European Urology

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European Urology

Volume 8, issue 5, pages 417-488, April 2009

Focal Targeted Therapy Will Be a Future Treatment Modality for Early Stage Prostate Cancer

Jean J.M.C.H. de la Rosette, Vladimir Mouraviev, Thomas J. Polascik lowast .

pages 424 - 432

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Abstract

Context

Focal targeted therapy of early stage prostate cancer (PCa) can ideally facilitate the concept of personalized medicine in contemporary surgical oncology.

Objective

To present indications and outcomes of subtotal glandular ablation. This treatment approach aims at the elimination of the cancer with preservation of uninvolved tissue in an attempt to maintain a patient's quality of life (QoL), including undisturbed erectile function as well as urinary and bowel control.

Evidence acquisition

In 2002, the idea of a “lumpectomy” using an organ-sparing approach for very localized PCa was proposed in parallel with organ-sparing breast cancer treatment in women. Since then, a few pilot clinical studies have demonstrated an acceptable short-term cancer control while minimizing the complication rate. At the same time, progress in PCa screening has led to a significant stage and tumor volume migration toward early stage disease. In the past few years, a collection of accumulated data has created a scientific background for further development of this concept toward a wider implementation into clinical practice. In this paper, we review all available literature from PubMed of the past 15 yr—from 1994 to 2008—including the terms localized prostate cancer, focal therapy, organ preservation, and morbidity.

Evidence synthesis

Several factors were identified that need to be taken into account to further develop an organ-sparing treatment approach for early stage localized PCa and turn this concept into clinical practice. First, novel thermoablative techniques such as third-generation cryosurgery, high-intensity focused ultrasound (HIFU), vascular photodynamic therapy and, electroporation can precisely target a tumor lesion within the prostate while maintaining the integrity of the surrounding tissues. Second, new ultrasound, magnetic resonance imaging (MRI) and molecular imaging techniques may provide new means to detect small PCa lesions. Third, extended image-guided biopsy protocols using a transperineal rather than a transrectal approach can provide a more exact spatial distribution of PCa lesions within the prostate. Fourth, careful patient selection using an individualized approach is a prerequisite for optimal preoperative planning and a successful treatment outcome.

Conclusions

For patients with early stage localized PCa limited to one focus or lobe and who express a great desire not to jeopardize their QoL, targeted focal therapy will likely play a more significant role in the future as a tangible treatment option. Moreover, focal therapy may fill the gap between active surveillance for low-risk PCa and radical treatment for higher-risk forms.

Take Home Message

Focal targeted therapy is becoming an attractive and tangible treatment option for patients with early stage localized prostate cancer limited to one focus or lobe and who are interested in maintaining a higher quality of life.

Keywords: Prostate cancer, Focal therapy, Focal ablation.

Article Outline

1. Introduction

The rapid and wide introduction of prostate-specific antigen (PSA) testing along with the improvement in surgical techniques for the treatment of prostate cancer (PCa) has led to tremendous progress in whole-gland treatment as a radical approach [1]. From a pathologic and tumor biology point of view, it has provided a unique opportunity to establish a tissue bank to carefully investigate pathologic findings to validate clinical, biopsy, and demographic preoperative parameters. Ultimately, as commonly occurs in every scientific area, quantitative data can be transformed into a qualitative analysis to adjust current treatment strategies.

