Radioiodine Research Articles

Inhibition of ALK-Signaling Overcomes STRN-ALK-Induced Downregulation of the Sodium Iodine Symporter and Restores Radioiodine Uptake in Thyroid Cells.

Background: Radioiodine (RAI) is commonly used for thyroid cancer treatment, although its therapeutic benefits are restricted to iodine-avid tumors. The RAI-refractory disease develops with tumor dedifferentiation involving loss of sodium-iodine symporter (NIS). Thyroid cancers driven by ALK fusions are prone to dedifferentiation, and whether targeted ALK inhibition may enhance RAI uptake in these tumors remains unknown. The aim of this study was to determine the levels of NIS expression during the progression of ALK fusion-driven thyroid cancer, assess the effects of ALK activation on NIS-mediated RAI uptake, and test pharmacological options for its modulation. Methods: The expression of NIS at different stages of ALK-driven carcinogenesis was analyzed using a mouse model of STRN-ALK-driven thyroid cancer. For in vitro experiments, a system of doxycycline-inducible expression of STRN-ALK was generated using PCCL3 normal thyroid cells. The STRN-ALK-induced effects were evaluated with quantitative reverse transcription polymerase chain reaction, Western blot, immunofluorescence, RNA sequencing, and gene sets pathways analyses. RAI uptake was measured using 131I. Treatment experiments were done with FDA-approved ALK inhibitors (crizotinib and ceritinib), MEK inhibitor selumetinib, and JAK1/2 inhibitor ruxolitinib. Results: We found that Nis downregulation occurred early in ALK-driven thyroid carcinogenesis, even at the stage of well-differentiated cancer, with a complete loss in poorly differentiated thyroid carcinomas. Acute STRN-ALK expression in thyroid cells resulted in increased MAPK, JAK/STAT3, and PI3K/AKT/mTOR signaling outputs associated with significant ALK-dependent downregulation of the majority of thyroid differentiation and iodine metabolism/transport genes, including Slc5a5 (Nis), Foxe1, Dio1, Duox1/2, Duoxa2, Glis3, Slc5a8, and Tg. Moreover, STRN-ALK expression in thyroid cells induced a significant loss of membranous NIS and a fourfold decrease of the NIS-mediated RAI uptake, which were reversed by ALK inhibitors crizotinib and ceritinib. In addition, a strong dose-dependent restoration of NIS with its membranous redistribution in STRN-ALK-expressing thyroid cells was observed after inhibition of MAPK signaling with selumetinib, which exhibited a cumulative effect with JAK1/2 inhibitor ruxolitinib. Conclusions: The findings of this preclinical study showed that ALK fusion-induced downregulation of NIS, the prerequisite of RAI refractoriness, could be reversed in thyroid cells by either direct inhibition of ALK or its downstream signaling pathways.

Genomic and Transcriptomic Characteristics of Metastatic Thyroid Cancers with Exceptional Responses to Radioactive Iodine Therapy.

The determinants of response or resistance to radioiodine (RAI) are unknown. We aimed to identify genomic and transcriptomic factors associated with structural responses to RAI treatment of metastatic thyroid cancer, which occur infrequently, and to test whether high MAPK pathway output was associated with RAI refractoriness. Exceptional response to RAI was defined as reduction of tumor volume based on RECIST v1.1. We performed a retrospective case-control study of genomic and transcriptomic characteristics of exceptional responders (ER; n = 8) versus nonresponders (NR; n = 16) matched by histologic type and stage at presentation on a 1:2 ratio. ER are enriched for mutations that activate MAPK through RAF dimerization (RAS, class 2 BRAF, RTK fusions), whereas NR are associated with BRAFV600E, which signals as a monomer and is unresponsive to negative feedback. ER have a lower MAPK transcriptional output and a higher thyroid differentiation score (TDS) than NR (P < 0.05). NR are enriched for 1q-gain (P < 0.05) and mutations of genes regulating mRNA splicing and the PI3K pathway. BRAFV600E tumors with 1q-gain have a lower TDS than BRAFV600E/1q-quiet tumors and transcriptomic signatures associated with metastatic propensity. ER tumors have a lower MAPK output and higher TDS than NR, whereas NR have a high frequency of BRAFV600E and 1q-gain. Molecular profiling of thyroid cancers and further functional validation of the key findings discriminating ER from NR may help predict response to RAI therapy.

