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RADIATION RESEARCH 164, 221–229 (2005)0033-7587/05 $15.00q 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

Harling, O. K., Riley, K. J., Binns, P. J., Patel, H. and Cod-erre, J. A. The MIT User Center for Neutron Capture Ther-apy Research. Radiat. Res. 164, 221–229 (2005).

Neutron capture therapy (NCT) research encompasses awide range of preclinical and clinical studies needed to devel-op this promising but complex cancer treatment. Many spe-cialized facilities and capabilities including thermal and epi-thermal neutron irradiation facilities, boron analysis, special-ized mixed-field dosimetry, animal care facilities and proto-cols, cell culture laboratories, and, for human clinical studies,licenses and review board approvals are required for NCTresearch. Such infrastructure is essential, but much of it is notreadily available within the community. This is especially truefor neutron irradiation facilities, which often require signifi-cant development and capital investment too expensive to du-plicate at each site performing NCT research. To meet thisneed, the NCT group at the Massachusetts Institute of Tech-nology (MIT) has established a User Center for NCT re-searchers that is already being accessed successfully by vari-ous groups. This paper describes the facilities, capabilities andother resources available at MIT and how the NCT researchcommunity can access them. q 2005 by Radiation Research Society

INTRODUCTION

Neutron capture therapy (NCT) for cancer is an experi-mental tumor cell targeting therapy. This promising butcomplex radiation therapy requires the administration of tu-mor-seeking compounds, usually containing 10B, that con-centrate preferentially in tumor cells followed by irradiationwith suitable neutron beams.

Although research in NCT with boron compounds(BNCT) has a long history of development since its origi-nation in the U.S. in the 1950s [see for example Slatkin(1)], the last 15 years have seen a significant expansion of

1 Address for correspondence: Department of Nuclear Science and En-gineering, Massachusetts Institute of Technology, NW13-200, 138 Al-bany Street, Cambridge, MA 02139; e-mail: oharling@mit.edu.

2 Present address: Wyeth Pharmaceuticals, Clinical Research/Oncology,35 Cambridge Park Drive, CPD 3100-2, Cambridge, MA 02140.

this research in the U.S. and elsewhere. The current statusof this modality has been reviewed in a recent special vol-ume of the Journal of Neuro-Oncology (2). Major progresshas been made on many fronts, including the developmentand construction of high-performance neutron beams (3).Although boron delivery compounds have also improved(4), there is still general agreement that better compoundswith greater selectivity are needed. Improved compoundsare on the critical path to the successful development ofBNCT, and a coordinated approach is needed to developand investigate new capture compounds that can be usedto treat various disease sites. The necessary supportingtechnologies such as boron analysis (5, 6) and treatmentplanning (7, 8) are established, and our understanding ofthe radiobiology of BNCT (9) has progressed significantly.Clinical trials of BNCT were initiated with better-penetrat-ing epithermal neutron beams in the mid-1990s (10, 11)and have continued in the U.S., Japan and several Europeancountries. BNCT research and development in all relevantareas has become a truly international effort with new re-search and clinical activities in Taiwan, Russia and Argen-tina as well as preliminary studies that have begun in ad-ditional European and Asian countries.

Primary brain cancer, glioblastoma multiforme (GBM),has been the main target of Phase I/II BNCT clinical studiesin the U.S. and Europe. The tolerance of normal brain tissueto BNCT irradiations has been determined from these lim-ited studies, and the median survival using p-boronophe-nylalanine (BPA) appears comparable to that for conven-tional radiotherapy (10). BNCT has also been studied formelanoma metastases in a limited number of intracranial aswell as peripheral subcutaneous cases where local tumorcontrol was observed (12–15). Recently, liver metastases ofcolo-rectal cancer in two European patients exhibited goodresponse to intraoperative BNCT (16). In Japan, brain tu-mors have been a major focus of BNCT, with an increasingnumber of treatments directed at melanoma and head andneck cancers. In all, a few hundred brain tumor patientshave been treated with BNCT in Japan using either BPA,sodium borocaptate (BSH) or, in a few cases, a combinationof these two boron delivery agents. Several long-term sur-

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FIG. 1. Isometric view of the MITR with the thermal neutron irradiation facility, M-011, directly beneath thecore 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-perience with BNCT (17). Good local control was observedin a few recently treated head and neck cancers (18, 19).Further advancement in the clinical application of BNCTrequires new, more selective boron delivery agents, manyof which are currently available but must undergo extensivetesting in animal experiments before they can be consideredfor testing in clinical trials.