Already in the early PSA era (1988–1996), Stamey et al [2] reported on the basis of a radical prostatectomy (RP) series of 896 patients that a frequency of small lesions (<0.5 cm3) did not have a highly significant change during these 9 yr. Further, the proportion of low-risk tumors in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database almost doubled from 27.5% between 1990 and 1994 to 46.4% between 2000 and 2001 [3]. The proportion of patients with clinical stage T1c disease increased dramatically and continues to increase from 29.9% between 1990 and 1994 to 78.3% between 2004 and 2006 [3]. Clinical T2a tumors were less prevalent, and cT1a and cT1b tumors combined accounted for approximately 1% of tumors diagnosed between 2002 and 2006 [3]. Recently, Polascik et al [4] found in a large cohort of 3676 men based upon final pathology assessment of RP specimens that the percent of tumor involvement (PTI) analysis shifted toward low-volume disease (eg, PTI < 5% increased from 10% between 1988 and 1995 to 37% between 2001 and 2006). At the same time, cases with stage pT2a tumors increased from 2.8% of men undergoing RP from 1988–1995 to 13.0% during 2001–2006. Of all pT2 cases throughout 1988–2006, an increase in the proportion of pT2a tumors from 10% during 1988–1995 to 69.4% during 2001–2006 was identified. Over three eras, pT2a tumors had minimal (65% had a PTI ≤ 5%) or small-volume (14% had a PTI of 5.01–10.00) disease, and 59% of cases were low grade (pathologic Gleason score [pGs] ≤6) [4]. Recent reports of prostatectomy series [5], [6], and [7] confirmed smaller-size cancer foci per prostate for patients with low-risk disease. Furthermore, contemporary final pathology results from large RP series in the literature have documented a shift of mainly bilateral tumors toward unifocal (≤67%) and/or unilateral (≤63%) lesions in patients with low-risk features [7], [8], and [9].

This trend demands a reevaluation of the contemporary radical approach to the treatment of the whole gland. In this manuscript, we critically review the possible role of focal treatment of localized PCa and the conditions for assessment and follow-up to safely do so.

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2. Evidence acquisition

2.1. Quality of life as a milestone in modern oncology

The public demand of an increasing number of women for breast-conservation therapy with excellent cosmetic results dramatically accelerated the development of organ-sparing lumpectomy, which can be combined with other neo- and adjuvant treatments for breast cancer. This challenging approach has fueled the search for innovative therapies within other fields of medicine, including urology. In the recent, large Prostate Cancer Outcomes Study, a population-based study of 1291 men who underwent RP for localized PCa, patients were followed for 2 yr to determine quality-of-life (QoL) outcomes [10]. A total of 42% of men reported that sexual performance was a moderate to large problem at 24 mo (compared with 18% at baseline), and 60% were not able to have erections sufficient for sexual intercourse (compared with 16% at baseline). At 24 mo postoperatively, men >60 yr of age were more likely to be impotent than younger men (78–85% vs 61%, respectively). As to other bothersome complications such an incontinence, 1.6% men from this study reported no urinary control at 24 mo following surgery (compared with 0.7% at baseline prior to surgery), while 7% and 42% reported frequent and occasional leakage, respectively (compared with 2% and 9%, respectively, at baseline) [10].

Almost a decade ago, Onik [11] introduced the technique of “male lumpectomy” for localized PCa but only in the past 2–3 yr has significant progress been made in this direction. The first clinical studies on focal and unilateral cryoablation demonstrated excellent results for maintaining potency (71–89%) and continence while achieving acceptable short-term cancer control (Table 1) [12], [13], [14], [15], and [16]. This trade-off is one of the most attractive features of focal targeted therapy for both sides: patients and oncologic urologists.

Table 1 Cancer control and complication rates after focal and unilateral cryoablation*

Reference No. of patients Mean follow-up bDFS (%) Biopsy-proven recurrence (%) Potency preserved (%) Incontinence (%)
Focal targeted cryoablation of unifocal lesion
Onik et al [12] 55 3.6 yr 52 (95%) ASTRO 4 (7%), untreated area 44 (85%) 1 (5%), previous TURP

Unilateral cryoablation
Bahn et al [13] 31 70 mo 26/28 (93%) 1/25 (4%), untreated lobe 24/27 (88.9%) totals: 31 (100%)
ASTRO 13/27 (48.1%) fully recovered
11/27 (40.8%) medication assisted

Lambert et al [14] 25 28 mo 21 (88%) 3 (12%) totals: 17 (71%) 25 (100%)
<50% PSA nadir 2 (8%), untreated lobe
1 (4%), treated lobe

Ellis et al [15] 60 16.7 mo 42 (80%) 4 (23%) totals: 24/34 (70.6%) with sexual rehabilitation 2 (3.6%)
ASTRO 13 (22%), untreated lobe
1 (1%), treated lobe

Extended unilateral HIFU (plus peripheral zone of contralateral lobe)
Muto et al [16] 29 34 mo 2-yr bDFS 3/28 (10.7%) at 6 mo follow-up NA NA
ASTRO 4/17 (23.5%) at 12 mo follow-up
83.3% low risk
53.6% intermediate risk

ASTRO = American Society for Therapeutic Radiology and Oncology; bDFS = biochemical disease-free survival; HIFU = high-intensity focused ultrasound; NA = not available; PSA = prostate-specific antigen; TURP = transurethral resection of the prostate.

