Investigation of a measurement-based dosimetry approach to beta particle-emitting radiopharmaceutical therapy nuclides across tissue interfaces.

Objective.In this work, we present and evaluate a technique for performing interface measurements of beta particle-emitting radiopharmaceutical therapy agents in solution.Approach.Unlaminated EBT3 film was calibrated for absorbed dose to water using a NIST matched x-ray beam. Custom acrylic source phantoms were constructed and placed above interfaces comprised of bone, lung, and water-equivalent materials. The film was placed perpendicular to these interfaces and measurements for absorbed dose to water using solutions of90Y and177Lu were performed and compared to Monte Carlo absorbed dose to water estimates simulated with EGSnrc. Surface and depth dose profile measurements were also performed.Main results.Surface absorbed dose to water measurements agreed with predicted results within 3.6% for177Lu and 2.2% for90Y. The agreement between predicted and measured absorbed dose to water was better for90Y than177Lu for depth dose and interface profiles. In general, agreement withink= 1 uncertainty bounds was observed for both radionuclides and all interfaces. An exception to this was found for the bone-to-water interface for177Lu due to the increased sensitivity of the measurements to imperfections in the material surfaces.Significance. This work demonstrates the feasibility and limitations of using radiochromic film for performing absorbed dose to water measurements on beta particle-emitting radiopharmaceutical therapy agents across material interfaces.

Active and passive dosimetry for beta-emitting radiopharmaceutical therapy agents in a custom SPECT/CT compatible phantom.

Objective. This work introduces a novel approach to performing active and passive dosimetry for beta-emitting radionuclides in solution using common dosimeters. The measurements are compared to absorbed dose to water (Dw) estimates from Monte Carlo (MC) simulations. We present a method for obtaining absorbed dose to water, measured with dosimeters, from beta-emitting radiopharmaceutical agents using a custom SPECT/CT compatible phantom for validation of Monte Carlo based absorbed dose to water estimates.Approach. A cylindrical, acrylic SPECT/CT compatible phantom capable of housing an IBA EFD diode, Exradin A20-375 parallel plate ion chamber, unlaminated EBT3 film, and thin TLD100 microcubes was constructed for the purpose of measuring absorbed dose to water from solutions of common beta-emitting radiopharmaceutical therapy agents. The phantom is equipped with removable detector inserts that allow for multiple configurations and is designed to be used for validation of image-based absorbed dose estimates with detector measurements. Two experiments with131I and one experiment with177Lu were conducted over extended measurement intervals with starting activities of approximately 150-350 MBq. Measurement data was compared to Monte Carlo simulations using the egs_chamber user code in EGSnrc 2019.Main results. Agreement withink= 1 uncertainty between measured and MC predictedDwwas observed for all dosimeters, except the A20-375 ion chamber during the second131I experiment. Despite the agreement, the measured values were generally lower than predicted values by 5%-15%. The uncertainties atk = 1 remain large (5%-30% depending on the dosimeter) relative to other forms of radiation therapy.Significance. Despite high uncertainties, the overall agreement between measured and simulated absorbed doses is promising for the use of dosimeter-based RPT measurements in the validation of MC predictedDw.

Radio-Guided Surgery with a New-Generation ß-Probe for Radiolabeled Somatostatin Analog, in Patients with Small Intestinal Neuroendocrine Tumors.