Pros and cons of an aggressive initial treatment with surgery and radioiodine treatment in minimally invasive follicular thyroid carcinoma

BackgroundCurrently, surgery alone is the gold standard treatment for minimally invasive follicular thyroid cancer (mi-FTC).Case presentationA case of a mi-FTC diagnosed in 1994 was treated with total thyroidectomy and radioiodine (RAI) ablation, according to the therapeutic algorithm used at that time. Nevertheless, he had a recurrence with distant metastasis after 24 years from the initial treatment.ConclusionTotal thyroidectomy and RAI ablation might have delayed the development of distant metastasis but they were not sufficient to avoid disease recurrence. Certainly, remnant ablation simplified the follow-up and the monitoring of serum thyroglobulin allowed the early detection of the biochemical recurrence, but didn’t change the outcome of the disease. Moreover, because of this early detection the patient was exposed to useless biochemical and imaging examinations. The aim of this report is to discuss the pros and cons of an aggressive treatment of a patient with mi-FTC.

Early Dynamic Risk Stratification Decreases Rate of Ablative and Adjuvant Radioiodine Use in ATA Low and Intermediate Risk Papillary Thyroid Cancer Patients.

In differentiated thyroid cancer (DTC), radioiodine (RAI) therapy is most frequently employed for remnant ablation or as adjuvant therapy for the remaining disease. The application of RAI to patients classified as intermediate risk (InR) is still a matter of debate. The aim of this study is to analyze the effect of early postoperative risk assessment on RAI use on papillary thyroid cancer patients who are classified as low risk (LoR) or InR. This is a single-center, prospective registry study. One-hundred-eighty-six patients operated between January 2012 and August 2021 and categorized as LoR or InR were included in this study. All patients had total thyroidectomy and central lymph node dissection by the same endocrine surgeon. An early dynamic risk assessment (EDRA) consisting of neck ultrasonography, serum thyroglobulin (Tg) and anti-Tg levels was performed 6 weeks after surgery. Most of the patients were either followed up without RAI or received ablative low activity (30-50 mCi) RAI based on predetermined criteria. Median follow-up was 63 months. Sixty-six (61%) patients in the LoR group and 43 (56%) patients in the InR group did not receive RAI treatment. Thirty-eight (35%) and 22 (29%) patients in LoR and InR groups received ablative (30-50 mCi) RAI therapy, respectively. In LoR group 5 (4.6%) patients and in InR group 12 (16%) patients received 100 mCi or more RAI activity. Only one patient in the InR group recurred during follow-up. No statistically significant difference regarding local recurrence was found between patients who didn't receive RAI or were treated with RAI within both LoR (p=0.152) and InR (p=0.272) groups. There is consensus for LoR patients about omitting RAI therapy after surgery. Indications for RAI treatment in InR DTC are still under debate. RAI use based on EDRA seems to be a better option than decisions solely made on histopathological risk factors and decreases adjuvant high-activity RAI use without increasing recurrence risk.

Response to Surgery Assessments for Sparing Radioiodine Remnant Ablation in Intermediate-Risk Papillary Thyroid Cancer.

Using response to surgery when tailoring radioiodine (RAI) therapy for papillary thyroid cancer (PTC) is valued but lacks prospective validation. To spare RAI thyroid remnant ablation among patients with intermediate-risk PTCs using 3-tiered assessments with response to surgery highlighted, in addition to the risk of the recurrence stratification and TNM staging. Patients with no evidence of disease (NED) identified as excellent response (ER) or indeterminate response (IDR) to surgery were spared from RAI thyroid remnant ablation after informed consent and prospectively enrolled under active surveillance. Those involved in other trials or without sufficient follow-up data were excluded. Dynamic responses were followed and compared longitudinally. The main outcome measures were NED presenting as durable ER or IDR for over 12 months. Of the enrolled 215 patients, 47.4% (102/215) ER and 52.6% (113/215) IDR were identified regarding RAI decision-making. After a median of 23.6 (interquartile range 13.8-31.6) months, the share of ER increased to 82.8% (178/215) and IDR decreased to 16.3% (35/215), with 85 patients shifting from IDR to ER over time, only 0.5% (1/215) structural incomplete response and 0.5% (1/215) biochemical incomplete response observed. Successful remnant ablation was observed in 27.7% (26/94) of the patients completing 2 diagnostic whole-body scans after a median interval of 13.0 months, indicating a theranostic effect. In the 173 patients followed for over 12 months, the NED rate did not differ between ER and IDR subgroups (100% vs 97.9%, P = .20). Through the 3-tiered assessments with response to surgery highlighted, postoperative ER and IDR spared from RAI remnant ablation may indicate similar favorable responses in intermediate-risk patients with PTC during 23.6 months of follow-up.

