1. RADIATION RESEARCH 164, 221–229 (2005)
0033-7587/05 $15.00
2005 by Radiation Research Society.
All rights of reproduction in any form reserved.
TECHNICAL ADVANCE
The MIT User Center for Neutron Capture Therapy Research
Otto K. Harling,a,1 Kent J. Riley,b Peter J. Binns,b Hemant Patelc,2 and Jeffrey A. Coderrea
a
Department of Nuclear Science and Engineering and b Nuclear Reactor Laboratory, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139; and c Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215
this research in the U.S. and elsewhere. The current status
Harling, O. K., Riley, K. J., Binns, P. J., Patel, H. and Cod- of this modality has been reviewed in a recent special vol-
erre, J. A. The MIT User Center for Neutron Capture Ther- ume of the Journal of Neuro-Oncology (2). Major progress
apy Research. Radiat. Res. 164, 221–229 (2005). has been made on many fronts, including the development
Neutron capture therapy (NCT) research encompasses a and construction of high-performance neutron beams (3).
wide range of preclinical and clinical studies needed to devel- Although boron delivery compounds have also improved
op this promising but complex cancer treatment. Many spe- (4), there is still general agreement that better compounds
cialized facilities and capabilities including thermal and epi- with greater selectivity are needed. Improved compounds
thermal neutron irradiation facilities, boron analysis, special- are on the critical path to the successful development of
ized mixed-field dosimetry, animal care facilities and proto- BNCT, and a coordinated approach is needed to develop
cols, cell culture laboratories, and, for human clinical studies, and investigate new capture compounds that can be used
licenses and review board approvals are required for NCT to treat various disease sites. The necessary supporting
research. Such infrastructure is essential, but much of it is not technologies such as boron analysis (5, 6) and treatment
readily available within the community. This is especially true
planning (7, 8) are established, and our understanding of
for neutron irradiation facilities, which often require signifi-
cant development and capital investment too expensive to du-
the radiobiology of BNCT (9) has progressed significantly.
plicate at each site performing NCT research. To meet this Clinical trials of BNCT were initiated with better-penetrat-
need, the NCT group at the Massachusetts Institute of Tech- ing epithermal neutron beams in the mid-1990s (10, 11)
nology (MIT) has established a User Center for NCT re- and have continued in the U.S., Japan and several European
searchers that is already being accessed successfully by vari- countries. BNCT research and development in all relevant
ous groups. This paper describes the facilities, capabilities and areas has become a truly international effort with new re-
other resources available at MIT and how the NCT research search and clinical activities in Taiwan, Russia and Argen-
community can access them. 2005 by Radiation Research Society tina as well as preliminary studies that have begun in ad-
ditional European and Asian countries.
Primary brain cancer, glioblastoma multiforme (GBM),
INTRODUCTION has been the main target of Phase I/II BNCT clinical studies
in the U.S. and Europe. The tolerance of normal brain tissue
Neutron capture therapy (NCT) for cancer is an experi- to BNCT irradiations has been determined from these lim-
mental tumor cell targeting therapy. This promising but ited studies, and the median survival using p-boronophe-
complex radiation therapy requires the administration of tu- nylalanine (BPA) appears comparable to that for conven-
mor-seeking compounds, usually containing 10B, that con- tional radiotherapy (10). BNCT has also been studied for
centrate preferentially in tumor cells followed by irradiation melanoma metastases in a limited number of intracranial as
with suitable neutron beams. well as peripheral subcutaneous cases where local tumor
Although research in NCT with boron compounds control was observed (12–15). Recently, liver metastases of
(BNCT) has a long history of development since its origi- colo-rectal cancer in two European patients exhibited good
nation in the U.S. in the 1950s [see for example Slatkin response to intraoperative BNCT (16). In Japan, brain tu-
(1)], the last 15 years have seen a significant expansion of mors have been a major focus of BNCT, with an increasing
number of treatments directed at melanoma and head and
1
Address for correspondence: Department of Nuclear Science and En- neck cancers. In all, a few hundred brain tumor patients
gineering, Massachusetts Institute of Technology, NW13-200, 138 Al-
bany Street, Cambridge, MA 02139; e-mail: oharling@mit.edu. have been treated with BNCT in Japan using either BPA,
2
Present address: Wyeth Pharmaceuticals, Clinical Research/Oncology, sodium borocaptate (BSH) or, in a few cases, a combination
35 Cambridge Park Drive, CPD 3100-2, Cambridge, MA 02140. of these two boron delivery agents. Several long-term sur-
221

2. 222 TECHNICAL ADVANCE
FIG. 1. Isometric view of the MITR with the thermal neutron irradiation facility, M-011, directly beneath the
core of the 5 MW research reactor and the epithermal beam facility, FCB, shown on the right-hand side of the figure.
vivors with GBM have been observed in the Japanese ex- REACTOR FACILITIES AND CAPABILITIES
perience with BNCT (17). Good local control was observed
Thermal Neutron Irradiation Facility
in a few recently treated head and neck cancers (18, 19).