A wide range of research facilities and interdisciplinarycapabilities are required for the development of BNCT asa clinically useful therapy. Some facilities, in particular theneutron irradiation facilities, needed for preclinical andclinical research require significant capital investments andare available at very few sites. Currently the only U.S. sitewith high-performance epithermal and thermal neutron ir-radiation facilities suitable for preclinical and clinical stud-ies is located at the Massachusetts Institute of TechnologyResearch Reactor (MITR). The 5 MW MITR operates witha high capacity factor, 24 h per day, 250–300 days per year.These specialized neutron facilities, along with a variety ofsupporting technologies and capabilities, were developed tosupport preclinical and clinical NCT programs for MIT re-searchers and their medical collaborators. Recently it hasbecome possible, with the support of the U.S. Departmentof Energy, to make this unique suite of facilities and ca-pabilities available to non-MIT researchers. In this paperwe describe the resources available, the level of supportthat can be provided currently, and how interested userscan access the NCT User Center.

REACTOR FACILITIES AND CAPABILITIES

Thermal Neutron Irradiation Facility

Low-energy (thermal) neutron beams are necessary forpreclinical studies with small animals or cell cultures andfor clinical irradiations of shallow malignancies. The re-cently upgraded and renovated thermal neutron irradiationfacility located beneath the core of the MITR is shown onthe lower left portion of Fig. 1.

Source neutrons for the thermal neutron beam, known asthe M-011 beam, originate in the D2O reflector/moderatorbelow the core of the MITR. These neutrons reach thermalequilibrium with the moderator before they enter the ver-tical beam line and have an energy spectrum optimal forNCT irradiations of targets up to approximately 3.5 cmdeep in tissue. The thermal neutrons are collimated by thereactor-grade graphite walls of the vertical beam line thatminimize intensity loss by elastically scattering many neu-trons back into the main beam that would otherwise be lost.Three separate shutters, water, Boralt (boron carbide in analuminum honeycomb), and lead plus borated polyethylene,are located upstream of the beam aperture in the medicalroom and are used to control the beam during irradiations.

Irradiations are monitored by four similar fission coun-ters located at the edge of the beam and spaced at 908intervals. Their outputs are sent to industrial-quality pro-grammable logic controllers (PLCs). The four detectorsmonitor not only beam intensity but also symmetry duringirradiation. This provides an overall system check of beam

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TABLE 1In-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(109 n cm22 s21)

Fast-neutron doserate (mGy min21)

Photon dose rate(mGy min21)

Specific fast-neutrondose (10213 Gy cm2)

Specific photon dose(10213 Gy cm2)

5.9 6 0.3 ,20 188 6 10 ,0.5 5.3 6 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 systemsuse redundant monitors, signal processing, electronic cir-cuits, and PLCs to permit safe continuation of irradiationsshould any individual component fail. The PLCs log essen-tial data and control shutter opening and closing to ensurethat neutron fluences (doses) are delivered to within 1% oftarget. Safety interlocks to protect the staff and patients arealso monitored continuously by the PLCs. A PC with alarge-screen monitor is used for online display of the statusof the irradiation and for record keeping but does not con-trol the irradiations. This important function is assigned ex-clusively to the redundant PLCs. All important systemshave back-up power from an uninterruptible power supply(UPS). Manual controls, located on the M-011 operator’sconsole, can override the automated functions of the PLCsat any time to close shutters or, if necessary, scram thereactor.

