Random Forest for Predicting Treatment Response to Radioiodine and Thyrotropin Suppression Therapy in Patients With Differentiated Thyroid Cancer But Without Structural Disease.

BACKGROUND: We aimed to develop a machine-learning model for predicting treatment response to radioiodine (131I) therapy and thyrotropin (TSH) suppression therapy in patients with differentiated thyroid cancer (DTC) but without structural disease, based on pre-treatment information. PATIENTS AND METHODS: Overall, 597 and 326 patients with DTC but without structural disease were randomly assigned to "training" cohorts for predicting treatment response to 131I therapy and TSH suppression therapy, respectively. Six supervised algorithms, including Logistic Regression, Support Vector Machine, Random Forest (RF), Neural Networks, Adaptive Boosting, and Gradient Boost, were used to predict effective response (ER) to 131I therapy and biochemical remission (BR) to TSH suppression therapy. RESULTS: Stimulated and suppressed thyroglobulin (Tg) and radioiodine uptake before the current course of 131I therapy were mostly attributed to ER to 131I therapy, while thyroid remnant available on the post-therapeutic whole-body scan at the last course of 131I therapy and TSH were greatly contributed to Tg decline under TSH suppression therapy. RF showed the best performance among all models. The accuracy and area under the receiver operating characteristic curve (AUC) for segregating ER from non-ER during 131I therapy with RF were 81.3% and 0.896, respectively. The accuracy and AUC for predicting BR to TSH suppression therapy with RF were 78.7% and 0.857, respectively. CONCLUSION: This study demonstrates that machine learning models, especially the RF algorithm are useful tools that may predict treatment response to 131I therapy and TSH suppression therapy in DTC patients without structural disease based on pre-treatment routine clinical variables and biochemical markers.

Early and long-term responses of intestinal microbiota and metabolites to 131I treatment in differentiated thyroid cancer patients.

BACKGROUND: Multiple high doses of 131I therapy in patients with differentiated thyroid cancer (DTC) might disrupt the balance of gut microbiota and metabolites. This study aimed to investigate the alterations of intestinal bacteria and metabolism over two courses of 131I therapy, explore the interactions, and construct diagnostic models reflecting enteric microecology based on 131I therapy. METHODS: A total of 81 patients were recruited for the first 131I therapy (131I-1st), among whom 16 received a second course (131I-2nd) after half a year. Fecal samples were collected 1 day before (Pre-131I-1st/2nd) and 3 days after (Post-131I-1st/2nd) 131I therapy for microbiome (16S rRNA gene sequencing) and metabolomic (LC-MS/MS) analyses. RESULTS: A total of six microbial genera and 11 fecal metabolites enriched in three pathways were identified to show significant differences between Pre-131I-1st and other groups throughout the two courses of 131I treatment. In the Post-131I-1st group, the beneficial bacteria Bifidobacterium, Lachnoclostridium, uncultured_bacterium_f_Lachnospiraceae, and Lachnospiraceae_UCG004 were abundant and the radiation-sensitive pathways of linoleic acid (LA), arachidonic acid, and tryptophan metabolism were inhibited compared with the Pre-131I-1st group. Compared with the Pre-131I-1st group, the Pre-131I-2nd group exhibited a reduced diversity of flora and differentially expressed metabolites, with a low abundance of beneficial bacteria and dysregulated radiation-sensitive pathways. However, less significant differences in microbiota and metabolites were found between the Pre/Post-131I-2nd groups compared with those between the Pre/Post-131I-1st groups. A complex co-occurrence was observed between 6 genera and 11 metabolites, with Lachnoclostridium, Lachnospiraceae_UCG004, Escherichia-Shigella, and LA-related metabolites contributing the most. Furthermore, combined diagnostic models of charactered bacteria and metabolites answered well in the early, long-term, and dose-dependent responses for 131I therapy. CONCLUSIONS: Different stages of 131I therapy exert various effects on gut microecology, which play an essential role in regulating radiotoxicity and predicting the therapeutic response.

Disrupted gut microecology after high-dose 131I therapy and radioprotective effects of arachidonic acid supplementation.

