Forecasting Strategy Study On Uterine Fibroids With Difficulty In Ablation By High Intensity Focused Ultrasound (HIFU)

Ultrasound ablation (UA), under guide of medical image, is able to develop high-energy focus in targeting tissue in vivo through concertrition of low intensity ultrasonic beams, and can only cause coagulative necrosis to tissues in focus region while tissues outside are free of damage. As a non-invasive modality for uterine fibroids, high intensity focused ultrasound(HIFU) ablation, has been applied in an increasingly broader clinical setting due to its safety and effectiveness, minimal invasiveness and the ability to preserve organ without damage to endocrine function. With the development of clinical application, researchers found that some uterine fibroids with difficulty in ablation by HIFU demand high-energy, even increasing dosage, non-perfusion volume (NPV) are still considered to be unsatisfactory. As a result, this portion of uterine fibroids are not suitable for ultrasound ablation. Thus, doctors are urgent in desiring an accurate method to screen and exclude this portion of patients.This project retrospectively studied the relationship between effect of ultrasound ablation for uterine fibroids and energy efficiency factor (EEF) by large sample through conventional MRI, and multivariate analysis on factors influencing EEF was carried out. Preliminarily, a quantitative prediction method based on EEF to analyze factors affecting sonication dose was built. According to study on the correlation between the dosimetry of uterine fibroids with difficulty in ablation by HIFU and functional MRI (DWI, DTI, MRS), we aims to build a functional MRI predicting dosimetry model of HIFU ablation for uterine fibroids, and to obtain value of EEF to quantitatively evaluate uterine fibroids with difficulty in ablation by HIFU. Moreover study on acoustic characteristics and histopathological features of ex vivo sample of uterine fibroids with difficulty in ablation by HIFU was conducted to verify results of multi mode MRI and to completely evaluate characteristics of uterine myoma with difficulty in ablation by HIFU. Finally, through clinical dosimetry guide based on multi mode MRI, it’s expected to provide forecasting strategy for screening patients with difficulty in treatment for uterine fibroids before HIFU ablation, and to optimize HIFU clinical protocol for uterine fibroids.Objective(1) To analyze factors affecting sonication dose and to build a preliminary method to quantitatively evaluate uterine fibroids being difficult to be ablated based on EEF through conventional MRI.(2) To analyze the correlation between the dosimetry of uterine fibroids with difficulty in ablation by HIFU and functional MRI (DWI, DTI, MRS), to build a functional MRI predicting dosimetry model of HIFU ablation for uterine fibroids, and to obtain the EEF value of uterine fibroids with difficulty in ablation by HIFU through quantitative evaluation with functional MRI.(3) To analyze, with multi mode MRI, acoustic characteristics and histopathological features of uterine myomas with difficulty in ablation by HIFU so as to completely evaluate characteristics of uterine fibroids being difficult to be ablated by HIFU.Materials and Methods(1) Four hundred and three patients with 403 uterine fibroids underwent ultrasound guided HIFU (USgHIFU) treatment at the First Affiliated Hospital of Chongqing Medical University from February 2012 to February 2014 were retrospectively analyzed. The energy efficiency factor (EEF) was set as dependent variable, factors possibly affecting sonication dose including age, body mass index (BMI), size of uterine fibroid, abdominal wall thickness, the distance from uterine fibroid dorsal side to sacrum, the distance from uterine fibroid ventral side to skin, location of uterus, location of uterine fibroids, type of uterine fibroids, abdominal wall scar, signal intensity on T2WI, and enhancement type on T1WI were set as predictors to build a multiple regression model. Prediction model for dosimetry was verified by comparing EEF actual value with EEF predicting value. Receiver operating characteristic curve (ROC) was used to analyze predictive value of ablation effect to EEF, and find out cut-off value of EEF.