Association of Valproic Acid and Its Main Metabolites' Plasma Concentrations with Clinical Outcomes among Epilepsy Patients: A 10-Year Retrospective Study Based on Therapeutic Drug Monitoring.

Valproic acid (VPA) is a first-line antiepileptic drug with broad efficacy. Due to significant individual differences in its metabolism, therapeutic drug monitoring is commonly used. However, the recommended therapeutic range (50-100 µg/mL) is inadequate for predicting clinical outcomes. Additionally, the relationship between VPA metabolites and clinical outcomes remains unclear. In this retrospective study, 485 Chinese Southern Han epilepsy patients receiving VPA monotherapy were analyzed after reaching steady-state levels. Plasma concentrations of VPA and its five main metabolites were determined by liquid chromatography-mass spectrometry (LC-MS). We assessed the relevance of the recommended therapeutic VPA range for clinical outcomes and explored the association between VPA/metabolites levels and treatment efficacy/adverse effects. Vitro experiments were conducted to assess 4-ene-VPA hepatotoxicity. The therapeutic range of VPA exhibited no significant correlation with clinical outcomes, and plasma concentrations of VPA failed to serve as predictive indicators for treatment response/adverse effects. Treatment responders had higher 2-PGA concentrations (median, 26.39 ng/mL versus 13.68 ng/mL), with a threshold of 36.5 ng/mL for optimal epilepsy treatment. Patients with abnormal liver function had a higher 4-ene-VPA median concentration (6.41 µg/mL versus 4.83 µg/mL), and the ratio of 4-ene-VPA to VPA better predicted VPA-induced hepatotoxicity (area under the curve, 0.718) than 4-ene-VPA concentration. Vitro experiments revealed that 4-ene-VPA was more hepatotoxic than VPA in HepaRG and L02 cell lines. Total plasma VPA concentration does not serve as a predictor of clinical outcomes. 2-PGA concentrations may be associated with efficacy, whereas the ratio of 4-ene-VPA to VPA may be considered a better biomarker (threshold 10.03%) for VPA-induced hepatotoxicity. SIGNIFICANCE STATEMENT: This was the first and largest observational cohort in China to explore the relationship between patients' parent and metabolites concentrations of VPA and clinical outcomes during the maintenance of VPA monotherapy in epileptic patients. This study provided feasible references of VPA for epilepsy clinical treatment with a larger sample of patients compared with previous studies for a more definitive conclusion based on real-world situations. We found two potential biomarkers in predicting efficacy and liver injury, respectively. This breakthrough has the potential to assist in the rational use of VPA.

Biomechanical properties of articular cartilage in different regions and sites of the knee joint: acquisition of osteochondral allografts.

Osteochondral allograft (OCA) transplantation involves grafting of natural hyaline cartilage and supporting subchondral bone into the cartilage defect area to restore its biomechanical and tissue structure. However, differences in biomechanical properties and donor-host matching may impair the integration of articular cartilage (AC). This study analyzed the biomechanical properties of the AC in different regions of different sites of the knee joint and provided a novel approach to OCA transplantation. Intact stifle joints from skeletally mature pigs were collected from a local abattoir less than 8 h after slaughter. OCAs were collected from different regions of the joints. The patella and the tibial plateau were divided into medial and lateral regions, while the trochlea and femoral condyle were divided into six regions. The OCAs were analyzed and compared for Young's modulus, the compressive modulus, and cartilage thickness. Young's modulus, cartilage thickness, and compressive modulus of OCA were significantly different in different regions of the joints. A negative correlation was observed between Young's modulus and the proportion of the subchondral bone (r = - 0.4241, P < 0.0001). Cartilage thickness was positively correlated with Young's modulus (r = 0.4473, P < 0.0001) and the compressive modulus (r = 0.3678, P < 0.0001). During OCA transplantation, OCAs should be transplanted in the same regions, or at the closest possible regions to maintain consistency of the biomechanical properties and cartilage thickness of the donor and recipient, to ensure smooth integration with the surrounding tissue. A 7 mm depth achieved a higher Young's modulus, and may represent the ideal length.

Development of a Dual Factor Activatable Covalent Targeted Photoacoustic Imaging Probe for Tumor Imaging.

