Radioguided surgery with ß radiation: a novel application with Ga68.

Radio Guided Surgery is a technique helping the surgeon in the resection of tumors: a radiolabeled tracer is administered to the patient before surgery and then the surgeon evaluates the completeness of the resection with a handheld detector sensitive to emitted radiation. Established methods rely on γ emitting tracers coupled with γ detecting probes. The efficacy of this technique is however hindered by the high penetration of γ radiation, limiting its applicability to low background conditions. To overtake such limitations, a novel approach to RGS has been proposed, relying on ß- emitting isotopes together with a dedicated ß probe. This technique has been proved to be effective in first ex-vivo trials. We discuss in this paper the possibility to extend its application cases to 68Ga, a ß+ emitting isotope widely used today in nuclear medicine. To this aim, a retrospective study on 45 prostatic cancer patients was performed, analysing their 68Ga-PSMA PET images to asses if the molecule uptake is enough to apply this technique. Despite the expected variability both in terms of SUV (median 4.1, IQR 3.0-6.1) and TNR (median 9.4, IQR 5.2-14.6), the majority of cases have been found to be compatible with ß-RGS with reasonable injected activity and probing time (5 s).

Is Beta Radiation Better than 5 Flurouracil as an Adjunct for Trabeculectomy Surgery When Combined with Cataract Surgery? A Randomised Controlled Trial.

INTRODUCTION: In an African setting surgery is generally accepted as the treatment of first choice for glaucoma. A problem with trabeculectomy surgery for the glaucomas is the frequent co-existence and exacerbation of cataract. We report a randomized controlled trial to compare the use of beta radiation with 5FU in combined cataract and glaucoma surgery. PARTICIPANTS AND METHODS: Consenting adults aged >40 years with glaucoma, an IOP>21mmHG and cataract were enrolled and randomised to receive either 1000cG ß radiation application or sub-conjunctival 5fluorouracil (5FU) at the time of combined trabeculectomy and phaco-emulsification with lens implant surgery. RESULTS: 385 individuals were eligible for inclusion of whom 301 consented to inclusion in the study (one eye per patient). 150 were randomised to the 5FU arm and 151 received ß radiation. In the 12 months following surgery there were 40 failures (IOP>21mmHg) in the 5FU arm and 34 failures in the beta arm. The hazard ratio for the beta radiation arm compared to the 5FU arm, adjusted for IOP at baseline, was 0.83 (95% c.i. 0.54 to 1.28; P = 0.40). The improvement from mean presenting visual acuities of 0.91 and 0.86 logMAR to 0.62 and 0.54 in the 5FU and beta arms respectively was comparable between groups (P = 0.4 adjusting for baseline VA). Incidence of complications did not differ between the two groups. DISCUSSION: This study highlights several important issues in the quest for a therapeutic strategy for the glaucomas in an African context. Firstly, there is no evidence of an important difference between the use of 5FU and beta radiation as an anti-metabolite in phacotrabeculectomy. Secondly phacotrabeculectomy is a successful operation that improves visual acuity as well as controlling IOP in a majority of patients. Although the success of trabeculectomy in lowering IOP is reduced when combined with phacoemulsification compared with trabeculectomy alone, this finding has to be set against the possible need for subsequent cataract surgery following trabeculectomy alone, which represents a second trip and expense for the patient and results in 10-61% failure of the trabeculectomy at one year post-cataract surgery. TRIAL REGISTRATION: ISRCTN Registry ISRCTN36436933.

Phosphorus-32, a clinically available drug, inhibits cancer growth by inducing DNA double-strand breakage.

