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FLaparoscopy

A Novel Approach to Energy Ablative Therapy of Small RenalTumours: Laparoscopic High-Intensity Focused Ultrasound

H. Christoph Klingler a,*, M. Susani b, R. Seip c, J. Mauermann a, N. Sanghvi c, M. Marberger a

aDepartment of Urology and Pathology, Medical University of Vienna, Vienna, AustriabDepartment of Pathology, Medical University of Vienna, Vienna, AustriacAustria, Focus Surgery Inc, Indianapolis, IN, USA

e u r o p e a n u r o l o g y x x x ( 2 0 0 7 ) x x x – x x x

avai lab le at www.sciencedi rect .com

journa l homepage: www.europeanurology.com

Article info

Article history:Accepted November 7, 2007Published online ahead ofprint on � � �

Keywords:Laparoscopic HIFURenal cell cancerLaparoscopyLaparoscopic partialnephrectomyEnergy ablative techniquesHigh-intensity focusedultrasoundHIFU

Abstract

Objective: High-intensity focused ultrasound (HIFU) permits targetedhomogeneous ablation of tissue. The objective of this phase 1 studywas to evaluate the feasibility of HIFU ablation of small renal tumoursunder laparoscopic control.Patients and methods: Ten kidneys with solitary renal tumours weretreated with a newly developed 4.0 MHz laparoscopic HIFU probe. Inthe first two patients with 9-cm tumours, a defined marker lesion wasplaced prior to laparoscopic radical nephrectomy. In eight patients witha mean tumour size of 22 mm (range, 11–40), the tumour was completelyablated as in curative intent, followed by laparoscopic partial nephrect-omy in seven tumours. One patient had post-HIFU biopsies and wasfollowed radiologically. Specimens were studied by detailed and whole-mount histology, including NADH stains.Results: Mean HIFU insonication time was 19 min (range, 8–42), with amean targeted volume of 10.2 cm3 (range, 9–23). At histological evalua-tion both marker lesions showed irreversible and homogeneous thermaldamage within the targeted site. Of the seven tumours treated andremoved after HIFU, four showed complete ablation of the entiretumour. Two had a 1- to 3-mm rim of viable tissue immediately adjacentto where the HIFU probe was approximated, and one tumour showed acentral area with about 20% vital tissue. There were no intra- or post-operative complications related to HIFU.Conclusion: The morbidity of laparoscopic partial nephrectomy mainlycomes from the need to incise highly vascularized parenchyma. Tar-geted laparoscopic HIFU ablation may render this unnecessary, butfurther studies to refine the technique are needed.

# 2007 Published by Elsevier B.V. on behalf of European Association of Urology.

* Corresponding author. Department of Urology, Medical University of Vienna,Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel. +43 1 404 00 2616; Fax: +43 1 408 99 66.E-mail address: christoph.klingler@meduniwien.ac.at (H.C. Klingler).

0302-2838/$ – see back matter # 2007 Published by Elsevier B.V. on behalf of European Association of Urology. doi:10.1016/j.eururo.2007.11.020

Please cite this article in press as: Klingler HC, et al., A Novel Approach to Energy Ablative Therapy of Small Renal Tumours:

Laparoscopic High-Intensity Focused Ultrasound, Eur Urol (2007), doi:10.1016/j.eururo.2007.11.020

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Fig. 1 – Intraoperative setup with laparoscopic high-

intensity focused ultrasound (HIFU) probe in place (center),

HIFU treatment unit (left), and laparoscopic ultrasound

probe (right).

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1. Introduction

Renal tumours with a diameter <4 cm are reliablycured by partial nephrectomy [1,2], but there is anassociated complication rate of up to �15%, whichmainly comes from the need to incise the highlyperfused renal parenchyma [3]. Less invasive energyablative techniques avoiding this therefore appearattractive, especially when performed through apercutaneous route. Percutaneous needle ablationusing radiofrequency has been utilized extensivelyfor this purpose, but recent meta-analyses reflectresidual tumour/early recurrences in up to 14–18% ofpatients [4,5]. Reports on needle cryoablation givesimilar failure rates [6,7]. The obvious problemcomes from the need for precise percutaneousneedle placement in a mobile organ and a fairlysmall target. Energy ablative techniques adminis-tered under laparoscopic control are more reliablebecause the needles can be placed under visual andlaparoscopic ultrasonography control. Radiofre-quency ablation has an inherent problem of skip-ping even in this situation [8], but cryoablationachieves reliable tumor ablation, with residual/recurrent tumour rates of 1.6% with follow-up over3 yr [9]. Nevertheless, the tumour still has to bepunctured, which may result in bleeding [10] andcarries an inherent risk of tumour cell spillage [11]. Atechnique ablating the tumour clearly appears moreattractive.