Molecular features of aggressive thyroid cancer.

Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have a worse prognosis with respect to well differentiated TC, and the loss of the capability of up-taking 131I is one of the main features characterizing aggressive TC. The knowledge of the genomic landscape of TC can help clinicians to discover the responsible alterations underlying more advance diseases and to address more tailored therapy. In fact, to date, the antiangiogenic multi-targeted kinase inhibitor (aaMKIs) sorafenib, lenvatinib, and cabozantinib, have been approved for the therapy of aggressive radioiodine (RAI)-resistant papillary TC (PTC) or follicular TC (FTC). Several other compounds, including immunotherapies, have been introduced and, in part, approved for the treatment of TC harboring specific mutations. For example, selpercatinib and pralsetinib inhibit mutant RET in medullary thyroid cancer but they can also block the RET fusion proteins-mediated signaling found in PTC. Entrectinib and larotrectinib, can be used in patients with progressive RAI-resistant TC harboring TRK fusion proteins. In addition FDA authorized the association of dabrafenib (BRAFV600E inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAFV600E-mutated ATC. These drugs not only can limit the cancer spread, but in some circumstance they are able to induce the re-differentiation of aggressive tumors, which can be again submitted to new attempts of RAI therapy. In this review we explore the current knowledge on the genetic landscape of TC and its implication on the development of new precise therapeutic strategies.

Reinducing Radioiodine-Sensitivity in Radioiodine-Refractory Thyroid Cancer Using Lenvatinib (RESET): Study Protocol for a Single-Center, Open Label Phase II Trial.

Background: Management of patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) is a challenge as I-131 therapy is deemed ineffective while standard-of-care systemic therapy with tyrosine kinase inhibitor (TKI) lenvatinib is associated with frequent toxicities leading to dose reductions and withdrawal. A potential new treatment approach is to use TKIs as redifferentiation agent to restore RAI uptake to an extent that I-131 therapy is warranted. Prior studies show that short-term treatment with other TKIs restores RAI uptake in 50-60% of radioiodine-refractory DTC patients, but this concept has not been investigated for lenvatinib. Furthermore, the optimal duration of treatment with TKIs for maximal redifferentiation has not been explored. Methods and Design: A total of 12 patients with RAI-refractory DTC with an indication for lenvatinib will undergo I-124 PET/CT to quantify RAI uptake. This process is repeated after 6 and 12 weeks post-initiating lenvatinib after which the prospective dose estimate to target lesions and organs at risk will be determined. Patients will subsequently stop lenvatinib and undergo I-131 treatment if it is deemed effective and safe by predefined norms. The I-124 PET/CT measurements after 6 and 12 weeks of the first six patients are compared and the optimal timepoint will be determined for the remaining patients. In all I-131 treated patients post-therapy SPECT/CT dosimetry verification will be performed. During follow-up, clinical response will be evaluated using serum thyroglobulin levels and F-18 FDG PET/CT imaging for 6 months. It is hypothesized that at least 40% of patients will show meaningful renewed RAI uptake after short-term lenvatinib treatment. Discussion: Shorter treatment duration of lenvatinib treatment is preferred because of frequent toxicity-related dose reductions and drug withdrawals in long-term lenvatinib treatment. Short-term treatment with lenvatinib with subsequent I-131 therapy poses a potential new management approach for these patients. Since treatment duration is reduced and I-131 therapy is more tolerable for most patients, this potentially leads to less toxicity and higher quality of life. Identifying RAI-refractory DTC patients who redifferentiate after lenvatinib therapy is therefore crucial. Trial Registration: ClinicalTrials.gov, NTC04858867.

