High-intensity sound:II.effects and applications

New findings of the effects and developments of new applications in high-intensity sound, especially of low frequencies, in recent years, are discussed. These developments not only open up new fields of technology but also affect the physical theory of acoustics.

High-intensity sound:I.fundamentals

significance of non-linear acoustics in aerial sound is discussed. In this instalment, basic theory and effects of high-intensity sound are reviewed, interesting points are stressed and further investigations are suggested.

High-intensity focused ultrasound ablation:An effective bridging therapy for hepatocellular carcinoma patients

AIM:To analyze whether high-intensity focused ultrasound(HIFU) ablation is an effective bridging therapy for patients with hepatocellular carcinoma(HCC).METHODS:From January 2007 to December 2010,49 consecutive HCC patients were listed for liver transplantation(UCSF criteria).The median waiting time for transplantation was 9.5 mo.Twenty-nine patients received transarterial chemoembolization(TACE) as a bringing therapy and 16 patients received no treatment before transplantation.Five patients received HIFU ablation as a bridging therapy.Another five patients with the same tumor staging(within the UCSF criteria) who received HIFU ablation but not on the transplant list were included for comparison.Patients were comparable in terms of Child-Pugh and model for end-stage liver disease scores,tumor size and number,and cause of cirrhosis.RESULTS:The HIFU group and TACE group showed no difference in terms of tumor size and tumor number.One patient in the HIFU group and no patient in the TACE group had gross ascites.The median hospital stay was 1 d(range,1-21 d) in the TACE group and two days(range,1-9 d) in the HIFU group(P < 0.000).No HIFU-related complication occurred.In the HIFU group,nine patients(90%) had complete response and one patient(10%) had partial response to the treatment.In the TACE group,only one patient(3%) had response to the treatment while 14 patients(48%) had stable disease and 14 patients(48%) had progressive disease(P = 0.00).Seven patients in the TACE group and no patient in the HIFU group dropped out from the transplant waiting list(P = 0.559).CONCLUSION:HIFU ablation is safe and effective in the treatment of HCC for patients with advanced cirrhosis.It may reduce the drop-out rate of liver transplant candidate.

High-intensity focused ultrasound treatment for patients with unresectable pancreatic cancer

BACKGROUND: High-intensity focused ultrasound (HIFU) is a non-invasive method of solid tissue ablation therapy. However, only a few studies have reported the effect of HIFU for unresectable pancreatic cancer. This study aimed to evaluate the clinical benefits, survival time and complications associated with the use of HIFU ablation in patients with unresectable pancreatic cancer. METHODS: Twenty-five patients with unresectable pancreatic cancer were enrolled in our study. All patients received HIFU therapy for tumors at least once. The therapeutic effects of HIFU was evaluated in terms of Karnofsky performance status (KPS) scores, pain relief, serum CA19-9, and imaging by B-US and CT before and after the therapy. We also recorded median overall survival time and complications caused by the treatment. RESULTS: In the 25 patients, KPS scores were above 60, and increased KPS was observed in 23 patients after treatment. Pain relief occurred in 23 patients. Serum CA19-9 levels were significantly reduced one month after HIFU treatment and became negative in 5 patients. B-US revealed enhanced tumor echogenicity in 13 patients and decreased tumor blood supply in 9. Tumor necrosis was confirmed by CT in 8 patients one month after HIFU treatment. The median overall survival time was 10 months, and the 1-year survival rate was 42%. No severe complications were observed after HIFU treatment. CONCLUSION: HIFU can effectively relieve pain, increase KPS, decrease tumor growth and prolong the survival time of patients with unresectable pancreatic cancer.