High-intensity focused ultrasound (HIFU) avoidsthe need to puncture because ultrasound waves arefocused to achieve high temperatures sufficient forimmediate thermal destruction of all tissues withinthe target zone. Ideally this procedure is done by anextracorporeal approach; however, because of theacoustic complexity of intervening structures andthe mobility of the kidney, attempts at this approachwere unsatisfactory [12]. Such problems are avoidedif the HIFU transducer is brought directly to thetarget (ie, with laparoscopic HIFU). This studyexamines the histological effects of laparoscopicHIFU ablation of small renal tumours to determinethe viability of the approach from the standpoint ofcomplete tumour ablation and potential technicallimitations.

2. Materials and methods

After being approved by the Institutional Ethics Review Board

(EK 536/2005), we conducted this clinical phase 1 study

between November 2006 and March 2007. The selection for

oncological treatment was based on standard surgical

principles (laparoscopic radical nephrectomy for large

tumours, laparoscopic partial nephrectomy in tumours

Please cite this article in press as: Klingler HC, et al., A Novel A

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<4 cm, and palliative renal tumour treatment in metastasized

renal cell carcinoma [RCC]). Ten patients with a solitary renal

mass suspicious for RCC on the basis of helical computed

tomography (CT) or magnetic resonance imaging (MRI) scans

were treated with laparoscopic HIFU. In two patients with

9-cm tumours, a defined marker lesion was generated with

HIFU at the external side of the tumour followed immediately

by laparoscopic radical nephrectomy to prove feasibility of the

technique. HIFU ablation of the entire tumour with a margin of

2–3 mm of surrounding parenchyma (‘‘curative intent’’) was

performed in the remaining eight patients with small tumors.

In seven patients, laparoscopic partial nephrectomy with

temporary clamping of the renal artery was conducted post-

HIFU as described elsewhere [8]. The plane of resection was

well outside of the treatment zone to be able to evaluate the

extent of ablation and to prove efficacy of HIFU ablation. In

patient 10 who had high comorbidity and proven lung

metastases, the tumour was not excised after HIFU, but the

same target zone was treated twice. Biopsies were performed

before and after HIFU. The patient was subsequently followed

with helical CT scans.

Laparoscopic surgical access, with the use of four 12-mm

access ports, was performed under general anesthesia as a

standard transperitoneal procedure with the patient in a 458lateral decubitus position. In all patients, the diseased kidney

was completely mobilized and cleared of fat. The hilar

structures were dissected, but the artery was not primarily

occluded. Intraoperative renal power Doppler ultrasonogra-

phy was performed with a 10-Hz laparoscopic ultrasound

probe (BK Medical, Denmark) to precisely locate the renal

lesion to be treated. Prior to HIFU treatment, two core tumour

biopsies were obtained from the tumour with an 18-G biopsy

needle (Boston Scientific, USA). One port was then changed to

an 18-mm port (Ethicon, USA) to allow access for the HIFU

probe.

The laparoscopic HIFU system (Sonatherm1, Misonix Inc,

Farmingdale, NY, USA) used consisted of the treatment

console, an articulated probe arm, a pump unit, and the

laparoscopic probe (Fig. 1). The latter is gas-sterilisable and

covered with a flexible bolus through which gas-free cold

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Fig. 2 – Intraoperative view of laparoscopic high-intensity

focused ultrasound of lower pole renal cell cancer; the

kidney is held in place with an endoretractor.

Fig. 3 – Marker lesion in large renal cell cancer (patient no. 2).

(a) Overview: The area within the dotted line shows

‘‘homogeneous severe thermal damage’’ (a), viable tissue

(v). (Hematoxylin-eosin stain; original magnification: T40.)

(b) Detail of 3a, showing ‘‘severe thermal damage’’defined

as diffuse pycnosis of nuclei, rupture of cell membranes,

erythrocytes with disrupted cell membranes.

(Hematoxylin-eosin stain; original magnification: T200.)