The Prospective Implementation of the 2015 ATA Guidelines and Modified ATA Recurrence Risk Stratification System for Treatment of Differentiated Thyroid Cancer in a Canadian Tertiary Care Referral Setting.

Objective: To present clinical outcomes of the prospective implementation of the 2015 American Thyroid Association (ATA) guidelines for the management of thyroid nodules and differentiated thyroid cancer (DTC) using the modified ATA recurrence risk (RR) stratification system. Methods: We prospectively analyzed 612 patients with DTC treated between April 2017 and December 2021 in Calgary, Alberta. Each patient was prospectively assigned a modified ATA RR and American Joint Committee Cancer 8th edition stage. Initial risk stratification and consideration of the 2015 ATA guidelines guided surgical management as well as the indication for and dose of radioiodine (RAI) and other adjuvant therapies. Patients were assessed for their response to treatment (RTT) at 2-years postoperatively. Results: There were 479 patients who had 2-year follow-up data and were included in the study. Of these patients, there were 253 (53%) low-, 129 (27%) intermediate-, and 97 (20%) high-RR patients. Of these, 227 patients (47%) underwent total thyroidectomy (TTX) plus RAI, 178 (37%) underwent TTX only, and 74 (16%) underwent lobectomy. The RTT at 2 years was excellent for 89% (66) of patients with lobectomy, 84% (149) for TTX only, and 53% (121) for TTX plus RAI. Among 253 patients who were deemed low RR, 85% (216) had excellent RTT, 13% (32) indeterminate RTT, 2% (4) biochemical incomplete RTT, and 1 patient had structural incomplete RTT. The intermediate RR group had the following RTT outcomes: 64% (83) excellent, 23% (30) indeterminate, 6% (7) biochemical incomplete, and 7% (9) structural incomplete. The high RR group had the worst RTT outcomes, with 38% (37) excellent, 19% (18) indeterminate, 10% (10) biochemical incomplete, and 33% (32) structural incomplete RTT. Conclusions: The 2015 ATA RR stratification system is useful for predicting disease status at 2-year post-treatment in patients with DTC. The 2015 ATA guidelines and modified ATA RR stratification treatment recommendations may reduce thyroid cancer overtreatment by including lobectomy as a definitive treatment option for low-risk thyroid cancers and selective use of RAI for intermediate and high-risk patients.

Analysis of the key ligand receptor CADM1_CADM1 in the regulation of thyroid cancer based on scRNA-seq and bulk RNA-seq data.

Advanced papillary thyroid cancer (PTC) has a poor prognosis, 60~70% of which become radio iodine refractory (RAI-R), but the molecular markers that assess PTC progress to advanced PTC remain unclear. Meanwhile, current targeted therapies are badly effective due to drug resistance and adverse side effects. Ligand-receptor pairs (L/R pairs) play an important role in the interactions between tumor cells and other cells in the tumor microenvironment (TME). Nowadays, therapies targeting ligand-receptor pairs in the TME are advancing rapidly in the treatment of advanced cancers. However, therapies targeting L/R pairs applied to advanced PTC remains challenging because of limited knowledge about L/R pairs in PTC. We screened the critical L/R pair: CADM1-CADM1 using 65311 single-cell RNA sequencing (scRNA-seq) samples from 7 patients in different stage of PTC and bulk RNA-seq datasets containing data from 487 tumor samples and 58 para-carcinoma samples. Moreover, the expression levels of CADM1-CADM1 was assessed by quantitative real time polymerase chain reaction (qRT-PCR) and the function was analyzed using Transwell immigration assay. We found that CADM1_CADM1 could be regarded as a biomarker representing a good prognosis of PTC. In addition, the high expression of CADM1_CADM1 can strongly increase the sensitivity of many targeted drugs, which can alleviate drug resistance. And the results of qRT-PCR showed us that the expression of CADM1_CADM1 in PTC was down-regulated and overexpression of CADM1 could suppresses tumor cell invasion migration. Our study identified that CADM1_CADM1 played an essential role in the progression of PTC for the first time and our findings provide a new potential prognostic and therapeutic ligand-receptor pair for advanced PTC.