BACKGROUND: Despite the potential radiotoxicity in differentiated thyroid cancer (DTC) patients with high-dose 131I therapy, the alterations and regulatory mechanisms dependent on intestinal microecology remain poorly understood. We aimed to identify the characteristics of the gut microbiota and metabolites in DTC patients suffering from high-dose 131I therapy and explore the radioprotective mechanisms underlying arachidonic acid (ARA) treatment. METHODS: A total of 102 patients with DTC were recruited, with fecal samples collected before and after 131I therapy for microbiome and untargeted and targeted metabolomic analyses. Mice were exposed to total body irradiation with ARA replenishment and antibiotic pretreatment and were subjected to metagenomic, metabolomic, and proteomic analyses. RESULTS: 131I therapy significantly changed the structure of gut microbiota and metabolite composition in patients with DTC. Lachnospiraceae were the most dominant bacteria after 131I treatment, and metabolites with decreased levels and pathways related to ARA and linoleic acid were observed. In an irradiation mouse model, ARA supplementation not only improved quality of life and recovered hematopoietic and gastrointestinal systems but also ameliorated oxidative stress and inflammation and preserved enteric microecology composition. Additionally, antibiotic intervention eliminated the radioprotective effects of ARA. Proteomic analysis and ursolic acid pretreatment showed that ARA therapy greatly influenced intestinal lipid metabolism in mice subjected to irradiation by upregulating the expression of hydroxy-3-methylglutaryl-coenzyme A synthase 1. CONCLUSION: These findings highlight that ARA, as a key metabolite, substantially contributes to radioprotection. Our study provides novel insights into the pivotal role that the microbiota-metabolite axis plays in radionuclide protection and offers effective biological targets for treating radiation-induced adverse effects.

Synthesis, Screening, and Evaluation of Theranostic Molecular CPCR4-Based Probe Targeting CXCR4.

Chemokines and chemokine receptors are indispensable to play a key role in the development of malignant tumors. As one of the most widely expressed chemokine receptors, chemokine (C-X-C motif) receptor 4 (CXCR4) has been a popular research focus. In most tumors, CXCR4 expression is significantly upregulated. Moreover, integrated nuclide diagnosis and therapy targeting CXCR4 show great potential. [68Ga]Ga-pentixafor, a radioligand targeting CXCR4, exhibits a strong affinity for CXCR4 both in vivo and in vitro. However, [177Lu]Lu-pentixather, the therapeutic companion of [68Ga]Ga-pentixafor, requires significant refinement to mitigate its pronounced hepatic biodistribution. The objective of this study was to synthesize theranostic molecular tracers with superior CXCR4 targeting functions. The Daudi cell line, which highly expressed CXCR4, and the MM.1S cell line, which weakly expressed CXCR4, were used in this study. Based on the pharmacophore cyclo (-d-Tyr-n-me-d-Orn-l-Arg-L-2-NAL-Gly-) (CPCR4) of pentixafor, six tracers were synthesized: [124I]I-1 ([124I]I-CPCR4), [99mTc]Tc-2 ([99mTc]Tc-HYNIC-CPCR4), [124I]I-3 ([124I]I-pentixafor), [18F]AlF-4 ([18F]AlF-NETA-CPCR4), [99mTc]Tc-5 ([99mTc]Tc-MAG3-CPCR4) and [124I]I-6 ([124I]I-pentixafor-Ga) and their radiochemical purities were all higher than 95%. After positron emission tomography (PET)/single-photon emission computed tomography (SPECT) imaging, the [124I]I-6 group exhibited the best target-nontarget ratio. At the same time, comparing the [68Ga]Ga-pentixafor group with the [124I]I-6 group, we found that the [124I]I-6 group had a better target-nontarget ratio and lower uptake in nontarget organs. Therefore, compound 6 was selected for therapeutic radionuclide (131I) labeling, and the tumor-bearing animal models were treated with [131I]I-6. The volume of the tumor site was significantly reduced in the treatment group compared with the control group, and no significant side effects were found. [124I]I-6 and [131I]I-6 showed excellent affinity for targeting CXCR4, and they showed great potential for the integrated diagnosis and treatment of tumors with high CXCR4 expression.

Reaching the target dose with one single 131 I-mIBG administration in high-risk neuroblastoma: The determinant impact of the primary tumour.