* Adapted from Moul et al [55].

2.2. Overtreatment by radical therapies and undertreatment by active surveillance as an existing “double-edged sword”

Oncologic urologists now realize that one potential problem with the liberal use of PSA testing and/or widespread PCa includes overdiagnosis and subsequent overtreatment as a serious concern [17], and [18]. QoL issues are becoming of paramount importance for many patients who may pay a high price in the side effects of treatment to reach acceptable cancer control. In fact, a significant number of men may be able to avoid these side effects of radical therapy with a less aggressive approach [19], [20], and [21]. From a patient point of view, this may make the side effects worse than living with the disease itself. CaPSURE data indicate that in 2002, 94% of men with low-grade PCa received radical treatment, many of whom may have been overtreated [22]. A recent update to this database showed that the use of active surveillance (AS) increased from a nadir of 6.2% in 2000–2001 to 10.2% between 2004 and 2006 [3]. In the Toronto study with a 7-yr follow-up of almost 400 patients, approximately one-third converted to active therapy by 7 yr [23].

A variety of physician, patient, and social factors influence a patient's choice of treatment. For instance, some patients would not accept the psychological burden of bearing a tumor requiring more active treatment. Furthermore, the difference between disease progression and the trigger for intervention remains controversial. Criteria for reclassification include a PSA doubling time (PSA-DT) <3 yr and a higher grade on the biopsy along with an AS nomogram, according to the Toronto study. At the same time, however, it is suggested that more definitive and robust molecular markers should be identified and established for this purpose [24]. Therefore, focal therapy makes conceptual sense for eradicating clinically significant prostate tumors without compromising QoL [25].

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3. Evidence synthesis

3.1. Advances to facilitate focal targeted ablation
3.1.1. Technical developments

Within the perspective of these developments, we more easily embrace medical devices and technologies that can potentially target small tumors with precise accuracy and efficacy. The current treatment armamentarium for focal therapy includes cryoablation, high-intensity focal ultrasound (HIFU), vascular targeted photodynamic therapy, and interstitial laser thermotherapy [12], [13], [14], [15], [16], [20], [26], [27], [28], and [29]. Within a research setting, early experience with some of these devices has been gathered.

Focal therapies may have certain advantages over traditional treatments. One potential advantage of prostate cryoablation as a nonsurgical therapeutic option is that the operator can manipulate the ice ball to extend beyond the prostate capsule on the side involved with unilateral cancer when treating in a focal manner [14], [30], and [31]. In contrast, other potential focal treatment techniques such as HIFU and vascular targeted photodynamic therapy may be better suited to destroying tumor lesions within the prostate (eg, under the capsule) [16], [28], [32], and [33].

Clearly, long-term oncologic efficacy will need to be determined before these approaches become widely available in clinical practice. Potential technologies that can be implemented in the near future after promising further studies are intensity-modulated radiotherapy (IMRT) and proton therapy, radiotherapy (RT) using the CyberKnife (Accuray, Sunnyvale, CA, USA), galvanotherapy, electroporation, and local injection of oncolytic proteins [34], [35], [36], and [37].

3.1.2. Imaging

Despite advances in PCa imaging, no imaging modality is available at present that can accurately diagnose low-volume PCa. However, studies are ongoing to identify novel diagnostic techniques to image PCa. Some investigators have conducted correlation studies between radiographic images and whole-mount RP pathology slides.