ODP531 Worsening of pretibial myxedema following repeated doses of radioiodine treatment in a patient with hyperthyroid Graves’ disease

Abstract Introduction The development of new-onset pretibial myxedema following radioiodine (RAI) treatment has been occasionally reported from the probable influences of thyrotropin receptor antibodies (TRAbs) similar to the RAI-associated Graves’ ophthalmopathy (GO). However, the worsening of pre-existing pretibial myxedema after RAI treatment has never been reported. Herein, we report an interesting case of fluctuating clinical course of pretibial myxedema following treatments of hyperthyroid Graves’ disease for over 3 years. Case Report A 49-year-old Thai woman with underlying hyperthyroid Graves’ disease with GO and pretibial myxedema for 1 year came to our hospital for relapsed hyperthyroidism and active, moderate-to-severe GO in 2019. A plague form of pretibial myxedema with indurated hyperpigmented lesion was found on both legs. Intravenous pulse methylprednisolone (IVMP) was given to control her active GO. Both GO and pretibial myxedema significantly improved after IVMP treatments. Then, RAI (30 mCi) was administered at 1 month later as a definitive treatment. Low dose of oral prednisolone (20 mg/ day) was also given before and after RAI treatment. Transient hypothyroidism developed at 4 months post-RAI and the estimated weights of the thyroid decreased from 60 grams to 30 grams. However, hyperthyroidism relapsed again within 6 months post-RAI treatment. At that time, her pretibial myxedema flared up slightly but her GO was still inactive. Eventually, a second dose of RAI (20 mCi) was given at 11 months apart from the first RAI administration. Low dose of oral prednisolone was also given. She developed post-radiation thyroiditis at 4 months after RAI with worsening of pretibial myxedema and mild exacerbation of GO. Topical corticosteroid ointment was given for pretibial myxedema and only local supportive measures was applied to treat GO. Finally, permanent hypothyroidism was achieved at 6 months after the second course of RAI. Currently, her pretibial myxedema is stable without further flareup. Conclusion Our case highlights the potential of RAI treatment to precipitate both GO and pretibial myxedema in patients with pre-existing skin lesions. Low dose prednisolone prophylaxis might not ensure preventative effect in exacerbation. Whether the risk of worsening of pretibial myxedema is higher in patients with persistent hyperthyroidism requiring a second dose of RAI is a question that warrants further studies. Presentation: No date and time listed

Radioactive Decontamination using Bamboo Activated Carbon for Healthy Environment in Nuclear Medicine

Radioactive wastes by products excreted from radioiodine (RAI) therapy patient waste such as urine, faeces, sweat and puke might risk to radiation contamination if not systematically manage. These wastes can affect human health and environment, thus sustain and systematic management must be strictly considered. In addition, radiopharmaceutical preparations in nuclear medicine risk to radioactive spillage by chances. In this study, new sustainable adsorption technique by using agriculture product was proposed to decontaminate the possibilities of radioactive spillage in RAI therapy where different concentrations of bamboo activated carbon (BAC) was mixed with pure 131I and filtered by using filter paper. Radioactivity for each filtered sample (sediment) was measured using dose calibrator to determine kinetic reactions of adsorbed radioactive substances. The data shows the sediment radioactivity was increased with increased of BAC concentrations. The radioactivity loss after filtration was 76.1% (50 mg/ml), 76.3% (100 mg/ml), 83.5% (150 mg/ml), 80.4% (200 mg/ml), 85% (250 mg/ml) and 68% (control) due to high agglomeration between BAC and 131I. Mixtures with highest BAC concentration was then characterized using FESEM and EDX for morphology and elemental analysis. FESEM image proved there were porous structures on the BAC to attract 131I and other molecules. EDX revealed that 131I and other elements were attracted to BAC layered sheets. This study revealed that BAC performed different capabilities as an adsorbent material under different experimental conditions and has high potential for sustainable radionuclide decontamination agents especially for RAI therapy in ensuring continuous healthy environment for staff, patients and public in Nuclear Medicine Department.

Euthyroidism: following a course of radio iodine therapy for Graves' disease

Euthyroidism: following a course of radio iodine therapy for Graves' disease

Effect of COVID-19 pandemic on diagnosis and treatment of thyroid cancer in Brazil.