BACKGROUND: 131 I-metaiodobenzylguanidine (131 I-mIBG) effectiveness in children with metastasised neuroblastoma (NB) is linked to the effective dose absorbed by the target; a target of 4 Gy whole-body dose threshold has been proposed. Achieving this dose often requires administering 131 I-mIBG twice back-to-back, which may cause haematological toxicity. In this study, we tried identifying the factors predicting the achievement of 4 Gy whole-body dose with a single radiopharmaceutical administration. MATERIALS AND METHODS: Children affected by metastatic NB and treated with a high 131 I-mIBG activity (>450 MBq (megabecquerel)/kg) were evaluated retrospectively. Kinetics measurements were carried out at multiple time points to estimate the whole-body dose, which was compared with clinical and activity-related parameters. RESULTS: Seventeen children (12 females, median age 3 years, age range: 1.5-6.9 years) were included. Eleven of them still bore the primary tumour. The median whole-body dose was 2.88 Gy (range: 1.63-4.22 Gy). Children with a 'bulky' primary (>30 mL) received a higher whole-body dose than those with smaller or surgically removed primaries (3.42 ± 0.74 vs. 2.48 ± 0.65 Gy, respectively, p = .016). Conversely, the correlation between activity/kg and the whole-body dose was moderate (R: 0.42, p = .093). In the multivariate analysis, the volume of the primary tumour was the most relevant predictor of the whole-body dose (p = .002). CONCLUSIONS: These data suggest that the presence of a bulky primary tumour can significantly prolong the 131 I-mIBG biological half-life, effectively increasing the absorbed whole-body dose. This information could be used to model the administered activity, allowing to attain the target dose without needing a two-step radiopharmaceutical administration.

Norepinephrine transporter and vesicular monoamine transporter 2 tumor expression as a predictor of response to 131 I-MIBG in patients with relapsed/refractory neuroblastoma.

BACKGROUND: Prior studies suggest that norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) mediate meta-iodobenzylguanidine (MIBG) uptake and retention in neuroblastoma tumors. We evaluated the relationship between NET and VMAT2 tumor expression and clinical response to 131 I-MIBG therapy in patients with neuroblastoma. METHODS: Immunohistochemistry (IHC) was used to evaluate NET and VMAT2 protein expression levels on archival tumor samples (obtained at diagnosis or relapse) from patients with relapsed or refractory neuroblastoma treated with 131 I-MIBG. A composite protein expression H-score was determined by multiplying a semi-quantitative intensity value (0-3+) by the percentage of tumor cells expressing the protein. RESULTS: Tumor samples and clinical data were available for 106 patients, of whom 28.3% had partial response (PR) or higher. NET H-score was not significantly associated with response (≥PR), though the percentage of tumor cells expressing NET was lower among responders (median 80% for ≥PR vs. 90% for

Thyroid ultrasound findings in young and middle-aged adults living in the region of the Chornobyl Nuclear Power Plant.

Nearly forty years have passed since the Chornobyl Nuclear Power Plant accident, which resulted in childhood and adolescent thyroid cancers increasing due to internal exposure to iodine-131. Therefore, the Fukushima Daiichi Nuclear Power Station accident, in 2011, raised serious anxiety about potential risks of thyroid cancers. Considering the causal relationship between thyroid cancer and the Chornobyl accident, radiation dose to the thyroid due to this accident should be considered carefully. In addition, a thorough investigation of any influence of ultrasound screening of the thyroid on the detection of thyroid diseases was still missing. Consequently, from 2019 to 2021, the frequency of abnormal thyroid findings from screening of residents in Zhytomyr, Ukraine, which was heavily contaminated by the accident, was evaluated in this study. For this, the same diagnostic classification of any thyroid ultrasound findings as those of the Fukushima Health Management Survey were used. This classification used the categories "A1" (no findings), "A2" (thyroid cysts less than 20 mm and/or thyroid nodules less than 5 mm), and "B" (thyroid cysts more than 20 mm and/or thyroid nodules more than 5 mm). 2,978 participants were analyzed. It was found that the frequency of "B" findings increased with age. This may be due to the observed increased incidence of not only malignant but also benign thyroid nodules. It may well be that such an increase will also be observed in Fukushima in the future. It is concluded that future thyroid examiners in Fukushima should be aware of findings specific to adults, such as chronic thyroiditis. For comparison, it will be necessary to perform longitudinal studies in the Japanese population not exposed to radiation from the Fukushima accident.

Atorvastatin-loaded cubosome: a repurposed targeted delivery systems for enhanced targeting against breast cancer.