Photoacoustic imaging (PAI) is an emerging modality in biomedical imaging with superior imaging depth and specificity. However, PAI still has significant limitations, such as the background noise from endogenous chromophores. To overcome these limitations, we developed a covalent activity-based PAI probe, NOx-JS013, targeting NCEH1. NCEH1, a highly expressed and activated serine hydrolase in aggressive cancers, has the potential to be employed for the diagnosis of cancers. We show that NOx-JS013 labels active NCEH1 in live cells with high selectivity relative to other serine hydrolases. NOx-JS013 also presents its efficacy as a hypoxia-responsive imaging probe in live cells. Finally, NOx-JS013 successfully visualizes aggressive prostate cancer tumors in mouse models of PC3, while negligibly detected in tumors of non-aggressive LNCaP mouse models. These findings show that NOx-JS013 has the potential to be used to develop precision PAI reagents for detecting metastatic progression in various cancers.

The Effects of Drug Exposure and Single Nucleotide Polymorphisms on Aaptinib-Induced Severe Toxicities in Solid Tumors.

To investigate the value of drug exposure and host germline genetic factors in predicting apatinib (APA)-related toxicities. METHOD: In this prospective study, plasma APA concentrations were quantified using liquid chromatography with tandem mass spectrometry, and 57 germline mutations were genotyped in 126 advanced solid tumor patients receiving 250 mg daily APA, a vascular endothelial growth factor receptor II inhibitor. The correlation between drug exposure, genetic factors, and the toxicity profile was analyzed. RESULTS: Non-small cell lung cancer (NSCLC) was more prone to APA-related toxicities and plasma concentrations of APA, and its main metabolite M1-1 could be associated with high-grade adverse events (AEs) (P < 0.01; M1-1, P < 0.01) and high-grade antiangiogenetic toxicities (APA, P = 0.034; P < 0.05), including hypertension, proteinuria, and hand-foot syndrome, in the subgroup of NSCLC. Besides, CYP2C9 rs34532201 TT carriers tended to have higher levels of APA (P < 0.001) and M1-1 (P < 0.01), whereas CYP2C9 rs1936968 GG carriers were predisposed to higher levels of M1-1 (P < 0.01). CONCLUSION: Plasma APA and M1-1 exposures were able to predict severe AEs in NSCLC patients. Dose optimization and drug exposure monitoring might need consideration in NSCLC patients with CYP2C9 rs34532201 TT and rs1936968 GG. SIGNIFICANCE STATEMENT: Apatinib is an anti-VEGFR2 inhibitor for the treatment of multiple cancers. Though substantial in response, apatinib-induced toxicity has been a critical issue that is worth clinical surveillance. Few data on the role of drug exposure and genetic factors in apatinib-induced toxicity are available. Our study demonstrated a distinct drug-exposure relationship in NSCLC but not other tumors and provided invaluable evidence of drug exposure levels and single nucleotide polymorphisms as predictive biomarkers in apatinib-induced severe toxicities.

Photoacoustic Imaging of COVID-19 Vaccine Site Inflammation of Autoimmune Disease Patients.

Based on the observations made in rheumatology clinics, autoimmune disease (AD) patients on immunosuppressive (IS) medications have variable vaccine site inflammation responses, whose study may help predict the long-term efficacy of the vaccine in this at-risk population. However, the quantitative assessment of the inflammation of the vaccine site is technically challenging. In this study analyzing AD patients on IS medications and normal control subjects, we imaged the inflammation of the vaccine site 24 h after mRNA COVID-19 vaccinations were administered using both the emerging photoacoustic imaging (PAI) method and the established Doppler ultrasound (US) method. A total of 15 subjects were involved, including 6 AD patients on IS and 9 normal control subjects, and the results from the two groups were compared. Compared to the results obtained from the control subjects, the AD patients on IS medications showed statistically significant reductions in vaccine site inflammation, indicating that immunosuppressed AD patients also experience local inflammation after mRNA vaccination but not in as clinically apparent of a manner when compared to non-immunosuppressed non-AD individuals. Both PAI and Doppler US were able to detect mRNA COVID-19 vaccine-induced local inflammation. PAI, based on the optical absorption contrast, shows better sensitivity in assessing and quantifying the spatially distributed inflammation in soft tissues at the vaccine site.