IntroductionThe COVID-19 pandemic delayed the diagnosis, treatment, and follow-up visits of patients with thyroid cancer. However, the magnitude with which these restrictions affected the Brazilian health care is still unknown.MethodsRetrospective analysis of thyroid cancer-related procedures performed in the Brazilian public health system from 2019 to 2021. Data were retrieved from the Department of Informatics of the Unified Health System (DATASUS). The following procedures were evaluated: fine-needle aspiration biopsies (FNABs), oncologic thyroidectomies, and radioiodine (RAI) therapies for thyroid cancer. The year of 2019 served as baseline control.ResultsCompared with 2019, FNABs, oncologic thyroidectomies, and RAI therapies performed in 2020 decreased by 29%, 17% and 28%, respectively. In 2021, compared with 2019, FNABs increased by 2%, and oncologic thyroidectomies and RAI therapies decreased by 5% and 25%, respectively. Most pronounced reductions were observed in the first months of the pandemic. In April 2020, FNABs decreased by 67%, oncologic thyroidectomies by 45%, and RAI therapies by 75%. In 2021, RAI therapies were the only procedure with a statistically significant decrease.ConclusionThe restrictions to public health care during the COVID-19 pandemic resulted in a significant reduction in diagnostic and treatment procedures for thyroid cancer in Brazil. The effects of these transitory gaps in thyroid cancer care, due to COVID-19, are still unclear.

Role of locoregional disease in the definition of radioiodine refractory thyroid cancer

Definition of RAI refractory cancer does not include the cervical lymph nodes (LN) radioiodine (RAI) uptake status. The aim of this study is to assess the outcome and the frequency of distant metastases (DM) and RAI uptake status in patients with non-RAI-avid metastatic LN compared with patients having RAI-avid metastatic LN. A retrospective study of consecutive patients followed in Gustave Roussy institute between 1990 and 2015 who underwent at least one RAI therapy and one cervical LN relapse surgery with Proven pathology. Finding Study cohort consisted of 145 patients [58.6 % females, median age at diagnosis of 38 years, papillary 135 (93 %), median follow-up of 14 years (2–42)]. All patients underwent total thyroidectomy and at least one RAI administration. Seventy-seven (53 %) patients disclosed uptake in neck LN (LN-RAI-pos) and 68 did not have any RAI uptake or disclosed a heterogeneous uptake (overall considered LN-RAI-neg). The risk of structural incomplete response at the last assessment was greater in LN-RAI-neg patients (38 %) compared with LN-RAI-pos patients (13 %) (p 0.0005). LN-RAI-neg was associated with an increased risk of DM compared with patients with LN-RAI-pos (35 % vs 18 % OR 2.4 95 %CI : 1.0747–5.715 ; p 0.024). The risk of occurrence of DM not disclosing RAI uptake was higher in the LN-RAI-neg group compared with the LN-RAI-pos group (58 % vs. 21 %, OR 89.4 95 %CI 6.1202–6154.8943 ; p < 0.0002). LN-RAI-neg status is significantly associated to a worse patient outcome and to the occurrence of DM and RAI-refractory DM.

1658P rs4646 is found to be associated with the efficacy of radioiodine (RAI) uptake on thyroid carcinomas: A retrospective study

Patients with thyroid carcinomas usually exhibits heterogenous response to radioiodine therapy, however, the genetic contribution to this heterogenous response hasn’t been well studied. In this study, we aimed to screen for radioiodine uptake-related SNP sites from a list of 41 well-studied drug related SNP sites.

1657P Clinical and molecular profiles of radioiodine refractory differentiated thyroid cancer