Cancer ranks as one of the most challenging illnesses to deal with because progressive phenotypic and genotypic alterations in cancer cells result in resistance and recurrence. Thus, the creation of novel medications or alternative therapy approaches is mandatory. Repurposing of old drugs is an attractive approach over the traditional drug discovery process in terms of shorter drug development duration, low-cost, highly efficient and minimum risk of failure. In this study Atorvastatin, a statin drug used to treat abnormal cholesterol levels and prevent cardiovascular disease in people at high risk, was introduced and encapsulated in cubic liquid crystals as anticancer candidate aiming at sustaining its release and achieving better cellular uptake in cancer cells. The cubic liquid crystals were successfully prepared and optimized with an entrapment effieciency of 73.57% ±1.35 and particle size around 200 nm. The selected formulae were effectively doped with radioactive iodine 131I to enable the noninvasive visualization and trafficking of the new formulae. The in vivo evaluation in solid tumor bearing mice was conducted for comparing131I-Atorvastatin solution,131I-Atorvastatin loaded cubosome and 131I-Atorvastatin chitosan coated cubosome. The in vivo biodistribution study revealed that tumor radioactivity uptake of 131I-Atorvastatin cubosome and chitosan coated cubosome exhibited high accumulation in tumor tissues (target organ) scoring ID%/g of 5.67 ± 0.2 and 5.03 ± 0.1, respectively 1h post injection compared to drug solution which recorded 3.09 ± 0.05% 1h post injection. Concerning the targeting efficiency, the target/non target ratio for 131I-Atorvastatin chitosan coated cubosome was higher than that of 131I-Atorvastatin solution and 131I ATV-loaded cubosome at all time intervals and recorded T/NT ratio of 2.908 2h post injection.

Gut microbiota is associated with response to 131I therapy in patients with papillary thyroid carcinoma.

PURPOSE: Radioactive iodine (131I) therapy is a conventional post-surgery treatment widely used for papillary thyroid carcinoma (PTC). Since 131I is orally administered, we hypothesize that it may affect gut microbiome. This study aims to investigate alterations of intestinal microbiome caused by 131I therapy in PTC patients and explore its association with response to 131I therapy. METHODS: Fecal samples of 60 PTC patients pre- and post-131I therapy were collected to characterize the 131I therapy-induced gut microbiota alterations using 16S rRNA gene sequencing. According to the inclusion criteria, sequence data of 40 out of the 60 patients, divided into excellent response (ER) group and non-excellent response (NER) group, were recruited to investigate the possible connection between gut microbiota and response to 131I therapy. Multivariate binary logistic regression was employed to construct a predictive model for response to 131I therapy. RESULTS: Microbial richness, diversity, and composition were tremendously altered by 131I therapy. A significant decline of Firmicutes to Bacteroides (F/B) ratio was observed post-131I therapy. 131I therapy also led to changes of gut microbiome-related metabolic pathways. Discrepancies in ß diversity were found between ER and NER groups both pre- and post-131I therapy. Furthermore, a predictive model for response to 131I therapy with a p value of 0.003 and an overall percentage correct of 80.0% was established, with three variables including lymph node metastasis, relative abundance of g_Bifidobacterium and g_Dorea. Among them, g_Dorea was identified to be an in independent predictor of response to 131I therapy (p = 0.04). CONCLUSION: For the first time, the present study demonstrates the gut microbial dysbiosis caused by 131I therapy in post-surgery PTC patients and reveals a previously undefined role of gut microbiome as predictor for 131I ablation response. G_Dorea and g_Bifidobacterium may be potential targets for clinical intervention to improve response to 131I in post-operative PTC patients. TRIAL REGISTRATION: ChiCTR2100048000. Registered 28 June 2021.

Phase II study of 131 I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP.

PURPOSE: We report the results of the French multicentric phase II study MIITOP (NCT00960739), which evaluated tandem infusions of 131 I-metaiodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory metastatic neuroblastoma (NBL). METHODS: Patients received 131 I-mIBG on day 1, with intravenous topotecan daily on days 1-5. A second activity of 131 I-mIBG was given on day 21 to deliver a whole-body radiation dose of 4 Gy, combined with a second course of topotecan on days 21-25. Peripheral blood stem cells were infused on day 31. RESULTS: Thirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2-20). Twenty-one had very high-risk NBL (VHR-NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1-26). Median number of prior lines of treatment was 3 (1-7). Objective response rate was 13% (95% confidence interval [CI]: 4-31) for the whole population, 19% for VHR-NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade-2 nausea/vomiting in eight patients. Two-year event-free survival was 17% (95% CI: 6-32). Among the 16 patients with VHR-NBL who had not received prior myeloablative busulfan-melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan-melphalan; four of them were alive (median follow-up: 7 years). CONCLUSION: MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan.

Recall of residential history and dietary habits during pregnancy and lactation in the distant past: reliability of questionnaire-based radiation doses for persons exposed in utero and early life.