Radioisotopes that emit electrons (beta particles), such as radioiodine, can effectively kill target cells, including cancer cells. Aqueous 32P[PO4] is a pure beta-emitter that has been used for several decades to treat non-malignant human myeloproliferative diseases. 32P[PO4] was directly compared to a more powerful pure beta-emitter, the clinically important 90Y isotope. In vitro, 32P[PO4] was more effective at killing cells than was the more powerful isotope 90Y (P ≤ 0.001) and also caused substantially more double-stranded DNA breaks than did 90Y. In vivo, a single low-dose intravenous dose of aqueous elemental 32P significantly inhibited tumor growth in the syngeneic murine cancer model (P ≤ 0.001). This effect is exerted by direct incorporation into nascent DNA chains, resulting in double-stranded breakage, a unique mechanism not duplicatable by other, more powerful electron-emitting radioisotopes. 32P[PO4] should be considered for human clinical trials as a potential novel anti-cancer drug.

A unique matched quadruplet of terbium radioisotopes for PET and SPECT and for α- and ß- radionuclide therapy: an in vivo proof-of-concept study with a new receptor-targeted folate derivative.

UNLABELLED: Terbium offers 4 clinically interesting radioisotopes with complementary physical decay characteristics: (149)Tb, (152)Tb, (155)Tb, and (161)Tb. The identical chemical characteristics of these radioisotopes allow the preparation of radiopharmaceuticals with identical pharmacokinetics useful for PET ((152)Tb) and SPECT diagnosis ((155)Tb) and for α- ((149)Tb) and ß(-)-particle ((161)Tb) therapy. The goal of this proof-of-concept study was to produce all 4 terbium radioisotopes and assess their diagnostic and therapeutic features in vivo when labeled with a folate-based targeting agent. METHODS: (161)Tb was produced by irradiation of (160)Gd targets with neutrons at Paul Scherrer Institute or Institut Laue-Langevin. After neutron capture, the short-lived (161)Gd decays to (161)Tb. (149)Tb, (152)Tb, and (155)Tb were produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. The isotopes were purified by means of cation exchange chromatography. For the in vivo studies, we used the DOTA-folate conjugate cm09, which binds to folate receptor (FR)-positive KB tumor cells. Therapy experiments with (149)Tb-cm09 and (161)Tb-cm09 were performed in KB tumor-bearing nude mice. Diagnostic PET/CT ((152)Tb-cm09) and SPECT/CT ((155)Tb-cm09 and (161)Tb-cm09) studies were performed in the same tumor mouse model. RESULTS: Carrier-free terbium radioisotopes were obtained after purification, with activities ranging from approximately 6 MBq (for (149)Tb) to approximately 15 MBq (for (161)Tb). The radiolabeling of cm09 was achieved in a greater than 96% radiochemical yield for all terbium radioisotopes. Biodistribution studies showed high and specific uptake in FR-positive tumor xenografts (23.8% ± 2.5% at 4 h after injection, 22.0% ± 4.4% at 24 h after injection, and 18.4% ± 1.8% at 48 h after injection). Excellent tumor-to-background ratios at 24 h after injection (tumor to blood, ≈ 15; tumor to liver, ≈ 5.9; and tumor to kidney, ≈ 0.8) allowed the visualization of tumors in mice using PET ((152)Tb-cm09) and SPECT ((155)Tb-cm09 and (161)Tb-cm09). Compared with no therapy, α- ((149)Tb-cm09) and ß(-)-particle therapy ((161)Tb-cm09) resulted in a marked delay in tumor growth or even complete remission (33% for (149)Tb-cm09 and 80% for (161)Tb-cm09) and a significantly increased survival. CONCLUSION: For the first time, to our knowledge, 4 terbium radionuclides have been tested in parallel with tumor-bearing mice using an FR targeting agent. Along with excellent tumor visualization enabled by (152)Tb PET and (155)Tb SPECT, we demonstrated the therapeutic efficacy of the α-emitter (149)Tb and ß(-)-emitter (161)Tb.

Transient cytotoxicity of ¹³¹I beta radiation in hyperthyroid patients treated with radioactive iodine.

