Publications by authors named "Catherine Poh"

66 Publications

Prognostic value and cost benefit of HPV testing for oropharyngeal cancer patients.

Oral Dis 2021 Jun 15. Epub 2021 Jun 15.

Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada.

Objectives: High-risk human papillomavirus (HR-HPV) can cause oropharyngeal squamous cell carcinoma (OpSCC). The revised 8 edition of the AJCC Staging Manual now stages OpSCC by incorporating p16 immunohistochemistry (IHC), the surrogate marker for HPV status. This study assessed the prognostic values of p16 and HPV markers.

Methods: We identified 244 OpSCC patients diagnosed between 2000-2008 from the British Columbia Cancer Registry with enough tissue to conduct experiments. Formalin-fixed, paraffin-embedded tissue sections were stained for p16 IHC, RNA in situ hybridization (ISH) HPV 16 and 18, and DNA ISH HR-HPV. Electronic charts were reviewed to collect clinical and outcome data. Combined positive RNA and/or DNA ISH was used to denote HPV status.

Results: HPV was positive among 77.9% of samples. Using HPV as the benchmark, p16 IHC had high sensitivity (90.5%), but low specificity (68.5%). Distinct subgroups of patients were identified by sequential separation of p16 then HPV status. Among both p16-positive and p16-negative groups, HPV-positive patients were younger, more males, and had better clinical outcomes, especially 5-year overall survival. We further evaluated the technical costs associated with HPV testing.

Conclusion: HPV is more prognostic than p16 for OpSCC. Clinical laboratories can adopt HPV RNA ISH for routine analysis.
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http://dx.doi.org/10.1111/odi.13938DOI Listing
June 2021

An improved algorithm using a Health Canada-approved DNA-image cytometry system for non-invasive screening of high-grade oral lesions.

J Oral Pathol Med 2021 May 3;50(5):502-509. Epub 2021 Feb 3.

Faculty of Dentistry, Oral Medical and Biological Sciences, The University of British Columbia, Vancouver, BC, Canada.

Background: DNA-image cytometry (DNA-ICM) is able to detect gross alterations of cellular DNA-content representing aneuploidy, a biomarker of malignancy. A Health Canada-approved DNA-ICM system, ClearCyte in combination with a cytopathologist's review, has demonstrated high sensitivity (89%) and specificity (97%) in identifying high-grade oral lesions. The study objective was to create an improved automated algorithm (iClearcyte) and test its robustness in differentiating high grade from benign reactive oral lesions without a cytopathologist's input.

Methods: A set of 214 oral brushing samples of oral cancer (n = 92), severe dysplasia (n = 20), reactive lesions (n = 52), and normal samples (n = 50) were spun down onto slides and stained using Feulgen-Thionin reaction. Following ClearCyte scan, nuclear features were calculated, and nuclei categorized into "diploid," "hyperdiploid," "tetraploid," and "aneuploid" DNA ploidy groups by the ClearCyte software. The samples were randomized into training and test sets (70:30) based on patient's age, sex, tobacco use, and lesion site risk. The training set was used to create a new algorithm which was then validated using the remaining samples in the test set, where sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated.

Results: The proposed iClearCyte algorithm (>1 "aneuploid" cell or ≥ 1.7% combined "hyperdiploid" and "tetraploid" nuclei frequency) identified high-grade samples with sensitivity, specificity, PPV, and NPV of 100.0%, 86.7%, 89.7%, and 100.0%, respectively, in the test set.

Conclusion: The iClearCyte test has potential to serve as a robust non-invasive automated oral cancer screening tool promoting early oral cancer detection and decreasing the number of unnecessary invasive biopsies.
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http://dx.doi.org/10.1111/jop.13149DOI Listing
May 2021

Effect of Fluorescence Visualization-Guided Surgery on Local Recurrence of Oral Squamous Cell Carcinoma: A Randomized Clinical Trial.

JAMA Otolaryngol Head Neck Surg 2020 12;146(12):1149-1155

Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada.

Importance: High local recurrence rates with aggressive disease remain the main concern in oral cancer survival. Use of a translational device using fluorescence visualization (FV) approved by the US Food and Drug Administration and Health Canada, has shown a marked reduction in the 3-year local recurrence rate of high-grade oral lesions in a single-center observational study.

Objective: To determine whether FV- guided surgery can improve local control rates in the treatment of in situ or T1 to T2 category oral squamous cell carcinoma (OSCC).

Design, Setting, And Participants: A multicenter randomized clinical trial was conducted in a surgical setting. A total of 457 patients were enrolled between January 18, 2010, and April 30, 2015. Data analysis of the intention-to-treat population was performed from April 3, 2019, to March 20, 2020. Patients with histologically confirmed high-grade dysplasia/carcinoma in situ or T1 to T2 category OSCC were randomized to receive traditional peroral surgery or FV-guided surgery.

Intervention: Fluorescence visualization during surgery.

Main Outcomes And Measures: The primary outcome was local recurrence of OSCC. Secondary outcomes were failure of the first-pass margin, defined as a histologically confirmed positive margin for severe dysplasia or greater histologic change of the main specimen (ie, not the margins taken from the resection bed), regional or distant metastasis, and death due to disease.

Results: Of the 457 patients enrolled in the study, 443 patients (264 [59.6%] men; mean [SD] age, 61.5 [13.3] years) completed the randomized treatment: 227 FV-guided and 216 non-FV guided surgery. The median follow-up was 52 (range, 0.29-90.8) months. In total, 45 patients (10.2%) experienced local recurrence. The 3-year local recurrence rate was 9.4% in the FV-guided group and 7.2% in the non-FV group (difference, 2.2%; 95% CI, -3.2% to 7.4%). Other similarities between the FV vs non-FV groups included failure of first-pass margin (68/227 [30.0%]) vs 65/216 [30.1%]), regional failure (39/227 [17.2%] vs 37/216 [17.1%]), disease-specific survival (23/227 [10.1%] vs 19/26 [8.8%]), and overall survival (41/227 [18.1%] vs 38/216 [17.6%]) were also similar between groups. No adverse events were judged to be related to the intervention.

Conclusions And Relevance: In this randomized clinical trial, FV-guided surgery did not improve local control rates in the treatment of patients with in situ or T1 to T2 category oral cancer. Under a controlled environment, FV-guided surgery did not have an evident effect in reduction of local recurrence for localized OSCC. This result suggests that attention be directed to strategies other than improving definitions of nonapparent disease at clinical margins to identify the sources of local recurrence.