BACKGROUND: Radio-guided surgery (RGS) holds promise for improving surgical outcomes in neuroendocrine tumors (NETs). Previous studies showed low specificity (SP) using γ-probes to detect radiation emitted by radio-labeled somatostatin analogs. OBJECTIVE: We aimed to assess the sensitivity (SE) and SP of the intraoperative RGS approach using a ß-probe with a per-lesion analysis, while assessing safety and feasibility as secondary objectives. METHODS: This prospective, single-arm, single-center, phase II trial (NCT05448157) enrolled 20 patients diagnosed with small intestine NETs (SI-NETs) with positive lesions detected at 68Ga-DOTA-TOC positron emission tomography/computed tomography (PET/CT). Patients received an intravenous injection of 1.1 MBq/Kg of 68Ga-DOTA-TOC 10 min prior to surgery. In vivo measurements were conducted using a ß-probe. Receiver operating characteristic (ROC) analysis was performed, with the tumor-to-background ratio (TBR) as the independent variable and pathology result (cancer vs. non-cancer) as the dependent variable. The area under the curve (AUC), optimal TBR, and absorbed dose for the surgery staff were reported. RESULTS: The intraoperative RGS approach was feasible in all cases without adverse effects. Of 134 specimens, the AUC was 0.928, with a TBR cut-off of 1.35 yielding 89.3% SE and 86.4% SP. The median absorbed dose for the surgery staff was 30 µSv (range 12-41 µSv). CONCLUSION: This study reports optimal accuracy in detecting lesions of SI-NETs using the intraoperative RGS approach with a novel ß-probe. The method was found to be safe, feasible, and easily reproducible in daily clinical practice, with minimal radiation exposure for the staff. RGS might potentially improve radical resection rates in SI-NETs. CLINICAL TRIALS REGISTRATION: 68Ga-DOTATOC Radio-Guided Surgery with ß-Probe in GEP-NET (RGS GEP-NET) [NCT0544815; https://classic. CLINICALTRIALS: gov/ct2/show/NCT05448157 ].

Alpha and Beta Radiation for Theragnostics.

Targeted radionuclide therapy (TRT) has significantly evolved from its beginnings with iodine-131 to employing carrier molecules with beta emitting isotopes like lutetium-177. With the success of Lu-177-DOTATATE for neuroendocrine tumors and Lu-177-PSMA-617 for prostate cancer, several other beta emitting radioisotopes, such as Cu-67 and Tb-161, are being explored for TRT. The field has also expanded into targeted alpha therapy (TAT) with agents like radium-223 for bone metastases in prostate cancer, and several other alpha emitter radioisotopes with carrier molecules, such as Ac-225, and Pb-212 under clinical trials. Despite these advancements, the scope of TRT in treating diverse solid tumors and integration with other therapies like immunotherapy remains under investigation. The success of antibody-drug conjugates further complements treatments with TRT, though challenges in treatment optimization continue.

Prostate Cancer Radioligand Therapy: Beta-labeled Radiopharmaceuticals.

Prostate cancer is the most common malignancy in men worldwide, with an estimated 174,650 new cases per year in the United States, and the second cancer-related cause of death, after lung cancer, with 31,620 deaths per year. While the 5 year survival rate for prostate cancer in patients without metastatic spread is nearly 100%, those with distant metastases have 5 year survival rates of approximately 30%. Initial diagnosis and assessment are based on PSA levels, Gleason score (derived from prostate biopsy), and advanced imaging modalities, including prostate MR imaging and PSMA-PET/computed tomography in patients with high-risk features.

A diffusion-leakage model coupled with dose point kernels (DPK) for dosimetry of diffusing alpha-emitters radiation therapy (DaRT).

BACKGROUND: Diffusing alpha-emitters radiation therapy (DaRT) is a novel brachytherapy technique that leverages the diffusive flow of 224Ra progeny within the tumor volume over the course of the treatment. Cell killing is achieved by the emitted alpha particles that have a short range in tissue and high linear energy transfer. The current proposed absorbed dose calculation method for DaRT is based on a diffusion-leakage (DL) model that neglects absorbed dose from beta particles. PURPOSE: This work aimed to couple the DL model with dose point kernels (DPKs) to account for dose from beta particles as well as to consider the non-local deposition of energy. METHODS: The DaRT seed was modeled using COMSOL multiphysics and the DL model was implemented to extract the spatial information of the diffusing daughters. Using Monte-Carlo (MC) methods, DPKs were generated for 212Pb, 212Bi, and their progenies since they were considered to be the dominant beta emitters in the 224Ra radioactive decay chain. A convolution operation was performed between the integrated number densities of the diffusing daughters and DPKs to calculate the total absorbed dose over a 30-day treatment period. Both high-diffusion and low-diffusion cases were considered. RESULTS: The calculated DPKs showed non-negligible energy deposition over several millimeters from the source location. An absorbed dose >10 Gy was deposited within a 1.8 mm radial distance for the low diffusion case and a 2.2 mm radial distance for the high diffusion case. When the DPK method was compared with the local energy deposition method that solely considered dose from alpha particles, differences above 1 Gy were found within 1.3 and 1.8 mm radial distances from the surface of the source for the low diffusion and high diffusion cases, respectively. CONCLUSIONS: The proposed method enhances the accuracy of the dose calculation method used for the DaRT technique.

