Ex-situ BNCT for multifocal unresectable liver metastases employing whole or partial autograft techniques requires knowledge of boron concentrations in healthy liver and metastases following perfusion and immersion in Wisconsin solution (W), the procedure employed for organ preservation during ex-situ irradiation. Measurements of boron concentration in blood, liver and metastases following an intravenous infusion of BPA-F in five colorectal liver metastases patients scheduled for surgery were performed. Tissue samples were evaluated for boron content pre and post perfusion and immersion in W. Complementary histological studies were performed. The data showed a dose-dependent BPA uptake in liver, a boron concentration ratio liver/blood close to 1 and a wide spread in the metastases/liver concentration ratios in the range 0.8-3.6, partially attributable to histological variations between samples. Based on the boron concentrations and dose considerations (liver < or =15 Gy-Eq and tumor> or =40 Gy-Eq) at the RA-3 thermal neutron facility (mean flux of about (6+/-1) x 10(9) n cm(-2)s(-1)), ex-situ treatment of liver metastases at RA-3 would be feasible.

Objective: We previously proposed the hamster cheek pouch model of oral cancer for BNCT studies. We herein present the biodistribution of a non-toxic boron compound, GB-10 (Na210B10H10), in this model to assess its potential for BNCT or BNCT enhanced Fast Neutron Therapy. Materials and methods: We evaluated the uptake and retention of GB-10 in tumour and precancerous tissue and in potentially dose-limiting, clinically relevant normal tissues. Results: Mean tumour boron concentration delivered by GB-10 (50mgB/kg) peaked to 77.7±28.0ppm at 20min post-administration and remained at therapeutically useful values of 31.9±21.4ppm at 3h. The clearance rate for normal tissues was faster than for tumour tissue. The consistently low brain and spinal cord values would preclude normal tissue toxicity. The uptake of GB-10 by precancerous tissue may be of potential use in the treatment of field cancerized areas. GB-10 was deposited homogeneously in different tumour areas, an asset when treating heterogenous tumours. The data suggests that the joint administration of BPA and GB-10 may improve the therapeutic efficacy of BNCT. Conclusions: GB-10 is a potential boron carrier for BNCT of head and neck tumours and for BNCT-FNT.

Boron Neutron Capture Therapy (BNCT) is a bimodal cancer treatment based on the selective accumulation of 10B in tumors and concurrent irradiation with thermalized neutrons. The short-range, high-LET radiation produced by the capture of neutrons by 10B could potentially control tumor while sparing normal tissue if the boron compound targets tumor selectively within the treatment volume. In previous studies, we proposed and validated the hamster cheek pouch model of oral cancer for BNCT studies, proved that absolute and relative uptake of the clinically employed boron compound boronophenylalanine (BPA) would be potentially therapeutic in this model and provided evidence of the efficacy of in vivo BPA-mediated BNCT to control hamster oral mucosa tumors with virtually no damage to normal tissue. We herein present the biodistribution and pharmacokinetics of a lipophilic, carborane-containing tetraphenylporphyrin (CuTCPH) in the hamster oral cancer model. CuTCPH is a novel, non-toxic compound that may be advantageous in terms of selective and absolute delivery of boron to tumor tissues. For potentially effective BNCT, tumor boron concentrations from a new agent should be greater than 30 ppm and tumor/blood and tumor/normal tissue boron concentration ratios should be greater than 5/1 without causing significant toxicity. We administered CuTCPH intraperitoneally (i.p.) as a single dose of 32 μg/g body weight (b.w.) (10 μg B/g b.w.) or as four doses of 32 μg/g b.w. over 2 days. Blood (Bl) and tissues were sampled at 3, 6, 12, 24, 48, and 72 h in the single-dose protocol and at 1–4 days after the last injection in the multidose protocol. The tissues sampled were tumor (T), precancerous tissue surrounding tumor, normal pouch (N), skin, tongue, cheek and palate mucosa, liver, spleen, parotid gland and brain. The maximum mean B ratios for the single-dose protocol were T/N: 9.2/1 (12 h) and T/Bl: 18.1/1 (72 h). The B value peaked to 20.7±18.5 ppm in tumor at 24 h. The multidose protocol maximum mean ratios were T/N: 11.9/1 (3 days) and T/Bl: 235/1 (4 days). Absolute boron concentration in tumor reached a maximum value of 116 ppm and a mean value of 71.5±48.3 ppm at 3 days. The fact that absolute and relative B values markedly exceeded the BNCT therapeutic threshold with no apparent toxicity may confer on this compound a therapeutic advantage. CuTCPH-mediated BNCT would be potentially useful for the treatment of oral cancer in an experimental model.