Safety trial of high-intensity focused ultrasound therapy for pancreatic cancer

AIM:To evaluate the safety and clinical application of high-intensity focused ultrasound(HIFU)therapy for unresectable pancreatic cancer(PC).METHODS:Thirty PC patients(16 cases in stage III and 14 cases in stage IV)with visualized pancreatic tumors were admitted for HIFU therapy as an optional local therapy in addition to systemic chemotherapy or chemoradiotherapy.Informed consent was obtained.This study began at the end of 2008 and was approved by the ethics committee of our hospital[Institutional Review Board(IRB):890].The HIFU device used was the FEP-BY02(Yuande Bio-Medical Engineering,Beijing,China).RESULTS:The mean tumor size after HIFU therapy changed to 30.9±1.7 mm from 31.7±1.7 mm at pre-therapy.There were no significant changes in tumor size,mean number of treatment sessions(2.7±0.1 mm),or mean total treatment time(2.4±0.1 h).The rate of symptom relief effect was 66.7%.The effectiveness of primary lesion treatment was as follows:complete response,0;partial response,4;stable disease,22;progressive disease,4.Treatment after HIFU therapy included 2 operations,24 chemotherapy treatments,and 4 best supportive care treatments.Adverse events occurred in 10%of cases,namely pseudocyst formation in 2 cases and mild pancreatitis development in 1.However,no severe adverse events occurred in this study.CONCLUSION:We suggest that HIFU therapy is safe and has the potential to be a new method of combination therapy for PC.

Enhancement of antitumor vaccine in ablated hepatocellular carcinoma by high-intensity focused ultrasound

AIM:To investigate whether tumor debris created by high-intensity focused ultrasound(HIFU)could trigger antitumor immunity in a mouse hepatocellular carcinoma model. METHODS:Twenty C57BL/6J mice bearing H22 hepatocellular carcinoma were used to generate antitumor vaccines.Ten mice underwent HIFU ablation,and the remaining 10 mice received a sham-HIFU procedure with no ultrasound irradiation.Sixty normal mice were randomly divided into HIFU vaccine,tumor vaccine and control groups.These mice were immunized with HIFU-generated vaccine,tumor-generated vaccine,and saline,respectively.In addition,20 mice bearing H22 tumors were successfully treated with HIFU ablation. The protective immunity of the vaccinated mice was investigated before and after a subsequent H22 tumor challenge.Using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide assay,the cytotoxicity of splenic lymphocytes co-cultured with H22 cells wasdetermined in vitro before the tumor challenge,and tumor volume and survival were measured in vivo after the challenge in each group.The mechanism was also explored by loading the vaccines with bone marrowderived dendritic cells(DCs). RESULTS:Compared to the control,HIFU therapy, tumor-generated and HIFU-generated vaccines significantly increased cytolytic activity against H22 cells in the splenocytes of the vaccinated mice(P<0.001). The tumor volume was significantly smaller in the HIFU vaccine group than in the tumor vaccine group(P <0.05)and control group(P<0.01).However,there was no tumor growth after H22 rechallenge in the HIFU therapy group.Forty-eight-day survival rate was 100%in mice in the HIFU therapy group,30%in both the HIFU vaccine and tumor vaccine groups,and 20% in the control group,indicating that the HIFU-treated mice displayed significantly longer survival than the vaccinated mice in the remaining three groups(P< 0.001).After bone marrow-derived DCs were incubated with HIFU-generated and tumor-generated vaccines, the number of mature DCs expressing MHC-Ⅱ + ,CD80 + and CD86 + molecules was significantly increased,and interleukin-12 and interferon-γlevels were significantly higher in the supernatants when compared with immature DCs incubated with mouse serum(P<0.001). However,no differences of the number of mature DCs and cytokine levels were observed between the HIFU- generated and tumor-generated vaccines(P>0.05). CONCLUSION:Tumor debris remaining after HIFU can improve tumor immunogenicity.This debris releases tumor antigens as an effective vaccine to develop host antitumor immune response after HIFU ablation.

The Efficacy of High-Intensity Focused Ultrasound (HIFU) in Advanced Pancreatic Cancer

OBJECTIVE To observe the efficacy of high-intensity focused ultrasound (HIFU) in the treatment of late-stage pancreatic cancer. METHODS Sixteen patients with advanced pancreatic cancer received HIFU therapy.Evaluation of efficacy was made on the basis of changes in clinical symptoms and variations in the tumor echo and size. RESULTS Clinical symptoms such as pain were significantly alleviated,echo of the tumor was enhanced with B-US and the quality of life such as eating,sleeping and mental status was markedly improved;no serious complications were observed. CONCLUSION The use of HIFU in the treatment of advanced pancreatic cancer is feasible and safe.It is effective in killing the carcinoma cells and alleviating pain.This technique may offer non-invasive therapy for the treatment of patients with late-stage pancreatic cancer.