At present, identification of radioiodine (RAI) refractory differentiated thyroid cancer (RAIR-DTC) is mainly based on the clinical characteristics of the lesions rather than the pathological changes. Here, we reported preliminary results of the genomic characteristics underlying RAIR-DTC. The formalin-fixed paraffin-embedded samples of 94 patients diagnosed as DTC were sequenced in a 24-gene commercial panel (ThyroLeadTM). Microsatellite instability (MSI) was detected with the MSIsensor2 tool (MSI-H was defined as score greater than 20%). 43 of them were identified as RAIR-DTC by manual inspection according to the 2015 American Thyroid Association guidelines. Among 94 patients, 73 patients (77.7%) had distant metastases, to the lungs in 93.3%, bone in 20.6%, both sites in 16.5%, brain in 6.9%, and liver in 1.4%. Overall, a higher rate of being RAIR-DTC is associated with older age at diagnosis (p=0.0059). In consistent with previous studies, it was found that BRAF V600E (p=0.046) and TERT promoter (p =0.0017) mutation were associated with worse RAI uptake. Of 43 RAIR-DTC cases, tumor from 25 patients (58.1%) harbored BRAF V600E mutations, 16 (37.2%) had TERT promoter mutation, 6 (14.0%) had TP53 mutation and 3 (7.0%) had KRAS mutation. Concomitant BRAF V600E and TERT promoter mutations were found in 2 patients, and all of them were in the RAIR stage. Meanwhile, 29 (67.4%) of RAIR-DTC cases harbored mutations in the RAS/RAF pathway. In clinical aspects, gene fusion is related to the younger age at diagnosis (standard deviation = 14, p＜0.001), while without statistical significance in indicating RAIR-DTC. Only 1 RAIR-DTC patient had an MSI-H result, and the rest exhibited microsatellite stability. Here we illustrated several factors associated with RAI uptake. Further stratification study is required to establish a more detailed profiling of RAI uptake, to reduce the overtreatment of RAIR-DTC.

Developing novel amine-linked covalent organic frameworks towards reversible iodine capture

Radio iodine is one of the essential gaseous pollutions needed to be removed by the growth in nuclear energy consumption. The current paper deals with preparing an amine-linked covalent organic framework (COF) with certain advantages compared to the mainstream rigid imine-linked COFs. The flexibility and abundance of the NH groups in the structure provide an excellent medium for adopting iodine from liquid and gas phases. A hydrazone-linked COF (Hz-COF) was synthesized in a room temperature solvent-mediated method, and its linkages were reduced using NaBH4 (NH-COF). The synthesized Hz-COF and NH-COF were utilized in the iodine adsorption experiment from solution and gas phases. The NH-COF exhibited an excellent iodine uptake from gas phase at 80 °C as high as 2.60 g g−1 that is higher than Hz-COF at the same conditions (2.05 g g−1). More interestingly, NH-COF represents a qe of 173 mg g−1 for iodine uptake from iodine solution (300 mg L−1). The iodine adsorption isotherm is best fitted to the Langmuir model, and the adsorption kinetic obeys the pseudo-second-order model. The flexibility of NH-COF and the presence of –NH– groups in the NH-COF structure endows it with accommodative adaptability to guest molecules, increasing the adsorption capacities compared to Hz-COF. Full reusability, high thermal and chemical stabilities, and a high level of polar functional groups made NH-COF an excellent adsorbent for I2 capture performance.

The Initial ATA Risk Classification, but Not the AJCC/TNM Stage, Predicts the Persistence or Relapse of Differentiated Thyroid Cancer in Long-Term Surveillance

Background: The American Joint Commission on Cancer on Tumor Node Metastasis (AJCC/TNM) staging system provides adequate information on the risk of differentiated thyroid cancer (DTC)-specific mortality in totally thyroidectomized patients, but its role in predicting persistence and relapse of disease is uncertain. The relatively new 2015 American Thyroid Association (ATA) guidelines recommend stratifying patients at the time of DTC diagnosis with its own risk classification system, in order to identify those at high risk of residual or recurrent morbidity who may benefit from post-operative radioiodine (RAI) administration and/or need additional work-up. Methods: To verify the prevalence proportion of persistence or relapse of disease, a consecutive cohort of 152 patients with a diagnosis of DTC, subjected to total thyroidectomy (+/− post-operative RAI administration as per guidelines indication) and to neck ultrasonography (US), as well as biochemical surveillance for a minimum of 2 years at the Endocrinology Unit of Mater-Domini Hospital (Catanzaro, Italy), was enrolled. The prognostic role of the AJCC/TNM stage and ATA risk classification system was analyzed by logistic regression. Results: At a mean of 9 years after surgical treatment, DTC was found to persist or relapse in 19 (12.5%) participants. The initial risk for these outcomes, based on the ATA classification, was mostly low (53.9%) or intermediate (39.5%). AJCC/TNM stages were predominantly stage I or stage II. Despite a small representation in this cohort, high-risk patients according to the ATA classification had 8-fold higher odds of persistence or relapse of disease than those of low-risk participants, while controlling for potential risk modifiers, including age at DTC diagnosis, male gender, and post-operative RAI administration (p = 0.008). In contrast, the AJCC/TNM stage was not associated with the disease status at the last follow-up visit (p = 0.068 for the 7th Edition; p = 0.165 for the 8th Edition). Furthermore, low-risk participants subjected to post-operative RAI administration had the same probability of persistence or relapse of DTC when compared to those who had undergone total thyroidectomy only. Conclusions: There is a need for the endocrine community to revise the current work-up of DTC. The initial ATA risk classification is a reliable tool for predicting the persistence or relapse of disease in long-term surveillance.

