| Preface:Uterine fibroid is the most common benign tumor of the femalereproductive system and the research of high intensity focused ultrasound(HIFU) treatment for symptomatic uterine fibroids receives more and more attention.HIFU is a rapidly developing method in recent years. It is a completelynon-invasive method of treating tumors and its effective treatment of benign andmalignant tumors have been clinically proven. However, ultrasonic energyattenuation occurs during the propagation due to tissue absorption, reflection,scattering, resulting in a longer irradiation time of HIFU and low treatmentefficiency. Therefore, how to improve the efficiency of HIFU treatment and shortentreatment time has become a research hot. Improving HIFU ablation effect hasbecome a common hot topic of concern in HIFU research area and has potentiallyhuge research and application value. Research has shown that, in HIFU treatmentprocess, some substances can used to change the acoustic environment organizationto increase ultrasound energy deposition in target tissue. Such substances are knownas HIFU synergist.HIFU synergist can alter acoustic environment, increase high-intensity focusedultrasound energy deposition, and improve the efficiency of tumor therapy fromthree aspects: firstly, applying the higher acoustic impedance substances to increaseits acoustic impedance difference between biological tissue, thereby enhancing thethermal effect; secondly, applying effective nuclear to reduce cavitation threshold ofultrasonic cavitation, enhancing the thermal effect; Thirdly, changing the internalbiological tissue blood supply state, reducing the target energy loss, therebyincreasing high-intensity focused ultrasound energy target tissue deposition.This study discusses the effectiveness of ethanol as a synergist used in HIFUtreatment, and the safety and effectiveness of HIFU treatment combined with ethanol for uterine fibroids. In addition, the application effect of oxytocin on the treatmenteffect is discussed.OBJECTIVE:In this study, the bovine liver tissue and uterine fibroids underwent injection ofethanol and then high intensity focused ultrasound (HIFU), their bovine liver tissueand the target tissue leiomyoma sonographic gray scale and the damage effect ofuterine are analyzed. The objective is to provide a strong theoretical basis forimproving the high-intensity focused ultrasound ablation efficiency. The feasibility,safety and effectiveness of HIFU treatment combined with anhydrous ethanolinjection are discussed. Compared with the pure HIFU treatment, the clinical efficacyand side effects are explored. And the application effect of oxytocin on the treatmenteffect is discussed.Material and Method:1〠Freshly slaughtered bovine liver tissue in vitro is immersed in aconcentration of0.9%saline. Parts containing less blood vessels and connectivetissue are selected and cut into the size of40mm×40mm×40mm(a total of40), andwere randomly divided into the experimental group and the control group. At roomtemperature, they are conventional degassed for30minutes. In the experimentalgroup, guided by ultrasound therapy to percutaneous ethanol21G needle is used tocut the central direction of bovine liver tissue piercing with2ml ethanol injection.30min later they are underwent high-intensity focused ultrasound irradiation of JCtype of focused ultrasound tumor therapy system (provided by the Chongqing HIFUTechnology Co.,). Ultrasonic transducer frequency is0.8MHz, power0-400W(continuous wave form output) and physics focal region is1.5mm×1.5mm×10mm.The degassed water is used as the medium. HIFU setting parameters are: the spotscanning, irradiation depth (focused ultrasound beam from the surface of the tumorfocus to the incident direction)20mm, a single irradiation time1s, interval2s, thenumber of repetitions5, treatment probe power200W, frequency0.8MHz, focallength155mm. The control group with saline instead of ethanol and the other settings are the same with the experimental group. Then irradiated target B-graychange and the longest diameter of the bovine coagulation necrosis of the liverformed by high-intensity focused ultrasound are recorded, and then the cow liver arecut into slices at room temperature, fixed in10%formalin solution for24hours,phosphate buffer (Phosphate buffer solution, PBS) wash, embedded in paraffin,sliced, hematoxylin-eosin (HE) staining. At last, the difference of HE staining ofliver colored area between the two groups are calculated.2ã€Select surgical dissection uterine fibroid tissue within six hours, soaked insaline. Select fibroids without liquefaction necrosis of tissue and cut them into20mm×20mm×20mm square (a total of40). They were randomly divided intoexperimental and control groups (20each group). At room temperature, they areconventional degassed for30minutes. In the experimental group, guided byultrasound therapy, percutaneous ethanol21G needle is used for center fibroid tissuepenetration with2ml ethanol injection. Thirty minutes later they are underwenthigh-intensity focused ultrasound irradiation. HIFU setting parameters are: the spotscanning, irradiation depth (focused ultrasound