High-intensity focused ultrasound ablation as a bridging therapy for hepatocellular carcinoma patients awaiting liver transplantation

The scarcity of liver grafts in Asia leads to a significant dropout of patients from liver transplant waiting lists, particularly patients with hepatocellular carcinoma and a low model for end-stage liver disease score. In order to reduce dropping out, different bridging therapies are employed. We report the use of high-intensity focused ultrasound ablation as a bridging therapy for a patient with hepatocellular carcinoma of stage two and an extremely low platelet count (20×10 9 /L). The ablation was successful. Blood tests showed that his liver function was similar before and after the treatment. No adhesion was encountered in the liver transplantation performed six months later.

The feasibility and safety of high-intensity focused ultrasound combined with low-dose external beam radiotherapy as supplemental therapy for advanced prostate cancer following hormonal therapy

The aim of this study was to investigate the feasibility and safety of high-intensity focused ultrasound （HIFU） combined with （＋） low-dose external beam radiotherapy （LRT） as supplemental therapy for advanced prostate cancer （PCa） following hormonal therapy （HT）. Our definition of HIFU＋LRT refers to treating primary tumour lesions with HIFU in place of reduced field boost irradiation to the prostate, while retaining four-field box irradiation to the pelvis in conventional-dose external beam radiotherapy （CRT）. We performed a prospective, controlled and non-randomized study on 120 patients with advanced PCa after HT who received HIFU, CRT, HIFU＋LRT and HT alone, respectively. CT/MR imaging showed the primary tumours and pelvic lymph node metastases visibly shrank or even disappeared after HIFU ＋LRT treatment. There were significant differences among four groups with regard to overall survival （OS） and disease-specific survival （DSS） curves （P=0.018 and 0.015）. Further comparison between each pair of groups suggested that the long-term DSS of the H IFU ＋ LRT group was higher than those of the other three groups, but there was no significant difference between the HIFU＋LRT group and the CRT group. Multivariable Cox＇s proportional hazard model showed that both HIFU＋LRT and CRT were independently associated with DSS （P=0.001 and 0.035） and had protective effects with regard to the risk of death. Compared with CRT, HIFU ＋LRT significantly decreased incidences of radiation-related late gastrointestinal （GI） and genitourinary （GU） toxicity grade ≥ II. In conclusion, long-term survival of patients with advanced PCa benefited from strengthening local control of primary tumour and reRional lymph node metastases after HT. As an alternative to CRT, HIFU＋LRT showed Rood efficacy and better safety.

Sequential transcatheter arterial chemoembolization,three-dimensional conformal radiotherapy,and high-intensity focused ultrasound treatment for unresectable hepatocellular carcinoma patients

The purpose of this study was to evaluate the outcome of patients with unresectable hepatocellular carcinoma（HCC） treated by sequential therapy of transcatheter arterial chemoembolization（TACE）,three-dimensional conformal radiotherapy（3-DCRT） and high-intensity focused ultrasound（HIFU）.From October,2005 to September,2010,120 patients with unresectable HCC received the sequential treatments of several courses of TACE followed in 2-4 weeks by 3-DCRT and then a single session of HIFU with a curative intent.The median tumor irradiation dose was 40 Gy.Tumor response,toxicity and overall survival rate were analyzed.Clinicopathologic factors affecting the primary technique effectiveness and overall survival rates were investigated by univariate analysis or multivariate analysis.All 120 HCC patients were followed up by the last follow-up time.Among these patients,hepatic toxicities due to treatment were notable in 9 cases.Gastrointestinal bleeding after the overall treatment occurred in 2 cases,leukopenia of grade III was detected in 1 case,radiation-induced liver disease（RILD） was observed in 2 patients,and first-and second-degree skin burn around the HIFU treatment zone were observed in 2 patients and 1 patient,respectively.Among 120 patients,23,83 and 14 cases achieved partial response,stable disease and progressive disease,respectively.The overall survival rates at 1 year,3 years and 5 years were 70%,35% and 15%,respectively,with a median survival time of 26 months.Both Child-Pugh liver function grading and radiation dose were determined to be independent predictors for overall survival revealed by the multivariate analysis.It is concluded that the sequential therapy of TACE,3-DCRT and HIFU is a promising therapeutic regimen for unresectable HCC.