Irradiations using the M-011 beam are performed in awell-shielded irradiation room (shown in Fig. 1). Experi-ments or patients can be viewed during an irradiationthrough a shielded window and with closed-circuit televi-sion. Background dose rates with all shutters closed are lowenough to allow staff to enter and work in the irradiationroom even with the reactor operating at full power. Ashielding box constructed of lithiated polyethylene is po-sitioned in the neutron beam to perform small-animal orcell culture irradiations. Small animals are shielded by a2.5-cm-thick lithiated polyethylene lid that covers most ofthe animals and contains an aperture of the desired size andshape, depending on the application. A variety of sites canbe irradiated with a rectangular aperture of 2 cm 3 14 cmwhere, for example, two rats can be positioned side by sidefor brain tumor irradiations or four mice can be positionedfor irradiation of subcutaneous tumors on the legs. Cellculture irradiations do not require a shielding lid becausethe largest possible beam aperture is used to irradiate thecultures uniformly. Phantoms, ionization chambers, andgold foils can also be mounted in the irradiation box todetermine dose rates from thermal neutrons, g rays and fastneutrons. The box is inserted into a recess in the boratedpolyethylene shutter that accurately positions the animalsor cells in the beam line when the shutter is opened. Irra-diation times vary between approximately 5 and 25 mindepending on the dose required to achieve the desired ra-diation response as well as experimental conditions such asgeometry, boron concentration and reactor operating power.

To account for these variables, irradiations are administeredby programming the automated control system with beammonitor counts that are determined separately for each ex-periment through prior calibration.

When patients or large animals are to be irradiated in thethermal beam, they are positioned on a couch that is raisedhydraulically toward the ceiling where a collimator ismounted beneath the lowest shutter. The size and shape ofthis patient collimator aperture can be changed readily. Cur-rently two circular collimator apertures are available withdiameters of 8 and 12 cm. Beam intensities for patient orlarge animal irradiations are lower than those for small an-imals irradiated in the shielding box. Nevertheless, withcompounds such as BPA, therapeutic doses for superficialmelanoma can be delivered in less than 10 min with a sin-gle field.

The M-011 beam has been fully characterized using theprocedures routinely employed for mixed-field dosimetryat MIT (20). Table 1 provides in-air measurements of thethermal neutron flux as well as photon and fast-neutrondose rates at the position typically used for small-animal orcell culture irradiations. The high thermal neutron flux of5.9 3 109 n cm22 s21 combined with the low photon andnegligible fast-neutron contamination is indicative of theexcellent performance of the beam for preclinical cell cul-ture and animal studies as well as clinical trials of BNCTfor superficial melanoma. As an example, the biologicallyweighted dose [Gy(w); see ref. (9) for a discussion ofBNCT weighting factors] as a function of depth with BPAis shown in Fig. 2. Measurements were performed alongthe central axis of an ellipsoidal water-filled phantom (21)using the 12-cm beam aperture to approximate conditionsduring therapy. The individual dose components are plottedas points and the total tumor and tissue doses are fitted witha least-squares polynomial to help guide the eye. The fast-neutron and photon components were measured usingpaired ionization chambers, while the 10B(n,g)7Li and14N(n,p)14C doses are determined from the measured ther-mal neutron flux using kerma coefficients of 8.66 3 1028

and 7.88 3 10212 Gy cm2, respectively. A boron concen-tration of 18 mg g21, which has been observed in preclinicaland clinical research, is used (22) together with a tissuenitrogen concentration of 3.5% in muscle and skin. A boronconcentration of 65 mg g21 is assumed for tumor. A weight-ing factor of 3.8 is applied for the boron capture reactionin tumor and normal tissues. Normal tissue dose is domi-

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FIG. 2. The weighted dose–depth distribution in the M-011 thermalneutron beam measured along the central axis of a water-filled ellipsoidalphantom for the 12-cm aperture using boron concentrations and weightingfactors representative of BPA as an example for treating superficial tu-mors such as subcutaneous melanoma. Fast-neutron dose rates are neg-ligible and therefore are not plotted.

nated by the 10B(n,a)7Li reaction due to the relatively highconcentration of boron. Photons and thermal neutron cap-ture reactions in tissue nitrogen also produce some adven-titious dose to normal tissue. However, the fast-neutrondose component in this high-purity beam is so low, evenat its expected maximum near the surface, that it has neg-ligible influence on the total normal tissue dose. The usefulpenetration or advantage depth (AD) and the maximumnormal tissue (skin or muscle) dose rate (or ADDR) shownin Fig. 2 are respectively 3.5 cm and 2.4 Gy(w) min21. Skintolerance doses of approximately 12 Gy(w) can be reachedin 5 min, and a therapeutic ratio greater than unity wouldbe achieved at depths up to the AD. A well-benchmarkedMonte Carlo model of the MITR-II core and M-011 beamline has also been developed. This model allows the ac-curate calculation of flux and absorbed doses for any con-ceivable experimental study including clinical trials.