De la Rosette et al introduced the concept of functional transrectal ultrasound (TRUS) imaging, which may provide clinicians a better means to image PCa. The clinical utility of new nonlinear contrast-enhanced ultrasonography (CEUS), contrast pulse sequence (CPS) imaging, and microvascular imaging (MVI) were reviewed (Fig. 1) [38]. On a conceptual basis, microbubbles are injected into the vascular system, enabling the visualization of the microvasculature [38].

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Fig. 1 Transrectal ultrasonography (TRUS) and macroscopic pathology of prostate cancer lesions; (A) gray-scale (B-mode) imaging; (B) contrast-enhanced TRUS; (C) gross pathology. Adapted from Wink et al [38].

Zhai et al introduced three-dimensional (3D) transrectal acoustic radiation force impulse (ARFI) imaging, a novel elasticity technique capable of visualizing structures based upon differences in tissue stiffness with high resolution in an effort to detect high-density cancer lesions within the prostate [39]. ARFI imaging uses high-intensity focused acoustic beams to mechanically excite or push on tissue and ultrasonic correlation-based methods to monitor the tissue displacement response. The results suggest that ARFI imaging is a promising new tool for the visualization of different tumor lesions that may provide image guidance for targeted prostate needle biopsies and focal therapy (Fig. 2).

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Fig. 2 Transrectal ultrasonography: (A) gray-scale B-mode; (B) three-dimensional transrectal acoustic radiation force impulse imaging of cancer lesions; (C) matching pathology. Adapted from Zhai et al [39].
ARFI = acoustic radiation force impulse.

Braeckman et al recently introduced Histoscanning (Advanced Medical Diagnostics, Waterloo, Belgium), a new ultrasound-based technology that uses computer-aided analysis to quantify tissue disorganization induced by malignant processes [40]. The concordance regarding multifocality (present/absent) and unilateral/bilateral disease between imaging data and final pathology assessment was 100% in 29 patients. These data suggest the potential for identifying and characterizing PCa foci noninvasively with a high degree of precision.

Newer cross-sectional imaging techniques that may improve cancer detection include state-of-the-art magnetic-resonance spectroscopy imaging (MRSI; sensitivity: 77%; specificity: 84%), dynamic contrast-enhanced magnetic resonance imaging (MRI; sensitivity: 84%; specificity: 83%), and diffusion-weighted MRI (DW-MRI; sensitivity: 81%; specificity; 84%) [41]. Puech et al demonstrated the feasibility and efficacy with dynamic contrast-enhanced (DCE) MRI in 93 patients with localized PCa who later underwent RP [42]. The technique was efficacious in detecting cancer lesions having a volume >0.33 cm3. The sensitivity, specificity, positive predictive value(PPV)/negative predictive value (NPV), and accuracy of the DCE-MRI sequences were 91%, 88%, 89%, 95%, and 89%, respectively. Kurhanewicz et al highlighted the superiority of higher field MRI scanners (3T) coupled with other functional information (diffusion and dynamic contrast-weighted imaging), new spectroscopic biomarkers, and more sensitive spectroscopic imaging techniques (hyperpolarized 13C MRSI) compared to the limited value of standard 1.5T MRI/MRSI for the diagnosis of small-volume (<0.5 cm3), low-grade (less than or equal to Gleason 3 + 3) PCa [43]. In addition, molecular imaging has been studied as a novel tool that can potentially elaborate a critical chain of genomic and proteomic alterations transformed into an imaging signal [44]. There are indications that molecular features distinguishing high-grade from low-grade carcinomas may be exploited to standardize cancer grading and possibly as biomarkers capable of identifying aggressive disease.

3.1.3. Image-guided prostate biopsy

The lack of reliable imaging modalities for PCa diagnosis has accelerated the development of the extended prostate biopsy protocols. For example, Barzell et al used template-guided transperineal, 3D pathologic mapping (3DPM) to identify clinically significant PCa prior to recommending treatment [45]. These authors then carefully selected eight patients for focal cryoablation based on multicore biopsies comprising an average of 80.7 cores per patient or 1.88 cores per cubic centimeter of prostate tissue [46]. Recently, Onik and Barzell updated their series of 110 patients, all of whom had unilateral disease on TRUS biopsies and were restaged using the 3DPM method prior to focal therapy [46]. The median number of biopsy cores taken was 46 (standard deviation [SD] ± 19). Bilateral cancer was demonstrated in 60 (55%) patients (all of whom had only unilateral cancer shown on TRUS biopsy). The Gleason score based on 3DPM was increased in 25 patients (23%) compared to the conventional TRUS biopsy. The authors concluded that transperineal 3DPM biopsy of the prostate is well tolerated and provides superior staging information compared with TRUS biopsy [46].