Is there a role for diagnostic scans in the management of intermediate-risk thyroid cancer?

Radioiodine (RAI) is selectively recommended for intermediate-risk differentiated thyroid carcinomas (DTC). The information gleaned from pretherapy stimulated thyroglobulin levels (sTg) and diagnostic 131I whole-body scans (DxWBS) to guide therapy remains controversial. The present study aimed at evaluating the impact of preablation sTg and DxWBS in the management of intermediate-risk DTC. A retrospective analysis of 301 intermediate-risk DTC patients submitted to total thyroidectomy and RAI therapy was performed. Pretherapy sTg and DxWBS and post-therapy WBS (RxWBS) findings were analyzed and compared to outcomes. Fifty-two patients (17.3%) had metastases diagnosed by DxWBS and/or RxWBS. The DxWBS identified 10.6% of patients with functioning metastases, including unexpected distant metastases. If combined with SPECT-CT, DxWBS detected RAI-avid metastases more frequently, particularly lymph node metastases (13.1% vs 4.2% planar WBS, P = 0.015). The DxWBS findings modified patient management in 8.3%. A pretherapy sTg <1 ng/mL was associated with a low false-negative rate for the presence of metastases (5.2%), and its performance in excluding metastasis was improved by a negative DxWBS (2.7% of patients with both negative exams had metastases in RxWBS). A sTg <1 ng/mL predicted statistically significant lower rates of recurrent/persistent disease and biochemical/structural incomplete responses. In conclusion, preablation sTg and DxWBS contribute to the detection of unknown or persistent metastatic disease in intermediate-risk DTC patients. A sTg <1 ng/mL in combination with a negative DxWBS is highly suggestive of the absence of remaining malignant disease, and one may consider deferring RAI ablation if both exams are negative. A stunning effect is rarely observed and it does not impair proper treatment of metastases.

Indoleamine 2,3-Dioxygenase Immune Status as a Potential Biomarker of Radioiodine Efficacy for Advanced Distant Metastatic Differentiated Thyroid Cancer.

PurposeHost immunity influences the impact of cancer therapy but the effect of immune status in radioiodine (RAI)-treated differentiated thyroid cancer (DTC) remains obscure. Here we investigated indoleamine 2,3-dioxygenase (IDO) activity as a biomarker of response to RAI in patients with distant metastatic DTC (dmDTC).MethodsPatients with dmDTC receiving RAI were evaluated for serum IDO activity (kynurenine and kynurenine:tryptophan ratio) at baseline and 3 months after RAI. The optimal cut-off value for these biomarkers to predict response was established by receiver operating characteristic analysis. The relationship between disease outcomes, overall survival (OS) and progression-free survival (PFS), and IDO activity levels was studied.ResultsHigher baseline kynurenine:tryptophan ratio (>2.46) was correlated with poorer RAI response as well as shorter median PFS (45 mo versus not reached, p=0.002) and OS (78 mo versus not reached, p=0.035). High baseline kynurenine:tryptophan ratio was also correlated with a reduced number of tumor-infiltrating lymphocytes. Higher post/pre-kynurenine ratio (>1.69) was associated with survival endpoints: shorter median PFS (48 mo versus not reached, p=0.002) and OS (68 mo versus not reached, p=0.010). Favorable baseline and favorable change corresponded with better PFS and OS.ConclusionsOur results suggest that RAI also alters IDO activity in dmDTC patients. IDO activity could predict progression and survival outcomes for advanced dmDTC patients. Serum IDO biomarker levels could be used to select dmDTC likely to benefit from RAI therapy, although further studies are necessary.