Dataset Information

Precision Medicine Starts With Preanalytics: Real-Time Assessment of Tissue Fixation Quality by Ultrasound Time-of-Flight Analysis.

ABSTRACT: Personalized medicine promises diagnosis and treatment of disease at the individual level and relies heavily on clinical specimen integrity and diagnostic assay quality. Preanalytics, the collection and handling steps of a clinical specimen before immunohistochemistry or other clinical assay, are critically important to enable the correct diagnosis of disease. However, the effects of preanalytics are often overlooked due to a lack of standardization and limited assessment tools to quantify their variation. Here, we report a novel real-time ultrasound time-of-flight instrument that is capable of monitoring and imaging the critical step in formalin fixation, diffusion of the fixative into tissue, which provides a quantifiable quality metric for tissue fixation in the clinical laboratory ensuring consistent downstream molecular assay results. We analyzed hundreds of tissue specimens from 34 distinct human tissue types and 12 clinically relevant diseased tissues for diffusion and fixation metrics. Our measurements can be converted into tissue diffusivity constants that correlate with the apparent diffusion constant calculated using magnetic resonance imaging (R=0.83), despite the differences in the approaches, indicating that our approach is biophysically plausible. Using data collected from time-of-flight analysis of many tissues, we have therefore developed a novel rapid fixation program that could ensure high-quality downstream assay results for a broad range of human tissue types.

SUBMITTER: Lerch ML

PROVIDER: S-EPMC5359782 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Precision Medicine Starts With Preanalytics: Real-Time Assessment of Tissue Fixation Quality by Ultrasound Time-of-Flight Analysis.

Lerch Melissa L ML Bauer Daniel R DR Chafin David D Theiss Abbey A Otter Michael M Baird Geoffrey S GS

Applied immunohistochemistry & molecular morphology : AIMM 20170301 3

Personalized medicine promises diagnosis and treatment of disease at the individual level and relies heavily on clinical specimen integrity and diagnostic assay quality. Preanalytics, the collection and handling steps of a clinical specimen before immunohistochemistry or other clinical assay, are critically important to enable the correct diagnosis of disease. However, the effects of preanalytics are often overlooked due to a lack of standardization and limited assessment tools to quantify their ...[more]

PMID: 28027117

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Project description:The purpose of these clinical studies was to validate a Tissue Change Monitoring (TCM) algorithm in vivo. TCM is a quantitative tool for the real-time assessment of HIFU dose. TCM provides quantitative analysis of the backscatter pulse echo signals (pre and immediately post HIFU) for each individual ablative site, using ultrasonic tissue characterization as a surrogate for monitoring tissue temperature. Real-time analysis generates an energy difference parameter (?E in dB) that is proportional to tissue temperature.Post in vitro studies, two clinical studies were conducted to validate the TCM algorithm on the Sonablate® device. Studies enrolled histologically confirmed, organ confined prostate cancer patients. The first clinical study was conducted in two phases for whole gland ablation. First eight patients' data were used to measure the algorithm performance followed by 89 additional patients for long term outcome. The second clinical study enrolled five patients; four patients with focal cancer had hemi-ablation only and one had whole gland ablation. Four 3 Fr. needles containing three thermocouples each were placed transperineally in the prostate to record tissue temperatures in the focal zone, posterior to the focal zone and on the lateral gland where no HIFU was applied. Tissue temperatures from the focal zone were correlated to the ?E parameter.In the first clinical study, the average TCM rate was 86%. Pre and 6 months post HIFU, median PSA was 7.64 and 0.025 ng/ml respectively and 97% patients had negative biopsy. For the second clinical study, the measured prostate tissue temperatures (Average, Max, and Min) in the ablation zones were 84°, 114° and 60 °C and the corresponding ?E (dB/10) parameters were 1.05, 2.6 and 0.4 resulting in 83% of temperatures in the range of 75°-100 °C and 17% in the 60°-74 °C range. Outside the focal zone, the average temperature was 50 °C and in the lateral lobe where no HIFU was applied, peak temperature was 40.7 °C.The TCM algorithm is able to estimate tissue changes reliably during the HIFU procedure for prostate tissue ablation in real-time and can be used as a guide for HIFU dose delivery and tissue ablation control.

Project description:Modern histopathology is built on the cornerstone principle of tissue fixation, however there are currently no analytical methods of detecting fixation and as a result, in clinical practice fixation is highly variable and a persistent source of error. We have previously shown that immersion in cold formalin followed by heated formalin is beneficial for preservation of histomorphology and have combined two-temperature fixation with ultra-sensitive acoustic monitoring technology that can actively detect formalin diffusing into a tissue. Here we expand on our previous work by developing a predictive statistical model to determine when a tissue is properly diffused based on the real-time acoustic signal. We trained the model based on the morphology and characteristic diffusion curves of 30 tonsil cores. To test our model, a set of 87 different tonsil samples were fixed with four different protocols: dynamic fixation according to our predictive algorithm (C/H:Dynamic, N = 18), gold-standard 24 hour room temperature (RT:24hr, N = 24), 6 hours in cold formalin followed by 1 hour in heated formalin (C/H:6+1, N = 21), and 2 hours in cold formalin followed by 1 hour in heated formalin (C/H:2+1, N = 24). Digital pathology analysis revealed that the C/H:Dynamic samples had FOXP3 staining that was spatially uniform and statistically equivalent to RT:24hr and C/H:6+1 fixation protocols. For comparison, the intentionally underfixed C/H:2+1 samples had significantly suppressed FOXP3 staining (p<0.002). Furthermore, our dynamic fixation protocol produced bcl-2 staining concordant with standard fixation techniques. The dynamically fixed samples were on average only submerged in cold formalin for 4.2 hours, representing a significant workflow improvement. We have successfully demonstrated a first-of-its-kind analytical method to assess the quality of fixation in real-time and have confirmed its performance with quantitative analysis of downstream staining. This innovative technology could be used to ensure high-quality and standardized staining as part of an expedited and fully documented preanalytical workflow.

Dataset Information

Precision Medicine Starts With Preanalytics: Real-Time Assessment of Tissue Fixation Quality by Ultrasound Time-of-Flight Analysis.

Publications

Precision Medicine Starts With Preanalytics: Real-Time Assessment of Tissue Fixation Quality by Ultrasound Time-of-Flight Analysis.

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