Surgical radioguidance with beta-emitting radionuclides; challenges and possibilities: A position paper by the EANM.

Radioguidance that makes use of ß-emitting radionuclides is gaining in popularity and could have potential to strengthen the range of existing radioguidance techniques. While there is a strong tendency to develop new PET radiotracers, due to favorable imaging characteristics and the success of theranostics research, there are practical challenges that need to be overcome when considering use of ß-emitters for surgical radioguidance. In this position paper, the EANM identifies the possibilities and challenges that relate to the successful implementation of ß-emitters in surgical guidance, covering aspects related to instrumentation, radiation protection, and modes of implementation.

A new in vitro model applied 90Y microspheres to study the effects of low dose beta radiation on colorectal cancer cell line in various oxygenation conditions.

We propose a new in vitro model to assess the impact of 90Y-microspheres derived low-dose beta radiation on colorectal cancer cell line under various oxygenation conditions that mimic the tumor environment. Cancer cells (HCT116) proliferation was assessed using Alamar Blue (AB) assay after 48, 72, and 96 h. FLUKA code assessed changes in cancer cell populations relative to the absorbed dose. In normoxia, mitochondrial activity measured by Alamar Blue after 48-72 h was significantly correlated with the number of microspheres (48 h: r = 0.87 and 72 h: r = 0.89, p < 0.05) and absorbed dose (48 h: r = 0.87 and 72 h: r = 0.7, p < 0.05). In hypoxia, the coefficients were r = 0.43 for both the number of spheres and absorbed dose and r = 0.45, r = 0.47, respectively. Impediment of cancer cell proliferation depended on the absorbed dose. Doses below 70 Gy could reduce colorectal cancer cell proliferation in vitro. Hypoxia induced a higher resistance to radiation than that observed under normoxic conditions. Hypoxia and radiation induced senescence in cultured cells. The new in vitro model is useful for the assessment of 90Y radioembolization effects at the micro-scale.

PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates.

PURPOSE: Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA (KLK3). EXPERIMENTAL DESIGN: LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and KLK3_Hi-Myc transgenic mice were imaged with 89Zr- or treated with 90Y- or 225Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [225Ac]hu5A10 and [90Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [89Zr]hu5A10 in nonhuman primates (NHP) were determined using PET. RESULTS: Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [90Y]/[225Ac]hu5A10 effectively reduced tumor burden and prolonged survival (P ≤ 0.0054). Effects of [90Y]hu5A10 were more immediate than [225Ac]hu5A10 (TTN, P < 0.0001) but less sustained (TTP, P < 0.0001). Complete responses were observed in 7 of 18 [225Ac]hu5A10 and 1 of 9 mice [90Y]hu5A10. Pharmacokinetics of [89Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [89Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period. CONCLUSIONS: We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.

Comparison of CD38-Targeted α- Versus ß-Radionuclide Therapy of Disseminated Multiple Myeloma in an Animal Model.

Targeted therapies for multiple myeloma (MM) include the anti-CD38 antibody daratumumab, which, in addition to its inherent cytotoxicity, can be radiolabeled with tracers for imaging and with ß- and α-emitter radionuclides for radioimmunotherapy. Methods: We have compared the potential therapeutic efficacy of ß- versus α-emitter radioimmunotherapy using radiolabeled DOTA-daratumumab in a preclinical model of disseminated multiple myeloma. Multiple dose levels were investigated to find the dose with the highest efficacy and lowest toxicity. Results: In a dose­response study with the ß-emitter 177Lu-DOTA-daratumumab, the lowest tested dose, 1.85 MBq, extended survival from 37 to 47 d but did not delay tumor growth. Doses of 3.7 and 7.4 MBq extended survival to 55 and 58 d, respectively, causing a small equivalent delay in tumor growth, followed by regrowth. The higher dose, 11.1 MBq, eradicated the tumor but had no effect on survival compared with untreated controls, because of whole-body toxicity. In contrast, the α-emitter 225Ac-DOTA-daratumumab had a dose-dependent effect, in which 0.925, 1.85, and 3.7 kBq increased survival, compared with untreated controls (35 d), to 47, 52, and 73 d, respectively, with a significant delay in tumor growth for all 3 doses. Higher doses of 11.1 and 22.2 kBq resulted in equivalent survival to 82 d but with significant whole-body toxicity. Parallel studies with untargeted 225Ac-DOTA-trastuzumab conferred no improvement over untreated controls and resulted in whole-body toxicity. Conclusion: We conclude, and mathematic modeling confirms, that maximal biologic doses were achieved by targeted α-therapy and demonstrated 225Ac to be superior to 177Lu in delaying tumor growth and decreasing whole-body toxicity.