Trial Registration: ClinicalTrial.gov Identifier: NCT01039298.
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http://dx.doi.org/10.1001/jamaoto.2020.3147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545352PMC
December 2020

Tumor microRNA profile and prognostic value for lymph node metastasis in oral squamous cell carcinoma patients.

Oncotarget 2020 Jun 9;11(23):2204-2215. Epub 2020 Jun 9.

Department of Oral Medical and Biological Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, Canada.

Neck lymph node metastasis (LN+) is one of the most significant prognostic factors affecting 1-in-2 patients diagnosed with oral squamous cell carcinoma (OSCC). The different LN outcomes between clinico-pathologically similar primary tumors suggest underlying molecular signatures that could be associated with the risk of nodal disease development. MicroRNAs (miRNAs)are short non-coding molecules that regulate the expression of their target genes to maintain the balance of cellular processes. A plethora of evidence has indicated that aberrantly expressed miRNAs are involved in cancers with either an antitumor or oncogenic role. In this study, we characterized miRNA expression among OSCC fresh-frozen tumors with known outcomes of nodal disease (82 LN+, 76 LN0). We identified 49 differentially expressed miRNAs in tumors of the LN+ group. Using penalized lasso Cox regression, we identified a group of 10 miRNAs of which expression levels were highly associated with nodal-disease free survival. We further reported a 4-miRNA panel (miR-21-5p, miR-107, miR-1247-3p, and miR-181b-3p) with high accuracy in discriminating LN status, suggesting their potential application as prognostic biomarkers for nodal disease.
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http://dx.doi.org/10.18632/oncotarget.27616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289532PMC
June 2020

Oral cancer in a 5-year-old boy: a rare case report and review of literature.

Oral Surg Oral Med Oral Pathol Oral Radiol 2020 Jul 17;130(1):e10-e19. Epub 2020 Apr 17.

Professor, Faculty of Dentistry, University of British Columbia; Oral and Maxillofacial Pathologist, Vancouver General Hospital, Vancouver, BC, Canada. Electronic address:

Oral cancer in children is rare. Diagnosis may be delayed as a result of confusion with reactive lesions. Furthermore, cancer staging, with or without bony invasion, can be complicated during tooth eruption. Literature on pediatric oral cancers is lacking, making determination of the possible etiopathology difficult. We describe an exceptional case of a 5-year-old male child who presented with anterior maxillary gingival pseudoepitheliomatous hyperplasia that progressed to carcinoma cuniculatum with invasive oral squamous cell carcinoma (OSCC). Because of the interesting timing of events, we hypothesize that human papillomavirus (HPV) inoculation through cutaneous squamous papilloma played a contributory role. A review of similar case reports in the literature is included. Biopsy of suspicious oral lesions should not be delayed because of the young age of the patient. Atypical hyperplasia should include squamous cell carcinoma (SCC) in the differential diagnoses. For surgical management of aggressive lesions during the mixed dentition, permanent successors should be included in the surgical margins to prevent recurrence.
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http://dx.doi.org/10.1016/j.oooo.2019.12.005DOI Listing
July 2020

Gene Expression Profiling of Head and Neck Tumors Identifies FOXP1 and SOX10 Expression as Useful for Distinguishing Ameloblastoma From Basaloid Salivary Gland Tumors.

Am J Surg Pathol 2020 05;44(5):665-672

Department of Pathology, Stanford University School of Medicine, Stanford.

Odontogenic tumors show considerable morphologic heterogeneity and at times the diagnosis can be challenging. Ameloblastoma, the most common odontogenic tumor, can have morphologic similarity to some salivary gland tumors and therefore we sought to identify biomarkers that might aid in the diagnosis by performing transcriptome wide gene expression profiling of 80 odontogenic and salivary gland neoplasms. These data identified the FOXP1/SOX10 expression profile as characteristic of many odontogenic tumors including ameloblastoma but largely absent in salivary gland tumors. We then assessed 173 salivary gland tumors and 108 odontogenic tumors by immunohistochemistry for FOXP1 and SOX10 expression and found that 34/35 (97%) cases of ameloblastomas were diffusely positive for FOXP1 but completely negative for SOX10. None of the basaloid salivary neoplasms (basal cell adenoma, adenoid cystic carcinoma, polymorphous adenocarcinoma, and myoepitheloma) demonstrated FOXP1/SOX10 expression pattern. Taken together, the results of this study suggest that the FOXP1/SOX10 immunophenotype is common in odontogenic tumors including ameloblastoma and might be useful distinguishing these from similar appearing basaloid salivary gland tumors.
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http://dx.doi.org/10.1097/PAS.0000000000001421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156310PMC
May 2020

Salivary Sialadenoma Papilliferum Consists of Two Morphologically, Immunophenotypically, and Genetically Distinct Subtypes.

Head Neck Pathol 2020 Jun 31;14(2):489-496. Epub 2019 Aug 31.

Department of Dentistry, National Taiwan University Hospital, No. 1, Changde St., Zhongzheng Dist., Taipei City, 100, Taiwan, ROC.

Papillary salivary gland neoplasms are rare tumors usually arising in the minor salivary glands of the oral cavity. Their classification has been historically confusing due to overlapping histologic features, but molecular analysis may clarify these entities. Sialadenoma papilliferum (SP) is a peculiar member of this group that demonstrates both an endophytic ductal and an exophytic squamous component. SP closely resembles syringocystadenoma papilliferum of the skin, a tumor which has recently been shown to harbor BRAF V600E or HRAS mutations. We sought to perform histologic and immunophenotypic analysis of a group of SP, along with BRAF and HRAS mutational analysis. We collected 13 SP cases from 7 females and 6 males ranging from 2 to 91 years (mean 62.8). Five exophytic ductal papillomas were also analyzed as controls. Histological analysis was performed along with immunohistochemistry for CK7, p63, and SOX10. BRAF VE1 immunohistochemistry was done in all tumors, and BRAF V600E and HRAS Sanger sequencing was successfully performed in all but two cases. Histologic analysis revealed that SP consisted not only of classic SP (9 of 13 cases) but also an oncocytic variant (4 of 13 cases) characterized by a glandular component that uniformly exhibited abundant granular cytoplasm and prominent nucleoli. By immunohistochemistry, all SP demonstrated luminal CK7 and basal p63 expression, but SOX10 was expressed only in conventional SP (9 of 9 cases). BRAF VE1 immunohistochemistry was positive in 9 of 9 conventional SP but 0 of 4 oncocytic SP; staining was present in both the exophytic and endophytic components. BRAF V600E mutational status was confirmed by Sanger sequencing in 11 cases (7 conventional and 4 oncocytic). The exophytic ductal papillomas were negative for BRAF mutations, and all tumors tested were negative for HRAS mutations. In summary, we demonstrated that SP consists of two variants: (1) conventional SP which is SOX10-positive and harbors BRAF V600E mutations similar to syringocystadenoma papilliferum of the skin; and (2) an oncocytic variant which is SOX10-negative and negative for BRAF mutations. We also demonstrated that both the endophytic glandular component and exophytic squamous components of conventional SP harbor BRAF V600E mutations and are therefore neoplastic.
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http://dx.doi.org/10.1007/s12105-019-01068-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235136PMC
June 2020

Plasma-Derived Inflammatory Proteins Predict Oral Squamous Cell Carcinoma.