beam from the surface of the tumorfocus to the incident direction)20mm, a single irradiation time1s, interval2s, thenumber of repetitions5, treatment probe power200W, frequency0.8MHz, focallength155mm. The control group with saline instead of ethanol and the othersettings are the same with the experimental group. Then irradiated target B-graychange and the longest diameter of the coagulation necrosis of the liver formed byhigh-intensity focused ultrasound after1sã€5sã€10s are recorded, and then theirradiation fibroid tissues are cut into slices at room temperature, fixed in10%formalin solution for24hours, phosphate buffer (Phosphate buffer solution, PBS)wash, embedded in paraffin, sliced, hematoxylin-eosin (HE) staining. At last, thedifference of HE staining of liver colored area between the two groups arecalculated.3ã€Forty hospitalized patients with uterine fibroids (a total of52fibroids) in ourhospital from December2011to March2012were chosen as our sample population. They are aged from27to47, with an average age of41.5±5.6; their fibroidsdiameters were from40to121mm, with an average of62.2±17.0mm. The selectioncriteria were:(1) those at childbearing age;(2) those who had a strong desire topreserve the uterus and refuse to undergo surgery;(3) those with fibroids that could beclearly seen in the ultrasound location and had a secure treatment channel;(4) thosewho could communicate with doctors easily; and (5) those who were not allergic toalcohol. The exclusion criteria were:(1) pregnant and lactating women;(2) those whohad other gynecological diseases (such as vaginitis, pelvic inflammation, cervicalcancer and other tumors);(3) those who had connective tissue disease;(4) thosewhose abdomen underwent large doses (≥45G y) of radiotherapy;(5) those who hadcerebral infarction or cerebral hemorrhage within six months; and (6) those who hadsevere heart, brain, lung, kidney and other system diseases.They were randomly divided into two groups of the same size: Group H andGroup H+A, each consisting of20patients. All the patients took an abdominalultrasound examination (with Color Doppler) after admission, and weresemi-quantitatively classified according to the blood supply of fibroids. Grade0: noblood flow signal; Grade1: a few blood flows, with1-2spotty blood flow signals;Grade2: a medium amount of blood flows, with a major blood vessel longer than theradius of fibroid, or2to3small blood vessels indicated; Grade3: a rich amount ofblood flows, with more than4blood vessels interconnected; Grade4: very richblood flows, with more than4blood vessels interconnected like reticulation, ordiameter of blood vessel larger than3mm. All patients underwent pelvic admissionenhanced magnetic resonance equipment (philips3.0T Achieva), abdomen phasedarray surface coil, the patient supine, surface coil placed in the center of the bed, thebody midline sagittal plane is consistent with the bed, collecting center alignment theupper edge of the pubic bone. Axial unenhanced MRI: T2-weighted SPAIR (fatsuppression) sequence, T1-weighted FSE sequences; coronal: T2-weighted SPAIR(fat suppression) sequence; sagittal: T2-weighted SPIR (fat suppression) sequence;dynamic contrast-enhanced MRI Scan using Gd contrast agent (Omniscan15ml), sagittal: five consecutive, T1-weighted sequences e-THRIVE; transverse position:T1-weighted sequences e-THRIVE. T2-weighted measure fibroids in maximumdiameter (mm) and the shortest distance between the surface and the second deepestfibroids between caudal (mm). The results are confirmed that there is no exception.Eating preparation begins three days before the treatment. The evening before thetreatment day the patients took conduction that produces no gas. On treatment day,they underwent the cleansing enema, lower abdominal skin preparation, degreasing,degassing and indwelling catheter. According to the body weight, a certain amountof fentanyl and midazolam is given, so that patients achieve grade rating Ramsy3-4.This is necessary for the patient to tolerate the unpleasant treatment, maintainadequate cardiorespiratory function, while they can make the appropriate response tolanguage and light touch stimulation. It is suitable to make patients have sedationscore less than4. Pain score ranges from0to10points:0is painless and10is theworst pain imaginable. Fifteen minutes before treatment intravenous infusion ofoxytocin is applied (Shanghai Hefeng Pharmaceutical Co., Ltd., specification:1ml:10units, the drip rate of30drops/min, a dose of0.12U/min) until the end ofsurgery.H group patients were on the treatment bed of JC type focused ultrasoundtumor therapy system, prone position, surface ECG connection monitoring of vitalsigns, intravenous fluids, bladder poured into the appropriate amount of saline40℃,regular observation urine output. Airborne ultrasound is used to scan position toensure safe passage to avoid intestinal injury. Then a treatment plan is developed:the power is set to400W and point scanning mode is used to select the appropriatearea for treatment. When lumpy gray increase or significantly increase appear in thetreatment area is used as the overall gradation