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 ].

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.

Radioactive Main Group and Rare Earth Metals for Imaging and Therapy.

Radiometals possess an exceptional breadth of decay properties and have been applied to medicine with great success for several decades. The majority of current clinical use involves diagnostic procedures, which use either positron-emission tomography (PET) or single-photon imaging to detect anatomic abnormalities that are difficult to visualize using conventional imaging techniques (e.g., MRI and X-ray). The potential of therapeutic radiometals has more recently been realized and relies on ionizing radiation to induce irreversible DNA damage, resulting in cell death. In both cases, radiopharmaceutical development has been largely geared toward the field of oncology; thus, selective tumor targeting is often essential for efficacious drug use. To this end, the rational design of four-component radiopharmaceuticals has become popularized. This Review introduces fundamental concepts of drug design and applications, with particular emphasis on bifunctional chelators (BFCs), which ensure secure consolidation of the radiometal and targeting vector and are integral for optimal drug performance. Also presented are detailed accounts of production, chelation chemistry, and biological use of selected main group and rare earth radiometals.

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.

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.

Prostate-specific membrane antigen radioligand therapy of prostate cancer.

Defining an optimal therapeutic approach in metastatic castration-resistance prostate cancer (mCRPC) patients in advanced stages is still challenging in routine clinical practice. Prostate-specific membrane antigen (PSMA) targeted radionuclide therapy with ß- or α-emitters such as 177-Lutethium (177Lu) or 225-Actinium (225A) has been a main focus at multiple academic research centers in the last few years. This review article provides an overview of PSMA characteristics, clinical performance, safety and toxicity of PSMA targeted ß- or α-radiation therapy.

Clinical estimation of α/ß values for prostate cancer from isoeffective phase III randomized trials with moderately hypofractionated radiotherapy.

BACKGROUND: The α/ß values for prostate cancer (PCa) are usually assumed to be low (1.0-1.8 Gy). This study estimated the α/ß values of PCa from phase III randomized trials of conventional (CRT) versus hypofractionated (HRT) external beam radiotherapy (RT), reported as isoeffective in terms of their 5-year biochemical (BF) or biochemical and/or clinical failure (BCF) rates. MATERIAL AND METHODS: The α/ß for each trial was estimated from the equivalent biological effective doses using the linear-quadratic model for each of their HRT and CRT schedules. The cumulative outcomes of these trials were evaluated by meta-analysis for odds ratio (OR), risk ratio (RR) and risk difference (RD). RESULTS: Eight trials from seven studies, randomized 6993 patients between CRT (n = 2941) and HRT (n = 4052). RT treatment varied between the two treatment groups in terms of dose/fraction, total dose, overall treatment time and %patients on androgen deprivation therapy (ADT). Differences in OR, RR, and RD for both BF and BCF were nonsignificant. The computed α/ß ranged from 1.3 to 11.1 Gy (4.9 ± 3.9 Gy; 95% CI: 1.6-8.2). On multivariate regression, %ADT was the sole determinant of computed α/ß (model R2: 0.98, p < .001). CONCLUSIONS: Clinically estimated α/ß for PCa from isoeffective randomized trials using known variables in the linear-quadratic expression ranged between 1.3 and 11.1 Gy. The estimated α/ß values were inversely related to %ADT usage, which should be considered when planning future RT dose-fractionation schedules.

Stability and Biodistribution of Thiol-Functionalized and (177)Lu-Labeled Metal Chelating Polymers Bound to Gold Nanoparticles.