Front Oncol 2018 4;8:585. Epub 2018 Dec 4.

Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada.

Oral squamous cell carcinoma (OSCC) is a major concern with high morbidity and mortality worldwide, even with the current knowledge and the advancement in treatment. OSCCs diagnosed at late-stage often require wide-excision with or without neck dissection, radiotherapy, or chemotherapy. When deemed successful, treatment often results in diminished quality of life, impaired function, and disfigurement. Strategies for early detection are urgently needed for patients afflicted with this disease. Inflammatory protein plasma biomarkers have shown to be potential tests for early detection and disease monitoring in several cancers. There has been no study on inflammation-related plasma biomarkers in OSCC. The objectives of the study were to use a multiplex approach to screen plasma-derived biomarkers and to examine the association of measurable proteins with OSCC. A total of 260 plasma samples (210 OSCC and 50 normal controls) were collected to measure for concentration of inflammatory related biomarkers using electrochemiluminescence multiplex assay. After screening of 82 potential biomarkers of the first 160 OSCC, 16 cytokines, chemokines, and growth factors were identified and verified in the second set of samples containing 50 OSCC and 50 normal. After adjustment of age and batch effects, the adjusted differential expression analysis showed that the OSCCs were markedly lower in 14 biomarkers and significantly higher level of interleukin 1 receptor antagonist (IL1Ra). By performing unsupervised clustering analysis, we observed distinctive groups of normal and two subgroups of OSCC. Linear regression of IL2, IL1Ra, and macrophage inhibitory factor (MIF) showed high accuracy in classifying OSCC with sensitivity of 0.96 and specificity of 0.92. In conclusion, this is the first paper to identify potential inflammatory plasma protein biomarkers of patients with OSCC. With further validation, the set of biomarkers can potentially be used to assist in early detection of OSCC when the disease is localized and in more treatable stage.
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http://dx.doi.org/10.3389/fonc.2018.00585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288174PMC
December 2018

Using ddPCR to assess the DNA yield of FFPE samples.

Biomol Detect Quantif 2018 Dec 7;16:5-11. Epub 2018 Nov 7.

Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.

Objectives: Detection of genomic alterations in diseases can be achieved with current molecular technologies. However, the molecules extracted from formalin-fixed, paraffin-embedded (FFPE) bio-samples are often limited possibly due to DNA fragmentation and crosslinking caused by the sample fixation and processing. The study objective was to design a droplet digital PCR (ddPCR) assay to assess the quality and quantity of DNA derived from various DNA extraction conditions on FFPE samples.

Methods: We used 10 μm-thick sections from 5 FFPE oral tumoral blocks, each consisting of 10-15 sections. The protocol variables tested included: 1) tissue staining; 2) duration and 3) temperature of post-digestion heat treatment; and 4) DNA extraction method. DNA quantity was assessed using the NanoDrop 2000 (Thermo Fisher Scientific, USA), the Qubit fluorometer (Thermo Fisher Scientific, USA), and a ddPCR-based assay. DNA quality was assessed using a ddPCR assay for the degree of fragmentation and the effectiveness of removing crosslinks with varying guanine-cytosine (GC)-content.

Results: Deparaffinization with xylene helped to increase the DNA yield. Tissue staining (methyl green staining, pH 6) prior to microdissection, comparing to no staining, caused additional DNA fragmentation. Compared to column-based method, DNA extracted with phenol chloroform and ethanol precipitation increased the degree of fragmentation and lowered the yield of amplifiable DNA. The cross-linking derived from GC-contents may not be the only factor impacting on the DNA quality.

Conclusions: Samples undergoing different pre-treatment conditions prior to extraction can impact the yield of amplifiable DNA. Our ddPCR assay can be used to assess for both DNA quantity and quality.
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http://dx.doi.org/10.1016/j.bdq.2018.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287546PMC
December 2018

Potential clinical implications of HPV status and expressions of p53 and cyclin D1 among oropharyngeal cancer patients.

J Oral Pathol Med 2018 Nov 27;47(10):945-953. Epub 2018 Sep 27.

Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada.

Background: There is increasing evidence that high-risk human papillomavirus plays significant role in oropharyngeal cancer; however, there is lack of knowledge on the interplay between the virus and its downstream-related molecules and their possible prognostic values. The objectives of the study are to better understand the interplay of the HR-HPV and its associated downstream molecules and to evaluate potential biomarkers for patient outcomes.

Methods: We conducted a retrospective study with available formalin-fixed, paraffin-embedded tissue from 244 oropharyngeal cancer patients that received curative radiotherapy or concurrent chemoradiotherapy from 2000 to 2008. In addition to chart review, we performed HPV DNA and RNA in situ hybridization and immunohistochemistry for p53, the retinoblastoma protein, p16, and cyclin D1 analysis. Cox proportional hazard and Kaplan-Meier survival analysis were used to determine the prognostic markers for clinical outcomes.

Results: Patients averaged 57.3 ± 9.4 year-old and were mostly males (76.2%) and ever-smokers (76.2%). All patients received curative radiotherapy, and 44.3% received concurrent chemoradiotherapy. We detected the human papillomavirus in 77.9% of study patients. Ever-smokers, more advanced tumor stage, and receiving radiotherapy only had poorer 5-year overall survival, disease-specific survival, and loco-regional recurrence. Cases with positive human papillomavirus and p53 overexpression had poorer disease-specific survival. Cases without human papillomavirus, but cyclin D1 overexpression, were associated with poorer 5-year overall survival.

Conclusions: Our data suggest that additional p53 and cyclin D1 testing may benefit oropharyngeal cancer patients with known human papillomavirus status.
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http://dx.doi.org/10.1111/jop.12779DOI Listing
November 2018

Molecular markers associated with development and progression of potentially premalignant oral epithelial lesions: Current knowledge and future implications.