criteria for real-time evaluation ofeffective treatment and to determine the end time of treatment. H+A group emptiedurine, supine on the couch, surface ECG connection monitoring of vital signs, givingvitamin C3.0g+10%glucose injection500ml infusion. Conventional treatment areaprepped and draped, ultrasound puncture point selection,0.5%lidocaine hydrochloride2ml partial satisfaction after anesthesia, the abdomen or through thevagina. A21G needle is inserted percutaneously alcohol treatment fibroids deepsurface, according to the ethanol in fibroids dispersion range, and injection (fibroidsanteroposterior diameter×long diameter×diameter×0.5233)×1/12to1/20amount of anhydrous ethanol, the maximum amount is not more than30ml, needleinjection hemostasis complete treatment. The next day they underwent another lineof high intensity focused ultrasound therapy, the same process with high-intensityfocused ultrasound therapy group (H group). Statistics for all patients with highintensity focused ultrasound treatment time (s), dose (J). After high-intensity focusedultrasound therapy patients were asked to give pain scores themselves according tothe treatment feelings; according to the International Association of interventionalradiology treatment SIR taxonomy developed for the treatment of complicationswere evaluated. It is divided into A-F Grades: A: without treatment, No adverseconsequences B: there is a simple treatment, observation, no adverse consequences C:necessary hospitalization, length of stay is not long (<48h) D: There are importanttreatment, care rating increases, prolonged hospitalization (>48h) E: permanentsequelae F: death. After HIFU treatment, all the patients immediately took acontrast-enhanced ultrasound imaging examination and pelvic-enhanced MRI thenext day for the evaluation of the therapeutic effect. The volume of thenon-perfusion area of the fibroids in the enhanced MRI was calculated as (fibroid’slength×width×height×0.5233). The therapeutic effect was evaluated as: if thevolume of the non-perfusion area of the fibroids after treatment was equal to orgreater than95%of the corresponding volume before treatment, the treatment wasconsidered to be excellent. One month after the treatment, contrast-enhancedultrasound imaging was performed again to calculate the absorption rate, which wasdefined as the volume of residual necrosis one month after treatment divided by thenecrotic volume of the fibroids immediately after treatment×100%.4ã€Sixty our hospital’s patients diagnosed with uterine fibroids longer than oneyear from June2012to August2012were selected. They aged from33to48, with an average age of40.40±3.81; their fibroids volumes were from33491.20mm3to927057.87mm3, with an average size of109.78±49.29cm3mm3. The selectioncriteria were:(1) those at childbearing age;(2) those who had a strong desire topreserve the uterus and refuse to undergo surgery;(3) those with fibroids that couldbe clearly seen in the ultrasound location and had a secure treatment channel;(4)those who could communicate with doctors easily; and (5) those who were notallergic to alcohol. The exclusion criteria were:(1) pregnant and lactating women;(2)those who had other gynecological diseases (such as vaginitis, pelvic inflammation,cervical cancer and other tumors);(3) those who had connective tissue disease;(4)those whose abdomen underwent large doses (≥45G y) of radiotherapy;(5) thosewho had cerebral infarction or cerebral hemorrhage within six months; and (6) thosewho had severe heart, brain, lung, kidney and other system diseases.The relativeposition of the lesion is evaluated by measuring pelvic fibroids distance from thecoccyx by MRI in patients. By via of transabdominal color doppler ultrasoundexamination, according to the richness of the blood supply to the fibroids inside,semi-quantitative grading is used to evaluate lesions rich blood supply degree.Eligible patients were randomly divided into the application of oxytocin group andthe control group,30patients in each group. Intratumoral ethanol injection therapyfor high-intensity focused ultrasound is completed the day before treatment underultrasound guidance. Using GE LOGIO9color Doppler ultrasound guidedabdominal convex array probe, after local anesthesia, ultrasound-guidedtransabdominal or transvaginal biopsy with21G needle is inserted inside the deepsurface of the fibroids. According to ethanol in fibroids dispersion range,1/12to1/20of fibroid volume of anhydrous ethanol was injected with the maximum amountof not more than30mL and needle injection hemostasis completes the treatment.High Intensity Focused Ultrasound treats before routine skin preparation, cleansingenema, catheter and indwelling catheter. For oxytocin group,15min before treatment,intravenous infusion of oxytocin is made (Shanghai Hefeng Pharmaceutical Co., Ltd.,specification:1ml:10units), adjusting the drip rate of30drops/min, a dose of 0.12U/min; for control group only intravenous infusion of5%dextrose solution ismade. Treatment was carried out under sedation analgesia drug fentanyl andmidazolam, drug dosage calculation based on patient quality. Real-time monitoringof