Further advancement in the clinical application of BNCT Low-energy (thermal) neutron beams are necessary for
requires new, more selective boron delivery agents, many preclinical studies with small animals or cell cultures and
of which are currently available but must undergo extensive for clinical irradiations of shallow malignancies. The re-
testing in animal experiments before they can be considered cently upgraded and renovated thermal neutron irradiation
for testing in clinical trials. facility located beneath the core of the MITR is shown on
A wide range of research facilities and interdisciplinary the lower left portion of Fig. 1.
capabilities are required for the development of BNCT as Source neutrons for the thermal neutron beam, known as
a clinically useful therapy. Some facilities, in particular the the M-011 beam, originate in the D2O reflector/moderator
neutron irradiation facilities, needed for preclinical and below the core of the MITR. These neutrons reach thermal
clinical research require significant capital investments and equilibrium with the moderator before they enter the ver-
are available at very few sites. Currently the only U.S. site tical beam line and have an energy spectrum optimal for
with high-performance epithermal and thermal neutron ir- NCT irradiations of targets up to approximately 3.5 cm
radiation facilities suitable for preclinical and clinical stud- deep in tissue. The thermal neutrons are collimated by the
ies is located at the Massachusetts Institute of Technology reactor-grade graphite walls of the vertical beam line that
Research Reactor (MITR). The 5 MW MITR operates with minimize intensity loss by elastically scattering many neu-
a high capacity factor, 24 h per day, 250–300 days per year. trons back into the main beam that would otherwise be lost.
These specialized neutron facilities, along with a variety of Three separate shutters, water, Boral (boron carbide in an
supporting technologies and capabilities, were developed to aluminum honeycomb), and lead plus borated polyethylene,
support preclinical and clinical NCT programs for MIT re- are located upstream of the beam aperture in the medical
searchers and their medical collaborators. Recently it has room and are used to control the beam during irradiations.
become possible, with the support of the U.S. Department Irradiations are monitored by four similar fission coun-
of Energy, to make this unique suite of facilities and ca- ters located at the edge of the beam and spaced at 90
pabilities available to non-MIT researchers. In this paper intervals. Their outputs are sent to industrial-quality pro-
we describe the resources available, the level of support grammable logic controllers (PLCs). The four detectors
that can be provided currently, and how interested users monitor not only beam intensity but also symmetry during
can access the NCT User Center. irradiation. This provides an overall system check of beam

3. TECHNICAL ADVANCE 223
TABLE 1
In-Air Measurements of Thermal Neutron Flux as well as Fast-Neutron and Photon
Dose Components in the M-011 Thermal Neutron Beam at the Position Used for Small-
Animal or Cell Culture Irradiations
Thermal flux Fast-neutron dose Photon dose rate Specific fast-neutron Specific photon dose
(109 n cm 2 s 1) rate (mGy min 1) (mGy min 1) dose (10 13 Gy cm2) (10 13 Gy cm2)
5.9 0.3 20 188 10 0.5 5.3 0.4
Notes. The absorbed doses per neutron per cm2 or specific doses are also provided. Reactor power is 5 MW.
stability. The beam monitoring, control and safety systems To account for these variables, irradiations are administered
use redundant monitors, signal processing, electronic cir- by programming the automated control system with beam
cuits, and PLCs to permit safe continuation of irradiations monitor counts that are determined separately for each ex-
should any individual component fail. The PLCs log essen- periment through prior calibration.
tial data and control shutter opening and closing to ensure When patients or large animals are to be irradiated in the
that neutron fluences (doses) are delivered to within 1% of thermal beam, they are positioned on a couch that is raised
target. Safety interlocks to protect the staff and patients are hydraulically toward the ceiling where a collimator is
also monitored continuously by the PLCs. A PC with a mounted beneath the lowest shutter. The size and shape of
large-screen monitor is used for online display of the status this patient collimator aperture can be changed readily. Cur-
of the irradiation and for record keeping but does not con- rently two circular collimator apertures are available with
trol the irradiations. This important function is assigned ex- diameters of 8 and 12 cm. Beam intensities for patient or
clusively to the redundant PLCs. All important systems large animal irradiations are lower than those for small an-
have back-up power from an uninterruptible power supply imals irradiated in the shielding box. Nevertheless, with
(UPS). Manual controls, located on the M-011 operator’s compounds such as BPA, therapeutic doses for superficial
console, can override the automated functions of the PLCs melanoma can be delivered in less than 10 min with a sin-
at any time to close shutters or, if necessary, scram the gle field.
