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Perspective |
1 Department of Radiology, Children's Hospital Boston and Harvard Medical
School, 300 Longwood Ave., Boston, MA 02115.
2 Department of Radiology, St. Joseph's Hospital and Medical Center, Phoenix, AZ
85013.
Received March 22, 2006; accepted after revision April 25, 2007.
Address correspondence to S. D. Brown
(stephen.brown{at}childrens.harvard.edu).
OBJECTIVE. Despite the growing use of percutaneous imaging-guided tumor ablation in adults, few reports describe its use in children except for osteoid osteoma. Our objective is to describe how tumor ablation in children and adults may differ, both to facilitate dialogue on pediatric tumor ablation and to increase awareness and use of this valuable technique.
CONCLUSION. There are numerous indications for which various ablative techniques may be safe and effective for treatment of pediatric tumors. Nonetheless, important differences between the pediatric and adult populations warrant consideration.
Keywords: children • ethics • interventional radiology • research • tumor ablation
Imaging-guided tumor ablation has grown remarkably in the past few years. There are now estimated to have been thousands of procedures performed worldwide, with many hundreds of ablation systems installed in hospitals. An over-whelming number of these procedures have been performed in adults, but, excluding osteoid osteoma treatment in children, few cases of ablation have been reported in the pediatric group [1-5]. Nonetheless, the proven safety and efficacy of ablation in adults, the relative advantages of ablation compared with other treatment methods, and the generally longer life span of children, all suggest that this therapy should be investigated in children as well.
Having performed many ablations in adults and a smaller number in children, we have come to realize—and sometimes stumbled on—many differences between the two populations. As with other therapies that are brought to pediatrics after having been developed for adults, the often-heard refrain that, "children are not just little adults," is once again germane.
The purpose of this article is to summarize our experience and thoughts and to solicit discussion from others as this nascent field begins to be explored in children. In general, we have identified three broad categories that distinguish ablation in children from adults: technical considerations, differences in diseases, and philosophical and ethical issues.
Technical Issues
Like much of pediatric interventional radiology, tumor ablation entails numerous technical challenges that differ from similar procedures in adults. Some of these are common to many pediatric imaging-guided procedures (e.g., instrumentation), whereas others specifically relate to ablation.
Instrumentation
A common theme in pediatric interventional radiology is that instruments
designed primarily for use in adults tend to be poorly adapted for small
children; the instruments often are too long, too wide, too unwieldy, too
"something." The same is true for ablation. Thus, when standard
adult probes are used in children, they may be too long and awkward for use in
CT or MR gantries and are liable to become dislodged. Although many
instruments such as needles and catheters have been developed for pediatric
interventional radiology, this has not yet occurred with tumor ablation. This
is an important technical issue. The development of instruments, such as
shorter radiofrequency probes, that may be more appropriate for smaller
pediatric patients may require collaboration between pediatric interventional
radiologists and device manufacturers.
Access
When tumors are large and relatively superficial and accessible, the
relative paucity of body fat in children compared with adults is not a problem
(Fig. 1). However, when tumors
are deep and internal, shielded by over-lying structures, and perhaps small,
access to the lesion without the safety of traversing body fat becomes more of
an issue, and is exacerbated in children
[1]. Techniques to improve
access are being developed and include injecting water to displace structures
("hydro-dissection")
[6], injecting air or carbon
dioxide [7], and inserting
inflatable balloons [7].
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These techniques are all designed to increase safe routes. Each of these maneuvers is potentially helpful, albeit more complex, time-consuming, and costly. These techniques will necessitate increased radiation if performed under CT guidance. They all may be more difficult to perform in younger or smaller children who have minimal intra- and retroperitoneal fat. The salutary effect of hydrodisplacement for a pediatric renal tumor has been reported [1].
Grounding Pads
Grounding pads are essential for safe performance of radiofrequency
ablation, which relies on an electrical circuit to deliver the energy for
tissue heating. The primary components of the clinical system are the
radiofrequency generator, the active electrode, and the dispersive return
electrodes (also called grounding pads). The active electrode is placed into
the tumor and delivers current that creates the volume of ablation around the
tip. The current returns to the generator, dispersed over a broad area
provided by the grounding pads; usually, one or two are placed on each thigh.