therapeutic ultrasound was performed in order to point the way radiation therapyusing a hierarchical, irradiation power400W. According to gray scale ultrasoundlesions and patient tolerance, the treatment area, the intensity of treatment and dosewere adjusted. In treatment, vital signs monitoring electricity-related adversereactions in patients were recorded. Detailed records of treatment total treatmenttime (min), dose (J), lumpy gray enhanced appearance time (s) were made; aftertreatment the patients underwent pelvic examination contrast enhanced magneticresonance imaging to measure fibroids and non-perfusion head diameter (D1), aboutthe diameter (D2), anteroposterior diameter (D3), the volume of fibroids andnon-perfusion (V) was calculated (V=0.5233×D1×D2×D3); and volumetricablation rate was also calculated.Results：1ã€Ethanol reinforced high intensity focused ultrasound on bovine liver tissuedamage results: for the experimental group (HIFU plus ethanol treatment group),gray enhancement changes of the majority (13/20) of target tissues in bovine livertissue specimens occur immediately while, for the control group, only a minority(6/20) gray enhancement changes occur immediately (P<0.05). The lengths ofexposure ablation zone in the experimental group was significantly greater thanthose in control group (P <0.05). After HE staining, the color of staining necroticarea is shallow for most of the experimental group (15/20) on the slide, and mostcontrol group (16/20) shows homogeneous staining slides and no stainingdifferences. Through light microscopy it can be seen two specimens target cell gapwidened, membrane disintegration, have clear and non-target decomposition, and theexperimental group is more significant. This is because the experimental groupunderwent the bovine liver ethanol injection before focused ultrasound treatment andmake coagulation necrosis occur deep in the tissue surface area, leading to in the high-intensity "damage-damage interference effects", so that the ablation necrosislump hyperechoic proliferation is faster, the extent of necrosis is more thoroughly. Atthe same time the participation of ethanol can reduce the incidence of cavitationthreshold power, promote internal tissue temperature, so as to improve the ablationefficiency. Therefore, ultrasound-guided HIFU combined with injection of ethanolcan make the target tissue ablation range more thorough, immediate effect moreprecise. This shows that ethanol can play a role of synergist in the bovine liver tissueHIFU damage.2ã€Ethanol enhanced high-intensity focused ultrasound uterine fibroids damageeffects: high-intensity focused ultrasound irradiation1second,5seconds,10secondslater, the occur number of gray enhanced target tissue change cases in two specimensare: the experimental group were3/20,15/20, and20/20cases, respectively; thecontrol group were0/20,6/20, and11/20cases, respectively. After HIFU irradiation,the maximum necrosis diameter in experimental group was significantly higher: theexperimental group was10.65±2.48(mm); the control group was8.93±2.97(mm)(P <0.05). Through light microscopy, it can be seen two specimens target cell gapwidened membrane disintegration, have clear and non-target decomposition. Theexperimental group, compared with the control group, is more significant. Thisshows that, in human uterine fibroids HIFU damage, ethanol can play a positive role:at the same point in time, ethanol uterine fibroids increased the number of injurycases, aggravated injury, and is an effective synergist for high-intensity focusedultrasound treatment of uterine fibroids.3ã€High Intensity Focused Ultrasound (HIFU) combined with ultrasound-guidedpercutaneous ethanol injection for the treatment of uterine fibroids. HIFU in thetreatment of uterine blood flow grade:1cases grade1,18cases of grade2,0casesof grade3,1cases of grade4; HIFU plus ethanol treatment group：2casesof grade1,17cases of grade2，0cases of3level,1cases of4level. About patients’age, fibroid average volume, flow grade, fibroids distance from the coccyx, thedifference was not statistically significant (P>0.05). The impact of treatment between the two groups is the same, and, therefore, the results can be compared. ForH+A group, patients’ treatment time (2478.20±991.00) S and therapeutic dose(991280±396402) J were significantly less than those of H group (1714.25±666.55) S,(685700±266621) J,(P <0.05); for H+A group, necrotic fibroid volumeafter treatment percentage accounting for fibroids before treatment is (99.13±1.41)%; group H is (92.86±2.25)%; Excellent treatment is defined as the necrosisvolume of the fibroids accounting for95%or more of the total fibroid volume beforethe treatment. The excellent treatment of H+A group was significantly higher thanthat of H group (P <0.05). Contrast enhanced ultrasound and pelvic MRI showedcontrast agent filling before treatment and no contrast agent filling area (fibroidnecrosis) after treatment. But H+A group’s fibroid borders were clearer, sharperthan H group. With the same conditions described, combined with high-intensityfocused ultrasound tumor under ultrasound-guided percutaneous ethanol