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Ewater is circulated for cooling. The probe is inserted through

an 18-mm port to be brought into direct contact with the

tumour (Fig. 2). HIFU energy is delivered by a truncated

spherical shell 4-MHz transducer with a 30 � 13 mm aperture

and 35-mm focal length. Real-time imaging of the target area

in two planes is provided with an integrated single-element,

12-mm diameter imaging transducer aligned confocally with

the therapy transducer [13,14]. HIFU ablation was performed

in a ‘‘continuous ON’’ mode with the transducer moved under

computer control in a two-dimensional pattern within the

outlined treatment zone. HIFU delivery was interrupted every

30 s to obtain ultrasound images in two planes so that the

treatment process could be monitored. In addition to

continuous registration of areas covered by the focal zone,

energy deposition was also assessed qualitatively by examin-

ing hyperechoic changes in the treatment zone resulting from

boiling and cavitation events. The system was calibrated

according to results obtained in experimental studies in

porcine kidneys [14,15] to ablate tissue at an average rate of

0.6 cm3/min at typical power level between 30–38 W. The area

ablated by the probe has the shape of an ‘‘arctangle,’’ the

length and angular extent of which were defined by the

physician, so that the tumour was completely contained

within it. If, owing to tumour size, location, access port

placement, or probe geometry, the tumor area could not be

completely covered by a single treatment segment, a second

overlapping treatment segment was used to completely ablate

the entire tumour volume. The transducer’s focal length limits

the maximum HIFU penetration depth to approximately

35 mm. The maximum linear scanning extent of the transdu-

cer is 50 mm and the maximum angular scanning extent is 908.Specimens were sent for frozen section to check margin

status. Tumour specimens were thereafter evaluated by whole

mount, serial section hematoxylin-eosin staining, and exten-

sive histopathological evaluation. Before fixation in formal-

dehyde, one central slice of tumor tissue was snap-frozen in

liquid nitrogen for histochemical nicotinamide adenine

dinucleotide (NADH) staining, which was used as a marker

for irreversible heat damage [16]. ‘‘Severe thermal tissue

damage’’ was defined as homogeneous intravascular disrup-

Please cite this article in press as: Klingler HC, et al., A Novel A

Laparoscopic High-Intensity Focused Ultrasound, Eur Urol (2007),

tion of erythrocyte membranes, vacuolisation of tumour and

arterial smooth muscle cells, pycnosis and elongation of

tumour cell nuclei, rupture of tumour cell membranes, and

cell detachment throughout the area being investigated

(Fig. 3b). In our experience, severe thermal tissue damage

leads to irreversible and complete tissue necrosis if the time

between HIFU and removal of the specimen is longer [16]. In

addition, NADH staining of the entire region had to be negative

[17,18].

Patients were followed a mean 7.2 mo (range, 6–11) with

serum creatinin, renal ultrasonography, and helical contrast-

enhanced CT scan or MRI obtained at 1, 3, and 6 mo.

3. Results

Table 1 summarises patient characteristics prior totreatment, the treatment protocol used in individualpatients, and the final histological results.

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Table 1 – Pertinent patient characteristics and treatment details

Patno.

Age(yr)

Tumoursize

(mm)

Intentionto treat

Treatment details Targetedvolume

Final histologyof tumour

Severe thermaldamage ablation

within target

1 54 90 Marker 2 treatment zones 11 cm3 (33 W) Clear-cell RCC pT3a, G2 100%

Lap N 2.4 cm � 328: 13:58 min 9 cm3 (34 W)

2.0 cm � 428: 15:09 min

2 65 90 Marker 2 treatment zones 9 cm3 (35 W) Clear-cell RCC pT3b, G4 100%

Lap N 2.0 cm � 328: 17:09 min 5 cm3 (35 W)

and 1.4 cm � 248: 8:45 min

3 42 28 Curative 1 treatment zone 15 cm3 (30–32 W) Clear-cell RCC pT1a, G2 95%

Lap NSS 2.8 cm � 468: 31:39 min

4 77 25 Curative 1 treatment zone 7 cm3 (34–38 W) Clear-cell RCC pT1a, G2 96%

Lap NSS 2.3 cm � 268: 9:50 min

5 50 15 Curative 1 treatment zone 15 cm3 (32–33 W) Angiomyolipoma 100%

Lap NSS 2.6 cm � 508: 24:35 min

6 75 20 Curative 1 treatment zone 21 cm3 (33–36 W) Chronic inflammatory cyst 100%

Lap NSS 3.6 cm � 528: 30:16 min

7 79 10 Curative 1 treatment zone 5 cm3 (30 W) Clear-cell RCC pT1a, G2 80%

Lap NSS 1.6 cm � 268: 10:06 min skipping

8 33 48 Curative 1 treatment zone 23 cm3(30–34 W) Angiomyolipoma 100%

Lap NSS 3.4 cm � 588: 41:50 min

9 75 12 Curative 1 treatment zones 8 cm3 (35–37 W) Clear-cell RCC pT1a, G2 100%

Lap NSS 2.4 cm � 328: 13:58 min

10 55 23 Ablative 1 treatment zone treated twice 5 cm3 (35–37 W) Clear-cell RCC pT1a, G2 100%

Lap Bx 1.8 cm � 268: 7:46 min

Pat, patient; Lap N, laparoscopic nephrectomy; Lap NSS, laparoscopic nephron-sparing surgery; Lap Bx, laparoscopic biopsy; RCC, renal cell

carcinoma.