reactor. The M-011 beam has been fully characterized using the
Irradiations using the M-011 beam are performed in a procedures routinely employed for mixed-field dosimetry
well-shielded irradiation room (shown in Fig. 1). Experi- at MIT (20). Table 1 provides in-air measurements of the
ments or patients can be viewed during an irradiation thermal neutron flux as well as photon and fast-neutron
through a shielded window and with closed-circuit televi- dose rates at the position typically used for small-animal or
sion. Background dose rates with all shutters closed are low cell culture irradiations. The high thermal neutron flux of
enough to allow staff to enter and work in the irradiation 5.9 109 n cm 2 s 1 combined with the low photon and
room even with the reactor operating at full power. A negligible fast-neutron contamination is indicative of the
shielding box constructed of lithiated polyethylene is po- excellent performance of the beam for preclinical cell cul-
sitioned in the neutron beam to perform small-animal or ture and animal studies as well as clinical trials of BNCT
cell culture irradiations. Small animals are shielded by a for superficial melanoma. As an example, the biologically
2.5-cm-thick lithiated polyethylene lid that covers most of weighted dose [Gy(w); see ref. (9) for a discussion of
the animals and contains an aperture of the desired size and BNCT weighting factors] as a function of depth with BPA
shape, depending on the application. A variety of sites can is shown in Fig. 2. Measurements were performed along
be irradiated with a rectangular aperture of 2 cm 14 cm the central axis of an ellipsoidal water-filled phantom (21)
where, for example, two rats can be positioned side by side using the 12-cm beam aperture to approximate conditions
for brain tumor irradiations or four mice can be positioned during therapy. The individual dose components are plotted
for irradiation of subcutaneous tumors on the legs. Cell as points and the total tumor and tissue doses are fitted with
culture irradiations do not require a shielding lid because a least-squares polynomial to help guide the eye. The fast-
the largest possible beam aperture is used to irradiate the neutron and photon components were measured using
cultures uniformly. Phantoms, ionization chambers, and paired ionization chambers, while the 10B(n, )7Li and
gold foils can also be mounted in the irradiation box to 14
N(n,p)14C doses are determined from the measured ther-
determine dose rates from thermal neutrons, rays and fast mal neutron flux using kerma coefficients of 8.66 10 8
neutrons. The box is inserted into a recess in the borated and 7.88 10 12
Gy cm , respectively. A boron concen-
2
polyethylene shutter that accurately positions the animals tration of 18 g g 1, which has been observed in preclinical
or cells in the beam line when the shutter is opened. Irra- and clinical research, is used (22) together with a tissue
diation times vary between approximately 5 and 25 min nitrogen concentration of 3.5% in muscle and skin. A boron
depending on the dose required to achieve the desired ra- concentration of 65 g g 1 is assumed for tumor. A weight-
diation response as well as experimental conditions such as ing factor of 3.8 is applied for the boron capture reaction
geometry, boron concentration and reactor operating power. in tumor and normal tissues. Normal tissue dose is domi-

4. 224 TECHNICAL ADVANCE
cannot sustain the fission chain reaction by itself. Thermal
neutrons from the MITR-II are absorbed in the FCB fuel
and, in essence, are converted to higher-energy fission neu-
trons. The fission neutrons originating in the converter are
filtered and moderated by aluminum, polytetrafluoroethyl-
ene (Teflon ) and cadmium. Undesired photons are atten-
uated with a lead shield. The resulting large-area epithermal
neutron beam is directed toward the patient irradiation po-
sition by a lead-lined collimator. A final or patient colli-
mator protrudes into the well-shielded medical irradiation
room and features easily variable apertures 8 to 16 cm in
diameter. Apertures of different size or shape can easily be
implemented if required. The patient collimator with vari-
able aperture sizes and its extension into the medical room
allow easy positioning of patients for placement of the ra-
FIG. 2. The weighted dose–depth distribution in the M-011 thermal
diation field anywhere on the body. The right side of Fig.
neutron beam measured along the central axis of a water-filled ellipsoidal 1 provides an overall view of the FCB facility including
phantom for the 12-cm aperture using boron concentrations and weighting the shielded medical irradiation room. The irradiation room
factors representative of BPA as an example for treating superficial tu- has sufficient space for a gurney and positioning couch.
mors such as subcutaneous melanoma. Fast-neutron dose rates are neg- Patient observation during irradiations is facilitated by a
ligible and therefore are not plotted.
large shielded glass window and closed-circuit television
monitors. Two-way audio communication is also available
nated by the 10B(n, )7Li reaction due to the relatively high between the patient and clinical staff. Laser projections il-
concentration of boron. Photons and thermal neutron cap- luminate the central axis of the beam from both sides of
ture reactions in tissue nitrogen also produce some adven- the patient to help with positioning and optics that penetrate
titious dose to normal tissue. However, the fast-neutron the wall of the collimator provide the clinical staff a beam’s
dose component in this high-purity beam is so low, even eye view of field placement.