Too much current over too small an area or for too long a time can generate
skin burns. Further, poor placement of the pads (especially improperly sized
pads) or inappropriate overlapping can also result in an uneven distribution
of the current. Adult grounding pads can be used if circumstances
allow—that is, a large enough patient. Pediatric grounding pads are
available and offer an alternate solution to be considered if the placement of
adult-sized pads is difficult
[8]. The overall goal is the
return of the current over a maximized and smoothly adherent area for the
current. However, the wide variability in ages and sizes of children may make
placement on the child a challenge, particularly for the smallest
patients.
This problem in children contrasts with the commonly accepted standard in adults that, "one size fits all" [8]. The radiofrequency ablation device manufacturer's representative should be consulted and may have advice. However, because these applications are new, physician judgment and understanding of the issues are critical. Many pediatric operating rooms and cardiac catheterization laboratories are experienced in the placement of grounding pads for the use of electrical devices in children of varying sizes and ages. Collaboration or consultation with these resources may be helpful to radiologists who are establishing pediatric radiofrequency ablation programs.
Anesthesia
Although there is a trend toward increasing use of general anesthesia for
radiofrequency ablation in adults, some groups still prefer conscious
sedation. Virtually all radiofrequency ablation in children is performed using
general anesthesia. The alternative to radiofrequency ablation in many cases
is an operative procedure that presents similar issues of availability, cost,
and safety of anesthesia. Thus, avoidance of general anesthesia is not
adequate to justify using radiofrequency ablation over surgical
alternatives.
Unlike in adults, follow-up imaging after pediatric ablation, particularly with MRI, may require repeat administration of general anesthesia. For children, this issue is not unique to radiofrequency ablation; pediatric patients with malignancies may require general anesthesia for follow-up imaging, regardless of the form of treatment.
Guidance and Follow-Up Techniques
Protection from radiation is an essential consideration for ablation, as
with other aspects of imaging and intervention in children. Although CT
scanners are becoming faster and shielding methods have improved, the choice
of imaging technique for procedure guidance is influenced by numerous factors
that include size, site, and accessibility of the lesion in addition to
availability and radiation considerations. However, whereas sonography and MRI
may be preferred because of their lack of ionizing radiation, CT guidance is
increasingly preferred for tumor ablation in adults. Pediatric radiologists
performing CT-guided ablations should possess a strong understanding of the
technical parameters that affect radiation dosage and the as low as reasonably
achievable (ALARA) principle, as it applies to CT
[9].
Imaging follow-up to assess the effectiveness of ablation is a controversial issue that also involves consideration of radiation dosage. Optimal imaging of lesions treated with radiofrequency ablation may differ from the protocols that are used most commonly to assess effects of conventional therapies, such as surgery, chemotherapy, and radiation. Although CT is used most frequently, sonography, particularly with contrast administration, is gaining popularity outside the United States [10]. Although sonography contrast agents are being used in children in Europe, they do not have U.S. Food and Drug Administration (FDA) approval and have not yet been widely adopted clinically in the United States despite promising reports [11]. The uses of sonography contrast agents that relate specifically to ablation in children have not been addressed. Some groups prefer conducting follow-up studies with MRI using IV gadopentetate dimeglumine because MRI lacks radiation exposure, an important consideration in children. Follow-up imaging in children frequently will require general anesthesia, particularly when MRI is used. The need for general anesthesia when CT is used for routine imaging is increasingly uncommon in children.
Another important development that has not been well evaluated in children is the use of PET or PET/CT to assess the efficacy of ablation [12]. Radionuclide administration of 18F-FDG for PET has radiation exposure, thus confounding the role of PET for ablation follow-up. On the other hand, although there are few studies that specifically evaluate the utility of PET in pediatric oncology patients, early results suggest it may be of value in the management of several conditions that may prove amenable to radiofrequency ablation, including Wilms' tumor and various sarcomas [13, 14]. Whether PET or PET/CT should be used in the routine follow-up of children after ablative therapy and whether the additional radiation is considered worth-while remain to be studied. These questions are not unique to ablative therapy; the risks may not be significant compared with the burden of disease in children with malignancies.
Methods of Tumor Destruction
Radiofrequency ablation predominates in the United States and worldwide
compared with cryotherapy as the primary ablation method. Alcohol ablation has
been used frequently in Asia and parts of Europe for hepatocellular carcinoma,
a common tumor in these geographic regions. Because few groups perform both
radiofrequency ablation and cryotherapy, comparisons and controlled studies
are not yet available.