Oral Surg Oral Med Oral Pathol Oral Radiol 2018 06 4;125(6):650-669. Epub 2018 Apr 4.

Pathology, Surgical and Hospital Dentistry, University of Louisville, USA.

Identification and management of potentially premalignant oral epithelial lesions (PPOELs) at highest risk of malignant transformation holds great promise for successful secondary prevention of oral squamous cell carcinoma, potentially reducing oral cancer morbidity and mortality. However, to date, neither clinical nor histopathologic validated risk predictors that can reliably predict which PPOELs will definitively progress to malignancy have been identified. In addition, the management of PPOELs remains a major challenge. Arguably, progress in the prevention and treatment of oral premalignancy and cancer will require improved understanding of the underlying molecular mechanisms, facilitating the discovery of diagnostic, prognostic, and predictive markers, as well as the identification of novel targeted therapeutics. This review provides a synopsis of the molecular biomarkers that have been studied in PPOELs and have been correlated with the presence and grade of dysplasia and/or their propensity to undergo malignant transformation to oral squamous cell carcinoma. The emphasis is on highlighting new emerging research fields, particularly epigenetic events, including methylation and micro-RNA regulation. Several promising biomarkers are highlighted. Current limitations and challenges are discussed. Recommendations for future focused research areas, to validate and promote clinically useful applications, are offered.
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http://dx.doi.org/10.1016/j.oooo.2018.03.012DOI Listing
June 2018

Using quantitative tissue phenotype to assess the margins of surgical samples from a pan-Canadian surgery study.

Head Neck 2018 06 16;40(6):1263-1270. Epub 2018 Feb 16.

Department of Integrative Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.

Background: The purpose of this study was to use quantitative tissue phenotype (QTP) to assess the surgical margins to examine if a fluorescence visualization-guided surgical approach produces a shift in the surgical field by sparing normal tissue while catching high-risk tissue.

Methods: Using our QTP to calculate the degree of nuclear chromatin abnormalities, Nuclear Phenotypic Score (NPS), we analyzed 1290 biopsy specimens taken from surgical samples of 248 patients enrolled in the Efficacy of Optically-guided Surgery in the Management of Early-staged Oral Cancer (COOLS) trial. Multiple margin specimens were collected from each surgical specimen according to the presence of fluorescence visualization alterations and the distance to the surgical margins.

Results: The NPS in fluorescence visualization-altered (fluorescence visualization-positive) samples was significantly higher than that in fluorescence visualization-retained (fluorescence visualization-negative) samples. There was a constant trend of decreasing NPS of margin samples from non-adjacent-fluorescence visualization margins to adjacent-fluorescence visualization margins.

Conclusion: Our results suggested that using fluorescence visualization to guide surgery has the potential to spare more normal tissue at surgical margins.
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http://dx.doi.org/10.1002/hed.25106DOI Listing
June 2018

An actionable test using loss of heterozygosity in identifying high-risk oral premalignant lesions.

Oral Surg Oral Med Oral Pathol Oral Radiol 2017 Dec 18. Epub 2017 Dec 18.

Department of Oral Medical Biological Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada; Department of Integrative Oncology, BC Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Objectives: To develop an actionable test using fluorescence capillary electrophoresis (FCE) to assess loss of heterozygosity (LOH) of histologically similar low-grade lesions (LGLs) to identify high-risk lesions for oral cancer progression.

Study Design: To determine the cutoffs of LOH, the FCE results of 52 surgical margin samples were used to compare with the existing LOH results from the previously validated P-GE approach. Using the developed FCE workflow, an independent set of 102 LGLs with known progression status was used to determine the LOH molecular risk (MR) patterns and associated risk of progression.

Results: Using 65% cutoff LOH-FCE, the agreement of LOH- P-GE had an average of 82.3% (76.8-87.8). Compared with nonprogressors (n = 61), anatomic site and MR patterns (LOH at 9 p21, 3 p14, or 17 p13) were independent risk factors. High-risk profile of tongue and MR3 (LOH at 9 p21 and/or 3 p14 and 17 p13) was significantly associated with progression (hazard ratio [HR] 6.7; 95% confidence interval [CI] 2.6-17.6) with specificity of 98.4% at identifying progressors.

Conclusions: We have developed an objective test using LOH to stratify the risk of LGLs. With further validation, it can be used in the clinical settings to provide clinicians additional information guiding the management of these lesions.
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http://dx.doi.org/10.1016/j.oooo.2017.10.019DOI Listing
December 2017

Tumor-associated immune aggregates in oral cancer: Their cellular composition and potential prognostic significance.

Med Hypotheses 2017 Oct 16;108:17-23. Epub 2017 Jul 16.

Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Integrative Oncology, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada. Electronic address:

There is growing evidence supporting the importance of immune microenvironment in cancer development and progression, especially with the rapid development of immunotherapy. Presence of immune cell aggregates in solid tumors has been associated with clinical outcomes, but little is known about the immune microenvironment in oral squamous cell carcinoma (OSCC), which has high morbidity and mortality. Based on our preliminary observation, we hypothesize that there is the presence of tumor-associated immune aggregates (TaIAs) during oral cancer development. Adapting to the dynamic change of the composition of cellular membership and co-evolving with the tumor at invasion fronts, these TaIAs, either pro-inflammatory or immune suppressive, are associated with clinical consequences. With the unique access to a set of prospectively collected, highly annotated OSCC surgical samples and the use of multi-color immunostaining of key immune cells, the confirmation of our hypothesis may shed light of the underlying biology related to OSCC and the knowledge learned can potentially be used to identify prognostic markers, response predictive markers for immunotherapies, as well as novel therapeutic targets.
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http://dx.doi.org/10.1016/j.mehy.2017.07.017DOI Listing
October 2017

Detection of clinically relevant copy number alterations in oral cancer progression using multiplexed droplet digital PCR.

Sci Rep 2017 09 19;7(1):11855. Epub 2017 Sep 19.

Department of Oral Medical and Biological Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.