at its expected maximum near the surface, that it has neg- Three shutters control the FCB. A beam monitoring and
ligible influence on the total normal tissue dose. The useful control system similar to that described previously for the
penetration or advantage depth (AD) and the maximum M-011 thermal beam is used to automatically open and
normal tissue (skin or muscle) dose rate (or ADDR) shown close the three beam shutters: a thermal neutron absorbing
in Fig. 2 are respectively 3.5 cm and 2.4 Gy(w) min 1. Skin shutter on the reactor side of the fission converter, a large
tolerance doses of approximately 12 Gy(w) can be reached water shutter in the lead collimator, and a fast-acting lead
in 5 min, and a therapeutic ratio greater than unity would and boronated heavy concrete shutter close to the patient
be achieved at depths up to the AD. A well-benchmarked collimator. Neutron fluences are calibrated against mea-
Monte Carlo model of the MITR-II core and M-011 beam surements and treatment planning calculations of the ab-
line has also been developed. This model allows the ac- sorbed dose and are routinely delivered to within 1% of the
curate calculation of flux and absorbed doses for any con- prescribed target using this system.
ceivable experimental study including clinical trials. Table 2 provides the in-air epithermal neutron flux and
The MIT thermal neutron irradiation facility with its dose rates from photon and fast-neutron radiation in the
high-intensity, low-background beam and automated con- beam. The epithermal flux of 3.2 4.6 109 n cm 2 s 1,
trol systems is well suited for research in BNCT. Small- depending on final collimation, is currently the highest
animal and cell culture irradiations can easily be performed available of any epithermal neutron beam used for BNCT
in the facility, and clinical studies for shallow tumors can (23). If desired, higher intensity can be obtained by opti-
also be fully supported. mizing converter fuel loading and/or increasing reactor
power without affecting the excellent beam characteristics.
Epithermal Neutron Irradiation Facility Specific beam contamination from photons and neutrons is
also provided in Table 2. The contamination levels in the
MIT operates a state-of-the-art high-intensity, low-back- FCB are very low and have a minimal influence on clinical
ground epithermal neutron (0.5 eV En 10 keV) irra- beam performance. The performance of the FCB is illus-
diation facility known as the fission converter beam (FCB). trated by the example shown in Fig. 3, where the various
The FCB is the first epithermal neutron irradiation facility dose–depth distributions in a water-filled ellipsoidal head
to use a subcritical fission converter as a neutron source for phantom are plotted as points and a least-squares polyno-
NCT. Details concerning the design, construction and per- mial is fitted to the total tumor and tissue doses to guide
formance of the FCB are provided elsewhere (23, 24). The the eye (24). Tumor and normal brain (blood) concentra-
neutron source is a heavy water-cooled 235U fuel source that tions as well as the applied weighting factors are consistent

5. TECHNICAL ADVANCE 225
TABLE 2
In-Air Measurements of the Epithermal Flux as well as Fast-Neutron and Photon Dose
Rates in the FCB at the Patient Position with Several Different Collimators (24)
Fast-neutron Specific
Aperture Epithermal flux dose rate Photon dose rate fast-neutron dose Specific photon
diameter (cm) (109 n cm 2 s 1) (mGy min 1) (mGy min 1) (10 13 Gy cm2) dose (10 13 Gy cm2)
16 4.6 0.6 38 4 97 4 1.4 0.2 3.5 0.5
12 4.3 0.6 36 4 94 4 1.4 0.2 3.6 0.5
10 3.4 0.4 34 4 90 4 1.7 0.3 4.4 0.6
8 3.2 0.4 34 4 74 3 1.8 0.3 3.9 0.5
Notes. Specific doses are also provided. Reactor power is 5 MW and the converter power is 83 kW.
with those observed with the BPA capture compound (9, large animal irradiations where deep penetration to the can-
22) and are the same as those used for the thermal neutron cer site is required.
beam in Fig. 2 except that a nitrogen concentration of 2.2%
is applied for brain and a weighting factor of 1.3 is used Boron Analysis
instead of 3.8 to account for the microdistribution of boron
that accumulates in normal brain (9). The useful penetration Nondestructive analysis of biological samples for the 10B
(10) using the 12-cm aperture is 9.3 cm. This is adequate isotope is carried out using a prompt -ray neutron acti-
for treating the deepest locations in an average-sized human vation analysis (PGNAA) system at the MIT Research Re-
brain. The peak dose rate to normal tissue is 1.25 Gy(w) actor, shown schematically in Fig. 4. Typical samples con-
min 1, which means that a peak normal tissue dose of 12 sist of blood or tissue with volumes of 0.1 to 10 ml. No
Gy(w) can be delivered in 9.6 min with a single beam special sample preparation is required, and the high sensi-
placement. Assuming a homogeneous distribution of boron, tivity of the MIT prompt -ray system, 18 counts s 1 g 1
the tumor dose in this example is expected to vary from a
10
B, allows rapid analysis, usually in several minutes for 2
peak of 77 down to 12 Gy(w) at the maximum useful depth. g or more of 10B. A holder designed for 1- or 10-ml Teflon
A 6Li filter has been constructed to further increase the vials is used to position samples for analysis in the neutron
useful beam penetration by approximately 6 mm with the beam and can easily be adjusted to accommodate samples
BPA compound. An increase in converter power by 30– of different size or shape. A dedicated computer worksta-
50% is planned in the near future that will help compensate tion is used for acquiring, analyzing and storing data as
for the intensity loss with the filter inserted for an irradia- well as for printing results. The PGNAA facility is in the
tion. main experimental hall of the MITR and is convenient to
The intensity of the FCB is currently the highest avail- both the thermal and epithermal neutron beams so that bo-
able of any epithermal neutron source and, in conjunction ron concentrations can be measured concurrently with the
with high beam purity, is well suited for clinical trials or use of these facilities. PGNAA results can be readily in-
corporated into animal experiments or patient irradiations
to adjust beam delivery and precisely administer the desired
(or prescribed) dose from capture in boron. Detailed infor-
mation concerning the prompt -ray system is available
FIG. 3. The weighted depth–dose distribution in the FCB measured
along the central axis of a water-filled ellipsoidal phantom for the 12-
cm-diameter aperture using boron concentrations and weighting factors
representative of BPA as an example for treating deep-seated brain tu- FIG. 4. Schematic plane view of the prompt -ray activation analysis
mors. system located in the main reactor hall.