Cryotherapy probes and needles have generally been larger (wider) and perhaps riskier than those for radiofrequency ablation. On the other hand, compared with heating, cryotherapy may cause less damage to juxtaposed nontumorous cellular tissue [15]. Cryotherapy may be performed using MRI guidance, which holds advantages in reducing radiation exposure in children. The cryotherapy ice ball provides the technical advantage of allowing treatment margins to be visualized intraprocedurally [16]. MR-guided interventions in children may become more frequent as intraoperative MRI scanners become incorporated into pediatric surgical suites [17].
Microwaves present a newer heating method that currently uses even larger probes than those for radiofrequency ablation or percutaneous cryotherapy. The newest ablation method, high-intensity focused ultrasound (HIFU), is an exciting and novel technique that uses no probes. This focusing of ultrasound beams for heating is as yet untested in children and is in its infancy in adults as well. Nonetheless, it is well adapted to interventional MR guidance [18], which may be an advantage in children.
The Diseases and the Milieu Are Different
Although cancer is less prevalent in children than in adults, it remains a significant pediatric problem. Of concern for those performing tumor ablation, certain types of tumors are relatively more common in children than in adults, and the treatment options are not always the same.
Osteoid Osteoma
In children, osteoid osteoma undoubtedly is the prototype tumor for which
ablation is not only valuable but is also likely the preferred therapy
[19]. Although osteoid
osteomas are much less common in adults, incurable metastatic bone tumors in
adults are being treated increasingly with successful amelioration of pain
[20]. Successful
radiofrequency ablation of a small number of benign cartilaginous tumors in
children also has been reported
[21,
22].
Given the reported success of ablation for osteoid osteomas and other benign skeletal tumors in children and the success of treating painful skeletal metastases in adults, it would seem reasonable to apply the technology to the treatment of painful bone metastases or primary tumors in children. Severe pain often is seen in osteosarcoma and Ewing's sarcoma metastatic to the spine. Neuroblastoma, Wilms' tumor, and lymphoma may cause considerable pain in other bone sites, including the pelvis and femur. These diseases present both a challenge and an opportunity to bring a potentially valuable palliative therapy to an important sub-population of pediatric oncology patients.
Renal Tumors
Entities such as nephroblastoma, nephroblastomatosis, and Wilms' tumors do
not exist in adults. Hence, the natural history of this disease spectrum, the
likelihood of degeneration of benign disease, and the much longer life span of
a child compared with an adult are considerations when treatment options are
weighed. Although the pathologic and biologic properties of renal tumors in
children differ greatly from those in adults, certain indications for which
renal ablation is used in adults may apply to the pediatric group. These
include tumors in solitary kidneys that may not be amenable to partial
nephrectomy and tumors in patients with significant comorbidities.
In certain circumstances, percutaneous ablative therapies may be useful as temporizing measures for renal tumors. A case of radiofrequency ablation after degeneration of nephroblastomatosis into a Wilms' tumor in a 4-year-old child with a solitary kidney has been reported [1]. The procedure was performed to avoid or delay renal dialysis in the child and because the central location of the tumor within the kidney made it a high surgical risk.
Another report described the use of radiofrequency ablation in combination with brachytherapy to palliate pain in an 11-year-old child with recurrent Wilms' tumor [4]. It is tempting to consider the possibility of using radiofrequency ablation to treat visible nephrogenic rests. Variables to consider would include the number of lesions present, their locations, and whether they are unilateral or bilateral. Further, it would depend on the alternative treatments under consideration. For example, if one or two lesions easily accessible to radiofrequency ablation were going to be treated with chemotherapy, radiofrequency ablation might be a reasonable alternative. Conceptually, there is precedent in adults for treating premalignant dysplastic hepatic nodules with ethanol, radiofrequency ablation, or microwave ablation to prevent malignant degeneration [23]. Treatment of premalignant renal lesions in children may be a reasonable consideration, at least if done in an experimental protocol.
Sarcomas
In contradistinction to adults, sarcomas in children are more prevalent
relative to carcinomas. Although sarcomas can grow rapidly to become quite
large and extensive, they often can be managed for some time by chemotherapy.