Novel Clinical Biomarkers for Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) remains a critical clinical issue and has been a treatment challenge today as it was in the past. However, the traditional biomarkers or indicators are insufficient to predict the risks and outcome of patients with DILI due to its poor specificity and sensitivity. Recently, the development of high-throughput technologies, especially omics and multiomics has sparked growing interests in identification of novel clinical DILI biomarkers, many of which also provide a mechanistic insight. Accordingly, in this minireview, we summarize recent advances in novel clinical biomarkers for DILI prediction, diagnosis, and prognosis and highlight the limitations or challenges involved in biomarker discovery or its clinical translation. Although huge work has been done, most reported biomarkers lack comprehensive information and more specific DILI biomarkers are still needed to complement the traditional biomarkers such as alanine aminotransferase (ALT) or aspartate transaminase (AST) in clinical decision-making. SIGNIFICANCE STATEMENT: This current review outlines an overview of novel clinical biomarkers for drug-induced liver injury (DILI) identified in clinical retrospective or prospective clinical analysis. Many of these biomarkers provide a mechanistic insight and are promising to complement the traditional DILI biomarkers. This work also highlights the limitations or challenges involved in biomarker discovery or its clinical translation.

Age differential response to bevacizumab therapy in choroidal neovascularization in rabbits.

Choroidal neovascularization (CNV) in young rabbits has been shown to have a rapid, robust response after treatment with bevacizumab, an anti-vascular endothelial growth factor (VEGF) medication. This investigation evaluates an age differential response to bevacizumab in older populations of rabbits using multimodal high resolution molecular imaging. Young (4 months old) and life span (14 months old) rabbits were given subretinal injections of Matrigel and VEGF to produce CNV. All CNV rabbit models were then treated with a bevacizumab intravitreal injection. Rabbits were then monitored longitudinally using photoacoustic microscopy (PAM), optical coherence tomography (OCT), color photography, and fluorescence imaging. Chain-like gold nanoparticle clusters (CGNP) conjugated with tripeptide arginylglycylaspartic acid (RGD) was injected intravenously for molecular imaging. Robust CNV developed in both young and old rabbits. After intravitreal bevacizumab injection, fluorescence signals were markedly decreased 90.13% in the young group. In contrast, old rabbit CNV area decreased by only 10.56% post-bevacizumab treatment. OCT images confirmed a rapid decrease of CNV in the young group. CGNPs demonstrated high PAM signal in old rabbits and minimal PAM signal in young rabbits after bevacizumab, indicating CNV regression. There is a significant difference in response to intravitreal bevacizumab treatment between young and old rabbits with CNV which can be monitored with multimodal molecular imaging. Old rabbits demonstrate significant persistent disease activity. This represents the first large eye model of persistent disease activity of CNV and could serve as the foundation for future investigations into the mechanism of persistent disease activity and the development of novel therapies.

Rational application of gefitinib in NSCLC patients with sensitive EGFR mutations based on pharmacokinetics and metabolomics.

Gefitinib has been available in the market for 20 years, but its pharmacokinetic mechanism of response is little known. In this study, we examined the pharmacokinetic and metabolomic profiles in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. A total of 216 advanced NSCLC patients were enrolled, and administered gefitinib at the standard dosage of 250 mg/day, which was established in heterogeneous subjects with non-sensitive mutations. We identified and quantified three main metabolites (named as M1, M2 and M3) in the plasma of patients, the correlations between the concentration of gefitinib/metabolites and efficacy were analyzed. In exploratory and validation set, gefitinib concentration was not correlated with clinical effects. Considering the result that the therapeutic effects of 250 mg/2-day was better than that of 250 mg/day in a multiple center clinical trial, the standard dose might be higher than that for maximal efficacy according to the hypothetical dose-response curve. Among the three metabolites, the IC50 of M2 in HCC827 and PC9 cell lines was significantly lower, and Conc.brain/Conc.plasma of M2 in mice was significantly higher than those of gefitinib, suggesting its higher potential to penetrate blood-brain barrier and might be more effective in the treatment of brain metastatic tumor than gefitinib. Consistently and attractively, higher M2 plasma concentration was found to be correlated with better clinical outcome in patients with brain metastases (the median PFS of CM2 < 12 ng/mL and CM2 ≥ 12 ng/mL were 17.0 and 27.1 months, respectively, P = 0.038). The plasma concentration of M2 ≥ 12 ng/mL was a strong predictor of the PFS of NSCLC patients. In conclusion, for NSCLC patients with EGFR sensitive mutations, the standard dose is suspectable and could be decreased reasonably. M2 plays an important role in efficacy and may be more effective in the treatment of metastatic tumor than gefitinib.