We are studying a novel radiation nanomedicine approach to treatment of breast cancer using 30 nm gold nanoparticles (AuNP) modified with polyethylene glycol (PEG) metal-chelating polymers (MCP) that incorporate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the ß-particle emitter, (177)Lu. Our objective was to compare the stability of AuNP conjugated to MCP via a single thiol [DOTA-PEG-ortho-pyridyl disulfide (OPSS)], a dithiol [DOTA-PEG-lipoic acid (LA)] or multithiol end-group [PEG-pGlu(DOTA)8-LA4] and determine the elimination and biodistribution of these (177)Lu-labeled MCP-AuNP in mice. Stability to aggregation in the presence of thiol-containing dithiothreitol (DTT), L-cysteine or glutathione was assessed and dissociation of (177)Lu-MCP from AuNP in human plasma measured. Elimination of radioactivity from the body of athymic mice and excretion into the urine and feces was measured up to 168 h post-intravenous (i.v.) injection of (177)Lu-MCP-AuNP and normal tissue uptake was determined. ICP-AES was used to quantify Au in the liver and spleen and these were compared to (177)Lu. Our results showed that PEG-pGlu(DOTA)8-LA4-AuNP were more stable to aggregation in vitro than DOTA-PEG-LA-AuNP and both forms of AuNP were more stable to thiol challenge than DOTA-PEG-OPSS-AuNP. PEG-pGlu((177)Lu-DOTA)8-LA4 was the most stable in plasma. Whole body elimination of (177)Lu was most rapid for mice injected with (177)Lu-DOTA-PEG-OPSS-AuNP. Urinary excretion accounted for >90% of eliminated (177)Lu. All (177)Lu-MCP-AuNP accumulated in the liver and spleen. Liver uptake was lowest for PEG-pGlu((177)Lu-DOTA)8-LA4-AuNP but these AuNP exhibited the greatest spleen uptake. There were differences in Au and (177)Lu in the liver for PEG-pGlu((177)Lu-DOTA)8-LA4-AuNP. These differences were not correlated with in vitro stability of the (177)Lu-MCP-AuNP. We conclude that conjugation of AuNP with PEG-pGlu((177)Lu-DOTA)8-LA4 via a multithiol functional group provided the greatest stability in vitro and lowest liver uptake in vivo and is, therefore, the most promising for constructing (177)Lu-MCP-AuNP for radiation treatment of breast cancer.

²¹³Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience.

PURPOSE: Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as (90)Y/(177)Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with (213)Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. METHODS: Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with (90)Y/(177)Lu-DOTATOC were treated with an intraarterial infusion of (213)Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of (213)Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and (68)Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. RESULTS: The biodistribution of (213)Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. CONCLUSION: TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses.

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.

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.

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.

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.

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.

Target engagement of an anti-MT1-MMP antibody for triple-negative breast cancer PET imaging and beta therapy.

PURPOSE: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks effective diagnostic and therapeutic options. Membrane type 1 matrix metalloproteinase (MT1-MMP) is an attractive biomarker for improving patient selection. This study aimed to develop a theranostic tool using a highly tumour-selective anti-MT1-MMP antibody (LEM2/15) radiolabelled with 89Zr for PET and 177Lu for therapy in a TNBC murine model. METHODS: The LEM2/15 antibody and IgG isotype control were radiolabelled with 89Zr. PET imaging was performed in a TNBC orthotopic mouse model at 1, 2, 4, and 7 days after administration. Tissue biodistribution and pharmacokinetic parameters were analysed and Patlak linearisation was used to calculate the influx rate of irreversible uptake. The TNBC mice were treated with [177Lu]Lu-DOTA-LEM2/15 (single- or 3-dose regimen) or saline. Efficacy of [177Lu]Lu-DOTA-LEM2/15 was evaluated as tumour growth and DNA damage (γH2AX) in MDA 231-BrM2-831 tumours. RESULTS: At 7 days post-injection, PET uptake in tumour xenografts revealed a 1.6-fold and 2.4-fold higher tumour-to-blood ratio for [89Zr]Zr-Df-LEM2/15 in the non-blocked group compared to the blocked and IgG isotype control groups, respectively. Specific uptake of LEM2/15 in TBNC tumours mediated by MT1-MMP-binding was demonstrated by the Patlak linearisation method, providing insights into the potential efficacy of LEM2/15-based treatments. A similar uptake was found for [89Zr]Zr-Df-LEM2/15 and [177Lu]Lu-DOTA-LEM2/15 in tumours 7 days post-injection (6.80 ± 1.31 vs. 5.61 ± 0.66 %ID/g). Tumour doubling time was longer in the [177Lu]Lu-DOTA-LEM2/15 3-dose regimen treated group compared to the control (50 vs. 17 days, respectively). The percentage of cells with γH2AX-foci was higher in tumours treated with [177Lu]Lu-DOTA-LEM2/15 3-dose regimen compared to tumours non-treated or treated with [177Lu]Lu-DOTA-LEM2/15 single-dose (12 % vs. 4-5 %). CONCLUSIONS: The results showed that the 89Zr/177Lu-labelled anti-MT1-MMP mAb (LEM2/15) pair facilitated immune-PET imaging and reduced tumour growth in a preclinical TNBC xenograft model.