There is as yet little experience with ablation of sarcomas in children or
adults [24].
Thermal Effects
How children adapt to heat deposition induced by ablation is unknown.
Certainly, Bovie electrocautery, a form of radiofrequency energy deposition,
has been used successfully and safely in pediatric operating rooms for many
years. Nonetheless, heating a large tumor in a small child raises the
hypothetical possibility of dangerous hyperthermia. Measures to combat this
overheating include leaving the child blanket-free during the procedure and
using external body coolers such as a Bair Hugger temperature management
blanket (Arizant Healthcare)
[1,
2]. A converse situation of
hypothermia from cryotherapy also might be envisioned.
Comorbidities
A major justification for ablation in adults is that comorbidities may make
otherwise curative surgery less attractive and more hazardous. For example,
many adults with lung tumors have underlying chronic lung disease that confers
increased risk to surgery, thus making percutaneous ablation the more
attractive option. Common comorbid conditions that occur in adults, such as
obstructive lung disease, coronary artery disease, cerebral vascular disease,
and severe diabetes, are not nearly as prevalent in the pediatric population.
Thus, from the comorbidity perspective, there may be correspondingly fewer
opportunities to use ablation in children.
Complications
Although complications are anathema at any age, a complication in a child
has further potential for long-term, lifelong implications. Thus, risks must
be strongly considered in these treatment selections as well. Although
fortunately uncommon, some complications in adults who have undergone
radiofrequency ablation have been major, and even death has been reported
[25]. Other major
complications depend on the location of ablation and may include injury to
adjacent viscera, skin burns, liver abscess, pneumothorax, biliary or
urothelial strictures, and hemorrhage.
At this time, it is not known whether children are more, less, or equally susceptible to the complications of radiofrequency ablation as are adults or whether they will develop other complications that are unique. Children may handle current, heat, and cold differently than adults. Access may be more difficult in children and general anesthesia may be required more often. All of these conditions could affect the cumulative adverse events profile for radiofrequency ablation in children compared with adults. Certainly, the alternative treatments in these cases are not without risk as well. However, management of even the most common complications, such as pain and the flulike "postablation syndrome," may require more attention in children compared with adults. Children will likely need more supportive therapy and require hospitalization for procedures that are more commonly performed as outpatient procedures in adults.
Philosophical and Ethical Issues
Role of the Institutional Review Board (IRB)
As IRBs consider ablation in children, they likely will want to review the
adult experience. Pediatric IRBs will have to wrestle with many of the issues
discussed as they relate to novel uses in children. Our Children's Hospital
Boston IRB asked for two experienced outside adult ablation consultants to
review our initial application for intraabdominal ablation in children.
Although these consultants were highly experienced and were from renowned
academic institutions, they admittedly had no experience with the basic
pediatric disease with which we were dealing. Their experience, however, did
provide valuable technical insights.
We have used our IRB's guidelines for "Innovative Therapy," and more specific protocols for IRB sanction of ablation. Several factors help determine whether ablations in children should be undertaken as innovative therapy or within the framework of formal clinical research. On the one hand, except osteoid osteomas, the safety and efficacy of tumor ablation in children has yet to be established in a rigorous manner. Until this happens, all of these procedures remain investigational. On the other hand, placing these procedures into formal research protocols has several practical disadvantages. First, multicenter trials may be more necessary for the pediatric population than for adults to recruit adequate numbers of patients. For the sake of protocol uniformity, this may require institutions to use a single device, which may not be practical or desirable. Different institutions may have different means of pre- and postprocedural evaluation. This might, for example, exclude institutions that do not have PET/CT availability if such imaging is required in a protocol.
Second, rigorous protocols may not allow technical adjustments that may become important as the technology develops. Protocols that take several years to complete may not be able to incorporate subsequent, and possibly improved, innovations. In addition, formalized protocols may limit adjunctive or supportive therapy that may be necessary for control of pain, nausea, postablation syndrome, or other complications of ablation. Finally, because so much in children is dependent on age and weight, planning for a trial of ablation in different age and size groups becomes logistically complex.
None of the potentially confounding factors should deter pediatric interventionalists interested in tumor ablation from performing these procedures within the framework of established protocols. Empirically obtained data ultimately will provide the strongest support for the ongoing performance of these procedures. One reasonable solution, as our IRB agreed, is to perform the initial ablations using the Innovative Therapy mechanism, allowing technical adjustments before entering patients into formal protocols.