Experimental Study on the Effect of High-intensity Focused Ultrasound (HIFU) Using Sonablate-500 in the Ablation of Canine Prostate

To investigate the safety, feasibility and effectiveness of transrectal high-intensity focused ultrasound （HIFU） in the ablation of canine prostate, 20 dogs were divided randomly into 5 groups. Sixteen canine prostates were treated with the third-generation transrectal HIFU device （Sonablate-500^TM）. Transrectal ultrasound images of the prostate and prostatic urethra were observed preoperatively and postoperatively. Serial study was performed 30 min, 30 days, 60 days and 180 days after the therapy. The rectum, periprostatic tissues, and prostate were excised en bloc and the tissues were fixed for gross and histological analysis. Our results showed that the average maximal diameter of prostatic urethra was 0.59-0.11 cm before the operation and 2.57±0.98 cm 60 days after the operation. The volume of prostate was 6.5±3.12 cm^3 before the treatment while the volume was 4.13±0.23 cm^3 60 days after the treatment and the differences were statistically significant （P〈0.05）. Histologically, there was a clear demarcation between the necrotic area of the treated tissues and the unaffected surrounding tissues. All the necrotic tissues in the targeted zone broke off and the prostatic urethra became cavitary 60 days later. The more frequent complications were urinary retention and frequency and hematuria. No rectal injury occurred during the treatment. It is concluded that the third-generation transrectal HIFU is capable of destroying prostatic tissue, substantially increasing the width of the prostatic urethra without causing injury to the adjacent tissues. The risk of postoperative complications associated with HIFU was low. HIFU may become a safe, effective and minimally invasive alternative for the treatment of prostatic diseases.

In vivo hyperthermia effect induced by high-intensity pulsed ultrasound

Hyperthermia effects （39-44 ℃） induced by pulsed high-intensity focused ultrasound （HIFU） have been regarded as a promising therapeutic tool for boosting immune responses or enhancing drug delivery into a solid tumor. However, previous studies also reported that the cell death occurs when cells are maintained at 43 ℃ for more than 20 minutes. The aim of this study is to investigate thermal responses inside in vivo rabbit auricular veins exposed to pulsed HIFU （1.17 MHz, 5300 W/cm2, with relatively low-duty ratios （0.2%-4.3%）. The results show that： （1） with constant pulse repetition frequency （PRF） （e.g., 1 Hz）, the thermal responses inside the vessel will increase with the increasing duty ratio; （2） a temperature elevation to 43 ℃ can be identified at the duty ratio of 4.3%; （3） with constant duty ratios, the change of PRF will not significantly affect the temperature measurement in the vessel; （4） as the duty ratios lower than 4.3%, the presence of microbubbles will not significantly enhance the thermal responses in the vessel, but will facilitate HIFU-induced inertial cavitation events.

Treatable focal region modulated by double excitation signal superimposition to realize platform temperature distribution during transcranial brain tumor therapy with high-intensity focused ultrasound

Recently, the phase compensation technique has allowed the ultrasound to propagate through the skull and focus into the brain. However, the temperature evolution during treatment is hard to control to achieve effective treatment and avoid over-high temperature. Proposed in this paper is a method to modulate the temperature distribution in the focal region. It superimposes two signals which focus on two preset different targets with a certain distance. Then the temperature distribution is modulated by changing triggering time delay and amplitudes of the two signals. The simulation model is established based on an 82-element transducer and computed tomography （CT） data of a volunteer＇s head. A finite- difference time-domain （FDTD） method is used to calculate the temperature distributions. The results show that when the distances between the two targets respectively are 7.5-12.5 mm on the acoustic axis and 2.0-3.0 mm in the direction perpendicular to the acoustic axis, a focal region with a uniform temperature distribution （64-65 ℃） can be created. Moreover, the volume of the focal region formed by one irradiation can be adjusted （26.8-266.7 mm3） along with the uniform temperature distribution. This method may ensure the safety and efficacy of HIFU brain tumor therapy.