First Clinical Results for PSMA-Targeted α-Therapy Using 225Ac-PSMA-I&T in Advanced-mCRPC Patients.

Treatment of advanced metastatic castration-resistant prostate cancer after failure of approved therapy options remains challenging. Prostate-specific membrane antigen (PSMA)-targeting ß- and α-emitters have been introduced, with promising response rates. Here, we present the first-to our knowledge-clinical data for PSMA-targeted α-therapy (TAT) using 225Ac-PSMA imaging and therapy (I&T). Methods: Fourteen patients receiving 225Ac-PSMA-I&T were included in this retrospective analysis. Eleven of the 14 had prior second-line antiandrogen treatment with abiraterone or enzalutamide, prior chemotherapy, and prior 177Lu-PSMA treatment. Patients were treated at bimonthly intervals until progression or intolerable side effects. Prostate-specific antigen (PSA) was measured for response assessment. Hematologic and nonhematologic side effects were recorded according to the Common Terminology Criteria for Adverse Events, version 5.0. Results: Thirty-four cycles of 225Ac-PSMA-I&T were applied (median dose, 7.8 MBq; range, 6.0-8.5), with 1 cycle in 3 patients, 2 cycles in 7 patients, 4 cycles in 3 patients, and 5 cycles in 1 patient. No acute toxicity was observed during hospitalization. Baseline PSA was 112 ng/mL (range, 20.5-818 ng/mL). The best PSA response after TAT (a PSA decline ≥ 50%) was observed in 7 patients, and a PSA decline of any amount was observed in 11 patients. Three patients had no PSA decline at any time. A subgroup analysis of 11 patients with prior 177Lu-PSMA treatment showed any PSA decline in 8 patients and a decline of at least 50% in 5 patients. After TAT, grade 3 anemia was observed in 3 of the 14 patients, with 2 of them presenting with grade 2 anemia already at baseline. Grade 3 leukopenia was observed in 1 patient. Eight patients with preexisting xerostomia after 177Lu-PSMA showed no worsening after TAT. Newly diagnosed grade 1 or 2 xerostomia after TAT was observed in 5 patients. One patient reported no xerostomia at all. Conclusion: Our first clinical data for TAT using 225Ac-PSMA-I&T showed a promising antitumor effect in advanced metastatic castration-resistant prostate cancer. These results are highly comparable to data on 225Ac-PSMA-617 TAT.

Effect of microdistribution of alpha and beta-emitters in targeted radionuclide therapies on delivered absorbed dose in a GATE model of bone marrow.

Acute hematologic toxicity is a frequent adverse effect of beta-emitter targeted radionuclide therapies (TRTs). Alpha emitters have the potential of delivering high linear energy transfer (LET) radiation to the tumor attributed to its shorter range. Antibody-based TRTs have increased blood-pool half-lives, and therefore increased marrow toxicity, which is a particular concern with alpha emitters. Accurate 3D absorbed dose calculations focusing on the interface region of blood vessels and bone can elucidate energy deposition patterns. Firstly, a cylindrical geometry model with a central blood vessel embedded in the trabecular tissue was modeled. Monte Carlo simulations in GATE were performed considering beta (177Lu, 90Y) and alpha emitters (211At, 225Ac) as sources restricted to the blood pool. Subsequently, the radioactive sources were added in the trabecular bone compartment in order to model bone marrow metastases infiltration (BMMI). Radial profiles, dose-volume histograms and voxel relative differences were used to evaluate the absorbed dose results. We demonstrated that alpha emitters have a higher localized energy deposition compared to beta emitters. In the cylindrical geometry model, when the sources are confined to the blood pool, the dose to the trabecular bone is greater for beta emitting radionuclides, as alpha emitters deposit the majority of their energy within 70 µm of the vessel wall. In the BMMI model, alpha emitters have a lower dose to untargeted trabecular bone. Our results suggest that when alpha emitters are restricted to the blood pool, as when labeled to antibodies, hematologic toxicities may be lower than expected due to differences in the microdistribution of delivered absorbed dose.

