Label-free multimodal nonlinear optical imaging of needle biopsy cores for intraoperative cancer diagnosis

Yang, Lingxiao; Park, Jaena; Chaney, Eric J.; Sorrells, Janet E.; Marjanović, Marina; Phillips, Heidi S.; Spillman, Darold R.; Boppart, Stephen A.

doi:10.1117/1.jbo.27.5.056504

Cited by 8 publications

(7 citation statements)

References 59 publications

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“…• More aligned collagen is associated with better response to therapy in ex vivo breast cancer 47 . • Collagen in the canine ex vivo mammary tumor has a higher alignment ratio than in the tumor margin 23 . Fraction of NAD(P)H-rich pixels and a fraction of NAD(P)H-rich EVs Higher NAD(P)H levels may be indicative of more glycolytic metabolism in cells, which is also shown in EVs.…”

Section: Resultsmentioning

confidence: 93%

“…• Collagen in the canine ex vivo mammary tumor has a higher alignment ratio than in the tumor margin 23 .…”

Section: Resultsmentioning

confidence: 98%

“…For example, NADH is a cofactor for LDH and NADPH is a cofactor for NADPH oxidase enzymes. In addition to examining each channel individually, various other metrics can be examined, such as collagen alignment 23 , 24 , extracellular vesicle properties 25 – 27 , and the optical redox ratio (ORR). The ORR is calculated as the intensity of the 2PF channel over the sum of the 2PF and 3PF channels, to approximate the amount of FAD in proportion to the amount of FAD and NAD(P)H in order to assess mitochondrial metabolism of cells 22 , 28 .…”

Section: Introductionmentioning

confidence: 99%

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In vivo label-free optical signatures of chemotherapy response in human pancreatic ductal adenocarcinoma patient-derived xenografts

Park,

Sorrells,

Chaney

et al. 2023

Commun Biol

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Pancreatic cancer is a devastating disease often detected at later stages, necessitating swift and effective chemotherapy treatment. However, chemoresistance is common and its mechanisms are poorly understood. Here, label-free multi-modal nonlinear optical microscopy was applied to study microstructural and functional features of pancreatic tumors in vivo to monitor inter- and intra-tumor heterogeneity and treatment response. Patient-derived xenografts with human pancreatic ductal adenocarcinoma were implanted into mice and characterized over five weeks of intraperitoneal chemotherapy (FIRINOX or Gem/NabP) with known responsiveness/resistance. Resistant and responsive tumors exhibited a similar initial metabolic response, but by week 5 the resistant tumor deviated significantly from the responsive tumor, indicating that a representative response may take up to five weeks to appear. This biphasic metabolic response in a chemoresistant tumor reveals the possibility of intra-tumor spatiotemporal heterogeneity of drug responsiveness. These results, though limited by small sample size, suggest the possibility for further work characterizing chemoresistance mechanisms using nonlinear optical microscopy.

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Section: Resultsmentioning

confidence: 93%

“…• Collagen in the canine ex vivo mammary tumor has a higher alignment ratio than in the tumor margin 23 .…”

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

In vivo label-free optical signatures of chemotherapy response in human pancreatic ductal adenocarcinoma patient-derived xenografts

Park,

Sorrells,

Chaney

et al. 2023

Commun Biol

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“…Linear [9], [10], [11] and nonlinear [12], [13] microscopy modalities have been used to express several different metabolic [14], [15], [16], structural [17], [18], [19], [20], [21], [22] and chemical [23], [24], [25] biomarkers. This wealth of information can be used not only for the diagnosis of excised biopsies [26] or intraoperative assessment [27], but also they can be used to assess the healing process [18], [28], [29].…”

Section: Introductionmentioning

confidence: 99%

Nonlinear Imaging Histopathology: A Pipeline to Correlate Gold-Standard Hematoxylin and Eosin Staining With Modern Nonlinear Microscopy

Tehrani

Park

Chaney

et al. 2023

IEEE J. Select. Topics Quantum Electron.