Regardless of whether tumor ablation in children is performed as innovative therapy or as research, the informed consent process should explicitly convey to the child's parents that ablation in children, although potentially promising, has not yet been proven to be safe or effective. It should be clear to the parents and child that simply because a procedure is not performed as research, per se, does not mean that it is not experimental [26]. Research involves the systematic execution of a scientific protocol to test a hypothesis for obtaining new knowledge or benefiting future patients. However, parents should have an understanding that any use of a drug or device for new purposes that deviate substantially from standard care may be considered to be experimental [27]. Further, informed consent should make clear that the devices being used do not have approval by the FDA for procedures that are being performed in children.
Illustrative Cases
Our early experiences with the first cases we performed at our institution
illustrate some of the nuances of these ethical issues:
Case 1—The first radiofrequency ablation we were requested to perform was to treat a straightforward right tibial osteoid osteoma in a 13-year-old girl (Fig. 2A, 2B, 2C). The major articles on the subject around that time described the successful percutaneous treatment of osteoid osteomas using a single electrode with a 5-mm exposed tip [19, 28-30]. The electrode and generator system these articles describe had historically been used by neurosurgeons to treat trigeminal neuralgia [31]. In addition, these articles differed with respect to certain technical parameters. For example, one group performed 4-minute ablations [28, 29], whereas a second group had evolved to using 6-minute ablations [19]. The alternative to the system used by these teams was a single electrode with a 1-cm exposed tip and a newer generator that had been developed for both soft-tissue and bone ablations. Neither device had received FDA-approval for ablation of osteoid osteomas, and neither had been approved for use in children. Since both were commercially available, we could choose to use either one.
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We were confronted with basic and extremely common issues of novel and off-label use of medical products in children. Further, we needed to consider whether to use the device with which the most experience had been gained up to that time but without the vendor's assistance or whether to use a newer product that was well supported by the manufacturer but that was not yet as well described in the literature. Finally, we had to choose whether to use 4-minute or 6-minute ablations based on differing recommendations in the literature. For the purposes of this discussion, we needed to consider how to frame the informed consent for the patient and her parents. Was this experimentation, technical innovation, or standard of care? What information was it within the parents' rights to know?
Case 2—The second case we performed was an ablation of a Wilms' tumor in a 5-year-old girl with a solitary kidney. Clinical and technical details have been published previously [1, 4]. At the time of this procedure, no reports of soft-tissue ablation in a child had been published. As with the previous case, the latter situation raised issues of informed consent. It was not a hypothesis-driven study meant to address a specific question empirically. Rather, it was a treatment specifically targeted to benefit an individual patient. Thus, it fit under our institutional guidelines for a technical innovation, rather than research.
Nonetheless, as the first performance of a renal ablation in a child and as a significant deviation from standard care, it was still undoubtedly an experimental treatment. Once again, we needed to consider how much information the patient's parents had a right to know. Despite the discomfort at conveying the information, withholding it would have been paternalistic at best. It would have been incomplete and incorrect to convey only that the procedure was innovative rather than experimental. Certainly, it would have been inappropriate not to have informed the parents that such a procedure had never been described in children.
Performing Novel Procedures in Children
Similar scenarios are common when innovative treatments are provided to
adults and children. However, it is also true that a great number of therapies
that are used in children are developed initially for adults and then brought
to children after FDA approval is granted for use in adults.
Many drugs and devices are used in children before formal trials have been undertaken. Most medications prescribed for children lack FDA approval for pediatric usage, and there is widespread concern that insufficient information on safety and efficacy exists for drugs that are commonly prescribed for children [32-34].
Even fewer data exist on the use of devices in children. Thus, these admonitions are essential to protect families who may be desperate for any therapy that holds the promise of therapeutic benefit for a child who is in pain or has cancer (or both). Even if an innovative therapy mechanism is chosen, an IRB may provide valuable support, such as offering advice on the wording of the informed consent and record keeping. Such support may be quite helpful to protect not only the patient but also the investigators and the institution involved in the performance of these novel and potentially risky procedures.