This study evaluates the reliability of information obtained by standardized questionnaires used in by personal interviews for estimation of radiation thyroid doses of 1065 individuals in the Belarusian cohort of individuals who were exposed in utero and early life following the Chernobyl accident in April 1986. Data from two interviews conducted in 2012-2017 and in 2018-2022 with mothers, who were pregnant or gave birth shortly after the Chernobyl accident, were analysed. The most reliable answers dealt with various attributes related to residential history. In contrast, the reliability of answers regarding consumption rates of milk from privately owned cows or trade network was moderate, while the agreement in responses for consumption of milk products and leafy vegetables was fair. Information from the two interviews was used to calculate thyroid doses received by the cohort members. Specifically, 'model-based' thyroid doses due to 131I were estimated using input data on individual residential history and food consumption reported during the personal interviews and ecological data (131I ground deposition in the corresponding settlements). In addition, for a subset of cohort subjects (n = 205) whose mothers were measured for 131I thyroid activity, 'measurement-based' thyroid doses were calculated by adjusting the model-based dose using a scaling factor that is defined as the ratio of measured 131I thyroid activity to model-based 131I thyroid activity calculated for the date of measurement. A moderate agreement was observed for total (prenatal and postnatal) model-based thyroid doses due to 131I intake, the arithmetic mean ± standard deviation for the Jaccard similarity coefficient ([Formula: see text]) was 0.45 ± 0.34 (median = 0.39), while measurement-based doses showed a much better agreement with a [Formula: see text] of 0.78 ± 0.29 (median = 0.93). For model-based thyroid doses from external irradiation and from ingestion of 134Cs and 137Cs, [Formula: see text] was 0.82 ± 0.23 (median = 0.90) and 0.84 ± 0.24 (median = 0.96), respectively. Measurement-based doses due to ingestion of radiocaesium isotopes resulted in an almost perfect agreement, [Formula: see text] was 0.91 ± 0.19 (median = 1.0). The present findings suggest that long-term memory recall can be reliable, if a person is asked about unique or important life events, such as pregnancy and childbirth occurring around the time of a nuclear reactor accident. However, the substantial difference (more than 10 times) observed for model-bases doses calculated using the two questionnaires represents an important source of human factor uncertainties that needs to be considered in any dose response analyses. Other lessons learned from this study are that (i) individual measurements of radionuclides in the human body are the most valuable source of information for estimating radiation doses, and (ii) whenever a radiation accident occurs, a sample of affected people should be asked to keep a diary, if at all possible.

Radiosynthesis, Stability, Lipophilicity, and Cellular Uptake Evaluations of [131I]Iodine-α-Mangostin for Breast Cancer Diagnosis and Therapy.

The high rate of incidence and mortality caused by breast cancer encourage urgent research to immediately develop new diagnostic and therapeutic agents for breast cancer. Alpha mangostin (AM) is a natural compound reported to have anti-breast cancer properties. Its electron-donating groups structure allows it to be labeled with an iodine-131 radioisotope to develop a candidate of a diagnostic and therapeutic agent for breast cancer. This study aims to prepare the [131I]Iodine-α-mangostin ([131I]I-AM) and evaluate its stability, lipophilicity, and cellular uptake in breast cancer cell lines. The [131I]I-AM was prepared by direct radiosynthesis with Chloramine-T method in two conditions (A: AM dissolved in NaOH, B: AM dissolved in ethanol). Reaction time, pH, and mass of the oxidizing agent were optimized as crucial parameters that affected the radiosynthesis reaction. Further analysis was conducted using the radiosynthesis conditions with the highest radiochemical purity (RCP). Stability tests were carried out at three storage conditions, including -20, 2, and 25 °C. A cellular uptake study was performed in T47D (breast cancer cell line) and Vero cells (noncancerous cell line) at various incubation times. The results show that the RCP values of [131I]I-AM under conditions A and B were 90.63 ± 0.44 and 95.17 ± 0.80% (n = 3), respectively. In the stability test, [131I]I-AM has an RCP above 90% after three days of storage at -20 °C. A significant difference was obtained between [131I]I-AM uptake in T47D and Vero cells. Based on these results, [131I]I-AM has been prepared with high RCP, stable at -20 °C, and specifically uptaken by breast cancer cell lines. Biodistribution evaluations in animals are recommended as further research in developing [131I]I-AM as a diagnostic and therapeutic agent for breast cancer.

131I dose coefficients for a reference population using age-specific models.