Photo-mediated ultrasound therapy for the treatment of retinal neovascularization in rabbit eyes.

OBJECTIVES: Retinal neovascularization (RNV) is the growth of abnormal microvessels on the retinal surface and into the vitreous, which can lead to severe vision loss. By combining relatively low-intensity ultrasound and nanosecond-pulse-duration laser, we developed a novel treatment method, namely photo-mediated ultrasound therapy (PUT), which holds a potential to remove RNV with minimal or no damage to the adjacent tissues. METHODS: RNV was created in both albino and pigmented rabbits (n = 10) through a single intravitreal injection with DL-α-aminoadipic acid. RNV was treated with PUT 8 weeks postinjection. After PUT treatment, animals were evaluated longitudinally for up to 6 weeks. Treatment outcomes were evaluated through fundus photography, red-free fundus photography, fluorescein angiography (FA), and histopathology. RESULTS: In both albino and pigmented rabbits, there were no leakage in the treatment area immediately after PUT treatment as demonstrated by FA, indicating the cessation of blood perfusion of the RNV in the treated area. The fluorescence leakage did not recover in albino rabbits during the 6-week posttreatment monitoring period, and only 9.9 ± 9.8% of the neovascularization remained at the end of 6 weeks. In the pigmented rabbits, the fluorescence leakage partially returned, but the level of leakage decreased over time during the 6-week posttreatment monitoring period, and only 10.8 ± 9.8% of the neovascularization remained at the end of 6 weeks. Histology demonstrated removal of vasculature without damage to the surrounding neurosensory retina. CONCLUSIONS: These results demonstrate that PUT could precisely remove RNV without damage to the surrounding neurosensory retina in both rabbit strains.

LC-MS/MS quantification of levetiracetam, lamotrigine and 10-hydroxycarbazepine in TDM of epileptic patients.

BACKGROUND: To minimize drug-related toxicity and monitor dosing regimens, an ultra-sensitive, simple and high-throughput analytical method for therapeutic drug monitoring is required. A novel LC-MS/MS bioassay of levetiracetam, lamotrigine and 10-hydroxycarbazepine in human plasma was established. The analytes were separated on a Hypersil GOLD™ C18 column under a 2.5 min isocratic elution after one-step protein precipitation. MS detection was performed under electrospray ionization positive-mode fitted with selected reaction monitoring. The validated ranges were 0.1-20 µg/ml for LTG, 0.3-60 µg/ml for 10-hydroxycarbazepine and levetiracetam. The intra- and inter-batches of precision and accuracy was within ±15%. The novel method met all other criteria. CONCLUSION: This method can be used to monitor drug concentrations and decision-making in epileptic patients.

Retinal safety evaluation of photoacoustic microscopy.

Photoacoustic microscopy (PAM) has significant potential as a promising diagnostic method for eye diseases and can provide anatomic and functional information of the retinal and choroidal vasculature. However, there are no FDA-approved PAM systems for ophthalmic imaging. In this study, a comprehensive safety evaluation was performed to evaluate the safety of PAM retinal imaging and whether PAM causes damage to retinal structure or function in rabbit eyes. 12 Dutch-Belted pigmented rabbits received photoacoustic imaging to 57% of the retinal surface area with a laser energy of 5% of the ANSI safety limit for five consecutive days and followed before imaging and 3 days, 1, 2, 3, and 4 weeks post imaging. Retinal morphologic analyses using slit lamp examination, fundus photography, red free, FA, FAF, ICGA, and OCT showed no retinal hemorrhage, edema, detachment, vascular abnormalities, or pigmentary abnormalities in the retina or choroid after PAM imaging. Full-field ERG analysis showed no significant difference in scotopic or photopic a- and b-wave amplitudes or implicit times between the control and experimental eyes over time (n = 6, P values > 0.05). Retinal ultrastructural evaluation using TEM showed normal structure of organelles and nuclei, and no significant loss of cells after PAM. TUNEL assay showed no evidence of cells apoptosis in retina. Retinal histopathology indicated that the architecture and thickness of the retinal layers was well preserved in all experimental eyes. A positive control at 500% of the ANSI limit demonstrated significant damage. The comprehensive retinal safety evaluation demonstrated no damage to retinal structure or function for 4 weeks after PAM imaging in rabbits.