Ventral hernia after high-intensity focused ultrasound ablation for uterine fibroids treatment:A case report

BACKGROUND High-intensity focused ultrasound(HIFU) ablation is a minimally invasive approach in gynecology that is used to manage uterine fibroids.Although this procedure is safe and effective,adverse outcomes are becoming a major problem.CASE SUMMARY We present a case of ventral hernia that occurred as a rare and delayed complication of HIFU ablation for uterine fibroids treatment.The patient came to the hospital with abdominal bloating that occurred 6 mo after ultrasound-guided HIFU ablation for managing uterine fibroids.The ventral hernia,which occurred due to atrophied muscle layers following the procedure,was confirmed by imaging studies and intraoperative findings.She required a hernia repair with mesh and hysterectomy for definitive treatment of uterine fibroid.CONCLUSION High-intensity ultrasound ablation should be performed only on appropriate candidates.Patients should be educated about potential complications of the procedure and the possibility of subsequent treatment.Post-procedural long-term follow-up for detecting delayed adverse effects is important.

The clinical efficacy of percutaneous ethanol-lipiodol injection(PEI)combined with high-intensity focused ultrasound(HIFU)for small hepatocellularcarcinoma in special or high-risk locations

Objective The objective of this study was to explore the short-term effects and postoperative complications of ultrasound-guided percutaneous ethanol-lipiodol injection(PEI)combined with high-intensity focused ultrasound(HIFU)for the treatment of small hepatocellular carcinoma in a special or high-risk location.Methods Forty patients with small liver cancer in a special or high-risk location were randomly divided into two groups:20 patients were treated with PEI combined with HIFU(P+H group),and 20 patients were treated with HIFU alone(H group).There were no significant differences in average age,liver function,tumor location,tumor number,or tumor size between the two groups(P>0.05).Results Significant differences were observed in ablation parameters between the two groups(P<0.05).Under the same power,ablation rates of the P+H group were significantly higher than those in the H group,and postoperative complications in the P+H group were significantly lower than those in the H group(P<0.05).Conclusion The combination of PEI and HIFU has better clinical value than HIFU alone for small-cell liver cancer in special or high-risk locations.

Seismic Reduction and Isolation Design Strategies for Bridges in High-Intensity Earthquake Areas

High-intensity earthquakes can cause severe damage to bridges,buildings,and ground surfaces,as well as disrupt human activities.Such earthquakes can create long-distance,high-intensity surface movements that negatively impact bridge structures.This article delves into the seismic reduction and isolation design strategies for bridges in high-intensity earthquake areas.It analyzes various seismic reduction and isolation technologies and provides case studies to help relevant units understand the design strategies of these technologies.The results of this article can be used as a guideline to effectively enhance the seismic performance of bridges in high-intensity earthquake areas.

Analysis of the Risk of Water Breakout in the Bottom Plate of High-Intensity Mining of Extra-Thick Coal Seams

In order to clarify the danger of water breakout in the bottom plate of extra-thick coal seam mining, 2202 working face of a mine in the west is taken as the research object, and it is proposed to use the on-site monitoring means combining borehole peeping and microseismic monitoring, combined with the theoretical analysis to analyze the danger of water breakout in the bottom plate. The results show that: 1) the theoretically calculated maximum damage depth of the bottom plate is 27.5 m, and its layer is located above the Austrian ash aquifer, which has the danger of water breakout;2) the drill hole peeping at the bottom plate of the working face shows that the depth of the bottom plate fissure development reaches 26 m, and the integrity of the water barrier layer has been damaged, so there is the risk of water breakout;3) for the microseismic monitoring of the anomalous area, the bottom plate of the return air downstream channel occurs in the field with a one-week lag, which shows that microseismic monitoring events may reflect the water breakout of the underground. This shows that the microseismic monitoring events can reflect the changes of the underground flow field, which can provide a reference basis for the early warning of water breakout. The research results can provide reference for the prediction of sudden water hazard.

Effects of high-intensity focused ultrasound combined with interventional chemoembolization on the advanced cervical cancer lesion growth and cell invasion