Age-specific dose coefficients are required to assess internal exposure to the general public. This study utilizes reference age-specific biokinetic models of iodine to estimate the total number of nuclear disintegrations ã(rS,τ) occurring in source regions (rS) during the commitment time (τ). Age-specific S values are estimated for 35 target regions due to131I present in 22rSusing data from 10 paediatric reference computational phantoms (representing five ages for both sexes) published recently by the International Commission of Radiation Protection (ICRP). Monte Carlo transport simulations are performed in FLUKA code. The estimated ã(rS,τ) and S values are then used to compute the committed tissue equivalent dose HT(τ) for 27 radiosensitive tissues and dose coefficients e(τ) for all five ages due to inhalation and ingestion of131I. The derived ã(rS,τ) values in the thyroid source are observed to increase with age due to the increased retention of iodine in the thyroid. S values are found to decrease with age, mainly due to an increase in target masses. Generally, HT(τ) values are observed to decrease with age, indicating the predominant behaviour of S values over ã(rS,τ). On average, ingestion dose coefficients are 63% higher than for inhalation in all ages. The maximum contribution to dose coefficients is from the thyroid, accounting for 96% in the case of newborns and 98%-99% for all other ages. Furthermore, the estimated e(τ) values for the reference population are observed to be lower than previously published reference values from the ICRP. The estimated S, HT(τ) and e(τ) values can be used to improve estimations of internal doses to organs/whole body for members of the public in cases of131I exposure. The estimated dose coefficients can also be interpolated for other ages to accurately evaluate the doses received by the general public during131I therapy or during a radiological emergency.

Radiological study of a wastewater treatment plant associated with radioiodine therapy at a hospital in West Java, Indonesia.

Nuclear medicine (NM) services in Indonesia have rapidly developed due to the increasing number of patients, and this growth has been supported by standardized regulations in the field, including the management of solid waste generated. However, multiple reports indicate that licensing control does not regulate liquid waste disposal from patient excretions to protect personnel and the community from radiopharmaceutical exposure. One of the radiopharmaceuticals commonly used in NM and having the longest half-life among the radiopharmaceuticals used in NM is iodine 131(I-131). Thus, this study used a high-purity germanium detector to measure iodine-131 (I-131) activity in liquid waste from decay tanks, temporary collection channels, the hospital's wastewater treatment plant (WWTP) outlet, and six points around the NM service and liquid waste treatment unit. Concentration measurements in three decay tanks were carried out sequentially every 12 h for 3 d, corresponding to the therapy period. The results showed that the I-131 activity levels in the decay tanks and temporary collection channels, before being mixed with liquid waste from other units, were 95.9 × 106± 4.4 × 106Bq m-3.At the point where the liquid waste from other units was mixed, the activity level decreased significantly to 472 680 ± 22 160 Bq m-3, which was below the clearance level of 107Bq m-3. However, the recorded concentration exceeded the standard for environmental radioactivity at the hospital's WWTP outlet, namely 37 670 ± 2040 Bq m-3. The measurement results for I-131 in the air in the open space for two nuclear buildings was above the standard at 1.3 ± 0.27 Bq m-3. According to the RESRAD simulation, based on the initial dose taken from the liquid waste treatment outlet point, the accumulation of doses and the risk of cancer among workers and the community decreased within 3 months after the maximum exposure.

Phase I/II clinical trial of high-dose [131I] meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding single myeloablative chemotherapy and haematopoietic stem cell transplantation.

PURPOSE: Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of high-dose 131I-meta-iodobenzylguanidine (131I-mIBG) therapy combined with single high-dose chemotherapy (HDC) and haematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma in Japan. METHODS: Patients received 666 MBq/kg of 131I-mIBG and single HDC and HSCT from autologous or allogeneic stem cell sources. The primary endpoint was DLT defined as adverse events associated with 131I-mIBG treatment posing a significant obstacle to subsequent HDC. The secondary endpoints were adverse events/reactions, haematopoietic stem cell engraftment and responses according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and 123I-mIBG scintigraphy. Response was evaluated after engraftment. RESULTS: We enrolled eight patients with high-risk neuroblastoma (six females; six newly diagnosed and two relapsed high-risk neuroblastoma; median age, 4 years; range, 1-10 years). Although all patients had adverse events/reactions after high-dose 131I-mIBG therapy, we found no DLT. Adverse events and reactions were observed in 100% and 25% patients during single HDC and 100% and 12.5% patients during HSCT, respectively. No Grade 4 complications except myelosuppression occurred during single HDC and HSCT. The response rate according to RECIST 1.1 was observed in 87.5% (7/8) in stable disease and 12.5% (1/8) were not evaluated. Scintigraphic response occurred in 62.5% (5/8) and 37.5% (3/8) patients in complete response and stable disease, respectively. CONCLUSION: 131I-mIBG therapy with 666 MBq/kg followed by single HDC and autologous or allogeneic SCT is safe and efficacious in patients with high-risk neuroblastoma and has no DLT. TRIAL REGISTRATION NUMBER: jRCTs041180030. NAME OF REGISTRY: Feasibility of high-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and haematopoietic stem cell transplantation (High-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma). URL OF REGISTRY: https://jrct.niph.go.jp/en-latest-detail/jRCTs041180030 . DATE OF ENROLMENT OF THE FIRST PARTICIPANT TO THE TRIAL: 12/01/2018.