Long-term multimodal imaging characterization of persistent retinal neovascularization using DL-alpha-aminoadipic acid in pigmented and white rabbits.

PURPOSE: Intravitreal (IVT) injection of DL-alpha-aminoadipic acid (AAA) is a new animal model for retinal neovascularization (RNV) reported in rabbits. This study performs longitudinal multimodal imaging for up to 1 year to evaluate DL-AAA RNV in both New Zealand white (NZW) rabbits and Dutch-Belted pigmented (DBP) rabbits. METHOD: Detailed characterization and quantification of this model were performed in these two strains in 32 eyes by optical coherence tomography (OCT), fundus photography, and fluorescein angiography (FA) for up to 16 weeks following DL-AAA administration in 32 eyes and up to 52 weeks in 5 eyes. H & E histology was also performed in these two strains 8 weeks after injection of DL-AAA. RESULT: RNV was successfully generated using 50 µL 80 mM DL-AAA solution for DBP rabbits and 80 µL 80 mM DL-AAA for NZW rabbits. The incidence of persistent vascular leakage is 100% (15/15) for DBP rabbits and 70.6% (12/17) for NZW rabbits at 16 weeks. Complications with NZW rabbits ultimately decreased the efficiency in NZW rabbits to 58.8% (10/17) of NZW rabbits getting persistent (to 16 weeks) vascular leakage without ocular complications as compared with 100% (15/15) in DBP rabbits. Five eyes (2 DBP and 3 NZW) were selected from those demonstrating RNV at 16 weeks and were monitored for up to 52 weeks. All 5 demonstrated persistent RNV to 52 weeks. Quantification of the mean leakage area (MLA) in DBP rabbits is more accurate than in NZW rabbits since the reduced contrast between the leakage and background in NZW rabbits makes it more challenging to quantify. CONCLUSION: DL-AAA can induce persistent and quantifiable RNV in both DBP and NZW rabbits. DBP rabbits have a higher success rate, lower required volume of DL-AAA, and more accurate method for quantification that could be more desirable.

Low initial trough concentration of rituximab is associated with unsatisfactory response of first-line R-CHOP treatment in patients with follicular lymphoma with grade 1/2.

For follicular lymphoma (FL) with grade 1/2, the complete response (CR) rate of the first-line R-CHOP treatment was significantly low. In this study, we assessed the rationality of the administration of rituximab for FL patients with grade 1/2 based on concentration-response relationship analyses. Thus, we conducted a prospective pharmacokinetic (PK) study in 68 FL patients with grades 1-3 treated with R-CHOP at 21-day intervals. Plasma rituximab concentrations were quantified using ELISA and the population PK modeling was established with Phoenix® NLMETM. The first cycle trough concentration (C1-trough) of rituximab was a significant independent risk factor for achieving CR in matched-pair logistic regression analysis, rather than the concentrations in later cycles; the recommendatory minimum optimal C1-trough was 13.60 µg/mL. Patients with grade 1/2 had significantly lower C1-trough compared with grade 3 (12.21 µg/mL vs. 23.45 µg/mL, P < 0.001), only 30% patients with grade 1/2 could reach 13.60 µg/mL, compared with 91.67% in patients with grade 3, which was in accord with its unsatisfactory CR rates (43.33% vs. 76.32%). The stage indicating the tumor burden (the target) was a crucial influence factor for C1-trough, accounting for 40.70% of its variability, 70% patients with grade 1/2 were stage IV in this study, since the systemic therapy only started at the disseminated disease stage. The initial dose of 1800 mg was recommended by Monte Carlo simulation for patients with grade 1/2. In summary, low C1-trough accounted for low-grade FL's unsatisfactory CR rate, designing the first dosage of rituximab should be a very important component of individualized therapy for FL.

UPLC-QTOF-MS-Based Plasma Lipidomic Profiling Reveals Biomarkers for Inflammatory Bowel Disease Diagnosis.