The MIT thermal neutron irradiation facility with itshigh-intensity, low-background beam and automated con-trol systems is well suited for research in BNCT. Small-animal and cell culture irradiations can easily be performedin the facility, and clinical studies for shallow tumors canalso be fully supported.

Epithermal Neutron Irradiation Facility

MIT operates a state-of-the-art high-intensity, low-back-ground epithermal neutron (0.5 eV , En , 10 keV) irra-diation facility known as the fission converter beam (FCB).The FCB is the first epithermal neutron irradiation facilityto use a subcritical fission converter as a neutron source forNCT. Details concerning the design, construction and per-formance of the FCB are provided elsewhere (23, 24). Theneutron source is a heavy water-cooled 235U fuel source that

cannot sustain the fission chain reaction by itself. Thermalneutrons from the MITR-II are absorbed in the FCB fueland, in essence, are converted to higher-energy fission neu-trons. The fission neutrons originating in the converter arefiltered and moderated by aluminum, polytetrafluoroethyl-ene (Teflont) and cadmium. Undesired photons are atten-uated with a lead shield. The resulting large-area epithermalneutron 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 irradiationroom and features easily variable apertures 8 to 16 cm indiameter. Apertures of different size or shape can easily beimplemented if required. The patient collimator with vari-able aperture sizes and its extension into the medical roomallow easy positioning of patients for placement of the ra-diation field anywhere on the body. The right side of Fig.1 provides an overall view of the FCB facility includingthe shielded medical irradiation room. The irradiation roomhas sufficient space for a gurney and positioning couch.Patient observation during irradiations is facilitated by alarge shielded glass window and closed-circuit televisionmonitors. Two-way audio communication is also availablebetween the patient and clinical staff. Laser projections il-luminate the central axis of the beam from both sides ofthe patient to help with positioning and optics that penetratethe wall of the collimator provide the clinical staff a beam’seye view of field placement.

Three shutters control the FCB. A beam monitoring andcontrol system similar to that described previously for theM-011 thermal beam is used to automatically open andclose the three beam shutters: a thermal neutron absorbingshutter on the reactor side of the fission converter, a largewater shutter in the lead collimator, and a fast-acting leadand boronated heavy concrete shutter close to the patientcollimator. Neutron fluences are calibrated against mea-surements and treatment planning calculations of the ab-sorbed dose and are routinely delivered to within 1% of theprescribed target using this system.

Table 2 provides the in-air epithermal neutron flux anddose rates from photon and fast-neutron radiation in thebeam. The epithermal flux of 3.224.6 3 109 n cm22 s21,depending on final collimation, is currently the highestavailable of any epithermal neutron beam used for BNCT(23). If desired, higher intensity can be obtained by opti-mizing converter fuel loading and/or increasing reactorpower without affecting the excellent beam characteristics.Specific beam contamination from photons and neutrons isalso provided in Table 2. The contamination levels in theFCB are very low and have a minimal influence on clinicalbeam performance. The performance of the FCB is illus-trated by the example shown in Fig. 3, where the variousdose–depth distributions in a water-filled ellipsoidal headphantom are plotted as points and a least-squares polyno-mial is fitted to the total tumor and tissue doses to guidethe eye (24). Tumor and normal brain (blood) concentra-tions as well as the applied weighting factors are consistent

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TABLE 2In-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)

Aperturediameter (cm)

Epithermal flux(109 n cm22 s21)

Fast-neutrondose rate

(mGy min21)Photon dose rate

(mGy min21)

Specificfast-neutron dose(10213 Gy cm2)

Specific photondose (10213 Gy cm2)

16 4.6 6 0.6 38 6 4 97 6 4 1.4 6 0.2 3.5 6 0.512 4.3 6 0.6 36 6 4 94 6 4 1.4 6 0.2 3.6 6 0.510 3.4 6 0.4 34 6 4 90 6 4 1.7 6 0.3 4.4 6 0.6

8 3.2 6 0.4 34 6 4 74 6 3 1.8 6 0.3 3.9 6 0.5

Notes. Specific doses are also provided. Reactor power is 5 MW and the converter power is 83 kW.