Beta radiation for glaucoma surgery.

BACKGROUND: The outcome of glaucoma surgery can be affected by the rate at which the surgical wound heals. Beta radiation has been proposed as a rapid and simple treatment to slow down the healing response. OBJECTIVES: To assess the effectiveness of beta radiation during glaucoma surgery (trabeculectomy). SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 3), MEDLINE (January 1950 to March 2012), EMBASE (January 1980 to March 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 26 March 2012. SELECTION CRITERIA: We included randomised controlled trials comparing trabeculectomy with beta radiation to trabeculectomy without beta radiation. DATA COLLECTION AND ANALYSIS: We collected data on surgical failure (intraocular pressure > 21 mmHg), intraocular pressure and adverse effects of glaucoma surgery. We pooled data using a fixed-effect model. MAIN RESULTS: We found four trials that randomised 551 people to trabeculectomy with beta irradiation versus trabeculectomy alone. Two trials were in Caucasian people (126 people), one trial in black African people (320 people) and one trial in Chinese people (105 people). People who had trabeculectomy with beta irradiation had a lower risk of surgical failure compared to people who had trabeculectomy alone (pooled risk ratio (RR) 0.23 (95% CI 0.14 to 0.40). Beta irradiation was associated with an increased risk of cataract (RR 2.89, 95% CI 1.39 to 6.0). AUTHORS' CONCLUSIONS: Trabeculectomy with beta irradiation has a lower risk of surgical failure compared to trabeculectomy alone. A trial of beta irradiation versus anti-metabolite is warranted.

Changes in nitric oxide and superoxide levels in human endotheliocytes and carcinoma cells after exposure to low-dose ionizing radiation.

The exposure of HeLa G63 and ECV-304 cells to γ-rays of (137)Cs as well as ß-particles of (3)H(2)O and (3)H-thymidine induced changes in redox status of not only irradiated cells, but also their progeny. Increased intracellular levels of nitric oxide (NO) were observed only in HeLa G63 cells and persisted over three cell generations; ß-particles from (3)H(2)O were most efficient. Intracellular superoxide (O(2)(-)) level had similar dynamics in both cell lines. Intracellular O(2)(-) level decreased immediately after irradiation, but then increased and significantly surpassed the control level. These changes in the intracellular level of O(2)(-) were accompanied by decondensation of nuclear chromatin. Increased level of free radicals in the progeny of irradiated cells and changes in chromatin conformation and the absence of correlation between radiation-induced structural damage to chromosomes and intracellular level of free radicals suggest participation of epigenetic mechanisms of inheritance.

Evolution of treatment options for patients with CRPC and bone metastases: bone-targeted agents that go beyond palliation of symptoms to improve overall survival.

Metastasis to bone represents an all-too-frequent complication of advanced-stage prostate cancer (PCa): 50% to 70% of these patients will ultimately develop this devastating complication. PCa preferentially metastasizes to bone, and the skeletal complications increase mortality and decrease quality of life. The clinical consequences of skeletal metastasis also include pain, skeletal-related events (SREs), and increased costs of therapy. Recent advances in our understanding of the mechanisms of metastasis and the physiologic changes that occur with it, together with the introduction of new treatments, are furthering our ability to combat this problem. In this review, we examine bone-targeted palliative agents, nontargeted systemic cytotoxic therapies, and bone-targeted agents that go beyond palliation to also potentially improve progression-free and overall survival. We specifically focus on post-treatment outcomes--including pain relief, decreased opioid use, improvement in quality of life, freedom from SREs or new bony metastases, and increases in overall survival--in men with symptomatic, metastatic PCa. Treatments discussed include varied drug classes, such as bisphosphonates and human monoclonal antibodies; beta-emitting radiopharmaceuticals; external beam radiotherapy; systemic chemotherapies; Src inhibitors; endothelin-A receptor antagonists; clusterin inhibitors; and alpha-emitting radiopharmaceuticals.

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.