injectionspend less time with greater efficiency, for therapeutic purposes, and the effect ismore precise. This also proves that the former high-intensity focused ultrasoundtherapy to intratumoral injection of ethanol, high-intensity focused ultrasound canenhance the effects of treatment and ethanol can be used as a high-intensity focusedultrasound treatment of uterine fibroids synergist. H+A group’s pain scores (4.80±1.54) was significantly lower than that of H group (3.55±1.64)(P <0.05). H+Agroup’s incidence of side effects was lower than that of H group (P <0.05).High-intensity focused ultrasound combined with percutaneous ethanol injectiontherapy, compared with simple high intensity focused ultrasound therapy, reduces thediscomfort and side effects of patients after treatment. Thus, the use of high intensityfocused ultrasound combined with ultrasound-guided intratumoral anhydrousethanol injection treatment for uterine fibroids can maximize the anti-tumor effectwithout harming normal cells, shorten treatment time and reduce postoperative sideeffects. It can provide strong technical support for further high-intensity focusedultrasound therapy. Fibroids necrosis volume immediate after treatment and onemonth later necrotic fibroid volume and residual volume and absorption volume comparison: differences between H+A group and H group were not statisticallysignificant (P>0.05). It shows that absorption may be associated with fibroidspersonal physique, regardless of the cause of fibroids necrosis, and since thefollow-up time is short, we can not determine the long-term efficacy of the twogroups, and it needs further observation.4〠Oxytocin in high-intensity focused ultrasound combined withultrasound-guided intratumoral anhydrous ethanol injection for the treatment ofuterine fibroids: For the oxytocin group, fibroid volume ablation rate (92.38±2.07)%; lumpy gray appearance time (150.70±57.51) s; the total treatment energy(556835.0±202583) J, the total treatment time (116.70±28.61) min. For the controlgroup, fibroid volume ablation rate (92.81±2.53)%; lumpy gray appearance time(165.77±77.13) s; the total treatment energy (512610.0±158004) J, the totaltreatment time (107.40±23.22) min. The difference between the two groups has nostatistical difference. It shows that oxytocin in high-intensity focused ultrasoundcombined with ultrasound-guided intratumoral anhydrous ethanol injection in thetreatment of uterine fibroids did not play a synergistic role, the reason is thatoxytocin ‘s role model is: uterine smooth muscle contraction, blood oppression→vasoconstriction→improve the sound environment and improve the efficiency ofhigh-intensity focused ultrasound therapy. However, since ethanol’s role in thesmooth muscle fibers of uterine fibroids coagulation necrosis has occurred, it isdifficult for oxytocin receptors to play a role causing oxytocin invalidation.Therefore, in the treatment of high-intensity focused ultrasound combined withultrasound-guided intratumoral ethanol injection for uterine fibroids, oxytocin cannot further improve the treatment effect, and therefore, has no obvious applicationvalue.ConclusionsAnhydrous ethanol is an effective synergist for high intensity focusedultrasound ablation, which can expand coagulation necrosis zone length afterhigh-intensity focused ultrasound irradiation. Compared with the pure HIFU treatment, the Ultrasound guided HIFU treatment of ethanol injection in thetreatment of uterine fibroids requires less time and dose, less side reaction, and ismore effective. This technology is a feasible, safe, effective treatment method.In the treatment of HIFU combined with ultrasound-guided intratumoralethanol injection for uterine fibroids, oxytocin can not further improve the treatmenteffect, and therefore, has no obvious application value.Innovation points1. This study shows that, compared with the pure HIFU treatment, theUltrasound guided HIFU treatment of ethanol injection in the treatment of uterinefibroids requires less time and dose, less side reaction, and is more effective. Thestudy provides strong technical support for further high-intensity focused ultrasoundclinical therapy. High-intensity focused ultrasound combined with ultrasound-guidedpercutaneous ethanol injection for treatment of uterine fibroids combines theadvantages of both approaches, and make up with each other’s shortcomings, andprovides a new idea for enhancing the treatment of uterine tumors. There is nosimilar report at home and abroad, which is the main innovation of this study.2. In HIFU treatment for uterine fibroids, intravenous oxytocin and intratumoralethanol injection are two different ways of improving the efficiency of high-intensityfocused ultrasound therapy. Through the discussion of their mechanisms, combinedwith the final treatment results, in HIFU combined with intratumoral ethanolinjection treatment for uterine fibroids, oxytocin failed to further improve thetreatment efficiency, and has no clear value. At present, there is no similar study athome and abroad, which is another innovative point of this study. |
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