Phase I study of [131I] ICF01012, a targeted radionuclide therapy, in metastatic melanoma: MELRIV-1 protocol.

BACKGROUND: Benzamide-based radioligands targeting melanin were first developed for imaging melanoma and then for therapeutic purpose with targeted radionuclide therapy (TRT). [131I]ICF01012 presents a highly favorable pharmacokinetics profile in vivo for therapy. Tumour growth reduction and increase survival have been established in preclinical models of melanoma. According the these preclinical results, we initiate a first-in-human study aimed to determine the recommended dose of [131I]ICF01012 to administer for the treatment of patients with pigmented metastatic melanoma. METHODS: The MELRIV-1 trial is an open-label, multicentric, dose-escalation phase I trial. The study is divided in 2 steps, a selection part with an IV injection of low activity of [131I]ICF01012 (185 MBq at D0) to select patients who might benefit from [131I]ICF01012 TRT in therapeutic part, i.e. patient presenting at least one tumour lesion with [131I]ICF01012 uptake and an acceptable personalized dosimetry to critical organs (liver, kidney, lung and retina). According to dose escalation scheme driven by a Continual Reassessment Method (CRM) design, a single therapeutic injection of 800 MBq/m2, or 1600 MBq/m2, or 2700 MBq/m2 or 4000 MBq/m2 of [131I]ICF01012 will be administered at D11 (± 4 days). The primary endpoint is the recommended therapeutic dose of [131I]ICF01012, with DLT defined as any grade 3-4 NCI-CT toxicity during the 6 weeks following therapeutic dose. Safety, pharmacokinetic, biodistribution (using planar whole body and SPECT-CT acquisitions), sensitivity / specificity of [131I]ICF01012, and therapeutic efficacy will be assessed as secondary objectives. Patients who received therapeutic injection will be followed until 3 months after TRT. Since 6 to 18 patients are needed for the therapeutic part, up to 36 patients will be enrolled in the selection part. DISCUSSION: This study is a first-in-human trial evaluating the [131I]ICF01012 TRT in metastatic malignant melanomas with a diagnostic dose of the [131I]ICF01012 to select the patients who may benefit from a therapeutic dose of [131I]ICF01012, with at least one tumor lesion with [131I]ICF01012 uptake and an acceptable AD to healthy organ. TRIAL REGISTRATION: Clinicaltrials.gov : NCT03784625 . Registered on December 24, 2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2016-002444-17.

The efficacy and safety of Iodine-131-metaiodobenzylguanidine therapy in patients with neuroblastoma: a meta-analysis.

OBJECTIVE: Neuroblastoma is a common extracranial solid tumor of childhood. Recently, multiple treatments have been practiced including Iodine-131-metaiodobenzylguanidine radiation (131I-MIBG) therapy. However, the outcomes of efficacy and safety vary greatly among different studies. The aim of this meta-analysis is to evaluate the efficacy and safety of 131I-MIBG in the treatment of neuroblastoma and to provide evidence and hints for clinical decision-making. METHODS: Medline, EMBASE database and the Cochrane Library were searched for relevant studies. Eligible studies utilizing 131I-MIBG in the treatment of neuroblastoma were included. The pooled outcomes (response rates, adverse events rates, survival rates) were calculated using either a random-effects model or a fixed-effects model considering of the heterogeneity. RESULTS: A total of 26 clinical trials including 883 patients were analyzed. The pooled rates of objective response, stable disease, progressive disease, and minor response of 131I-MIBG monotherapy were 39%, 31%, 22% and 15%, respectively. The pooled objective response rate of 131I-MIBG in combination with other therapies was 28%. The pooled 1-year survival and 5-year survival rates were 64% and 32%. The pooled occurrence rates of thrombocytopenia and neutropenia in MIBG monotherapy studies were 53% and 58%. In the studies of 131I-MIBG combined with other therapies, the pooled occurrence rates of thrombocytopenia and neutropenia were 79% and 78%. CONCLUSION: 131I-MIBG treatment alone or in combination of other therapies is effective on clinical outcomes in the treatment of neuroblastoma, individualized 131I-MIBG is recommended on a clinical basis.