Copy number alterations (CNAs), a common genomic event during carcinogenesis, are known to affect a large fraction of the genome. Common recurrent gains or losses of specific chromosomal regions occur at frequencies that they may be considered distinctive features of tumoral cells. Here we introduce a novel multiplexed droplet digital PCR (ddPCR) assay capable of detecting recurrent CNAs that drive tumorigenesis of oral squamous cell carcinoma. Applied to DNA extracted from oral cell lines and clinical samples of various disease stages, we found good agreement between CNAs detected by our ddPCR assay with those previously reported using comparative genomic hybridization or single nucleotide polymorphism arrays. Furthermore, we demonstrate that the ability to target specific locations of the genome permits detection of clinically relevant oncogenic events such as small, submicroscopic homozygous deletions. Additional capabilities of the multiplexed ddPCR assay include the ability to infer ploidy level, quantify the change in copy number of target loci with high-level gains, and simultaneously assess the status and viral load for high-risk human papillomavirus types 16 and 18. This novel multiplexed ddPCR assay therefore may have clinical value in differentiating between benign oral lesions from those that are at risk of progressing to oral cancer.
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http://dx.doi.org/10.1038/s41598-017-11201-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605662PMC
September 2017

Dual-mode endomicroscopy for detection of epithelial dysplasia in the mouth: a descriptive pilot study.

J Biomed Opt 2017 Aug;22(8):1-10

British Columbia Cancer Research Centre, Department of Integrative Oncology, Vancouver, British Colu, Canada.

Dual-mode endomicroscopy is a diagnostic tool for early cancer detection. It combines the high-resolution nuclear tissue contrast of fluorescence endomicroscopy with quantified depth-dependent epithelial backscattering as obtained by diffuse optical microscopy. In an in vivo pilot imaging study of 27 oral lesions from 21 patients, we demonstrate the complementary diagnostic value of both modalities and show correlations between grade of epithelial dysplasia and relative depth-dependent shifts in light backscattering. When combined, the two modalities provide diagnostic sensitivity to both moderate and severe epithelial dysplasia in vivo.
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http://dx.doi.org/10.1117/1.JBO.22.8.086005DOI Listing
August 2017

Detection of precancerous lesions in the oral cavity using oblique polarized reflectance spectroscopy: a clinical feasibility study.

J Biomed Opt 2017 06;22(6):65002

University of Texas M.D. Anderson Cancer Center, Department of Imaging Physics, Houston, Texas, United StatesbUniversity of Texas at Austin, Department of Biomedical Engineering, Austin, Texas, United StatesdRice University, Department of Bioengineering, Houston, Texas, United States.

We developed a multifiber optical probe for oblique polarized reflectance spectroscopy (OPRS) in vivo and evaluated its performance in detection of dysplasia in the oral cavity. The probe design allows the implementation of a number of methods to enable depth resolved spectroscopic measurements including polarization gating, source–detector separation, and differential spectroscopy; this combination was evaluated in carrying out binary classification tasks between four major diagnostic categories: normal, benign, mild dysplasia (MD), and severe dysplasia (SD). Multifiber OPRS showed excellent performance in the discrimination of normal from benign, MD, SD, and MD plus SD yielding sensitivity/specificity values of 100%/93%, 96%/95%, 100%/98%, and 100%/100%, respectively. The classification of benign versus dysplastic lesions was more challenging with sensitivity and specificity values of 80%/93%, 71%/93%, and 74%/80% in discriminating benign from SD, MD, and SD plus MD categories, respectively; this challenge is most likely associated with a strong and highly variable scattering from a keratin layer that was found in these sites. Classification based on multiple fibers was significantly better than that based on any single detection pair for tasks dealing with benign versus dysplastic sites. This result indicates that the multifiber probe can perform better in the detection of dysplasia in keratinized tissues.
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http://dx.doi.org/10.1117/1.JBO.22.6.065002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469421PMC
June 2017

Oral health status and possible explanatory factors of an inner-city low-income community.

J Dent Sci 2017 Mar 11;12(1):49-55. Epub 2016 Nov 11.

Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada.

Background/purpose: Individuals with low income bear a number of health challenges to healthcare services. Vancouver's Downtown Eastside (DTES) is known to be a low-income community in a metropolitan city. Because it is difficult to reach, the oral health (OH) status of these residents is unknown. The objectives of this study are (1) to design a tool and strategy to collect OH information in a low-income community, (2) to characterize the OH status and related factors among low-income adults, and (3) to identify the explanatory factors for their OH status.

Materials And Methods: Mobile screening clinics were established in the gathering centers of the DTES, and those of 19 years of age or older were recruited. Data were collected through survey interviews and clinical examinations. Potential explanatory factors were investigated by regression analysis.

Results: The 356 screened participants were mostly males, middle-aged, less educated, and living with low income (≤CAD$20,000/y). About 80% had dental coverage, mostly from public programs (94%). Many (86%) perceived a dental need. Among dentate participants ( = 306), on average, 3.8 decayed, 8.6 missing, 4.9 filled teeth, and a care index of 41.5% were observed. Social factors (barriers to care and length of DTES residence), dental hygiene (brushing/flossing), and personal (hepatitis C virus infection/methadone usage) factors contributed to their care index level.

Conclusion: This is the first time that comprehensive information regarding OH status has been collected from a low-income, inner-city community in Canada. Further investigations in the challenges and needs in accessing dental care may develop solutions for better OH in similar communities.
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http://dx.doi.org/10.1016/j.jds.2016.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395230PMC
March 2017

Oral Squamous Cell Carcinomas are Associated with Poorer Outcome with Increasing Ages.

J Oncol Res Ther 2017 25;3(4). Epub 2017 Sep 25.

Department of Oral Biological and Medical Sciences, Faculty of Dentistry, The University of British Columbia (BC), Vancouver, Canada.

Objectives: 1.1.Although oral cancers traditionally occur in people between the age of 50 and 70, there are increasing incidences of this disease in younger and very old people. Objectives: to compare the demographics, habits, clinicopathological features, treatment and outcome of oral cancer in three age groups of patients: Young (≤ 45), Traditional (46 to 75), and Old (> 75).

Subjects: 1.2.Primary oral cancers (393 patients) in a longitudinal study were used.

Results: 1.3.Significant differences were noted in ethnicity (fewer Caucasian patients in Young), tobacco habit (more non-smokers in Young), location of cancer (more at tongue for Young and more at low-risk sites for Old) and treatment (more surgery for Young). Compared to Young (univariate analysis), Traditional and Old showed a 3- and 4.5-fold increase in local recurrences respectively; 1.9- and 2.7-fold increase in regional metastasis; 3.1- and 5.4-fold increase in death due to disease; and a 3.4- and 6.6-fold decrease in overall survival. Compared to Young (multivariate analysis), Traditional and Old showed a 2.4- and 3.3-fold increase in local recurrence; 2.7- and 5.4-fold increase in disease-specific survival; and 2.8- and 6.5-fold decrease in overall survival.

Conclusion: 1.4.Oral cancer in different age groups showed differing ethnicity, habit, location, treatment and outcome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498857PMC
September 2017

Improving public awareness and outcomes for oral cancer.

