Structured light imaging (SLI) with high spatial frequency (HSF) illumination provides a method to amplify native tissue scatter contrast and better differentiate superficial tissues. This was ...investigated for margin analysis in breast-conserving surgery (BCS) and imaging gross clinical tissues from 70 BCS patients, and the SLI distinguishability was examined for six malignancy subtypes relative to three benign/normal breast tissue subtypes. Optical scattering images recovered were analyzed with five different color space representations of multispectral demodulated reflectance. Excluding rare combinations of invasive lobular carcinoma and fibrocystic disease, SLI was able to classify all subtypes of breast malignancy from surrounding benign tissues (p-value < 0.05) based on scatter and color parameters. For color analysis, HSF illumination of the sample generated more statistically significant discrimination than regular uniform illumination. Pathological information about lesion subtype from a presurgical biopsy can inform the search for malignancy on the surfaces of specimens during BCS, motivating the focus on pairwise classification analysis. This SLI modality is of particular interest for its potential to differentiate tissue classes across a wide field-of-view (∼100 cm2) and for its ability to acquire images of macroscopic tissues rapidly but with microscopic-level sensitivity to structural and morphological tissue constituents.
Nationally, 25% to 50% of patients undergoing lumpectomy for local management of breast cancer require a secondary excision because of the persistence of residual tumor. Intraoperative assessment of ...specimen margins by frozen-section analysis is not widely adopted in breast-conserving surgery. Here, a new approach to wide-field optical imaging of breast pathology in situ was tested to determine whether the system could accurately discriminate cancer from benign tissues before routine pathological processing.
Spatial frequency domain imaging (SFDI) was used to quantify near-infrared (NIR) optical parameters at the surface of 47 lumpectomy tissue specimens. Spatial frequency and wavelength-dependent reflectance spectra were parameterized with matched simulations of light transport. Spectral images were co-registered to histopathology in adjacent, stained sections of the tissue, cut in the geometry imaged in situ. A supervised classifier and feature-selection algorithm were implemented to automate discrimination of breast pathologies and to rank the contribution of each parameter to a diagnosis.
Spectral parameters distinguished all pathology subtypes with 82% accuracy and benign (fibrocystic disease, fibroadenoma) from malignant (DCIS, invasive cancer, and partially treated invasive cancer after neoadjuvant chemotherapy) pathologies with 88% accuracy, high specificity (93%), and reasonable sensitivity (79%). Although spectral absorption and scattering features were essential components of the discriminant classifier, scattering exhibited lower variance and contributed most to tissue-type separation. The scattering slope was sensitive to stromal and epithelial distributions measured with quantitative immunohistochemistry.
SFDI is a new quantitative imaging technique that renders a specific tissue-type diagnosis. Its combination of planar sampling and frequency-dependent depth sensing is clinically pragmatic and appropriate for breast surgical-margin assessment. This study is the first to apply SFDI to pathology discrimination in surgical breast tissues. It represents an important step toward imaging surgical specimens immediately ex vivo to reduce the high rate of secondary excisions associated with breast lumpectomy procedures.
This study aims to determine if light scatter parameters measured with spatial frequency domain imaging (SFDI) can accurately predict stromal, epithelial, and adipose fractions in freshly resected, ...unstained human breast specimens. An explicit model was developed to predict stromal, epithelial, and adipose fractions as a function of light scattering parameters, which was validated against a quantitative analysis of digitized histology slides for N = 31 specimens using leave-one-out cross-fold validation. Specimen mean stromal, epithelial, and adipose volume fractions predicted from light scattering parameters strongly correlated with those calculated from digitized histology slides (r = 0.90, 0.77, and 0.91, respectively, p-value <1 × 10 − 6). Additionally, the ratio of predicted epithelium to stroma classified malignant specimens with a sensitivity and specificity of 90% and 81%, respectively, and also classified all pixels in malignant lesions with 63% and 79%, at a threshold of 1. All specimens and pixels were classified as malignant, benign, or fat with 84% and 75% accuracy, respectively. These findings demonstrate how light scattering parameters acquired with SFDI can be used to accurately predict and spatially map stromal, epithelial, and adipose proportions in fresh unstained, human breast tissue, and suggest that these estimations could provide diagnostic value.
To determine the pharmacokinetics (PK), maximum tolerated dose (MTD), safety, and antitumor activity of an oral formulation of rigosertib, a dual phosphoinositide 3-kinase (PI3K) and polo-like kinase ...1 (Plk1) pathway inhibitor, in patients with advanced solid malignancies.