Age-specific calibration for in vivo monitoring of thyroid: is it necessary?

Usually, an age-specific calibration of detectors used for in vivo monitoring of 131I thyroid radioactivity is not performed in practice. This study aimed to investigate the reduction in uncertainty that one can expect if an age-specific calibration is performed. For this, voxel and stylized computational phantoms of the thyroid, corresponding to children at different age groups, were used to simulate the calibration process of 131I detectors used for thyroid monitoring. SCK•CEN physical phantoms were also used for this purpose. Both analytical and Monte Carlo methods (MCNPX version 2.6.0) were used to estimate the counting efficiencies of the considered detectors. The results show that the uncertainties in the assessment of thyroid activity at a distance of 20 cm would be reduced from a range of +8% to +30%, to a range from - 6% to +15% when age-specific calibration was performed. Using a calibration based on thyroids of adults would result in an overestimation of the thyroid activity for children by up to 30% at a detector-neck distance of about 20 cm; a larger overestimation may be expected at closer distances. It is concluded that age-specific calibration of in vivo monitoring systems for the thyroid is important and has to be taken into consideration to improve the reliability of thyroid dose assessment for children.

Effect to Therapy of Sodium-Iodine Symporter Expression by Alpha-Ray Therapeutic Agent via Sodium/Iodine Symporter.

This study confirmed the effect of sodium/iodine symporter (NIS) expression on existing drugs by in vitro and in vivo tests using cultured cell lines. The tumor growth inhibitory effect of sodium astatide ([211At]NaAt) was evaluated by in vitro and in vivo tests using human thyroid cancer cells (K1, K1/NIS and K1/NIS-DOX). NIS expression in cancer cells was controlled using the Tet-On system. [131I]NaI was used as control existing drug. From the results of the in vitro studies, the mechanism of [211At]NaAt uptake into thyroid cancer cells is mediated by NIS, analogous to [131I]NaI, and the cellular uptake rate correlates with the expression level of NIS. [211At]NaAt's ability to inhibit colony formation was more than 10 times that of [131I]NaI per becquerel (Bq), and [211At]NaAt's DNA double-strand breaking (DSB) induction was more than ten times that of [131I]NaI per Bq, and [211At]NaAt was more than three times more cytotoxic than [131I]NaI (at 1000 kBq each). In vivo studies also showed that the tumor growth inhibitory effect of [211At]NaAt depended on NIS expression and was more than six times that of [131I]NaI per Bq.

Comparison of the Therapeutic Effects of [211At]NaAt and [131I]NaI in an NIS-Expressing Thyroid Cancer Mouse Model.

Astatine (211At) is an alpha-emitter with a better treatment efficacy against differentiated thyroid cancer compared with iodine (131I), a conventional beta-emitter. However, its therapeutic comparison has not been fully evaluated. In this study, we compared the therapeutic effect between [211At]NaAt and [131I]NaI. In vitro analysis of a double-stranded DNA break (DSB) and colony formation assay were performed using K1-NIS cells. The therapeutic effect was compared using K1-NIS xenograft mice administered with [211At]NaAt (0.4 MBq (n = 7), 0.8 MBq (n = 9), and 1.2 MBq (n = 4)), and [131I]NaI (1 MBq (n = 4), 3 MBq (n = 4), and 8 MBq (n = 4)). The [211At]NaAt induced higher numbers of DSBs and had a more reduced colony formation than [131I]NaI. In K1-NIS mice, dose-dependent therapeutic effects were observed in both [211At]NaAt and [131I]NaI. In [211At]NaAt, a stronger tumour-growth suppression was observed, while tumour regrowth was not observed until 18, 25, and 46 days after injection of 0.4, 0.8, and 1.2 MBq of [211At]NaAt, respectively. While in [131I]NaI, this was observed within 12 days after injection (1, 3, and 8 MBq). The superior therapeutic effect of [211At]NaAt suggests the promising clinical applicability of targeted alpha therapy using [211At]NaAt in patients with differentiated thyroid cancer refractory to standard [131I]NaI treatment.