BACKGROUND & OBJECTIVES: Radioiodine ( 131 I) or radioactive iodine in low doses is used worldwide as the first line of management in the treatment of hyperthyroidism. Information is available on the extent and severity of cell damage after a high dose radioiodine ( 131 I) therapy for thyroid cancer, but information is scanty on its cellular effects, its extent and severity of cell damage after a low dose 131 I therapy. The present investigation was aimed to study the cytotoxic effects of a low dose 131 I therapy in varying doses as is normally being used in routine clinical practice in the treatment of various forms of hyperthyroidism. METHODS: Peripheral blood lymphocytes were analyzed in 32 hyperthyroid patients. All of them received 131 I in the form of sodium iodide solution orally. Blood lymphocytes were studied for the presence of chromosomal aberrations (CA) and micro nucleus (MN) using micronucleus assay. Blood samples of these patients were drawn prior to the treatment, on 7 th and 30 th days after the treatment. RESULTS: The results indicated a positive relationship between 131 I dose, CA and MN frequency. A statistically significant increase in CA and MN frequency in day 7 post- therapy and a decrease in mean levels of CA and MN on day 30 post-therapy were observed when compared to pre-therapy. INTERPRETATION & CONCLUSIONS: This study showed that the cytogenetic damage induced by 131 I in low doses i.e., less than 555MBq was minimal and reversible. Patients can be motivated to undertake this safe and easy procedure as a first line of therapy in the treatment of hyperthyroidism.

Calculation of energy-deposition distributions and microdosimetric estimation of the biological effect of a 9C beam.

Among the alternative beams being recently considered for external cancer radiotherapy, (9)C has received some attention because it is expected that its biological effectiveness could be boosted by the beta-delayed emission of two alpha particles and a proton that takes place at the ion-stopping site. Experiments have been performed to characterise this exotic beam physically and models have been developed to estimate quantitatively its biological effect. Here, the particle and heavy-ion transport code system ( PHITS ) is used to calculate energy-deposition and linear energy transfer distributions for a (9)C beam in water and the results are compared with published data. Although PHITS fails to reproduce some of the features of the distributions, it suggests that the decay of (9)C contributes negligibly to the energy-deposition distributions, thus contradicting the previous interpretation of the measured data. We have also performed a microdosimetric calculation to estimate the biological effect of the decay, which was found to be negligible; previous microdosimetric Monte-Carlo calculations were found to be incorrect. An analytical argument, of geometrical nature, confirms this conclusion and gives a theoretical upper bound on the additional biological effectiveness of the decay. However, no explanation can be offered at present for the observed difference in the biological effectiveness between (9)C and (12)C; the reproducibility of this surprising result will be verified in coming experiments.

5-fluorouracil vs. beta-irradiation in the prevention of pterygium recurrence.

The aim of this study was to compare 5-fluorouracil (5-FU) with beta-irradiation in the prevention of pterygium recurrence. A retrospective non-randomised review of cases of fleshy pterygium treated with bare scleral excision and adjuvant 5-FU were compared with similar morphologically appearing pterygia, matched for age and sex, treated with bare scleral excision and adjuvant beta-irradiation. All surgeries were carried out at the university college hospital and Ojulowo eye hospital, Ibadan, Nigeria. Twenty-seven eyes of 24 patients who had pterygium excision with adjuvant treatment with 5-FU were compared with 31 eyes of 24 patients who were treated with excision and beta-irradiation. The mean age for the 5-FU group was 46.1 years while that for the beta-irradiation group was 46.9 years. Both sexes were equally represented, 12 males and 12 females. There were seven (25.9%) initial recurrences in the 5-FU group but four of these became atrophic, and therefore, cosmetically acceptable leaving three eyes (11%) with unacceptable recurrent pterygia. The beta-irradiation group, however, had seven (22.5) initial recurrence but five of these became atrophic and fell short of the cornea, leaving two (6.5%) with clinically unacceptable recurrence. The difference was, however, not statistically significant (Zc = 0.74 and p > 0.1). The associated complications were mostly mild in both groups and included cornea opacity of 10 (37%) complications, conjunctivitis of three (11%) complications, sclera granuloma of three (11%) complications and conjunctiva necrosis of one (3.7%) complication for the 5-FU group, and while the beta-irradiation group had corneal opacity of one (3.7%) complication and conjunctivitis of three (11%) complications. The non-statistical significance of a lower-pterigium recurrence rate with use of beta-irradiation for the treatment of fleshy pterygium compared with 5-FU may have been partly due to the small number of patients studied. A randomised-controlled study using a larger sample size is therefore proposed. However, the fact that over half of those with initial recurrence in the 5-FU group became atrophic (and therefore cosmetically acceptable) over time as well as less cost implication in the purchase of 5-FU relative to Strontium-90 association with few and mild complications makes it a desirable adjuvant therapy in depressed economies. However, beta-irradiation still has a place when cost issue is not an inhibiting factor in view of its clinically superior outcome.