Narayanan et al determined the potential clinical utility of a high-speed registration algorithm for a 3D PCa atlas [47]. This 3D PCa atlas provides the voxel-level likelihood of cancer and optimized biopsy locations on a template space. The authors created an atlas from 158 expert-annotated, 3D-reconstructed RP specimens outlined for cancers. For successful clinical implementation, the prostate atlas needs to be registered to each patient's TRUS image with high registration accuracy in a time-efficient manner. They developed a fast registration algorithm suitable for clinical applications of this PCa atlas. The PCa atlas–guided 7- and 12-core biopsy protocols had cancer-detection rates of 84.81% and 89.87%, respectively, when validated by histology of 158 RP specimens. The sextant biopsy approach without the utility of the 3D cancer atlas detected only 70.5% of the cancers using the same histology data. Therefore, the authors suggest a 10–20% increase in PCa detection rates when TRUS-guided biopsies are assisted by the 3D PCa atlas compared to the standard biopsy alone [47].

3.2. Patient selection

Available selection criteria of ongoing clinical studies using mostly focal cryoablation reported in the literature were mainly drawn from theory (Table 2) [12], [13], [14], and [15]. As a historical control, patient selection and prognostic indicators for RP have been aided by the use of the Partin tables and/or Kattan nomograms, which provide probabilities for extracapsular disease, seminal vesicle involvement (SVI), or lymph node involvement (LNI) as well as the likelihood of local or systemic recurrence [48], and [49]. In contrast, trying to identify appropriate candidates at an early stage of tumorigenesis does not facilitate the development of similar selection criteria for focal therapy because of the complexity of early stage carcinogenesis. Several investigators have used the D’Amico definition to select appropriate patients for focal therapy among low-risk candidates [50]. For example, in a clinical study of 538 patients with low- to moderate-risk features treated with RP, Polascik et al found that only two pretreatment clinical variables were significantly predictive of pathologic unilateral PCa: negative family history of PCa and clinical unilaterality based on prostate biopsy [51]. The strongest predictor in multivariate analysis of pathologic unilaterality was biopsy unilaterality. These variables can be used to assess men with low- to low–moderate-risk PCa prior to selection for subtotal ablation along with other established low-risk features of PCa [51]. Izkowski et al also revealed that only unilateral and unifocal PCa at biopsy strongly and independently predict unilateral, unifocal, margin-negative, and small-volume PCa [52].

Table 2 Current selection criteria for focal cryoablation*

Study PSA ng/ml Gs cT Biopsy criteria
Bahn et al** [13] All (mean: 4.9) 5–7 NA Initial 6–8 cores, then targeted biopsy, including NVB and SV if ECE was suspected
Ellis et al [15] All (mean: 7.2) 3–10 (mean: 6) T1c-T2c Unknown (retrospective study)
Onik et al [12] 0.9–18 3–8 T1c-T2b Second biopsy on negative side, TRUS
Lambert et al [14] 1–13.1 ≤6, 3 + 4 T1c Could have 1 or 2 contiguous cores and a tumor volume <10% in 12-core biopsies

cT = clinical stage; ECE = extracapsular extension; Gs = Gleason score; NA = not available; NVB = neurovascular bundle; PSA = prostate-specific antigen; SV = seminal vesicle; TRUS = transrectal ultrasound.

* Adapted from Mouraviev [54].

** No PSA, Gs, or cT selection criteria; required biopsy-proven, unilateral disease for entry.

At present, there is neither a consensus as to a strict definition of inclusion and exclusion criteria nor pretreatment planning guidance for focal therapy. For instance, Yoon et al, analyzing the pathologic features of 100 RP specimens with clinically unilateral disease by prostate biopsy, demonstrated that none of the seven patients with PSA levels >10 ng/ml had clinically significant PCa in the contralateral lobe [6]. Whether data from other studies imply that the baseline PSA level needs to be <10 ng/ml to consider focal therapy remains unclear and needs further study.