(2) Two hundred and ninety patients who underwent USgHIFU treatment at the First Affiliated Hospital of Chongqing Medical University from March 2014 to January 2015 were included. The DWI and DTI examination for patients were taken by using Singa HD Excite,3.0T (GE healthcare, USA) magnetic resonance imaging system, DWI signal on ADC, MD, FA and RA of myometrium and uterine fibroids were measured. And fiber bundles on DTI were classified as follow:long and dense, short and dense, long and loose, short and loose. The MRS examination for patients were carried out by using Magnetom ESSENZA 1.5T (Siemens, Germany) magnetic resonance imaging system, and Cho/Cr, NAA/Cr, Lip/Cr and Lac/Cr of uterine fibroids were measured. Predicting EEF value was calculated through the dosimetric prediction model established in the part one of this study and was used to classify cases as difficultly ablated group and easily ablated group. Parameters on DWI, DTI and MRS among both groups and myometrium were compared. Correlation between fiber bundle types on DTI and EEF was analyzed. The energy efficiency factor (EEF) was set as dependent variable, the factors possibly affecting sonication dose included DWI signal, ADC on DWI, MD on DTI, FA on DTI, RA on DTI, Cho/Cr on MRS, NAA/Cr on MRS, Lip/Cr on MRS and Lac/Cr on MRS were set as predictors to build a multiple regression model, the EEF between the actual value and the predicting value was compared to verify the functional MRI prediction model for dosimetry. Receiver operating characteristic curve (ROC) analysis on value of EEF for predicting ablation effect was employed, and to find out the cut-off value of EEF for functional MRI prediction.(3) Thirty eight fresh specimens of isolated uterine leiomyoma from thirty eight patients who underwent myomectomy or hysterectomy at the First Affiliated Hospital of Chongqing Medical University from December 2014 to February 2015 were included. Patients underwent examination of functional MRI with ADC on DWI, MD on DTI, FA on DTI, RA on DTI, Cho/Cr on MRS, NAA/Cr on MRS, Lip/Cr on MRS and Lac/Cr on MRS were measured before surgery. And fiber bundles on DTI were classified as follow:long and dense, short and dense, long and loose, short and loose. The postoperative specimens were divided into 4 parts to proceed acoustic detection, HIFU ablation, density measurement and pathological examination. Then, we collected the acoustic parameters of specimens: acoustic velocity and attenuation, the range of gray scale change and necrosis after HIFU ablation, tissue density and histopathological findings.The predicting value of EEF through the dosimetric prediction model established in the part two of this study was calculated, and was used to classify cases as difficultly ablated group and easily ablated group. The results of functional MRI, acoustic parameters, the range of gray scale change and necrosis, tissue density and histopathological findings between two groups were compared.Results(1) The size of uterine fibroid, distance from fibroid ventral side to skin, location of uterus, location of uterine fibroids, type of uterine fibroids, signal intensity on T2WT, and enhancement type on T1WI had a linear correlation with EEF. The distance from fibroid ventral side to skin, enhancement type on T1WI, size of uterine fibroid and signal intensity on T2WI were eventually incorporated into the dosimetry model. The effective dosimetry model through verification which can predict dosage delivery of HIFU for uterine fibroid by conventional MRI has been established in this study:y=0.233×X1+5.623×X2-0.235×X3+2.648xX4. variable:y=EEF; X1=Distance from fibroid ventral side to skin; X2=Enhancement type on T1WI (slight enhancement=1, irregular enhancement=2, progressive enhancement=3); X3=Size of uterine fibroid; X4=Signal intensity on T2WI (hypointense=1, isointense=2, heterogeneous hyperintense=3, markedly homogenous hyperintense=4, slightly homogenous hyperintense=5). And finally this study obtained the quantitative EEF value (≥10.9J/mm3) for forecasting uterine fibroids with difficulty in ablation by HIFU.(2) One hundred and thirty seven patients correspond with the inclusion criteria completed HIFU treatment and DWI examination. According to the classification standard:thirty cases were included in the group of difficult ablation, and one hundred and seven cases in the group of easy ablation; One hundred and thirty four patients correspond with the inclusion criteria completed HIFU treatment and DTI examination. According to the classification standard:twenty nine cases were included in the group of difficult ablation, and one hundred and five cases in the group of easy ablation; One hundred and thirty patients correspond with the inclusion criteria completed HIFU treatment and MRS examination. According to the classification standard:twenty eight cases were included in the group of difficult ablation, one hundred and two cases in the group of easy ablation; One hundred and thirty patients correspond with the inclusion criteria