6. 226 TECHNICAL ADVANCE
elsewhere (5). Small ( 0.1 ml) or low-concentration ( 0.5
g g 1) samples can be analyzed using the complementary
technique of ICP-AES. This destructive analysis system is
available at the laboratory but requires samples in liquid,
particulate-free solution and is capable of measuring bulk
boron concentrations as low as 20 ng g 1.
Microscopic Imaging of 10B in Tissue
MIT, in collaboration with scientists from New England
Medical Center and the Beth Israel Deaconess Medical
Center, developed a technique for imaging the boron mi-
crodistribution superimposed on the corresponding cell
morphology (25).3 High-resolution quantitative autoradi-
ography (HRQAR) has a spatial resolution of nearly 2 m
and a sensitivity for 10B of approximately 0.1 g g 1.
HRQAR can be applied to frozen tissue sections (2–4 m
thick) that have been stained to reveal cellular structures.
Figure 5 is an HRQAR image of rat skin with black su-
perimposed tracks indicating the location of boron atoms.
Though labor-intensive, this technique can be very useful
for evaluating the radiobiological effects arising from dif-
ferent boron compounds at disease sites where tumor re-
sponse to BNCT is mediated by parenchymal cells. Dedi-
cated resources and procedures are being developed so that
NCT center users can use this analytical technique in their
own research. Further details concerning HRQAR can be
found elsewhere.3
OTHER AVAILABLE SUPPORT
Animal Experiment Facilities
The User Center can assist experimenters with animal
studies.
Approvals and housing. All animal research must adhere
to local and federal guidelines and legal mandates regarding
the use, care and maintenance of laboratory animals (26–
28). These encompass both biological and radiation safety
issues. The Division of Comparative Medicine (DCM) at
MIT authorizes all animal experimentation protocols. Pro-
tocols and procedures that are already approved within the
user’s establishment can be adapted for use at MIT, or new
protocols can be written specifically for the planned exper-
FIG. 5. HRQAR autoradiogram showing tracks from thermal neutron
iments. These procedures can be complicated when animals capture reactions with boron in tissue. From the microscopic image anal-
arrive from outside institutions and require the use of quar- ysis of this sectioned rat skin, the boron concentrations in the epidermis,
antine facilities. The staff within the User Center are avail- dermis and subdermal muscle were measured at 20 g g 1 while the hair
able to assist all outside users in obtaining the appropriate bulb measured 60 g g 1.
permissions necessary for their particular experiments as
well as ensuring that their animals can be housed at the can also be made for receiving animals or transporting an-
MIT facilities for the duration of the irradiations. The User imals to and from the user’s laboratory. This is a major
Center will ensure that the appropriate housing and care advantage since it means that an outside user does not have
staff are available for the duration of the stay and arrange to be present at MIT in advance of the animals’ arrival.
for appropriate radiation safety monitoring. Arrangements Surgical facilities for animal experiments. Arrangements
3
W. S. Kiger III, Developments in micro and macro-dosimetry of neu- can also be made for the user to perform certain surgical
tron capture therapy, Part I. Ph.D. Thesis, Massachusetts Institute of Tech- procedures at MIT when necessary. Specially equipped and
nology, Cambridge, MA, 2000. approved laboratories are available for all aseptic surgical

7. TECHNICAL ADVANCE 227
procedures. The equipment available ranges from consum- valuable not only in meeting all regulatory, ethical and le-
ables such as sterile needles and syringes to closed-circuit gal requirements for clinical studies but also in providing
inhalation anesthesia. The User Center can also provide ex- advice and guidance on aspects of clinical studies to
pert assistance with in vivo research. Available staff are achieve the desired results. User Center staff serve as the
skilled in a broad range of procedures such as vessel can- interface between the outside users and the MIT IRBs. Due
nulation, tumor induction, stereotactic CNS injections, dis- to the high level of involvement required of the User Center
section and physiological experiments. This is particularly staff in any clinical studies, such studies are usually carried
useful for those users who have no previous experience in out as formal collaborations between the MIT NCT staff
or capability for animal research within their own institu- and the outside users.