Authors:
Catherine F Poh

Future Sci OA 2016 Mar 11;2(1):FSO103. Epub 2016 Feb 11.

Faculty of Dentistry, Department of Oral Biological & Medical Sciences, University of British Columbia, Vancouver, BC, Canada.

: Dr. C Poh gained a dental degree from the National Taiwan University in Taipei, Taiwan and went on to gain her PhD from the University of British Columbia in 1997, looking into molecular biology in oral cancer. In addition to her current role an associate professor in the Faculty of Dentistry at the University of British Columbia, she is a senior clinician scientist at the Integrative Oncology Department of the BC Cancer Agency's Research Centre. She has various other roles, including being active within the Oral Oncology Department at BC Cancer Agency and the Oral Mucosal Disease Program at Vancouver General Hospital. Her research focuses on the application of molecular and imaging tools for screening, detection and management of at-risk oral lesions. She is currently the principal investigator of a Terry Fox Research Institute-funded ($5 million), pan-Canadian multicenter randomized controlled surgical trial.
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http://dx.doi.org/10.4155/fsoa-2016-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137921PMC
March 2016

Prospects in the Application of Photodynamic Therapy in Oral Cancer and Premalignant Lesions.

Cancers (Basel) 2016 Sep 2;8(9). Epub 2016 Sep 2.

Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Oral cancer is a global health burden with significantly poor survival, especially when the diagnosis is at its late stage. Despite advances in current treatment modalities, there has been minimal improvement in survival rates over the last five decades. The development of local recurrence, regional failure, and the formation of second primary tumors accounts for this poor outcome. For survivors, cosmetic and functional compromises resulting from treatment are often devastating. These statistics underscore the need for novel approaches in the management of this deadly disease. Photodynamic therapy (PDT) is a treatment modality that involves administration of a light-sensitive drug, known as a photosensitizer, followed by light irradiation of an appropriate wavelength that corresponds to an absorbance band of the sensitizer. In the presence of tissue oxygen, cytotoxic free radicals that are produced cause direct tumor cell death, damage to the microvasculature, and induction of inflammatory reactions at the target sites. PDT offers a prospective new approach in controlling this disease at its various stages either as a stand-alone therapy for early lesions or as an adjuvant therapy for advanced cases. In this review, we aim to explore the applications of PDT in oral cancer therapy and to present an overview of the recent advances in PDT that can potentially reposition its utility for oral cancer treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040985PMC
http://dx.doi.org/10.3390/cancers8090083DOI Listing
September 2016

Nodal Disease Burden for Early-Stage Oral Cancer.

JAMA Otolaryngol Head Neck Surg 2016 11;142(11):1111-1119

Department of Oral Medical Biological Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, Canada2Department of Integrative Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada5Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.

Importance: Nodal disease has a significant effect on survival of patients with oral squamous cell carcinoma (OSCC). The decision for elective neck dissection for clinically node-negative (cN0) disease remains elusive.

Objectives: To determine the efficacy of prophylactic neck treatment and to assess the value of commonly used clinicopathologic factors associated with nodal disease for early-stage OSCC.

Design, Setting, And Participants: This retrospective study from a population-based cancer registry included patients diagnosed as having OSCC from January 11, 2001, to December 24, 2007, who were identified from the British Columbia Cancer Agency Registry. Comprehensive clinicopathologic data, treatment information, and time to outcome were collected. Five-year overall survival, disease-specific survival, and cumulative incidence of regional failure (RF) were analyzed. Receiver operating characteristic curve analysis with sensitivity and specificity was used to determine the association of these covariates with RF during follow-up. Data were analyzed from January 16 to June 30, 2015.

Interventions: Follow-up of patients with cN0 OSCC with or without prophylactic neck treatment (elective neck dissection [END] and or radiotherapy).

Main Outcomes And Measures: Patient demographic characteristics, clinicopathologic data, treatment data, and time from the initial surgery to last follow-up, the development of RF, or death due to oral cancer or other causes.

Results: Of the 469 patients with cN0 primary OSCC who underwent intent-to-cure surgery for the intraoral lesion, 447 received local excision (LE) for the primary tumor (256 men [57.3%] and 191 women [42.7%]; mean [SD] age, 63.3 [14.7] years). Patients who received prophylactic treatment of the neck (n = 125) compared with LE only (n = 322) had no survival advantage. The estimated 5-year overall and disease-specific survival rates were 61.9% (95% CI, 56.5%-67.8%) and 80.8% (95% CI, 76.1%-85.6%), respectively, for the LE-only group; 54.4% (95% CI, 45.9%-64.5%) and 73.1% (95% CI, 65%-82.3%), respectively, for the LE + END ± radiotherapy group; and 61.7% (95% CI, 52.3%-72.8%) and 80.3% (95% CI, 72%-89.4%), respectively, for the LE + END group. Among the patients with cN0 disease receiving LE only, 89 (27.6%; 95% CI, 23%-33%) developed RF at a median time of 10.8 months, and 71 of the RFs (79.8%) developed within 30 months. Tumor depth of invasion of at least 4 mm and tumor grade of 2 or 3 showed an association with RF but had poor sensitivity and specificity.

Conclusions And Relevance: Commonly used pathologic factors to decide neck dissection for cN0 OSCC are not effective and can cause overtreatment or undertreatment. The need for identification of new objective approaches for risk assessment of RF is urgent.
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http://dx.doi.org/10.1001/jamaoto.2016.2241DOI Listing
November 2016

A Robust Protocol for Using Multiplexed Droplet Digital PCR to Quantify Somatic Copy Number Alterations in Clinical Tissue Specimens.

PLoS One 2016 18;11(8):e0161274. Epub 2016 Aug 18.

Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, V6T 1Z4, Canada.

The ability of droplet digital PCR (ddPCR) to accurately determine the concentrations of amplifiable targets makes it a promising platform for measuring copy number alterations (CNAs) in genomic biomarkers. However, its application to clinical samples, particularly formalin-fixed paraffin-embedded specimens, will require strategies to reliably determine CNAs in DNA of limited quantity and quality. When applied to cancerous tissue, those methods must also account for global genetic instability and the associated probability that the abundance(s) of one or more chosen reference loci do not represent the average ploidy of cells comprising the specimen. Here we present an experimental design strategy and associated data analysis tool that enables accurate determination of CNAs in a panel of biomarkers using multiplexed ddPCR. The method includes strategies to optimize primer and probes design to cleanly segregate droplets in the data output from reaction wells amplifying multiple independent templates, and to correct for bias from artifacts such as DNA fragmentation. We demonstrate how a panel of reference loci can be used to determine a stable CNA-neutral benchmark. These innovations, when taken together, provide a comprehensive strategy that can be used to reliably detect biomarker CNAs in DNA extracted from either frozen or FFPE tissue biopsies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161274PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990255PMC
July 2017

Cost-Effectiveness Analysis of Using Loss of Heterozygosity to Manage Premalignant Oral Dysplasia in British Columbia, Canada.