At the present time, it does not appear that any PSA threshold, biopsy Gleason grade, or clinical stage cut point within the low-risk category can better select men with unilateral or unifocal disease [6], [51], and [52]. This may be explained by the complexity of tumor biology of early stage PCa, which requires further inquiry for more valid molecular determinants of tumor diagnosis and progression. When selecting patients, we need to consider several critical questions about the possible goals of focal therapy: (1) Is the expectation cancer cure or cancer control? (2) Is clinically significant PCa being inadvertently missed in the untreated part of the gland? and (3) How can careful surveillance of the untreated parenchyma be optimized?

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4. Conclusions

When considering targeted focal ablation, the main goals at diagnosis are to determine (1) the spatial cancer distribution (3D location) within the gland, (2) cancer volume, and (3) biologic potential (eg, which aggressive foci require immediate therapy, while other indolent foci may be able to be followed or treated with a chemoprotectant agent). Currently, we can propose four options regarding preoperative planning for focal therapy (Fig. 3) [53]. The challenge is how to define the clinically significant PCa focus based on its natural biologic history tempered with patient life expectancy. Further research will be required to understand the biologic potential of each of the individual PCa foci within a cancerous gland. In addition, chemoprevention combined with focal treatment is a future viable concept that deserves further exploration.

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Fig. 3 Conceptual schematic of treatment options for focal therapy: (A) true focal ablation; (B) hemiablation: the ablation zone is extended to include the ipsilateral neurovascular bundle and margin (treatment of possible extracapsular extension of disease); (C) 75% ablation: note that 25% of the gland (untreated area) will be on an active surveillance protocol; (D) near-total ablation: some undetermined amount of parenchyma will not be treated to maintain the neurovascular bundle on that side. Adapted from Polascik [53].
NVB = neurovascular bundle.

The biggest achievement in the developing concept of focal therapy is the willingness of an interdisciplinary scientific community to steadily implement advances in imaging and ablative technologies into clinical practice. Although impediments to the widespread adoption of focal therapy exist primarily because of the multifocal nature of PCa and the current lack of precise imaging, research into clinical predictors of PCa unifocality or unilaterality is necessary to further develop the focal therapy concept [6], [12], [13], [14], [15], [54], and [55]. A major research goal is the identification and development of reliable pretreatment indicators that can accurately predict the natural history of a patient's tumor. Significant advances in tumor biology and the introduction of novel minimally invasive therapies may further facilitate the inclusion of minimally invasive treatment options for select candidates in contrast to radical whole-gland treatment as we move toward a more individually tailored therapy program. For those patients with unifocal or unilateral PCa lesions seeking a more targeted treatment with preservation of QoL, options such as focal targeted cryoablation are currently available [12], [13], [14], and [15]. However, only long-term results of prospective multi-institutional clinical trials will determine outcomes among patients with small-volume PCa and increase understanding of tumor biology.

The future of focal therapy for PCa seems very promising. To ignore an organ-sparing, image-guided ablation of localized PCa is to similarly ignore technical and scientific progress that has been done in this area for the past few decades. A new era of minimally invasive surgery is approaching, and we need to welcome these innovations into clinical practice, being ready to implement them in a wise and careful fashion.

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Conflicts of interest

Thomas J. Polascik is a research consultant for Galil Medical Inc. The other authors have nothing to disclose.

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Funding support

None.

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Footnotes

Department of Urology, AMC University Hospital Amsterdam, The Netherlands and Duke University Medical Center, Durham, North Carolina, USA

lowast Corresponding author. Duke University Medical Center, Box 2804 Yellow Zone, Durham, NC 27710, USA. Tel. +1 919 684 4946; Fax: +1 919 684 5220.

Article information

PII: S1569-9056(09)00006-2
DOI: 10.1016/j.eursup.2009.01.005
© 2009 European Association of Urology. Published by Elsevier B.V.

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