The potential application of beta-delayed particle decay beam 9C in cancer therapy.

A radioactive ion beam like 9C serves as a double radiation source and may be useful in cancer treatment, where the essential irradiation comes from the external beam itself and the extra one is due to the low-energy particles emitted internally during the decay of 9C. Based on the microdosimetric specific energy spectrum in cell nuclei, a model to evaluate the biological effect induced by the internally emitted particles from a beta-delayed particle decay beam has been developed. In this paper, using this model the additional contributions to the cell-killing effect due to the emitted particles from stopping 9C ions were incorporated in the design of spread-out Bragg peaks (SOBP) for radioactive 9C beams. For this purpose, a simulated annealing algorithm was employed to optimize the superposing weighting fractions of all monoenergetic beams so that a uniform cell survival level could be realized across the SOBP within an acceptable deviation of 5%. SOBPs with different widths and at different cell survival levels were designed for both therapeutic 9C and 12C beams for comparison. The potential use of the 9C beam in radiotherapy compared to the 12C beam, which is commonly adopted in the practices of current heavy-ion therapy, is shown systematically in terms of the distributions of biological effective dose and cell survival along the beam penetration.

Clinical beta radiation dosimetry for brachytherapy in terms of absorbed dose to water: ISO new work item proposal for international standardization.

PURPOSE: Beta radiation has found increasing interest in intravascular brachytherapy for successfully overcoming the severe problem of restenosis after interventional treatment of arterial stenosis. Prior to initiating procedures applying beta radiation there is a common need to specify methods for the determination and specification of the absorbed dose to water or tissue and their spatial distributions. The DIN-NAR standardization in radiology task group Dosimetry has initiated an international ad hoc working group for an ISO new work item proposal on the standardization of procedures in clinical beta radiation dosimetry. METHODS: The intent of this standard is to review methods and to give recommendations for the calibration of therapeutic beta sources, a code of practice for clinical beta radiation dosimetry and guidance for estimating the uncertainty of the absorbed dose to water delivered. The standard will be confined to "scaled" radioactive sources such as single seeds, source trains, line, shell and volume sources for which only the beta radiation emitted is of therapeutic relevance. The topics will include dosimetric quantities; source data; calibration and traceability; general principles and requirements for absorbed dose measurements; in phantom dosimetry; theoretical modeling; presentation of dose distributions; clinical dosimetry; clinical quality control; irradiation treatment planning; as well as uncertainties. The document is geared to organizations wishing to establish reference methods in dosimetry aiming at clinical demands for appropriate small measurement uncertainties. Existing normative documents as well as international recommendations, such as those from AAPM, DGMP, ESTRO, NCS, ICRU, or IAEA will be taken into account. RESULTS: The first meetings of the new international working group took place in March and September 2002 at Essen, Germany [IAEA-cn-96-73, 2002]. CONCLUSIONS: Based on the DGMP Report 16, the AAPM TG 60 up-date draft, other recommendations and normative documents, the DIN-NAR project has collected and prepared detailed material on the calibration and dosimetry of beta radiation brachytherapy sources in terms of absorbed dose to water. The ISO new work item proposal will be completed in spring 2003.

A statistical investigation of the scaling factor method of beta-ray dose distribution derivation: the scaling factor for water to bone.