tion. Thus the User Center is able to ease the burden of the
regulatory aspects as well as the practical considerations Licenses for Clinical Use of MIT Neutron Beams
for any outside user wanting to carry out NCT-related an- The epithermal neutron irradiation facility described in
imal studies. this paper is fully licensed for use in human irradiations,
and the thermal beam facility can be so licensed if desired.
Cell Culture Laboratory Detailed procedures for the conduct of human BNCT have
A fully equipped cell culture laboratory is located in the been developed and approved by the U.S. Nuclear Regu-
building directly adjacent to the MITR and is available to latory Commission and are part of the MITR’s Technical
outside users with staff and expertise in cell culture pro- Specifications. These procedures are carefully followed to
cedures. Alternatively, the MIT BNCT User Center is de- ensure the safety of patients and staff.
veloping the ability to screen new boron compounds sub-
mitted by outside chemists. In the past, the evaluation of Present Studies
new boron compounds has been largely informal, with no The NCT research community is using the facilities, ca-
fixed methodology for intercomparison of results for dif- pabilities and other support outlined above with over a doz-
ferent compounds. A more formal compound-screening en experiments proposed or in progress by scientists from
program has been established that evaluates compounds in universities, industry and national laboratories. These stud-
vitro and then, if warranted, in vivo. The objectives are to ies are evaluating new compounds, novel delivery methods,
identify improved boron compounds for BNCT of glio- and radiobiology to advance NCT toward an accepted clin-
blastoma or metastatic tumors in the brain and to identify ical modality. To date, 14 different experiments involving
new boron compounds suitable for BNCT of other possible nine outside users have successfully used the collaborative
tumor sites. Procedures have been developed to evaluate support of the in-house research staff, irradiation facilities,
the in vitro toxicity of new boron compounds in the pres- and MIT university infrastructure to conduct in vivo exper-
ence and absence of neutron irradiation that minimize the iments. Table 3 summarizes this research. Several in vitro
amount of test compound required. experiments are planned once various cell culture tech-
A Philips RT250 X-ray unit is also available for photon niques have been fully optimized to allow their efficient
control irradiations of cells or small animals. The dose rate use for the evaluation of trial compounds. The satisfactory
can be varied from approximately 0.1 to 2.0 Gy min 1. This completion of these experiments has demonstrated the suc-
unit is located only a short distance from the cell culture cess of the MIT NCT User Center in supporting scientists
laboratory. from all parts of the country and the experiences gained
are enabling the center to evolve and further adapt to the
IRB Oversight for Human Studies practical needs of the NCT research community.
Three internal review boards, or IRBs, have oversight
responsibilities for human experiments at MIT. While it is SUMMARY OF CAPABILITIES AND ACCESS
MIT’s policy that clinical aspects of human studies that TO USER CENTER
may be performed at MIT are the responsibility of non-
The available funding currently allows the MIT NCT
MIT clinicians, these IRBs must review and authorize all
User Center to provide the following:
such studies. The first of these review boards is the MITR
Reactor Safeguards Committee (RSC), which is concerned 1. Thermal and epithermal neutron irradiations.
primarily with physical safety. The other two review boards 2. Physical and computational dosimetry associated with
are the Committee on Radiation Experiments with Human irradiation experiments and clinical studies.
Subjects (COREHS) and the Committee on Use of Humans 3. Analyses of 10B in tissue samples.
as Experimental Subjects (COUHES). These committees 4. Use of surgical facilities for small-animal surgery.
approve documents such as the experimental protocol and 5. Use of a cell culture laboratory.
the patient’s consent form and require regular reporting of 6. Access to the MIT animal care facilities.
progress in trials, principal findings, and adverse events. 7. Assistance with the design of animal and cell culture
The broad-ranging expertise in the MIT IRBs has proven experiments as well as clinical trials.