Evaluating 225Ac and 177Lu Radioimmunoconjugates against Antibody-Drug Conjugates for Small-Cell Lung Cancer.

Interest in the use of 225Ac for targeted alpha therapies has increased dramatically over the past few years, resulting in a multitude of new isotope production and translational research efforts. However, 225Ac radioimmunoconjugate (RIC) research is still in its infancy, with most prior experience in hematologic malignancies and only one reported preclinical solid tumor study using 225Ac RICs. In an effort to compare 225Ac RICs to other current antibody conjugates, a variety of RICs are tested against intractable small-cell lung cancer (SCLC). We directly compare, in vitro and in vivo, two promising candidates of each α or ß- category, 225Ac and 177Lu, versus pyrrolobenzodiazepine (PBD) nonradioactive benchmarks. The monoclonal antibody constructs are targeted to either delta like 3 protein (DLL3), a recently discovered SCLC target, or CD46 as a positive control. An immunocompromised maximum tolerated dose assay is performed on NOD SCID mice, along with tumor efficacy proof-of-concept studies in vivo. We overview the conjugation techniques required to create serum-stable RICs and characterize and compare in vitro cell killing with RICs conjugated to nonspecific antibodies (huIgG1) with either native or site-specific thiol loci against tumor antigen DLL3-expressing and nonexpressing cell lines. Using patient-derived xenografts of SCLC onto NOD SCID mice, solid tumor growth was controlled throughout 3 weeks before growth appeared, in comparison to PBD conjugate controls. NOD SCID mice showed lengthened survival using 225Ac compared to 177Lu RICs, and PBD dimers showed full tumor suppression with nine out of ten mice. The exploration of RICs on a variety of antibody-antigen systems is necessary to direct efforts in cancer research toward promising candidates. However, the anti-DLL3-RIC system with 225Ac and 177Lu appears to be not as effective as the anti-DLL3-PBD counterpart in SCLC therapy with matched antibodies and portrays the challenges in both SCLC therapy as well as the specialized utility of RICs in cancer treatment.

ß-radiating radionuclides in cancer treatment, novel insight into promising approach.

Targeted radionuclide therapy, known as molecular radiotherapy is a novel therapeutic module in cancer medicine. ß-radiating radionuclides have definite impact on target cells via interference in cell cycle and particular signalings that can lead to tumor regression with minimal off-target effects on the surrounding tissues. Radionuclides play a remarkable role not only in apoptosis induction and cell cycle arrest, but also in the amelioration of other characteristics of cancer cells. Recently, application of novel ß-radiating radionuclides in cancer therapy has been emerged as a promising therapeutic modality. Several investigations are ongoing to understand the underlying molecular mechanisms of ß-radiating elements in cancer medicine. Based on the radiation dose, exposure time and type of the ß-radiating element, different results could be achieved in cancer cells. It has been shown that ß-radiating radioisotopes block cancer cell proliferation by inducing apoptosis and cell cycle arrest. However, physical characteristics of the ß-radiating element (half-life, tissue penetration range, and maximum energy) and treatment protocol determine whether tumor cells undergo cell cycle arrest, apoptosis or both and to which extent. In this review, we highlighted novel therapeutic effects of ß-radiating radionuclides on cancer cells, particularly apoptosis induction and cell cycle arrest.

89Zr-PET imaging of DNA double-strand breaks for the early monitoring of response following α- and ß-particle radioimmunotherapy in a mouse model of pancreatic ductal adenocarcinoma.