FIG. 3. The weighted depth–dose distribution in the FCB measuredalong the central axis of a water-filled ellipsoidal phantom for the 12-cm-diameter aperture using boron concentrations and weighting factorsrepresentative of BPA as an example for treating deep-seated brain tu-mors.

FIG. 4. Schematic plane view of the prompt g-ray activation analysissystem located in the main reactor hall.

with those observed with the BPA capture compound (9,22) and are the same as those used for the thermal neutronbeam in Fig. 2 except that a nitrogen concentration of 2.2%is applied for brain and a weighting factor of 1.3 is usedinstead of 3.8 to account for the microdistribution of boronthat accumulates in normal brain (9). The useful penetration(10) using the 12-cm aperture is 9.3 cm. This is adequatefor treating the deepest locations in an average-sized humanbrain. The peak dose rate to normal tissue is 1.25 Gy(w)min21, which means that a peak normal tissue dose of 12Gy(w) can be delivered in 9.6 min with a single beamplacement. Assuming a homogeneous distribution of boron,the tumor dose in this example is expected to vary from apeak of 77 down to 12 Gy(w) at the maximum useful depth.

A 6Li filter has been constructed to further increase theuseful beam penetration by approximately 6 mm with theBPA compound. An increase in converter power by 30–50% is planned in the near future that will help compensatefor the intensity loss with the filter inserted for an irradia-tion.

The intensity of the FCB is currently the highest avail-able of any epithermal neutron source and, in conjunctionwith high beam purity, is well suited for clinical trials or

large animal irradiations where deep penetration to the can-cer site is required.

Boron Analysis

Nondestructive analysis of biological samples for the 10Bisotope is carried out using a prompt g-ray neutron acti-vation analysis (PGNAA) system at the MIT Research Re-actor, shown schematically in Fig. 4. Typical samples con-sist of blood or tissue with volumes of 0.1 to 10 ml. Nospecial sample preparation is required, and the high sensi-tivity of the MIT prompt g-ray system, 18 counts s21 mg21

10B, allows rapid analysis, usually in several minutes for 2mg or more of 10B. A holder designed for 1- or 10-ml Teflonvials is used to position samples for analysis in the neutronbeam and can easily be adjusted to accommodate samplesof different size or shape. A dedicated computer worksta-tion is used for acquiring, analyzing and storing data aswell as for printing results. The PGNAA facility is in themain experimental hall of the MITR and is convenient toboth the thermal and epithermal neutron beams so that bo-ron concentrations can be measured concurrently with theuse of these facilities. PGNAA results can be readily in-corporated into animal experiments or patient irradiationsto adjust beam delivery and precisely administer the desired(or prescribed) dose from capture in boron. Detailed infor-mation concerning the prompt g-ray system is available

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FIG. 5. HRQAR autoradiogram showing tracks from thermal neutroncapture reactions with boron in tissue. From the microscopic image anal-ysis of this sectioned rat skin, the boron concentrations in the epidermis,dermis and subdermal muscle were measured at 20 mg g21 while the hairbulb measured 60 mg g21.

elsewhere (5). Small (,0.1 ml) or low-concentration (,0.5mg g21) samples can be analyzed using the complementarytechnique of ICP-AES. This destructive analysis system isavailable at the laboratory but requires samples in liquid,particulate-free solution and is capable of measuring bulkboron concentrations as low as 20 ng g21.

Microscopic Imaging of 10B in Tissue

MIT, in collaboration with scientists from New EnglandMedical Center and the Beth Israel Deaconess MedicalCenter, developed a technique for imaging the boron mi-crodistribution superimposed on the corresponding cellmorphology (25).3 High-resolution quantitative autoradi-ography (HRQAR) has a spatial resolution of nearly 2 mmand a sensitivity for 10B of approximately 0.1 mg g21.HRQAR can be applied to frozen tissue sections (2–4 mmthick) 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 usefulfor 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 thatNCT center users can use this analytical technique in theirown research. Further details concerning HRQAR can befound elsewhere.3

OTHER AVAILABLE SUPPORT

Animal Experiment Facilities

The User Center can assist experimenters with animalstudies.