Patients with advanced solid malignancies received rigosertib twice daily continuously in 21-day cycles. Doses were escalated until intolerable grade ≥2 toxicities, at which point the previous dose level was expanded to define the MTD. All patients were assessed for safety, PK, and response. Urinary PK were performed at the MTD. Archival tumors were assessed for potential molecular biomarkers with multiplex mutation testing. A subset of squamous cell carcinomas (SCC) underwent exome sequencing.
Forty-eight patients received a median of 2 cycles of therapy at 5 dose levels. Rigosertib exposure increased with escalating doses. Dose-limiting toxicities were hematuria and dysuria. The most common grade ≥2 drug-related toxicities involved urothelial irritation. The MTD is 560 mg twice daily. Activity was seen in head and neck SCCs (1 complete response, 1 partial response) and stable disease for ≥12 weeks was observed in 8 additional patients. Tumors experiencing ≥partial response had PI3K pathway activation, inactivated p53, and unique variants in ROBO3 and FAT1, two genes interacting with the Wnt/β-catenin pathway.
The recommended phase II dose of oral rigosertib is 560 mg twice daily given continuously. Urinary toxicity is the dose-limiting and most common toxicity. Alterations in PI3K, p53, and Wnt/β-catenin pathway signaling should be investigated as potential biomarkers of response in future trials.
The authors describe what is, to the best of their knowledge, the first quantitative hemoglobin concentration images of the female breast that were formed with model-based reconstruction of ...near-infrared intensity-modulated tomographic data. The results in 11 patients, including two with breast tumors with pathologic correlation, are summarized. Hemoglobin concentration appears to correlate with tumor vascularity without the need for exogenous contrast material and thereby has intrinsic diagnostic value.
To evaluate two methods of summarizing tomographic diffuse optical spectroscopic (DOS) data through region-of-interest (ROI) analysis to differentiate complete from incomplete responses in patients ...with locally advanced breast cancer undergoing neoadjuvant treatment and to estimate the standard deviations of these methods for power analysis of larger study designs in the future.
Subjects participating in the HIPAA-compliant imaging study, approved by the institutional review board, provided written informed consent and were compensated for their examination participation. Seven of 16 cases in women with complete study data were analyzed by using both fixed- and variable-size (full-width-at-half-maximum) ROI measures of the DOS total hemoglobin concentration (Hb(T)), blood oxygen saturation, water fraction, optical scattering amplitude, and scattering power in the ipsilateral and contralateral breasts. Postsurgical histopathologic analysis was used to categorize patients as having a complete or incomplete treatment response.
Average normalized change in Hb(T) was the only DOS parameter to show significant differences (P < or = .05) in the pathologic complete response (pCR) and pathologic incomplete response (pIR) outcomes in seven patients. Mean values of the changes for fixed-size ROIs were -64.2% +/- 50.8 (standard deviation) and 16.9% +/- 38.2 for the pCR and pIR groups, respectively, and those for variable-size ROIs were -96.7% +/- 91.8, and 14.1% +/- 26.7 for the pCR and pIR groups, respectively.
Tomographic DOS may provide findings predictive of therapeutic response, which could lead to superior individualized patient treatment.
http://radiology.rsnajnls.org/cgi/content/full/2522081202/DC1.
Localized measurements of scattering in biological tissue provide sensitivity to microstructural morphology but have limited utility to wide-field applications, such as surgical guidance. This study ...introduces sub-diffusive spatial frequency domain imaging (sd-SFDI), which uses high spatial frequency illumination to achieve wide-field sampling of localized reflectances. Model-based inversion recovers macroscopic variations in the reduced scattering coefficient Formula: see text and the phase function backscatter parameter (
). Measurements in optical phantoms show quantitative imaging of user-tuned phase-function-based contrast with accurate decoupling of parameters that define both the density and the size-scale distribution of scatterers. Measurements of fresh ex vivo breast tissue samples revealed, for the first time, unique clustering of sub-diffusive scattering properties for different tissue types. The results support that sd-SFDI provides maps of microscopic structural biomarkers that cannot be obtained with diffuse wide-field imaging and characterizes spatial variations not resolved by point-based optical sampling.