Rationale: The evaluation of early treatment response is critical for patient prognosis and treatment planning. When the current methods rely on invasive protocols that evaluate the expression of DNA damage markers on patient biopsy samples, we aim to evaluate a non-invasive PET imaging approach to monitor the early expression of the phosphorylated histone γH2AX in the context of pancreatic cancer targeted radionuclide therapy. Pancreatic ductal adenocarcinoma has a poor patient prognosis due to the absence of curative treatment for patients with advanced disease. There is therefore a critical need for the fast clinical translation of new therapeutic options. In line with these observations, our group has been focusing on the development of radiotheranostic agents based on a fully human monoclonal antibody (5B1) with exceptional affinity for CA19.9, an antigen overexpressed in PDAC. Two on-going clinical trials resulted from these efforts, one with 89Zr (diagnosis) and one with 177Lu (ß-particle therapy). More recently, we successfully developed and evaluated in PDAC mouse models a targeted α-therapy strategy with high clinical translation potential. We aim to expedite the clinical translation of the developed radioimmunotherapy approaches by investigating the early therapeutic response and effect of radiation therapy in a PDAC mouse model via PET imaging. Methods: Mice bearing BxPC3 tumor xenografts were treated with α- and ß-particle pretargeted radioimmunotherapy (PRIT), external beam radiotherapy (EBRT), or sham-treated (vehicle). The phosphorylated histone γH2AX produced as a response to DNA double strand breaks was quantified with the PET radiotracer, [89Zr]Zr-DFO-anti-γH2AX-TAT. Results: PET imaging studies in BxPC3 PDAC mouse models demonstrated increased uptake of [89Zr]Zr-DFO-anti-γH2AX-TAT (6.29 ± 0.15 %IA/g) following ß-PRIT in BxPC3 PDAC xenografts as compared to the saline control group (4.58 ± 0.76 %IA/g) and EBRT control group (5.93 ± 0.76 %IA/g). Similarly, significantly higher uptake of [89Zr]Zr-DFO-anti-γH2AX-TAT was observed in tumors of the 225Ac-PRIT and EBRT (10 Gy) cohorts (7.37 ± 1.23 and 6.80 ± 1.24 %IA/g, respectively) compared to the negative control cohort (5.08 ± 0.95 %IA/g). Ex vivo γH2AX immunohistochemistry and immunofluorescence analysis correlated with in vivo89Zr-anti-γH2AX PET/CT imaging with increased γH2AX positive cell and γH2AX foci per cell in the treated cohorts. When α-PRIT resulted in prolonged overall survival of treated animals (107.5 days) as compared to ß-PRIT (73.0 days), no evidence of difference in [89Zr]Zr-DFO-anti-γH2AX-TAT uptake at the tumor site was observed, highlighting that DNA damage is not the sole radiobiology paradigm and that off-targeted (bystander) effects should be considered. Conclusions: PET imaging studies with [89Zr]Zr-DFO-anti-γH2AX-TAT following α- and ß-particle PRIT in a BxPC3 PDAC subcutaneous xenograft mouse model allowed the monitoring of tumor radiobiological response to treatment.

Tumor-non-tumor discrimination by a ß- detector for Radio Guided Surgery on ex-vivo neuroendocrine tumors samples.

This paper provides a first insight of the potential of the ß- Radio Guided Surgery (ß--RGS) in a complex surgical environment like the abdomen, where multiple sources of background concur to the signal at the tumor site. This case is well reproduced by ex-vivo samples of 90Y-marked Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP NET) in the bowel. These specimens indeed include at least three wide independent sources of background associated to three anatomical districts (mesentery, intestine, mucose). The study is based on the analysis of 37 lesions found on 5 samples belonging to 5 different patients. We show that the use of electrons, a short range particle, instead of γ particles, allows to limit counts read on a lesion to the sum of the tumor signal plus the background generated by the sole hosting district.The background on adjacent districts in the same specimen/patient is found to differ up to a factor 4, showing how the specificity and sensitivity of the ß--RGS technique can be fully exploited only upon a correct measurement of the contributing background. This locality has been used to set a site-specific cut-off algorithm to discriminate tumor and healthy tissue with a specificity of 100% and a sensitivity, on this test data sample, close to 100%. Factors influencing the sensitivity are also discussed. One of the specimens set allowed us evaluate the volume of the lesions, thus concluding that the probe was able to detect lesions as small as 0.04 mL in that particular case.

The influence of the α/ß ratio on treatment time iso-effect relationships in the central nervous system.