Fig. 4 – Renal cell cancer treated with curative intent

showing a subcapsular rim of viable tissue adjacent to

entry of high-intensity focused ultrasound energy (v) with

otherwise homogenous severe thermal damage of entire

tumor (a) (patient no. 3). (Hematoxylin-eosin stain; original

magnification: T40.)

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Respiratory movement and/or kidney morbiditydid not impact delivery of HIFU energy. Comparisonof images taken at treatment planning with thoseduring insonication showed that target motion wasalways <5 mm.

The two marker lesions in patients 1 and 2 withextensive RCC showed homogenous severe thermaldamage that matched the site and volume targetedalmost precisely (Fig. 3a and b).

The mean diameter of the tumours treated in‘‘curative intent’’ in patients 3–10 was 22 mm(range, 11–48). Mean HIFU exposure time was19 min (range, 8–42), whereas the time needed forthe entire HIFU procedure (including port place-ment, probe insertion and positioning, treatmentplanning, and probe removal) was 39 min (range,27–59). Patients 3 and 4 showed a subcapsular rim of1–3 mm of vital tissue immediately adjacent towhere the HIFU probe was approximated to thekidney, with otherwise homogenous severe ther-mal damage of the entire tumour (Fig. 4). Assumingthat this outcome was caused by too aggressivecooling of the probe, we subsequently increased thetemperature of the coolant to 18 8C, and thisobservation was not experienced again. The tumour

Please cite this article in press as: Klingler HC, et al., A Novel A

Laparoscopic High-Intensity Focused Ultrasound, Eur Urol (2007),

Ctreated in patient 7 showed vital tissue in about 20%of the tumour, located centrally, with homogenoussevere thermal damage of the rest (Fig. 5). The otherfour tumours removed by partial nephrectomy afterHIFU were all found to have homogenous severe

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Fig. 5 – Renal cell cancer treated with curative intent with

homogeneous severe thermal damage within dotted line,

but viable tissue shown centrally (patient no. 7).

Fig. 6 – Renal cell cancer treated with curative intent

(patient no. 9). (a) Overview: The entire tumor shows

homogeneous severe thermal damage including margins

of normal parenchyma; viable tissue is only outside

treatment zone (v). (Hematoxylin-eosin stain; original

magnification: T40.) (b) Histochemical nicotinamide

adenine dinucleotide (NADH) stain from same patient.

Black arrows: positive NADH staining in a rim of normal

renal parenchyma (v); red arrows: homogeneous severe

thermal damage (a) with complete depletion of NADH.

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Ethermal damage of the entire tumour withoutevidence of skip lesions (Fig. 6).

In patient 10 intraoperative power Doppler ultra-sonography showed no sign of residual perfusionafter HIFU ablation, and core biopsies taken imme-diately thereafter likewise demonstrated homoge-nous severe thermal damage. Follow-up helical CTscans after 3 and 6 mo showed no contrastenhancement and shrinking of the lesion.

Patient 1 had a tumour 9 cm in diameter in theupper half of the left kidney. At radical nephrectomythe tail of the pancreas was lacerated when the leftadrenal gland was removed. This complicationresulted in prolonged wound drainage, but requiredno further treatment. Otherwise no complicationswere observed in the entire group. Follow-up for allpatients now is a mean 7.2 mo (range, 6–11). Follow-up CT scans showed no evidence of hematoma,residual/recurrent tumour, or any other abnorm-ality.

4. Discussion

As an ultrasound wave propagates through biolo-gical tissues, it is progressively absorbed and itsmechanical energy converted to heat. If brought toa tight focus at a selected depth within tissues(HIFU), the high energy density produced in thisregion rapidly results in temperatures exceedingthe threshold of irreversible protein degradationand subsequently coagulative necrosis [19]. Theenergy decreases sharply outside the focal zone, sothat surrounding tissues remain unharmed. This

Please cite this article in press as: Klingler HC, et al., A Novel A

Laparoscopic High-Intensity Focused Ultrasound, Eur Urol (2007),

permits targeted ablation within organs withoutthe need of directly accessing the target site. Asheat generation is extremely rapid, potential heatsinks such as large blood vessels impact lesioningto a lesser degree than with other, slowertechniques of thermal ablation [19]. Obviouslyfor the same reason, HIFU of malignant tumourshas not been shown to cause tumour cell dis-semination or an increased rate of metastases[20,21].