Oncologist 2016 09 11;21(9):1099-106. Epub 2016 Jul 11.

Department of Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada Department of Oral Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Management of low-grade oral dysplasias (LGDs) is complicated, as only a small percentage of lesions will progress to invasive disease. The current standard of care requires patients to undergo regular monitoring of their lesions, with intervention occurring as a response to meaningful clinical changes. Recent improvements in molecular technologies and understanding of the biology of LGDs may allow clinicians to manage lesions based on their genome-guided risk.

Methods: We used a decision-analytic Markov model to estimate the cost-effectiveness of risk-stratified care using a genomic assay. In the experimental arm, patients with LGDs were managed according to their risk profile using the assay, with low- and intermediate-risk patients given longer screening intervals and high-risk patients immediately treated with surgery. Patients in the comparator arm had standard care (biannual follow-up appointments at an oral cancer clinic). Incremental costs and outcomes in life-years gained (LYG) and quality-adjusted life-years (QALY) were calculated based on the results in each arm.

Results: The mean cost of assay-guided management was $8,123 (95% confidence interval [CI] $2,973 to $23,062 in 2013 Canadian dollars) less than the cost of standard care. This difference was driven largely by reductions in resource use among people who did not develop cancer. Mean incremental effectiveness was 0.18 LYG (95% CI 0.08 to 0.39) or 0.64 QALY (95% CI 0.46 to 0.89). Sensitivity analysis suggests that these findings are robust to both expected and extreme variation in all parameter values.

Conclusion: Use of the assay-guided management strategy costs less and is more effective than standard management of LGDs.

Implications For Practice: The findings of this study strongly suggest that the use of a risk-stratification method such as a genomic assay can result in improved quality-adjusted survival outcomes for patients with low-grade oral dysplasia (LGD). The use of such an assay in this study provides "precision medicine," allowing for a change in follow-up frequency or early intervention as compared with current standard care. As genomic technologies become more common in cancer care, it is hoped that such an assay, once validated, will become part of a new model for the standard management of LGDs in similar health systems.
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http://dx.doi.org/10.1634/theoncologist.2015-0433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016061PMC
September 2016

Fluorescence Visualization-Guided Surgery for Early-Stage Oral Cancer.

JAMA Otolaryngol Head Neck Surg 2016 Mar;142(3):209-16

Integrative Oncology and Cancer Control Research Program, BC Cancer Research Centre, Vancouver, British Columbia, Canada5Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.

Importance: The prevalence of genetically altered cells in oral cancers has a negative influence on the locoregional recurrence rate and lowers survival. Fluorescence visualization (FV) can identify clinically occult, high-risk oral lesions by allowing health care professionals and surgeons to visualize and map occult disease. This process may improve overall survival by decreasing rates of locoregional recurrence.

Objective: To assess the efficacy of FV-guided surgery in reducing locoregional recurrence and improving overall survival.

Design, Setting, And Participants: A retrospective, case-control observational study was conducted on patients registered at a single oral oncology clinic from September 1, 2004, to August 31, 2009. The study included 246 patients 18 years or older with a diagnosis of a high-grade lesion (severe dysplasia or carcinoma in situ) or squamous cell carcinoma of less than 4 cm who underwent curative surgical treatment with at least 1 follow-up visit. Among these patients, 154 underwent surgery with FV guidance (FV group) and the other 92 underwent conventional surgery (control group). Demographic and lesional characteristics and outcomes were collected, and the key factors for the efficacy of FV-guided surgery were examined. Follow-up was completed on December 31, 2011, and data were analyzed from May 1 to November 30, 2013.

Main Outcomes And Measures: Local recurrence of oral lesions with a histologic grade of severe dysplasia or higher, the presence of regional failure (ie, a metastatic lesion in the cervical lymph nodes), or disease-free survival after surgery.

Results: Among the 246 patients included in the study (mean [SD] age, 60 [12] years; 108 women and 138 men), 156 had squamous cell carcinoma and 90 had high-grade lesions. There were no significant differences between the FV (n = 154) and control (n = 92) groups in age, smoking history, anatomical site of the lesion, tumor size, and previous oral cancer. Among the 156 patients with squamous cell carcinoma, the 92 patients in the FV group showed significant reduction in the 3-year local recurrence rate, from 40.6% (26 of 64 patients) to 6.5% (6 of 92 patients) (P < .001). Among the 90 patients with high-grade lesions, the 62 patients in the FV group showed a reduction in local recurrence rate from 11 of 28 patients (39.3%) to 5 of 62 patients (8.1%) (P < .001). The data also indicated that, compared with conventional surgery, the FV-guided approach for squamous cell carcinoma was associated with less regional failure (14 of 92 patients [15.2%] vs 16 of 64 [25.0%]; P = .08) and death (12 of 92 patients [13.0%] vs 13 of 64 [20.3%]; P = .22), although these differences were not statistically significant.

Conclusions And Relevance: In this study, the use of FV as part of the surgical margin decision process significantly reduced the rate of local recurrence in preinvasive high-grade and early-stage oral cancers. An ongoing multicenter, phase 3, randomized surgical trial has completed accrual, and the data will be used to validate the results of this study.
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http://dx.doi.org/10.1001/jamaoto.2015.3211DOI Listing
March 2016

Wide-field in vivo oral OCT imaging.

Biomed Opt Express 2015 Jul 24;6(7):2664-74. Epub 2015 Jun 24.

Department of Integrative Oncology - Cancer Imaging Unit, British Columbia Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.

We have built a polarization-sensitive swept source Optical Coherence Tomography (OCT) instrument capable of wide-field in vivo imaging in the oral cavity. This instrument uses a hand-held side-looking fiber-optic rotary pullback catheter that can cover two dimensional tissue imaging fields approximately 2.5 mm wide by up to 90 mm length in a single image acquisition. The catheter spins at 100 Hz with pullback speeds up to 15 mm/s allowing imaging of areas up to 225 mm(2) field-of-view in seconds. A catheter sheath and two optional catheter sheath holders have been designed to allow imaging at all locations within the oral cavity. Image quality of 2-dimensional image slices through the data can be greatly enhanced by averaging over the orthogonal dimension to reduce speckle. Initial in vivo imaging results reveal a wide-field view of features such as epithelial thickness and continuity of the basement membrane that may be useful in clinic for chair-side management of oral lesions.
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http://dx.doi.org/10.1364/BOE.6.002664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505717PMC
July 2015

Recurring DNA copy number gain at chromosome 9p13 plays a role in the activation of multiple candidate oncogenes in progressing oral premalignant lesions.