Finally, the assent of the child should be obtained according to institutional standards. This practice is common in pediatric research. It acknowledges that, although children may not have the legal standing to provide informed consent, many are able cognitively to understand the nature of the procedures that they are asked to undergo and are mature enough to engage in the decision-making process. The age at which assent is obtained from pediatric patients varies among institutions and with the complexity and risks of the procedure being discussed.
Should the Procedure Always Be Done First in Adults?
Because much experience already has been gained in adults, fortunately, the
pathway is paved for many procedures. Although the organ-specific diseases
that occur in children and adults are biologically distinct from each other,
they often present similar indications for treatment. Although the experience
with radiofrequency ablation in children is limited, the considerable
experience that has been accumulated in adults can, in part, be extrapolated
reasonably to children. Thus, if radiofrequency ablation is useful for
treating renal tumors in adults with solitary kidneys and significant
comorbidities or unresectable hepatic and pulmonary metastases or painful
skeletal metastases in selected adult patients, it is reasonable to consider
using ablation for these clinical indications in children. Nonetheless, as
described previously, certain tumors or conditions that are found only, or
predominantly, in children may necessitate a seminal procedure in a child.
This scenario of the pediatric-only, or child-predominant, tumor coupled with
the creativity of pediatric interventional radiologists undoubtedly will
create the potential for heretofore untested applications of ablation.
Life Span
The obviously longer life span in children compared with adults speaks to
the importance of cure when possible, rather than just palliation. Palliation
is considered a perfectly reasonable indication, especially in elderly adults
or those with comorbid diseases, to slow tumor growth and to treat pain
[35]. Other than in the child
who may have a terminal disease, these indications, although appropriate, are
not likely to be encountered as frequently in children. The combined input
from surgeons, oncologists, and radiation therapists is especially important
in making the overall treatment plan for ablation in children.
Role of Biopsy
An ongoing, and as yet unresolved, debate exists with adult ablation in
regard to the need (or not) for preablation biopsy. For example, many
urologists will argue that a renal tumor likely will need to be removed in any
event, thus precluding the need for biopsy. Other authors argue that, albeit
uncommon, there are benign renal lesions that may mimic cancer and, hence, may
benefit from biopsy to avoid surgery
[36].
Similar issues may also be relevant with hepatic tumors in children because certain benign tumors (adenoma, focal nodular hyperplasia) may have imaging features that overlap with malignancy. Preprocedure biopsy can be performed at the same time as the proposed ablation, although a frozen-section cytopathologic interpretation will be necessary. On the other hand, a biopsy also might be performed in a separate preablation sitting. In children, however, this may necessitate another general anesthesia session and additional radiation.
Surgical Option
An alternative to radiologically guided percutaneous ablation is surgically
guided ablation. Surgical guidance may be performed either by laparoscopy or
with intraoperative sonography. In some situations, in children as with
adults, the tumor may be better accessed at surgery and risks may be less,
although the converse certainly exists as well. It is hoped that "turf
issues" may not strain an already complex situation regarding pediatric
ablation.
Patients' and Families' Desires
Interventionalists who undertake ablations in children, but who are most
experienced with adult patients, should be familiar with the different needs
of pediatric patients and their families in terms of communication and
psychosocial support. For example, it is becoming increasingly common for
adult patients to initiate requests for percutaneous ablation themselves.
Families commonly supply backup and support, although the patient usually
makes the final decision. This is not the case with pediatric tumor ablation.
In most situations, the child would be legally unable to make the final
decision. Hence, the onus and responsibility fall to the family. As mentioned
previously, this has important implications for informed consent. Counseling
with all physicians involved and perhaps with ethics, pastoral, and
psychosocial services as well may provide valuable and essential input when
pediatric patients are involved more commonly than for adults.
Conclusion
The exciting field of percutaneous imaging-guided tumor ablation, already well established in adults, is nascent in children. We believe that as sophisticated new diagnostic oncologic imaging technologies emerge and are incorporated into pediatric practice, novel and promising radiologic treatment options also should be considered for use in children. A host of technical issues, pediatric disease-specific situations, and philosophical and ethical conundrums will provide opportunities for research, thoughtful intellectual challenges, and creativity as the procedures develop. Ultimately, we anticipate that this will result in therapeutic advances that will provide palliative and curative benefits for children with malignancies and hope for their families.
Acknowledgments
We thank Paul R. Morrison for his invaluable technical commentary.
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