Unfortunately these principles of HIFU ablationalso require fairly homogeneous tissue structureswithout significant acoustic interphases along thepath of ultrasound delivery and a stationary target

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for precise energy deposition. Clinically this can beachieved trans-scrotally to the testis [22], transrec-tally to the prostate [19,23], and even to the kidneywhen the organ is surgically exposed [16]. HIFU ofrenal tumors by an extracorporeal approach hasproven unreliable both in animal experiments andclinical pilot studies [24–26]. The acoustical com-plexity of the abdominal wall and perirenal struc-tures, and the mobility of the kidney are eliminatedif the transducer is brought directly to the kidney.With the laparoscopic HIFU transducer with anoverall diameter of 18 mm used in this study, thisapproach becomes feasible with standard laparo-scopy techniques and equipment. Albeit moreinvasive than an extracorporeal HIFU approach,the time needed compares well with laparoscopiccryoablation. The morbidity of nephron-sparingexcision of renal tumours mainly arises from theneed to incise the renal parenchyma, with orwithout clamping the renal artery [3]. This compli-cation is avoided by laparoscopic HIFU ablation. NoHIFU-specific complications were observed in thestudy.

Homogeneous and severe thermal damage of theentire targeted zone was documented histologicallyin six of nine masses. Not all lesions treated wereconfirmed to be RCC. In a similar study of radio-frequency ablation, angiomyolipomas and septated,cystic tumours showed most pronounced skipping[8]. In contrast all nonmalignant tumours treatedherein, including the vascularised angiomyolipomaand the complex cyst, showed homogeneous severethermal damage of the entire lesion and 2–3 mm ofsurrounding parenchyma. The superficial zone ofvital tissue observed in two of the first patients withrenal cancer treated with curative intent wasassumed to result from overzealous cooling of theHIFU probe. It was not observed again when thecooling was limited to 18 8C. It may also haveresulted from insufficient energy coupling fromthe probe bolus to the kidney at HIFU insonication,which was routinely performed by securing thekidney in place with a fan retractor and by generousapplication of sterile ultrasonography gel. The geltends to dissipate rapidly during insonication, andonly with growing experience was the problemmastered satisfactory. The one tumour documentedto have a central area of vital tissue remains a reasonfor concern. It had a homogeneous structure andwas correctly insonicated according to the intrao-perative ultrasonography documentation. Unno-ticed problems at energy coupling are also themost likely explanation because we found small airbubbles at the HIFU probe at the end of theprocedure. The air bubbles may have interfered

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with energy deposition, even if the amount of airwas small.

The objective of this phase 1 study was toestablish clinical proof of principle and to docu-ment safety. These goals were achieved andunderline the results in porcine kidneys [15].Laparoscopic HIFU of small peripheral renaltumours is clinically feasible and resulted in noHIFU-specific complications. Nevertheless, it isimportant to note the limitations of the studyand the technique applied. Because of the probe’sfocal distance, only tumours (or target lesions) lessthan 3.5 cm diameter and in a peripheral exophyticposition were treated. With larger or more centrallylocated tumours, the entire lesion cannot beinsonicated and incomplete ablation has to beassumed. It appears fair to point out that centraland very large tumours are poorly suited for energyablative therapy in general and have a high failurerate regardless of the technique used [8,26,27].Although all lesions were assumed to be solidtumours at preoperative imaging, one was actuallya complicated cyst and three were benign tumours.This reflects the clinical experience when treatingthese tumors [28]. The ablation technique, espe-cially concerning energy coupling and definingtarget volume, was modified during the study inincremental steps with growing experience, but theoptimum technique may still not have beenreached. Finally the completeness of ablationwas concluded from homogeneity of histologicalsigns of severe acute thermal damage. Althoughthe criteria defined have been shown to correlatewith irreversible cell damage and, with more timebetween thermal insult and histological evalua-tion, the extent of coagulative necrosis [16,19,22],they cannot automatically be equated. Repairprocesses, but also additional posttraumatic mal-perfusion injury also impact the extent of ablationultimately achieved. Defining the clinical efficacyof laparoscopic HIFU ablation of renal tumoursrequires long-term follow-up studies [29], withserial cross-sectional imaging and percutaneousbiopsy of any residual contrast-enhancing lesion,and ultimately long-term data on recurrence-freesurvival.