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Hematoxylin and eosin (H&E) staining, the centuryold technique, has been the gold standard tool for pathologists to detect anomalies in tissues and diseases such as cancer. H&E staining is a cumbersome, time-consuming process that delays and wastes precious minutes during an intraoperative diagnosis. However, even in the modern era, real-time label-free imaging techniques such as simultaneous label-free autofluorescence multiharmonic (SLAM) microscopy have delivered several more layers of information to characterize a tissue with high precision. Still, they have yet to translate to the clinic. The slow translation rate can be attributed to the lack of direct comparisons between the old and new techniques. Our approach to solving this problem is to: 1) reduce dimensions by pre-sectioning the tissue in 500 µm slices, and 2) produce fiducial laser markings which appear in both SLAM and histological imaging. High peak-power femtosecond laser pulses enable ablation in a controlled and contained manner. We perform laser marking on a grid of points encompassing the SLAM region of interest. We optimize laser power, numerical aperture, and timing to produce axially extended marking, hence multilayered fiducial markers, with minimal damage to the surrounding tissues. We performed this co-registration over an area of 3 × 3 mm 2 of freshly excised mouse kidney and intestine, followed by standard H&E staining. Reduced dimensionality and the use of laser markings provided a comparison of the old and new Manuscript

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“…A promising imaging technique for label-free rapid on-site feedback is third harmonic generation (THG) and multiphoton excited autofluorescence (MPEF) microscopy, in short label-free microscopy. This technique provides images of fresh specimens revealing histology information without processing the tissue [4][5][6][7][8]. Previous studies using blood samples have shown that THG signals reveal discriminative information for the different leukocytes, providing cellular and nuclear morphological information [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Differentiation of leukocytes in bronchoalveolar lavage fluid samples using higher harmonic generation microscopy and deep learning

Huizen

Blokker

Rip

et al. 2022

Preprint

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In many diseases such as interstitial lung diseases (ILDs), patient diagnosis relies on diagnostic analysis of bronchoalveolar lavage fluid (BALF) and biopsies. In BALF the differentiation of neutrophils, eosinophils, lymphocytes, and macrophages can contribute to diagnose the underlying ILD entity. To analyze the BALF standard cytological techniques are labor-intensive and time-consuming. Studies have shown promising cell identification performance on blood fractions analyzed by third harmonic generation (THG) and multiphoton excited autofluorescence (MPEF) microscopy. Here, we extend this to BALF samples, and we trained a deep learning algorithm for automated analysis on the image level against reference cytology. We imaged blood fractions from three healthy individuals and one asthma patients, and six BALFs from ILD patients. We determined the leukocyte characteristics in terms of cellular and nuclear morphology, and THG and MPEF signal intensity. A deep learning model was trained on both blood fractions and BALF 2D images was used to estimate the leukocyte ratios by using only the standard cytology differential cell ratios at the image-level as reference. The deep learning network has learned to identify individual cells and was able to provide a reasonable estimate of the leukocyte percentage, coming within a 2 to 10% margin in BALF samples in the hold-out testing set. We suggest that the performance of the combined label free imaging and AI analysis can be improved further by collecting 3D data and data of additional fluid samples of various ILD diseases and healthy samples, THG/MPEF microscopy in combination with deep learning is a promising technique for instant differentiation and quantification of leukocytes. Immediate feedback on leukocyte ratios will not only speed-up the diagnostic process but can also reduce costs, the workload and reduce inter-observer variations.

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Label-free multimodal nonlinear optical imaging of needle biopsy cores for intraoperative cancer diagnosis

Cited by 8 publications

References 59 publications

In vivo label-free optical signatures of chemotherapy response in human pancreatic ductal adenocarcinoma patient-derived xenografts

In vivo label-free optical signatures of chemotherapy response in human pancreatic ductal adenocarcinoma patient-derived xenografts

Nonlinear Imaging Histopathology: A Pipeline to Correlate Gold-Standard Hematoxylin and Eosin Staining With Modern Nonlinear Microscopy

Differentiation of leukocytes in bronchoalveolar lavage fluid samples using higher harmonic generation microscopy and deep learning

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