Identification of new biomarkers may help in the early diagnosis of inflammatory bowel disease (IBD). In this study, ultrahigh-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used to analyze the untargeted lipidomics and compare plasma lipid profiles between IBD patients and control subjects. The principal component analysis and partial least-squares-discriminant analysis were carried out to distinguish IBD patients from control subjects. Using univariate and multivariate analysis, 55 significantly different metabolites from five lipid classes, fatty acyls (n = 19), glycerophospholipids (n = 5), prenol lipids (n = 10), sphingolipids (n = 2), and sterol lipids (n = 19) were identified. Forty-four of the 55 metabolites were analyzed by receiver operating characteristic (ROC) curve and area under curve (AUC) of >0.80. After validation in an independent cohort, IBD patients were differentiated from the control subjects by significantly altered plasma level of palmitic acid, 7alpha, 25-dihydroxycholesterol, 20-hydroxyeicosatetraenoic (HETE)-d6, (+/-)5,6-epoxy-eicosatrienoic acid (EpETrE), docosahexaenoic acid (DHA), 9-heptadecylenic acid, lactucaxanthin, α-carotene, traumatic acid, and neoquassin with both sensitivity and specificity above 80%. Pathway analysis suggested that IBD dysregulation was related to the biosynthesis of primary bile acid, the metabolism of arachidonic acid, the metabolism of sphingolipid, fatty acid elongation, and glycerophospholipid metabolism. Our results suggest that the lipidomic profiling of patients plasma could be a potential method for IBD diagnosis.

Polymorphisms of NF-κB pathway genes influence adverse drug reactions of gefitinib in NSCLC patients.

Gefitinib is a widely used targeted therapeutic drug in East Asian non-small cell lung cancer (NSCLC) patients. This research retrospectively investigated the relationship between the polymorphisms of genes involved in NF-κB pathways and gefitinib-related Adverse Drug Reactions (ADRs). From 2011 to 2016, 109 NSCLC patients were enrolled in this study. Thirty-two SNPs of 15 genes were genotyped with a Sequenom MassARRAY system. We collected 34 paired RNA samples before and after gefitinib administration for the detection of whole blood RNA expression of genes in NF-κB pathways (NFKBIA, NFKB1, NFKB2, RELA, RELB, and TNFAIP3). IKBKB rs2272733 (CC vs non-CC: OR = 0.256, 95% CI 0.087-0.753, P = 0.013) and IKBKE rs12142086 (CC vs non-CC: OR = 3.640, 95% CI 1.320-10.039, P = 0.013) were significantly associated with gefitinib-induced skin toxicity. IKBKE rs2151222 was associated with diarrhea with the odds ratio of non-TT vs TT as 0.162 (non-TT vs TT: 95% CI 0.034-0.775, P = 0.023). Furthermore, RELA rs11227247 was a predictor for hepatic toxicity (GG vs non-GG: OR = 0.212, 95% CI 0.062-0.726, P = 0.013). None of the gene expression levels after drug administration were determined to be significant predictors for adverse drug reactions by a logistics regression analysis. Polymorphisms of IKBKB, IKBKE, and RELA are potential biomarkers for predicting gefitinib-related ADRs. Further studies are needed to understand the underlying mechanisms for diagnostic and prophylactic therapy applications.

Photoacoustic spectral analysis at ultraviolet wavelengths for characterizing the Gleason grades of prostate cancer.

The diagnosis of aggressive prostate cancer (PCa) has relied on microscopic architectures, namely Gleason patterns, of tissues extracted through core biopsies. Technology capable of assessing the tissue architecture without tissue extraction will reduce the invasiveness of PCa diagnosis and improve diagnostic accuracy by allowing for more sampling locations. Our recently developed photoacoustic spectral analysis (PASA) has achieved quantification of tissue architectural heterogeneity interstitially. Taking advantage of the unique optical absorption of cell nuclei at ultraviolet (UV) wavelengths, this study investigated PASA at 266 nm for quantifying the tissue architecture heterogeneity in prostates. The results have shown significant differences among the normal, early cancer, and late cancer stages in mouse prostates ex vivo and in vivo (n=20, p<0.05). The study with human samples ex vivo has shown a correlation of 0.80 (n=11, p<0.05) between PASA quantification and pathologic diagnosis.

Removing Subcutaneous Microvessels Using Photo-Mediated Ultrasound Therapy.