8. 228 TECHNICAL ADVANCE
TABLE 3
Summary of Research Performed Using the MIT NCT User Center
Facility Tumor/cell line Animal Purpose
Non-MIT experiments
PGNAA — — Boron concentration assay of new compounds
Thermal beam F98 glioma Rats Evaluating efficacy of convection-enhanced delivery and
various compounds
Thermal beam L929 TK /TK — In vitro compound assay
Thermal beam F98 glioma Rats Evaluating efficacy of BNCT combined with gene-medi-
ated immunoprophylaxis
Thermal beam EMT-6 Mice Evaluating efficacy of porphyrin-based compounds
PGNAA T cells — Evaluating boron uptake in immunological cells
PGNAA FaDu Mice Biodistribution study of new compound
HRQAR F98 glioma Rats Analysis of boron microdistribution
Epithermal beam — — International dosimetry exchange
MIT experiments
Thermal beam — Rats Evaluating radiosensitivity of rat lung to NCT irradia-
tions
Epithermal beam and PGNAA — Mice Investigating mechanisms mediating the GI syndrome
HRQAR Various tissues — HRQAR development
Clinical trials
Epithermal beam GBM and intracranial melanoma Humans Phase I tolerance study
Epithermal beam Subcutaneous melanoma Humans Phase II dose–response study
8. IRB oversight for clinical studies. REFERENCES
9. In the future, we expect to be able to perform micro- 1. D. N. Slatkin, A history of boron neutron capture therapy for brain
scopic imaging of boron by HRQAR. This would in- tumors. Neurosurgery 44, 443–450 (1999).
clude computer-based radiobiological analysis of the 2. R. F. Barth, Guest Ed., Boron neutron capture therapy: A critical
measured boron distribution. assessment. J. Neuro-Oncol. 62, 1–219 (2003).
3. O. K. Harling and K. J. Riley, Fission reactor neutron sources for
neutron capture therapy—a critical review. J. Neuro-Oncol. 62, 7–
Users should be aware that funds and labor resources for 17 (2003).
the MIT NCT User Center are limited and are subject to 4. M. F. Hawthorne and M. W. Lee, A critical assessment of boron target
annual renewal. However, the User Center is committed to compounds for boron neutron capture therapy. J. Neuro-Oncol. 62,
making every effort within these constraints to assist NCT 33–45 (2003).
researchers by expediting important studies through the use 5. K. J. Riley and O. K. Harling, An improved prompt gamma neutron
activation analysis facility using a focused diffracted beam. Nucl.
of the facilities and capabilities described in this paper. Po- Instrum. Methods B 143, 414–421 (1998).
tential users are invited to contact the responsible MIT 6. W. Bauer, P. L. Micca and B. M. White, A rapid method for the direct
staff1,4 for general information and to schedule use of the analysis of boron in whole blood by atomic emission spectroscopy.
NCT User Center research facilities and capabilities. In Advances in Neutron Capture Therapy (A. H. Soloway, R. F. Barth
and D. E. Carpenter, Eds.), pp. 403–407. Plenum Press, New York,
1993.
ACKNOWLEDGMENTS 7. R. G. Zamenhof, E. Redmond, II, G. R. Solares, D. Katz, K. J. Riley,
W. S. Kiger and O. K. Harling, Monte-Carlo based treatment plan-
ning for boron neutron capture therapy using custom designed mod-
Support for the MIT NCT User Center has been provided by the U.S. els automatically generated from CT data. Int. J. Radiat. Oncol. Biol.
Department of Energy through the new program ‘‘Innovations in Nuclear Phys. 35, 383–397 (1996).
Infrastructure and Education’’, Office of Nuclear Energy, Science and
8. D. W. Nigg, Computational dosimetry and treatment planning con-
Technology (contract no. DE-FG07-02ID14420) as well as the Office of siderations for neutron capture therapy. J. Neuro-Oncol. 62, 75–86
Biological and Environmental Research (contract no. DE-FG02- (2003).
02ER63358). The Massachusetts Institute of Technology provides the 9. J. A. Coderre and G. M. Morris, The radiation biology of boron
bulk of the support needed to operate the MIT Reactor. The authors thank neutron capture therapy. Radiat. Res. 151, 1–18 (1999).
Dr. W. S. Kiger III for providing the HRQAR image shown in Fig. 5 and
10. A. D. Chanana, J. Capala, M. Chada, J. A. Coderre, A. Z. Diaz,
Jingli Kiger for assistance in designing the animal shielding box used in E. H. Elowitz, J. Iwai, D. D. Joel, H. B. Liu and L. Wielopolski,
the thermal neutron beam. Boron neutron capture therapy for glioblastoma multiforme: interim
results from the Phase I/II dose-escalation studies. Neurosurgery 44,
Received: June 16, 2004; accepted: March 29, 2005 1182–1193 (1999).
