pancreatic cancer, and other pancreatic malignancies. Evaluation of the performance of an independent testing set for discriminating healthy control patients from pancreatic cancer patients showed a 95% sensitivity, 71% specificity, and 85% area under the receiver operator characteristic (AUROC) curve. Importantly, this performance was uncompromised for detecting potentially curable stages of the disease. Additionally, optical markers in higher risk populations such as family history and pancreatitis had values between those of healthy control and pancreatic cancer patients, thus allowing for future investigations of screening from these high risk groups.

Spectral Slope from the Endoscopically-Normal Mucosa Predicts Concurrent Colonic Neoplasia: A Pilot Ex-Vivo Clinical Study

PurposeWe previously reported that analysis of histologically normal intestinal epithelium for spectral slope, a marker for aberrations in nanoscale tissue architecture, had outstanding accuracy in identifying field carcinogenesis in preclinical colorectal cancer models. In this study, we assessed the translatability of spectral slope analysis to human colorectal cancer screening.MethodsSubjects (n = 127) undergoing colonoscopy had spectral slope determined from two endoscopically normal midtransverse colonic biopsies using four-dimensional elastic light-scattering fingerprinting and correlated with clinical findings.ResultsFour-dimensional elastic light-scattering fingerprinting analysis showed the submicron particles size progressively shifted toward larger sizes in subjects harboring neoplasia. There was a corresponding decrease in spectral slope values from the endoscopically normal mucosa in subjects harboring adenomas (n = 41) and advanced adenomas (n = 10), compared to neoplasia-free subjects (P ≤ 0.00001). These factors did not appear to be confounded by either age or adenoma location. For detecting advanced adenomas, spectral slope had a negative and positive predictive value of 95 percent and 50 percent respectively.ConclusionsWe demonstrate, for the first time, that spectral slope in “normal” mucosa can accurately risk-stratify patients for colonic neoplasia. This proof of concept study serves to underscore the promise of four-dimensional elastic light-scattering fingerprinting analysis for colorectal cancer screening.

750 Identification of Inherited Predisposition to Colonic Neoplasia Through Partial Wave Spectroscopic Analysis of the Microscopically Normal Colonic Epithelium

While familial risk comprises ~20-30% of all colorectal cancers (CRC), in most cases the genetic etiology is not readily identifiable. Thus, counselling CRC-prone families members is not based on individized risk assessment (e.g. one size fits all approach). Our group has developed novel light scattering technologies such as partial wave spectroscopy (PWS)to quantitate nanoscale architecture. We have noted that pre-dysplastic mucosal optical signatures provided a highly sensitive means of detecting CRC risk in experimental models(Gastro 2004, CEBP 2005, Clin Cancer Res 2006). Moreover, the PWS parameter, disorder strength (Ld), was markedly elevated in the endoscopically normal rectal mucosa of patients harboring adenomas (i.e. “field effect”). We now explore whether colonic Ld could detect a genetic predisposition to CRC. Methods: Animal studies: MIN (murine model of FAP with APC gene mutation) or age-matched wildtype mice were euthanized and had intestinal brushings taken of neoplasia-free areas Human Studies 35 patients with HNPCC mutation-confirmed (hMLH-1&hMSH-2),adenoma-free or controls (age-matched but no personal/family history) had rectal brushings taken during colonoscopy. PWS analysis: Ld and standard deviation of Ld (SDLd) were calculated by investigator blinded to clinical findings Results Ld was markedly elevated in the normal mucosa of germline carriers when compared to controls (figure). This, coupled with SDLd, allowed clear descrimination between cases and controls(both murine and human model. Conclusions: Ld and SDLd from the visually normal mucosa identified APC and hMLH1/hMSH2 mutations prior to phenotype development. Thus, probing nanoscale perturbations from readily accessible mucosa (e.g. rectum) may provide a modality for determing both the carriage of these syndromic mutations and possibly allow detection of the more common lower penetrant CRC risk genes.