Cancer Med 2014 Oct 24;3(5):1170-84. Epub 2014 Jul 24.

Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.

Genomic alteration at chromosome 9p has been previously reported as a frequent and critical event in oral premalignancy. While this alteration is typically reported as a loss driven by selection for CDKN2A deactivation (at 9p21.3), we detect a recurrent DNA copy number gain of ~2.49 Mbp at chromosome 9p13 in oral premalignant lesions (OPLs) that later progressed to invasive lesions. This recurrent alteration event has been validated using fluorescence in situ hybridization in an independent set of OPLs. Analysis of publicly available gene expression datasets aided in identifying three oncogene candidates that may have driven selection for DNA copy number increases in this region (VCP, DCTN3, and STOML2). We performed in vitro silencing and activation experiments for each of these genes in oral cancer cell lines and found that each gene is independently capable of upregulating proliferation and anchorage-independent growth. We next analyzed the activity of each of these genes in biopsies of varying histological grades that were obtained from a diseased oral tissue field in a single patient, finding further molecular evidence of parallel activation of VCP, DCTN3, and STOML2 during progression from normal healthy tissue to invasive oral carcinoma. Our results support the conclusion that DNA gain at 9p13 is important to the earliest stages of oral tumorigenesis and that this alteration event likely contributes to the activation of multiple oncogene candidates capable of governing oral cancer phenotypes.
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http://dx.doi.org/10.1002/cam4.307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302668PMC
October 2014

Automated classification of oral premalignant lesions using image cytometry and Random Forests-based algorithms.

Cell Oncol (Dordr) 2014 Jun 10;37(3):193-202. Epub 2014 May 10.

Department of Integrative Oncology, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, Canada.

Purpose: A major challenge for the early diagnosis of oral cancer is the ability to differentiate oral premalignant lesions (OPL) at high risk of progressing into invasive squamous cell carcinoma (SCC) from those at low risk. Our group has previously used high-resolution image analysis algorithms to quantify the nuclear phenotypic changes occurring in OPLs. This approach, however, requires a manual selection of nuclei images. Here, we investigated a new, semi-automated algorithm to identify OPLs at high risk of progressing into invasive SCC from those at low risk using Random Forests, a tree-based ensemble classifier.

Methods: We trained a sequence of classifiers using morphometric data calculated on nuclei from 29 normal, 5 carcinoma in situ (CIS) and 28 SCC specimens. After automated discrimination of nuclei from other objects (i.e., debris, clusters, etc.), a nuclei classifier was trained to discriminate abnormal nuclei (8,841) from normal nuclei (5,762). We extracted voting scores from this trained classifier and created an automated nuclear phenotypic score (aNPS) to identify OPLs at high risk of progression.

Results: The new algorithm showed a correct classification rate of 80% (80.6% sensitivity, 79.3% specificity) at the cellular level for the test set, and a correct classification rate of 75% (77.8% sensitivity, 71.4% specificity) at the tissue level with a negative predictive value of 76% and a positive predictive value of 74% for predicting progression among 71 OPLs, performed on par with the manual method in our previous study.

Conclusions: We conclude that the newly developed aNPS algorithm serves as a crucial asset in the implementation of high-resolution image analysis in routine clinical pathology practice to identify lesions that require molecular evaluation or more frequent follow-up.
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http://dx.doi.org/10.1007/s13402-014-0172-xDOI Listing
June 2014

Decision making on detection and triage of oral mucosa lesions in community dental practices: screening decisions and referral.

Community Dent Oral Epidemiol 2014 Aug 25;42(4):375-84. Epub 2014 Jan 25.

Faculty of Dentistry, Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, BC, Canada.

Unlabelled: Oral cancer is a substantial, often unrecognized issue globally, with close to 300 000 new cases reported annually. It is a management conundrum: a cancer site that is easily examined; yet more than 40% of oral cancers are diagnosed at a late stage when prognosis is poor and treatment can be devastating. Opportunistic screening within the dental office could lead to earlier diagnosis and intervention with improved survival.

Objective: To describe how clinicians make decisions about referral based on the risk classification of the lesion.

Methods: Eighteen dentists from 15 dental offices participated in a 1-day workshop on oral cancer screening. Participants then screened patients (medical history, conventional oral exam, fluorescent visualization examination) in-office for 11 months, triaging patients by apparent clinical risk: low risk (common benign conditions, geographic tongue, candidiasis, trauma), intermediate risk (lichenoid lesions) and high risk (white or red lesions or ulcers without apparent cause). Clinicians made the decision on which lesions to reassess in 3 weeks based on risk assessment and clinical judgment. Lesions of concern were seen by a community facilitator or referred to an oral medicine specialist.

Results: Of 2542 patients were screened, and 389 lesions were identified (15% of patients). 350 were determined to be low risk (90%), 19 intermediate risk (IR) (5%), and 20 high risk (HR) (5%). One hundred and sixty-six (43%) patients were recalled for 3-week reassessment: 90% of HR lesions, 63% of IR lesions (63%), and 39% of low-risk lesions. Compliance to recall was high (92% of cases). Reassessment eliminated the referral of 99/166 (60%) of lesions that had resolved. six lesions were biopsied with three low-grade dysplasias identified.

Conclusions: Three key decision points were tested: risk assessment, need for reassessment, and need for referral. A 3-week reassessment appointment was invaluable to prevent the unnecessary referral due to confounders. There is a need for a well-defined triage pathway to facilitate oral cancer screening and a methodical and consistent approach to opportunistic screening in the dental office.
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http://dx.doi.org/10.1111/cdoe.12093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535694PMC
August 2014

In reply to letter to the editor regarding "can clinical and radiological features predict recurrence in solitary keratocystic odontogenic tumors?".

Oral Surg Oral Med Oral Pathol Oral Radiol 2014 Feb 22;117(2):259. Epub 2013 Nov 22.

University of British Columbia, Faculty of Dentistry, Vancouver, BC, Canada.

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http://dx.doi.org/10.1016/j.oooo.2013.08.014DOI Listing
February 2014