5. Conclusion

The morbidity of laparoscopic partial nephrect-omy mainly comes from the need to incisehighly vascularized parenchyma. Targeted laparo-scopic HIFU ablation may render this unnecessary,but further studies to refine the technique areneeded.

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Conflicts of interest

The HIFU equipment and the 18-mm disposableports were provided free of charge for this study byFocus Surgery Inc (Indianapolis, IN, USA) andMisonix Inc (Farmingdale, NY, USA).

R. Seip and N. Sanghvi are employees of FocusSurgery Inc. The other authors have no financialconnection with Focus Surgery Inc or other conflictsof interest.

References

[1] Fergany AF, Saad IR, Woo L, Novick AC. Open partial

nephrectomy for tumor in a solitary kidney: experience

with 400 cases. J Urol 2006;175:1630–3.

[2] Lane BR, Gill IS. 5-year outcomes of laparoscopic partial

nephrectomy. J Urol 2007;177:70–4.

[3] Gill IS, Matin SF, Desai MM, et al. Comparative analysis of

laparoscopic versus open partial nephrectomy for renal

tumors in 200 patients. J Urol 2003;170:64–8.

[4] Klingler HC. Energy ablative therapy of renal tumours.

Urologe A 2007;46:485–95.

[5] Park S, Cadeddu JA, Shingleton WB. Oncologic outcomes

for ablative therapy of kidney cancer. Curr Urol Rep

2007;8:31–7.

[6] Miki K, Shimomura T, Yamada H, et al. Percutaneous

cryoablation of renal cell carcinoma guided by horizontal

open magnetic resonance imaging. Int J Urol 2006;13:

880–4.

[7] Permpongkosol S, Link RE, Kavoussi LR, Solomon SB.

Percutaneous computerized tomography guided cryoa-

blation for localized renal cell carcinoma: factors influen-

cing success. J Urol 2006;176:1907–8.

[8] Klingler HC, Marberger M, Mauermann J, Remzi M, Susani

M. Skipping is still a problem with radiofrequency abla-

tion of small renal tumours. BJU 2007;99:998–1001.

[9] Aron M, Gill IS. Minimally invasive nephron-sparing sur-

gery (MINSS) for renal tumours. Part II: probe ablative

therapy. Eur Urol 2007;51:348–57.

[10] Wyler SF, Sulser T, Ruszat R, et al. Intermediate-term

results of retroperitoneoscopy-assisted cryotherapy for

small renal tumours using multiple ultrathin cryoprobes.

Eur Urol 2007;51:971–9.

[11] Krambeck AE, Farrell MA, Charboneau JW, Frank I,

Zincke H. Intraperitoneal drop metastasis after radiofre-

quency ablation of pararenal tumor recurrences. Urology

2005;65:797.

[12] Marberger M. Ablation of renal tumours with extracor-

poreal high-intensity focused ultrasound. BJU Int

2007;99:1273–6.

[13] Tavakkoli J, Mehta A, Miller C, et al. A laparoscopic HIFU

probe with integrated phased array ultrasound imagi-

ngIn: Proceedings of the International Symposium on

Therapeutic Ultrasound. 2003;417–22.

Please cite this article in press as: Klingler HC, et al., A Novel A

Laparoscopic High-Intensity Focused Ultrasound, Eur Urol (2007),

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[14] Paterson RF, Barret E, Siqueira TM, et al. Laparoscopic

partial kidney ablation with high intensity focused ultra-

sound. J Urol 2003;169:347–51.

[15] Orvieto M, Lyon M, Mikhail A, et al. High intensity focused

ultrasound renal tissue ablation in a laparoscopic porcine

model. J Urol 2006;175:338.

[16] Susani M, Madersbacher S, Kratzik C, Hennige LV, Mar-

berger M. Morphology of tissue destruction induced by

focused ultrasound. Eur Urol 1993;23(Suppl):34–43.

[17] Nikfarjam M, Malcontenti-Wilson C, Christophi C. Focal

hyperthermia produces progressive tumor necrosis inde-

pendent of the initial thermal effects. J Gastroent Surg

2005;9:410–7.

[18] Stern JM, Anderson JK, Lotan Y, Park S, Cadeddu JA.

Nicotinamide adenine dinucleotide staining following

radio frequency ablation of renal tumours—is a positive

stain synonymous with ablative failure? J Urol

2007;176:1969–72.

[19] Madersbacher S, Pedevilla M, Vinger L, Susani M, Marber-

ger M. Effect of high-intensity focused ultrasound of

human prostate cancer in vivo. Cancer Res

1995;55:3346–51.