Approvals and housing. All animal research must adhereto local and federal guidelines and legal mandates regardingthe use, care and maintenance of laboratory animals (26–28). These encompass both biological and radiation safetyissues. The Division of Comparative Medicine (DCM) atMIT authorizes all animal experimentation protocols. Pro-tocols and procedures that are already approved within theuser’s establishment can be adapted for use at MIT, or newprotocols can be written specifically for the planned exper-iments. These procedures can be complicated when animalsarrive from outside institutions and require the use of quar-antine facilities. The staff within the User Center are avail-able to assist all outside users in obtaining the appropriatepermissions necessary for their particular experiments aswell as ensuring that their animals can be housed at theMIT facilities for the duration of the irradiations. The UserCenter will ensure that the appropriate housing and carestaff are available for the duration of the stay and arrangefor appropriate radiation safety monitoring. Arrangements

3 W. S. Kiger III, Developments in micro and macro-dosimetry of neu-tron capture therapy, Part I. Ph.D. Thesis, Massachusetts Institute of Tech-nology, Cambridge, MA, 2000.

can also be made for receiving animals or transporting an-imals to and from the user’s laboratory. This is a majoradvantage since it means that an outside user does not haveto be present at MIT in advance of the animals’ arrival.

Surgical facilities for animal experiments. Arrangementscan also be made for the user to perform certain surgicalprocedures at MIT when necessary. Specially equipped andapproved laboratories are available for all aseptic surgical

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procedures. The equipment available ranges from consum-ables such as sterile needles and syringes to closed-circuitinhalation anesthesia. The User Center can also provide ex-pert assistance with in vivo research. Available staff areskilled in a broad range of procedures such as vessel can-nulation, tumor induction, stereotactic CNS injections, dis-section and physiological experiments. This is particularlyuseful for those users who have no previous experience inor capability for animal research within their own institu-tion. Thus the User Center is able to ease the burden of theregulatory aspects as well as the practical considerationsfor any outside user wanting to carry out NCT-related an-imal studies.

Cell Culture Laboratory

A fully equipped cell culture laboratory is located in thebuilding directly adjacent to the MITR and is available tooutside users with staff and expertise in cell culture pro-cedures. Alternatively, the MIT BNCT User Center is de-veloping the ability to screen new boron compounds sub-mitted by outside chemists. In the past, the evaluation ofnew boron compounds has been largely informal, with nofixed methodology for intercomparison of results for dif-ferent compounds. A more formal compound-screeningprogram has been established that evaluates compounds invitro and then, if warranted, in vivo. The objectives are toidentify improved boron compounds for BNCT of glio-blastoma or metastatic tumors in the brain and to identifynew boron compounds suitable for BNCT of other possibletumor sites. Procedures have been developed to evaluatethe in vitro toxicity of new boron compounds in the pres-ence and absence of neutron irradiation that minimize theamount of test compound required.

A Philips RT250 X-ray unit is also available for photoncontrol irradiations of cells or small animals. The dose ratecan be varied from approximately 0.1 to 2.0 Gy min21. Thisunit is located only a short distance from the cell culturelaboratory.

IRB Oversight for Human Studies

Three internal review boards, or IRBs, have oversightresponsibilities for human experiments at MIT. While it isMIT’s policy that clinical aspects of human studies thatmay be performed at MIT are the responsibility of non-MIT clinicians, these IRBs must review and authorize allsuch studies. The first of these review boards is the MITRReactor Safeguards Committee (RSC), which is concernedprimarily with physical safety. The other two review boardsare the Committee on Radiation Experiments with HumanSubjects (COREHS) and the Committee on Use of Humansas Experimental Subjects (COUHES). These committeesapprove documents such as the experimental protocol andthe patient’s consent form and require regular reporting ofprogress in trials, principal findings, and adverse events.The broad-ranging expertise in the MIT IRBs has proven

valuable not only in meeting all regulatory, ethical and le-gal requirements for clinical studies but also in providingadvice and guidance on aspects of clinical studies toachieve the desired results. User Center staff serve as theinterface between the outside users and the MIT IRBs. Dueto the high level of involvement required of the User Centerstaff in any clinical studies, such studies are usually carriedout as formal collaborations between the MIT NCT staffand the outside users.

Licenses for Clinical Use of MIT Neutron Beams

The epithermal neutron irradiation facility described inthis paper is fully licensed for use in human irradiations,and the thermal beam facility can be so licensed if desired.Detailed procedures for the conduct of human BNCT havebeen developed and approved by the U.S. Nuclear Regu-latory Commission and are part of the MITR’s TechnicalSpecifications. These procedures are carefully followed toensure the safety of patients and staff.