completed HIFU treatment and functional MRI (DWI, DTI and MRS) examination. Comparison of difficult and easy ablation in uterine fibroids:No significant difference was observed with DWI signal, NAA/Cr on MRS and Lip/Cr on MRS. ADC on DWI, MD on DTI and Cho/Cr on MRS are higher in group of difficult ablation. FA on DTI, RA on DTI and Lac/Cr on MRS are lower in group of difficult ablation. The relationship between fiber bundles classification on DTI and degree of difficulty for ultrasound ablation indicates:short and loose> long and loose > short and dense> long and dense. The effective dosimetry model through verification which can predict dosage delivery of HIFU for uterine fibroid by functional MRI has been established in this study:y=0.349×X1 9.676× X2-2.653×X3+5.242×X4. variable:y=EEF; X,=Cho/Cr on MRS; X2=FA on DTI; X3=Lac/Cr on MRS; X4=ADC on DWI. Using ROC analysis of EEF on the predictive value of ablation effective, this study obtained the quantitative EEF value (≥10.7J/mm3) for functional MRI forecasting uterine fibroids with difficulty in ablation by HIFU.(3) Twenty seven specimens of uterine leiomyomas, respectively collected from a total of twenty seven patients with results of acoustic parameters, histopathological findings and functional MRI, were included in the study. According to the grouping criteria, there were ten cases in group of difficult ablation and seventeen cases in group of easy ablation. Comparison of functional MRI parameters on both groups of difficult and easy ablation:Significant difference was observed with ADC on DWI, MD on DTI, FA on DTI, RA on DTI, Cho/Cr on MRS and Lac/Cr on MRS(P<0.05). No significant difference was observed with NAA/Cr on MRS and Lip/Cr on MRS (P>0.05). This result is coincided with the second part of this study. The average density of uterine fibroids with difficulty in ablation is 1.01±0.05 (0.95-1.08)g/ml, which is lower than that of uterine fibroids being easy to be ablated (1.10±0.12 [0.96-1.45] g/ml), and the difference is statistically significant. The average range of gray scale change and necrosis of uterine fibroids difficulty in ablation are 42.6±17.8 (13.3-68.8) mm2 and 22.3±13.1 (5.2-47.4) mm2, both of which are respectively lower than those of uterine fibroids being easy to be ablated (68.2±23.2 [30.4-115.2] mm2 and 43.8±21.8 [10.6-86.7]mm2), and the difference is statistically significant(P<0.05). The average acoustic velocity and attenuation of uterine fibroids with difficulty in ablation are 1561±12(1548-1582)m/s and 1.15±0.52 (0.51-2.22)dB/cm, both of which are respectively lower than those of uterine fibroids being easy to be ablated (1576±16 [1551-1610] m/s and 1.98±0.82 [0.98-3.63] dB/cm) and the difference is statistically significant(P<0.05). The histopathological findings of uterine fibroids with difficulty in ablation mainly present with rich smooth muscle cells and less collagen fiber. The average cells of uterine fibroids with difficulty in ablation under view of 400 times electron microscope is 384±46 (322-450), which is higher than that of uterine fibroids being easy to be ablated (171±55 [89-261]), and the difference is statistically significant (P<0.05).Conclusions(1) The distance from fibroid ventral side to skin, enhancement type on T1WI, size of uterine fibroid and signal intensity on T2WI can be used as predictors for dosimetry guide of HIFU for uterine fibroids.(2) Cho/Cr on MRS, FA on DTI, Lac/Cr on MRS and ADC on DWI from functional MRI can be used as predictors for dosimetry guide of HIFU for uterine fibroids. y=0.349×X19.676×X2-2.653×X3+5.242×X4. variable:y=EEF; X1=Cho/Cr on MRS; X2=FA on DTI; X3=Lac/Cr on MRS; X4=ADC on DWI.(3) Differences of different type uterine fibroids, in microstructure level, can be intuitively and quantitatively visualized by functional MRI from diffusion velocity, direction of water molecules and tissue metabolites so as to objectively and comprehensively evaluate how difficulty in ultrasound ablation for uterine fibroids would be. The quantitative EEF value for functional MRI forecasting uterine fibroids with difficulty in ablation by HIFU is greater than or equal to 10.7J/mm3.(4) The results of acoustics and histopathology of uterine fibroids further explain the reason of diversification on functional MRI. The density, acoustic velocity and acoustic attenuation of uterine fibroids with difficulty in ablation by HIFU are significantly lower than those of uterine fibroids being easily to be ablated by HIFU. The histopathological findings of uterine fibroids with difficulty in ablation by HIFU demonstrate those fibroids present with rich smooth muscle cells and less collagen fiber.