Purpose: To investigate the influence of changes in α/ß ratio (range 1.5-3 Gy) on iso-effective doses, with varying treatment time, in spinal cord and central nervous system tissues with comparable radio-sensitivity. It is important to establish if an α/ß ratio of 2 Gy, the accepted norm for neuro-oncology iso-effect estimations, can be used.Methods: The rat spinal cord irradiation data of Pop et al. provided ED50 values for radiation myelopathy for treatment times that varied from minutes to ∼6 days. Analysis using biphasic repair kinetics, allowing for variable dose-rates, provided the best fit with repair half-times of 0.19 and 2.16 hr, each providing ∼50% of overall repair; with an α/ß ratio 2.47 Gy (CI 1.5-3.95 Gy). Using the above data set, graphical methods were used to investigate changes in the repair parameters for differing fixed α/ß ratios between 1.5 and 3.0 Gy. Two different intermittent dose delivery equations were used to evaluate the implications in a radiosurgery setting.Results: Changes in the α/ß ratio (1.5-3.0 Gy) have a minor effect on equivalent doses for radiation myelopathy for treatment durations of a few hours. Changing the α/ß value from 2 Gy to 2.47 Gy, modified equivalent single doses by < 1% when overall treatment times ranged from 0.1 to 5.0 hr. Significant changes were only found for treatment times longer than 5-10 hr. These two α/ß ratios were also compared in a practical radiosurgery situation, using two different models for estimating BED, again there was no significant loss of accuracy.Conclusions: It is reasonable to use an α/ß ratio of 2 Gy for CNS tissue, with the same repair half-times as published in the original publication by Pop et al., in situations where the assessment of the BED in radiosurgery is used with other form of radiotherapy. In radiosurgery, the variation in BED with treatment duration (for a fixed physical dose) is very similar, but absolute BED values depend on the α/ß value. In radiosurgery, clinical recommendations obtained using BED calculations using the originally proposed α/ß ratio of 2.47 Gy are still appropriate. For calculations involving a combination of radiosurgery and other modalities, such as fractionated radiotherapy, it would be appropriate in all cases to apply a value of 2 Gy, the accepted norm in neuro-oncology, without significant loss of accuracy in the radio-surgical component. This may have important applications in retreatment situations.

Clustering effects in nanoparticle-enhanced ß- emitting internal radionuclide therapy: a Monte Carlo study.

We investigate the effects of an increase in the production of secondary electrons when a ß - source commonly used in internal radionuclide therapy, 67Cu, is radiolabelled to a super-paramagnetic iron oxide nanoparticle (SPION), with specific emphasis on the role of SPION cluster size and geometry. A positive relationship is found between the degree to which the nanoparticles are clustered and the associated radio-enhancement effects, with cluster population size playing a major role, as well as SPION separation within a cluster and the distance between clusters. Our simulation results indicate that SPIONs labelled with 67Cu can induce a nonlinear amplification in the number of secondary electrons produced of up to 4% in bulk, with localised regions of nearer inter-SPION separation producing an increase of over 400% for a 20 nm average SPION separation. Such variation in enhancement due to local concentration effects may help identify clinical strategies that enhance efficacy for a given radiation dosage, or achieve equal efficacy with reduced radiation dosage.

Peptide Receptor Radionuclide Therapy Using 225Ac-DOTATOC Achieves Partial Remission in a Patient With Progressive Neuroendocrine Liver Metastases After Repeated ß-Emitter Peptide Receptor Radionuclide Therapy.

We present here a case with ß-radiation-refractory metastatic neuroendocrine tumors, who demonstrated an excellent therapy response after 1 cycle of Ac-DOTATOC, without any significant adverse effects even after 10 cycles of ß-emitter peptide receptor radionuclide therapy followed by α-peptide receptor radionuclide therapy.

Superficial skin cancer therapy with Y-90 microspheres: A feasibility study on patch preparation.

BACKGROUND: Radiation therapy using beta particles is an interesting treatment for very superficial skin lesions. Due to their low penetration in tissue and rapid dose fall-off, beta particles can protect underlying bony structures and surrounding healthy tissue while irradiating the skin tumor. In the current work, a simple method for the fabrication of a radioactive patch for use in skin cancer therapy based on a beta-emitting isotope is presented. MATERIALS AND METHODS: The beta radiation sources were Y-90 microspheres currently used for catheter-based radioembolization of unresectable liver tumors. The microspheres were filtered through a syringe filter to trap them on the cellulose nitrate paper of the filter and create a radioactive patch. In the current study, to avoid the need for a hot laboratory, the experiment was done using nonradioactive microspheres. An optical microscope was used to verify the distribution of the particles on the filter paper. RESULTS: Visual evaluation of the patches showed that using the proposed method, therapeutic skin patches with a fairly uniform distribution of microspheres can be created. CONCLUSION: The proposed simple method may be used in creating radiotherapeutic patches using Y-90 microspheres for radiation therapy of thin skin lesions located close to sensitive structures.