Objective:To study the effects of high-intensity focused ultrasound (HIFU) combined with interventional chemoembolization on the advanced cervical cancer lesion growth and cell invasion.Methods:Patients with stage IIB-IVA cervical cancer treated in Suining Hospital of TCM between May 2014 and October 2016 were selected and randomly divided into two groups, HIFU group received HIFU combined with interventional chemoembolization, and the control group accepted interventional chemoembolization. The levels of tumor markers in serum as well as the expression of tumor suppressor genes and invasion genes in tumor lesions were determined before and after treatment.Results: 2 weeks, 3 weeks and 4 weeks after treatment, serum TK-1, SCC and CA125 levels of both groups were lower than those before treatment, serum TK-1, SCC and CA125 levels of HIFU group 2 weeks after treatment were not different from those of control group, and serum TK-1, SCC and CA125 levels of HIFU group 3 weeks and 4 weeks after treatment were significantly lower than those of control group;4 weeks after treatment, AIF, NDRG4, SARI and eIF4E3 mRNA expression in tumor lesions of both groups were higher than those before treatment while FAK, KGFR and MMP9 mRNA expression were lower than those before treatment, and AIF, NDRG4, SARI and eIF4E3 mRNA expression in tumor lesions of HIFU group were higher than those of control group while FAK, KGFR and MMP9 mRNA expression were lower than those of control group.Conclusion: HIFU combined with interventional chemoembolization can be more effective in suppressing the advanced cervical cancer lesion growth and cell invasion than interventional chemoembolization alone.

Numerical simulations of partial elements excitation for hemispherical high-intensity focused ultrasound phased transducer

The hemispherical phased transducer maximizes the coverage of the skull and the ultrasonic energy per unit area of the skull is minimized,thereby reducing the risk of skull burns,but the transducer has a small focal area adjustment range,increasing the focal length of treatment is an urgent question for this type of transducer.In this paper,a three-dimensional high-intensity focused ultrasound(HIFU)transcranial propagation model is established based on the human head structure.The finite difference time domain(FDTD)is combined with the Westervelt acoustic wave nonlinear propagation equation and Penne's biological heat conduction equation for numerical simulation of the sound pressure field and temperature field.Forming a treatable focal area in a small-opening hemispherical transducer with a small amount of numerical simulation calculation focusing at a set position to determine the minimum partial excitation area ratio of focusing.And then,applying these preliminary results to a large-opening diameter hemispherical transducer and the temperature field formed by it or full excitation is studied.The results show that the focus area with the excitation area ratio of less than 22%moves forward to the transducer side when the excitation sound is formed.When the excitation area ratio is greater than or equal to 23%,it focuses at the set position.In the case of partial incentives,using 23%of the partial array,the adjustable range of the treatable focal area formed in the three-dimensional space is larger than that of the full excitation.

Single application of high-intensity focused ultrasound as primary therapy of localized prostate cancer:Treatment-related predictors of biochemical outcomes

Objective:Recent reports on high-intensity focused ultrasound(HIFU)treatment of localized prostate cancer suggest that preoperative risk groups of tumor recurrence are strong predictors of oncological outcomes.The purpose of this study is to determine the prognostic significance of treatment-related factors in relation to patient characteristics for biochemical outcomes after HIFU.Methods:This retrospective single-center study included patients treated from December 2002 to December 2010 for localized prostate cancer with two generations of AblathermHIFU devices(A1 and A2).All the patients underwent single HIFU treatment session under the concept of whole-gland therapy.Prostate surgery was performed before HIFU to downsize enlarged glands.Androgen deprivation therapy(ADT)was discontinued before HIFU.Biochemical failure(BCF)was defined as prostate specific antigen(PSA)nadir t 1.2 ng/mL(Stuttgart definition).Predictors of BCF were determined using Cox regression models.As covariates,patient-related factors(age,tumor characteristics,ADT)were compared with treatmentrelated factors(prostate volume,HIFU device generation,conduct of therapy,prostate edema,patient movement,anesthetic modalities).Results:Three hundred and twenty-three(98.8%)out of 327 consecutive patients were evaluable for BCF.Median(interquartile range)follow-up was 51.2(36.6e80.4)months.The overall BCF-rate was 23.8%.In multivariate analyses,higher initial PSA-values(Hazard ratio[HR]:1.03;p<0.001)and higher D’Amico risk stages(HR:3.45;p<0.001)were patient-related predictors of BCF.Regarding treatment-related factors,the A2 HIFU device was associated with a decreased risk of BCF(HR:0.51;p Z 0.007),while prostate edema had an adverse effect(HR:1.8;p Z 0.027).Short follow-up and retrospective study design are the primary limitations.Conclusion:Success in a single HIFU session depends not merely on tumor characteristics,but also on treatment-related factors.Ablation is more efficacious with the technically advanced A2 HIFU device.Heat-induced prostate edema might adversely affect the outcome.