11. P. M. Busse, R. G. Zamenhof, O. K. Harling, I. Kaplan, J. Kaplan,
C. F. Chuang, J. T. Goorley, W. S. Kiger, K. J. Riley and M. R.
4
Additional contacts: P. J. Binns, binns@mit.edu, 617-253-2099; K. J. Palmer, The Harvard-MIT BNCT Program: Overview of the clinical
Riley, flavor@mit.edu, 617-258-5938. trials and translational research. In Frontiers in Neutron Capture

9. TECHNICAL ADVANCE 229
Therapy (M. F. Hawthorne, K. Shelley and R. J. Wiersema, Eds.), 19. I. Kato, K. Ono, Y. Sakurai, M. Ohmae, A. Maruhashi, Y. Imahori,
pp. 37–60. Plenum Press, New York, 2001. M. Kirihata, M. Nakazawa and Y. Yura, Effectiveness of BNCT for
12. P. M. Busse, O. K. Harling, M. R. Palmer, W. S. Kiger, III, J. Kaplan, recurrent head and neck malignancies. Appl. Radiat. Isot. 61, 1069–
I. Kaplan, C. F. Chuang, J. T. Goorley, K. J. Riley and R. G. Za- 1073 (2004).
menhof, A critical examination of the results from the Harvard-MIT 20. R. D. Rogus, O. K. Harling and J. C. Yanch, Mixed field dosimetry
NCT program phase I clinical trial of neutron capture therapy for of neutron beams for neutron capture therapy at the MITR-II research
intracranial disease. J. Neuro-Oncol. 62, 111–121 (2003). reactor. Med. Phys. 21, 1611–1625 (1994).
13. Y. Mishima, M. Ichihashi, S. Hatta, C. Honda, K. Yamamura and T. 21. O. K. Harling, K. A. Roberts, D. J. Moulin and R. D. Rogus, Head
Nakagawa, New thermal neutron capture therapy for malignant mel- phantoms for neutron capture therapy. Med. Phys. 22, 579–583
anoma: melanogenesis-seeking 10B molecule-melanoma cell interac- (1995).
tion from in vitro to first clinical trial. Pigment Cell Res. 2, 226–234 22. W. S. Kiger, III, M. R. Palmer, K. J. Riley, R. G. Zamenhof and
(1989). P. M. Busse, A pharmacokinetic model for the concentration of 10B
14. H. Fukuda, J. Hiratsuka, C. Honda, T. Kobayashi, K. Yoshino, H. in blood after boronophenylalanine-fructose administration in hu-
Karashima, J. Takahashi, Y. Abe, K. Kanda and Y. Mishima, Boron mans. Radiat. Res. 155, 611–618 (2001).
neutron capture therapy of malignant melanoma using 10B-parabo- 23. O. K. Harling, K. J. Riley, T. H. Newton, B. A. Wilson, J. A. Bernard,
ronophenylalanine with special reference to evaluation of radiation L-W. Hu, E. J. Fonteneau, P. T. Menadier, S. J. Ali and P. M. Busse,
dose and damage to the normal skin. Radiat. Res. 138, 435–442 The fission converter based epithermal neutron irradiation facility at
(1994). the Massachusetts Institute of Technology Reactor. Nucl. Sci. Eng.
15. S. J. Gonzalez, M. R. Bonomi, G. A. Santa Cruz, H. R. Blaumann, 140, 223–240 (2002).
O. A. Calzetta Larrieu, P. Menendez, R. Jimenez-Rebagliati, J.
24. K. J. Riley, P. J. Binns and O. K. Harling, Performance characteristics
Longhino, D. B. Feld and B. M. C. Roth, First BNCT treatment of
of the MIT fission converter based epithermal neutron beam. Phys.
a skin melanoma in Argentina: Dosimetric analysis and clinical out-
Med. Biol. 48, 943–958 (2003).
come. Appl. Radiat. Isot. 61, 1101–1105 (2004).
16. T. Pinelli, A. Zonta, S. Altieri, S. Barni, A. Braghieri, P. Pedroni, P. 25. G. R. Solares and R. G. Zamenhof, A novel approach to the micro-
Bruschi, P. Chiari, C. Ferrari and C. Zonta, TAOrMINA: From the dosimetry of neutron capture therapy. Part I. High-resolution quan-
first idea to the application to the human liver. In Research and De- titative autoradiography applied to microdosimetry in neutron capture
velopment in Neutron Capture Therapy (W. Sauerwein, R. Moss and therapy. Radiat. Res. 144, 50–58 (1995).
A. Wittig, Eds.), pp. 1065–1072. Monduzzi Editore, Bologna, 2002. 26. National Research Council, Guide for the Care and Use of Labora-
17. H. Hatanaka and Y. Nakagawa, Clinical results of long-surviving tory Animals, National Academy Press, Washington, DC, 1996.
brain tumor patients who underwent boron neutron capture therapy. 27. Public Health Service Policy on Humane Care and Use of Labora-
Int. J. Radiat. Oncol. Biol. Phys. 28, 1061–1066 (1994). tory Animals. Office of Laboratory Animal Welfare, National Insti-
18. M. Kouria, L. Kankaanrantaa, T. Seppala, L. Tervob, M. Rasilainenc, tutes of Health, Bethesda, MD, 2002.
H. Minni, O. Eskolaj, J. Vahatalo, A. Paetaud and H. Joensuu, Un- 28. Animal Welfare Act, U.S.C. 7 § 2131–2156, Animal and Plant Health
differentiated sinonasal carcinoma may respond to single-fraction bo- Inspection Service, U.S. Department of Agriculture, Riverdale, MD,
ron neutron capture therapy. Radiother. Oncol. 72, 83–85 (2004). 1990.