Present Studies

The NCT research community is using the facilities, ca-pabilities and other support outlined above with over a doz-en experiments proposed or in progress by scientists fromuniversities, industry and national laboratories. These stud-ies are evaluating new compounds, novel delivery methods,and radiobiology to advance NCT toward an accepted clin-ical modality. To date, 14 different experiments involvingnine outside users have successfully used the collaborativesupport of the in-house research staff, irradiation facilities,and MIT university infrastructure to conduct in vivo exper-iments. Table 3 summarizes this research. Several in vitroexperiments are planned once various cell culture tech-niques have been fully optimized to allow their efficientuse for the evaluation of trial compounds. The satisfactorycompletion of these experiments has demonstrated the suc-cess of the MIT NCT User Center in supporting scientistsfrom all parts of the country and the experiences gainedare enabling the center to evolve and further adapt to thepractical needs of the NCT research community.

SUMMARY OF CAPABILITIES AND ACCESSTO USER CENTER

The available funding currently allows the MIT NCTUser Center to provide the following:

1. Thermal and epithermal neutron irradiations.2. Physical and computational dosimetry associated with

irradiation experiments and clinical studies.3. Analyses of 10B in tissue samples.4. Use of surgical facilities for small-animal surgery.5. Use of a cell culture laboratory.6. Access to the MIT animal care facilities.7. Assistance with the design of animal and cell culture

experiments as well as clinical trials.

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TABLE 3Summary of Research Performed Using the MIT NCT User Center

Facility Tumor/cell line Animal Purpose

Non-MIT experiments

PGNAA — — Boron concentration assay of new compoundsThermal beam F98 glioma Rats Evaluating efficacy of convection-enhanced delivery and

various compoundsThermal beam L929 TK1/TK2 — In vitro compound assayThermal beam F98 glioma Rats Evaluating efficacy of BNCT combined with gene-medi-

ated immunoprophylaxisThermal beam EMT-6 Mice Evaluating efficacy of porphyrin-based compoundsPGNAA T cells — Evaluating boron uptake in immunological cellsPGNAA FaDu Mice Biodistribution study of new compoundHRQAR F98 glioma Rats Analysis of boron microdistributionEpithermal 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 syndromeHRQAR Various tissues — HRQAR development

Clinical trials

Epithermal beam GBM and intracranial melanoma Humans Phase I tolerance studyEpithermal beam Subcutaneous melanoma Humans Phase II dose–response study

8. IRB oversight for clinical studies.9. In the future, we expect to be able to perform micro-

scopic imaging of boron by HRQAR. This would in-clude computer-based radiobiological analysis of themeasured boron distribution.

Users should be aware that funds and labor resources forthe MIT NCT User Center are limited and are subject toannual renewal. However, the User Center is committed tomaking every effort within these constraints to assist NCTresearchers by expediting important studies through the useof the facilities and capabilities described in this paper. Po-tential users are invited to contact the responsible MITstaff1,4 for general information and to schedule use of theNCT User Center research facilities and capabilities.

ACKNOWLEDGMENTS

Support for the MIT NCT User Center has been provided by the U.S.Department of Energy through the new program ‘‘Innovations in NuclearInfrastructure and Education’’, Office of Nuclear Energy, Science andTechnology (contract no. DE-FG07-02ID14420) as well as the Office ofBiological and Environmental Research (contract no. DE-FG02-02ER63358). The Massachusetts Institute of Technology provides thebulk of the support needed to operate the MIT Reactor. The authors thankDr. W. S. Kiger III for providing the HRQAR image shown in Fig. 5 andJingli Kiger for assistance in designing the animal shielding box used inthe thermal neutron beam.

Received: June 16, 2004; accepted: March 29, 2005

4 Additional contacts: P. J. Binns, binns@mit.edu, 617-253-2099; K. J.Riley, flavor@mit.edu, 617-258-5938.

REFERENCES

1. D. N. Slatkin, A history of boron neutron capture therapy for braintumors. Neurosurgery 44, 443–450 (1999).

2. R. F. Barth, Guest Ed., Boron neutron capture therapy: A criticalassessment. J. Neuro-Oncol. 62, 1–219 (2003).

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