[20] Murat FJ, Poissonnier L, Pasticier G, Gelet A. High-inten-

sity focused ultrasound (hifu) for prostate cancer. Cancer

Control 2007;14:244–9.

[21] Oosterhof GO, Cornel EB, Smits GA, Debruyne FM,

Schalken JA. Influence of high-intensity focused ultra-

sound on the development of metastases. Eur Urol

1997;32:91–5.

[22] Kratzik C, Schatzl G, Lackner J, Marberger M. Transcuta-

neous high-intensity focused ultrasonography can cure

testicular cancer in solitary testis. Urology 2006;76:1269–

973.

[23] Poissonnier L, Chapelon JY, Rouviere O, et al. Control of

prostate cancer by transrectal HIFU in 227 patients. Eur

Urol 2007;51:381–7.

[24] Kohrmann KU, Michel MS, Gaa J, Marlinghaus E, Alken P.

High intensity focused ultrasound as non invasive ther-

apy for multifocal renal cell carcinoma: case study and

review of the literature. J Urol 2002;167:2397–403.

[25] Marberger M, Schatzl G, Cranston D, Kennedy JE. Extra-

corporeal ablation of renal tumours with high-intensity

focused ultrasound. BJU Int 2005;95(Suppl. 2):52–5.

[26] Illing RO, Kennedy JE, Wu F, et al. The safety and feasi-

bility of extracorporeal high-intensity focused ultrasound

(HIFU) for the treatment of liver and kidney tumours in a

Western population. Br J Cancer 2005;93:890–5.

[27] Hacker A, Michel MS, Marlinghaus E, Kohrmann KU,

Alken P. Extracorporeally induced ablation of renal tissue

by high-intensity focused ultrasound. BJU Int 2006;97:779–

85.

[28] Remzi M, Ozsoy M, Klingler HC, et al. Are small renal

tumors harmless? Analysis of histopathological features

according to tumors 4 cm or less in diameter. J Urol

2006;176:896–8.

[29] Patard JJ. With increasing minimally invasive options for

small renal tumours, it is time to develop patient-specific

treatment strategies. Eur Urol 2007;51:876–8.

pproach to Energy Ablative Therapy of Small Renal Tumours:

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Editorial Comment on: A Novel Approach toEnergy Ablative Therapy of Small RenalTumours: Laparoscopic High-Intensity FocusedUltrasoundAmnon ZismanUrology Department, Israelamnonz@asaf.health.gov.il

Assaf Harofeh M.C. ZerifinAffiliated to Sackler Faculty of Medicine,Tel-Aviv University, Tel Aviv, Israel

Technological advances as well as cultural andeconomic vectors have caused a dramatic shift fromtraditional ‘‘Robsonian’’ open, radical nephrectomyto nephron-sparing surgery (NSS) using laparoscopyand minimally invasive techniques. Three locomo-tives are driving the process: (1) NSS provideslifelong advantage (ie, freedom from dialysis) [1].(2) NSS for T1 masses provides a curative outcomethat is as good as nephrectomy [2]. (3) Laparoscopy islessmorbid than the supracostal open approach. Fora long period, high-intensity focused ultrasound(HIFU) has promised to deliver the ultimate non-invasive extracorporeal tumor ablation. Onlyrecently has HIFU, in conjunction with improvedimaging capabilities, materialized into a clinicaloption additional to laparoscopic partial nephrect-omy, radiofrequency ablation, and cryoablation.Within this framework, the authors report on aphase 1 study in a small group of patients withlimited follow-up using laparoscopic-guided intra-corporeal HIFU ablation of small renal tumors[3].Turning to laparoscopic guidance as opposedto an extracorporeal approach suggests that for thetime being, extracorporeal HIFU ablation is facinggreat technical difficulties. This is intensified by thedisturbing rate of residual viable tumor reported by

the authors. Two patients had a 1–3-mm rim ofviable tissue immediately adjacent to where theHIFU probe was approximated to the tumor. Onepatient had a central area of vital tissue of about 20%of its volume. Having that said, this is the newestablative technique introduced and still in theprocess of development. By no means will HIFUbe judged in the future by its ability to turn into aneffective extracorporeal procedure in a competitiveenvironment. On one hand the indication for NSS isalready being extended but, on the other hand,elderly patients or those with poor surgical risk arebeing followed expectantly within the frame of fewexperimental studies. Although controversial, abla-tive measures may perhaps have a role in thecytoreduction of primary tumors in patients withmetastatic disease in the present era of moreeffective targeted therapies.