BACKGROUND AND OBJECTIVES: We have developed a novel anti-vascular technique, termed photo-mediated ultrasound therapy (PUT), which utilizes nanosecond duration laser pulses synchronized with ultrasound bursts to remove the microvasculature through cavitation. The objective of the current study is to explore the potential of PUT in removing subcutaneous microvessels. STUDY DESIGN/MATERIALS AND METHODS: The auricular blood vessels of two New Zealand white rabbits were treated by PUT with a peak negative ultrasound pressure of 0.45 MPa at 0.5 MHz, and a laser fluence of 0.056 J/cm2 at 1064 nm for 10 minutes. Blood perfusion in the treated area was measured by a commercial laser speckle imaging (LSI) system before and immediately after treatment, as well as at 1 hour, 3 days, 2 weeks, and 4 weeks post-treatment. Perfusion rates of 38 individual vessels from four rabbit ears were tracked during this time period for longitudinal assessment. RESULTS: The measured perfusion rates of the vessels in the treated areas, as quantified by the relative change in perfusion rate, showed a statistically significant decrease for all time points post-treatment (P < 0.001). The mean decrease in perfusion is 50.79% immediately after treatment and is 32.14% at 4 weeks post-treatment. Immediately after treatment, the perfusion rate decreased rapidly. Following this, there was a partial recovery in perfusion rate up to 3 days post-treatment, followed by a plateau in the perfusion from 3 days to 4 weeks. CONCLUSIONS: This study demonstrated that a single PUT treatment could significantly reduce blood perfusion by 32.14% in the skin for up to 4 weeks. With unique advantages such as low laser fluence as compared with photothermolysis and agent-free treatment as compared with photodynamic therapy, PUT holds the potential to be developed into a new tool for the treatment of cutaneous vascular lesions. Lasers Surg. Med. © 2020 Wiley Periodicals, LLC.

Towards Clinical Translation of LED-Based Photoacoustic Imaging: A Review.

Photoacoustic imaging, with the capability to provide simultaneous structural, functional, and molecular information, is one of the fastest growing biomedical imaging modalities of recent times. As a hybrid modality, it not only provides greater penetration depth than the purely optical imaging techniques, but also provides optical contrast of molecular components in the living tissue. Conventionally, photoacoustic imaging systems utilize bulky and expensive class IV lasers, which is one of the key factors hindering the clinical translation of this promising modality. Use of LEDs which are portable and affordable offers a unique opportunity to accelerate the clinical translation of photoacoustics. In this paper, we first review the development history of LED as an illumination source in biomedical photoacoustic imaging. Key developments in this area, from point-source measurements to development of high-power LED arrays, are briefly discussed. Finally, we thoroughly review multiple phantom, ex-vivo, animal in-vivo, human in-vivo, and clinical pilot studies and demonstrate the unprecedented preclinical and clinical potential of LED-based photoacoustic imaging.

High Resolution Multimodal Photoacoustic Microscopy and Optical Coherence Tomography Visualization of Choroidal Vascular Occlusion.

Photoacoustic microscopy is a novel, non-ionizing, non-invasive imaging technology that evaluates tissue absorption of short-pulsed light through the sound waves emitted by the tissue and has numerous biomedical applications. In this study, a custom-built multimodal imaging system, including photoacoustic microscopy (PAM) and optical coherence tomography (OCT), has been developed to evaluate choroidal vascular occlusion (CVO). CVO was performed on three living rabbits using laser photocoagulation. Longitudinal imaging of CVO was obtained using multiple imaging tools such as color fundus photography, fluorescein angiography, indocyanine green angiography (ICGA), OCT, and PAM. PAM images were acquired at different wavelengths, ranging from 532 to 700 nm. The results demonstrate that the CVO was clearly observed on PAM in both two dimensions (2D) and 3D with high resolution longitudinally over 28 days. In addition, the location and margin of the CVO were distinguished from the surrounding choroidal vasculature after the injection of ICG contrast agent. PAM imaging was achieved using a laser energy of approximately 80 nJ, which is about half of the American National Standards Institute safety limit. The proposed imaging technique may provide a potential tool for the evaluation of different chorioretinal vascular disease pathogeneses and other biological studies.

Chemical Imaging in Vivo: Photoacoustic-Based 4-Dimensional Chemical Analysis.

We describe how 4-dimensional in vivo biochemical analysis can be performed using photoacoustic contrast nanoagents that have been designed to probe both structural and chemical information in vivo, enabling noninvasive, real time, spatially resolved chemical imaging. Early chemical imaging of a patient's tumor can inform the decision of effective treatment, regarding choices of chemotherapy, radiation, or immunotherapy.