Reliable methods of estimating doses are essential for the use of beta emitting radionuclides for radiotherapy. The passage of electrons through matter is a very complex phenomenon due to the large number of elastic and inelastic interactions resulting in scattering and energy losses. The analytical solution for the electron transport being intractable, the problem has been addressed by the Monte Carlo technique. Empirical or semiempirical less time consuming methods, such as the scaling factor method, may appear more preferable in practice when dealing with complicated source distributions. The method, proposed by Cross and co-workers [AECL Report Nos. AECL-1617 (1982), AECL 10521 (1992)] consists in the derivation of beta-ray dose distribution in other media from those in water by using a "scaling factor" or "relative attenuation factor" on distance and a closely related renormalization factor imposed by the energy conservation. This work investigates the accuracy of the scaling factor method using a statistical approach, a generalized chi 2 test, focusing on the particular case of potential interest, the scaling factor for water to bone. The direct comparison of the shapes of the depth dose deposition curves in the two media indicates discrepancies of less than 5% up to at least 60% of the range in bone, a depth within which 95% of the initial energy is deposited. The scaling factor derived by this method, 0.9720 +/- 0.0012, confirms the existing experimentally determined value of 0.973 +/- 1% [AECL Report No. AECL-10521 (1992)]. The accuracy of the determination is increased by almost a factor of 10. A way of improving the scaling method, especially for depth over the 60% continuous slowing down approximation range, by using a modulation function is also proposed.

Application of the scaling factor method to estimation of beta dose distributions for dissimilar media separated by a planar interface.

The most accurate method of calculating beta dose distribution currently relies on the Monte Carlo technique. The major drawback of the method is the long computing time required to follow a large number of "electron histories" in order to achieve good statistics, which makes the method unattractive for practical radiation therapy. A way to avoid the Monte Carlo calculations for homogeneous media was suggested by Cross and co-workers (AECL Report Nos. 7617, 1982; 10521, 1992), and is known as the "scaling factor" method. It consists of the determination of the depth dose distribution in a medium based on known data about the dose distribution in an arbitrary reference medium (e.g., air, water) by the use of a scaling factor on distance and a closely related renormalization factor imposed by energy conservation. This work is an attempt to extend the applicability of the scaling factor method to dissimilar media to a planar interface. The investigation was done for an isotropic source of the radioisotope 32P and an interface between water and medium "i," where medium "i" could be any medium with atomic number in the range 8 < Z < 50. The method was checked using three randomly chosen elements 40Zr, 32Ge, and 26Fe, each forming planar interfaces with water at either 100 or 350 mg/cm2. Discrepancies of less than 5% were detected (acceptable for practical radiotherapy) for the depth within which at least 95% of the initial energy is deposited.

Obstinate cases of stromal keratitis treated by combined traditional Chinese and Western medicine.

Twenty-two cases 23 eyes with obstinate stromal keratitis treated by combination of traditional Chinese and Western medicines are reported in this paper. According to clinical manifestations, they are consistent with the clinical diagnosis of stromal herpes simplex keratitis. Since no specific Western medicine is known to be effective in treating this disorder, it is proposed to apply systemic and topical TCM and, if necessary, add beta-ray irradiation to shorten the clinical course of disease, decrease or prevent recurrence and maintain useful visual acuity, avoiding frequent relapses leading to blindness.

[Thermotolerance of tumors MA737 and LA795 of mice].

The effects of splitted heating of tumor, alone or in combination with local radiation, were studied on mouse mammary cancer MA737 in JB 2 mice and lung cancer LA795 in 739 mice. Hyperthermia was done by immersing the tumor-bearing foot into a water bath at 44 +/- 0.2 degrees C. When combined with radiation, 8 Mev beta irradiation from a linear accelerator was given. The response was assessed by tumor growth retardation calculated according to a special computer program. A priming dose of 5 to 6-minute exposure to 44 degrees C was followed, after various time intervals (1, 4, 5, 24 hr), by a longer exposure. Thermotolerance was induced in these two animal tumor models. Tolerance to heat, however, did not affect the combined effect of hyperthermia and radiation. Electron microscopic examination of the treated tumors confirmed the synergistic killing effect of the combined treatment.