Abstract Late-onset Alzheimer disease (AD) has a complex genetic etiology, involving locus heterogeneity, polygenic inheritance, and gene-gene interactions; however, the investigation of interactions ...in recent genome-wide association studies has been limited. We used a biological knowledge-driven approach to evaluate gene-gene interactions for consistency across 13 data sets from the Alzheimer Disease Genetics Consortium. Fifteen single nucleotide polymorphism (SNP)-SNP pairs within 3 gene-gene combinations were identified: SIRT1 × ABCB1 , PSAP × PEBP4 , and GRIN2B × ADRA1A. In addition, we extend a previously identified interaction from an endophenotype analysis between RYR3 × CACNA1C. Finally, post hoc gene expression analyses of the implicated SNPs further implicate SIRT1 and ABCB1 , and implicate CDH23 which was most recently identified as an AD risk locus in an epigenetic analysis of AD. The observed interactions in this article highlight ways in which genotypic variation related to disease may depend on the genetic context in which it occurs. Further, our results highlight the utility of evaluating genetic interactions to explain additional variance in AD risk and identify novel molecular mechanisms of AD pathogenesis.
To investigate if changes in tumor angiogenesis associated with complete pathologic response (pCR) or partial pathologic response (pPR) to treatment can be demonstrated by using diffuse optical ...spectroscopic (DOS) tomography.
All participants in this prospective, HIPAA-compliant, institutional review board-approved study provided written informed consent. Eleven women with invasive breast carcinoma were imaged with DOS tomography prior to, during, and at completion of neoadjuvant chemotherapeutic regimens. By using region of interest (ROI) analysis, the DOS measure of total tissue hemoglobin (Hb(T)) was temporally correlated with quantitative measures of existing (CD31-expressing) and tumor-induced (CD105-expressing) vessels, in pretreatment and posttreatment tissue specimens, to assess change.
Quantified angiogenesis alone in pretreatment core biopsy specimens did not predict treatment response, but mean vessel density (MVD) and mean vessel area (MVA) of CD105-expressing vessels were significantly decreased in women with pCR (n = 7) (P < .001 and P = .003, respectively). MVA of CD105-expressing vessels was also significantly reduced at comparison of pre- and posttreatment residual tumor for women with pPR (n = 4) (P = .033). A longitudinal analysis showed significant decreases (P = .001) in mean Hb(T) levels during neoadjuvant chemotherapy in breast abnormality ROIs for women with pCR but not women with pPR. For women with pCR, but not women with pPR, pretreatment MVD of CD105-expressing vessels correlated with pretreatment Hb(T) (P ≤ .001).
DOS tomographic examinations in women with breast cancer who are receiving neoadjuvant chemotherapy show a mean decrease in Hb(T) with time in patients with pCR only. Observed pretreatment and posttreatment correlates with quantified angiogenesis markers confirm the likely biologic origin for this DOS signature and support its potential to predict angiogenic tissue response early in the treatment cycle.
http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11100699/-/DC1.
Targeted therapy development in head and neck squamous cell carcinoma (HNSCC) is challenging given the rarity of activating mutations. Additionally, HNSCC incidence is increasing related to human ...papillomavirus (HPV). We sought to develop an in vivo model derived from patients reflecting the evolving HNSCC epidemiologic landscape, and use it to identify new therapies. Primary and relapsed tumors from HNSCC patients, both HPV+ and HPV−, were implanted on mice, giving rise to 25 strains. Resulting xenografts were characterized by detecting key mutations, measuring protein expression by IHC and gene expression/pathway analysis by mRNA-sequencing. Drug efficacy studies were run with representative xenografts using the approved drug cetuximab as well as the new PI3K inhibitor PX-866. Tumors maintained their original morphology, genetic profiles and drug susceptibilities through serial passaging. The genetic makeup of these tumors was consistent with known frequencies of TP53, PI3KCA, NOTCH1 and NOTCH2 mutations. Because the EGFR inhibitor cetuximab is a standard HNSCC therapy, we tested its efficacy and observed a wide spectrum of efficacy. Cetuximab-resistant strains had higher PI3K/Akt pathway gene expression and protein activation than cetuximab-sensitive strains. The PI3K inhibitor PX-866 had anti-tumor efficacy in HNSCC models with PIK3CA alterations. Finally, PI3K inhibition was effective in two cases with NOTCH1 inactivating mutations. In summary, we have developed an HNSCC model covering its clinical spectrum whose major genetic alterations and susceptibility to anticancer agents represent contemporary HNSCC. This model enables to prospectively test therapeutic-oriented hypotheses leading to personalized medicine.
•This HNSCC xenograft model includes all clinical subtypes by location and HPV status.•Mutation profile is representative of seminal sequencing reports (Including NOTCH).•Morphology, gene expression and drug sensitivity are stable over generations.•Cases with PI3KCA alterations were sensitive to the novel PI3K inhibitor PX-866.•PI3K inhibition was effective in two cases harboring NOTCH1 mutations.
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