We previously proposed and validated the hamster cheek pouch (HCP) model of oral cancer for BNCT studies and reported the first evidence of the usefulness of BPA mediated BNCT for the treatment of oral cancer in an experimental model. Within the context of the search for new boron compounds that may afford a therapeutic advantage, the aim of the present study was to perform a biodistribution and pharmacokinetic study of the GB-10 Compound ((Na2B10H10)-B-10) provided by Neutron Therapies, LLC, U.S.A., in the HCP oral cancer model. This model serves to analyze the uptake and retention of GB-10 in tumor and precancerous tissue in an experimental tumor model without a Blood Brain Barrier and in clinically relevant normal tissues such as oral tissues, skin, brain, spinal cord and lung. These studies contribute to the analysis of the potential of GB-10 for the treatment of tumors by BNCT or by BNCT enhanced Fast Neutron Therapy.

OBJECTIVE:To evaluate the changes induced in silver-stained nucleolar organizer regions (AgNORs) by the first fraction of a radiotherapy protocol for gynecologic cancer on exfoliated cytologic samples to predict the therapeutic success of the full protocol.STUDY DESIGN:Thirteen gynecologic cancer patients who were scheduled for radiotherapy were included in the study. Cell smears were taken from the affected area before and after the first fraction of a radiotherapy protocol and silver stained for AgNORs. AgNORs per nucleus were counted under a light microscope. Local disease control by the full radiotherapy protocol was assessed at one year by the Papanicolaou technique.RESULTS:Local success of radiotherapy was greater for lesions with higher pretreatment AgNOR counts and for lesions that underwent a greater percentage reduction in AgNOR counts after the first fraction. We correlated local success of the full radiotherapy protocol with a predictive index based on AgNOR counts obtained before and after the first fraction.CONCLUSION:A predictive index based on AgNOR counts can predict, as early as after the first fraction, the local control of disease by a full radiotherapy protocol. Knowledge of the probability of success long before the protocol is completed would allow reevaluation of therapeutic options.

The possibility of detection of incipient cellular alterations is central to early diagnosis and to clinician's capacity to discriminate between samples that appear similar on routine preparations. We examined the value of silver-stained nucleolar organizer regions (AgNOR) in detecting radio-induced alterations in a model of squamous epithelium biologically similar to oral mucosa. Morphometry of AgNOR has been proven to be of value in the detection of incipient cellular alterations. This method allows for the quantitative evaluation of lesions induced by high doses of radiation long before they become apparent in routine preparations. We herein examine the capacity of AgNOR to reveal the response to low doses of radiation, closer to the therapeutic or accidental dose to which the epithelium of oral mucosa may be exposed.

The model of hamster cheek pouch carcinogenesis closely mimics the development of human oral cancer. The study of the interaction between chemical carcinogens and radiation in the process of oral carcinogenesis is of interest given that the oral cavity is frequently exposed to chemical carcinogens such as alcohol and tobacco and is the route of entry of therapeutic radiation. In this context, markers of incipient alterations associated to a process of malignant transformation would contribute to early diagnosis and follow-up. The aim of the present study was to assess the early changes produced by carcinogenic agents applied separately or combined in a two-stage carcinogenesis protocol in hamster cheek pouch. The cheek pouch of the hamsters was treated with a single dose of radiation (20 Gy) or 7,12-dimethylbenz(a)anthracene (DMBA) as initiating agents and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoting agent for 1 or 2 weeks. The end-points chosen to identify early alterations were hyperplastic foci and silver-stained nucleolar organizer regions (Ag NOR). The data show that both markers are useful in the detection of early alterations compatible with a process of malignant transformation.

Thepossibility ofdetection ofincipient cellular alterations iscentral toearly diagnosis andto clinician's capacity todiscriminate between samplesthatappearsimilar on routine preparations. We examined thevalue ofsilver- stained nucleolar organizer regions (AgNOR)in detecting radio-induced alterations inamodelof squamous epithelium biologically similar tooral mucosa.Morphometry ofAgNOR hasbeen proven tobeofvalue inthedetection ofincipient cellular alterations. Thismethodallows forthe quantitative evaluation oflesions induced byhigh dosesofradiation longbefore theybecome apparent inroutine preparations. We herein examinethecapacity ofAgNOR toreveal the response tolowdosesofradiation, closer tothe therapeutic oraccidental dosetowhichthe epithelium oforal mucosamaybeexposed.