References

[1] Huang WC, Levey AS, Serio AM, et al. Chronic kidney

disease after nephrectomy in patients with renal cortical

tumours: a retrospective cohort study. Lancet Oncol

2006;7:735.

[2] Dash A, Vickers AJ, Schachter LR, Bach AM, Snyder ME,

Russo P. Comparison of outcomes in elective partial vs

radical nephrectomy for clear cell carcinoma 4–7 cm.

BJU Int 2006;97:939.

[3] Klingler C, Martin S, Ralf S, Mauermann M, Naren S,

Marberger MJ. A novel approach to energy ablative ther-

apy of small renal tumours: laparoscopic high-intensity

focused ultrasound. Eur Urol. In press. doi:10.1016/j.eur-

uro.2007.11.020.

DOI: 10.1016/j.eururo.2007.11.021

DOI of original article: 10.1016/j.eururo.2007.11.020

Editorial Comment on: A Novel Approach toEnergy Ablative Therapy of Small RenalTumours: Laparoscopic High-Intensity FocusedUltrasoundQuoc-Dien TrinhDepartment of Urology, University of Montreal HealthCenter, Montreal, QC, Canadaquoc-dien.trinh@umontreal.ca

The widespread use of abdominal computedtomography and ultrasonography complicates the

management of small incidentally detected renalmasses. Their slow growth and the difficulty indifferentiating benign from malignant lesionspreoperatively make the clinical significance ofsuch lesions unclear. Although partial nephrect-omy is currently considered the standard of carefor these lesions, minimally invasive probe abla-tion techniques are now emerging as potentialalternative approaches [1,2]. Although laparo-scopic cryoablation represents the most widelyused of these novel techniques, high-intensity

e u r o p e a n u r o l o g y x x x ( 2 0 0 7 ) x x x – x x x8

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Laparoscopic High-Intensity Focused Ultrasound, Eur Urol (2007), doi:10.1016/j.eururo.2007.11.022

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focused ultrasound (HIFU) ablation has shownpromise in the treatment of solid tumors [3,4].

In this original study [5], Klingler et al report ontheir initial phase 1 experience with laparoscopicintracorporeal HIFU ablation of small renal tumors.Ten patients with radiographic suspicion of renalcell carcinoma (RCC) underwent laparoscopic HIFUablation, followed by, in nine of these patients,laparoscopic nephrectomy to pathologically vali-date the HIFU ablation.

The objective of this phase 1 study was todemonstrate proof of principle and to documentsafety and should only be considered as such. Asfar as a new ablative measure, it has to be furtherrefined because the rate of residual viable tumor isworrisome. Their experience is limited due to thesmall number of patients (n = 10) and the quiteshort reported median follow-up of 7.2 mo.

In conclusion, these results show that laparo-scopic HIFU ablation is not a suitable option for thetreatment of RCC, but further studies mightultimately demonstrate otherwise. Moreover, onehas to wonder if this study signals that theattempts for extracorporeal HIFU ablation of renalmasses are concluded, for the time being, due totechnical limitations.

References

[1] Patard JJ. With increasing minimally invasive options

for small renal tumours, it is time to develop patient-

specific treatment strategies. Eur Urol 2007;51:

876–8.

[2] Aron M, Gill IS. Minimally invasive nephron-sparing

surgery (MINSS) for renal tumours. Part II: probe ablative

therapy. Eur Urol 2007;51:348–57.

[3] Aus G. Current status of HIFU and cryotherapy in pros-

tate cancer—a review. Eur Urol 2006;50:927–34, discus-

sion 934.

[4] Hacker A, Michel MS, Marlinghaus E, Kohrmann KU,

Alken P. Extracorporeally induced ablation of renal tis-

sue by high-intensity focused ultrasound. BJU Int

2006;97:779–85.

[5] Klingler HC, Susani M, Seip R, Mauermann J, Sanghvi N,

Marberger MJ. A novel approach to energy ablative ther-

apy of small renal tumours: laparoscopic high-intensity

focused ultrasound. Eur Urol. In press. doi:10.1016/j.

eururo.2007.11.020.

DOI: 10.1016/j.eururo.2007.11.022

DOI of original article: 10.1016/j.eururo.2007.11.020

e u r o p e a n u r o l o g y x x x ( 2 0 0 7 ) x x x – x x x 9

EURURO 2293.2 1–9

Please cite this article in press as: Klingler HC, et al., A Novel Approach to Energy Ablative Therapy of Small Renal Tumours:

Laparoscopic High-Intensity Focused Ultrasound, Eur Urol (2007), doi:10.1016/j.eururo.2007.11.022