Multikinase Inhibitors for the Treatment of Asymptomatic Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Global Noninterventional Study (RIFTOS MKI).

Background: Sorafenib and lenvatinib are multikinase inhibitors (MKIs) approved for patients with radioactive iodine-refractory (RAI-R) differentiated thyroid cancer (DTC). There is no consensus on when to initiate MKI treatment. The objective of this study was to evaluate time to symptomatic progression (TTSP) in patients with RAI-R DTC for whom the decision to treat with an MKI was made at study entry. Methods: International, prospective, open-label, noninterventional cohort study (NCT02303444). Eligible patients had asymptomatic progressive RAI-R DTC, with ≥1 lesion ≥1 cm in diameter and life expectancy ≥6 months. The decision to treat with an MKI was at the treating physician's discretion. Primary endpoint was TTSP from study entry. Two cohorts were evaluated: patients for whom a decision to initiate an MKI was made at study entry (Cohort 1) and patients for whom there was a decision not to initiate an MKI at study entry (Cohort 2). Cohorts were compared descriptively. Results: The full analysis set (FAS) comprised 647 patients. The median duration of observation was 35.5 months (range <1-59.4). Of 344 MKI-treated patients, 209 received sorafenib, 191 received lenvatinib, and 19 received another MKI at some point. Median TTSP was 55.4 months (interquartile range [IQR] 18.6-not estimable [NE]) overall, 55.4 months (IQR 15.2-NE) in Cohort 1 (n = 169), and 51.4 months (IQR 20.0-NE) in Cohort 2 (n = 478). TTSP ≥36 months was achieved in 64.5% of patients overall, 59.5% of patients in Cohort 1, and 66.4% of patients in Cohort 2. Median overall survival from classification as RAI-R was 167 months and median progression-free survival from start of MKI therapy was 19.2 months and from start of sorafenib therapy 16.7 months. Among sorafenib-treated patients, 70% had dose modifications, 35% had a dose reduction, 89% experienced ≥1 treatment-emergent adverse event (TEAE), and 82% experienced ≥1 drug-related TEAE. Conclusions: This real-world study provides valuable insight into outcomes in patients with asymptomatic, progressive RAI-R DTC under observation or receiving MKI treatment. TTSP in the FAS provides insight into the current prognosis for patients with RAI-R DTC in the era of MKIs. Registration: NCT02303444.

[Oncoendocrinology - the innovative interdisciplinary base for personalized medicine].

Oncoendocrinology is a new vector in personalized medicine based on the scientific and creative communication of endocrinologists, oncologists, morphologists, radiologists, geneticists, medical physicists, biologists, chemists, and mathematicians. A section «Oncoendocrinology» has been introduced in the Problems of Endocrinology journal by the editorial board. It is planned to publish reviews and original articles in the aforementioned scientific and applied fields. We invite all interested authors and readers to cooperation.

[Radioiodine therapy outcome in toxic multinodular goiter patient with concomitant hereditary Hasharon hemoglobinopathy].

This research describes a clinical case of treatment of a patient with thyrotoxicosis with concomitant hematological pathology – carriage of unstable hemoglobin Hasharon. A patient diagnosed with «Diffuse toxic nodular goiter. Thyrotoxicosis of medium severity. Drug-induced hypothyroidism» was admitted to the Department of radionuclide therapy for the purpose of treatment with radioactive iodine. Onset of disease - summer 2018 (thyroid-stimulating hormone (TSH) – 0 mIU/ml). The instrumental studies (ultrasound, scintillation scanning of the thyroid gland) were performed at the pre-radioiodine therapy (RIT) diagnostic stage. The history of the disease indicates, that in 2000 the patient was suspected of having abnormal hemoglobin, since then no examinations have been conducted and anemia has never been detected. The diagnosis of ancestral hemoglobinopathy with the presence (17%) of unstable Hasharon-Sinai-Sealy hemoglobin in a heterozygous form was verified during the preparation to RIT. The radionuclide therapy I131 with activity of 400 MBq was performed on 02.07.2019. The monthly monitoring of laboratory and instrumental indicants was carried out during the post-therapeutic period: the state of hypothyroidism was reached by the end of 2 months after RT, no episodes of significant increase in bilirubin levels were observed during the observation period; no side effects from RT were stated. It becomes possible based on the example of the above observation, to judge the safety of conducting RT for treatment of thyrotoxicosis in patients with similar hemoglobinopathy, without excluding, however, the need for an individual approach in each case.

[IGG4-related diseases in endocrinology].

Immunoglobulin-G4-related disease (IgG4-RD) is a chronic immunomediated pathology of different organs of local or systemic nature, which has been established as a separate clinical entity in the early 2000s and is characterized by storiform fibroid inflammation of the affected tissues, their increase, and elevated serum immunoglobulin-G4 (IgG4) levels. The most common manifestations of the disease are major salivary and lacrimal gland enlargement, lymphadenopathy and type 1 autoimmune pancreatitis (AIP1), however, other organs may be also involved (the thyroid, eyes, meninges, heart, lungs, kidneys, aorta, upper airways, mesentery, etc.). The effectiveness of treatment of IgG4-RD, as well as other pathological conditions, is also determined by the timely diagnosis. However, the latter is complicated due to the variety of clinical manifestations and rather variable diagnostic criteria. It is necessary to constantly update the evidence-based knowledge and diagnostic algorithms within this pathology in order to overcome the difficulties, and involve immunologists, endocrinologists, pathologists and specialists in other spheres. This review provides information about the etiology, pathogenesis, and current methods of diagnosis and treatment of IgG4-related diseases, as well as examples of some manifestations of IgG4-RD that an endocrinologist may face in practice.

[Hereditary cancer syndromes: a modern paradigm].

About 5-10% of malignant neoplasms (MN) are hereditary. Carriers of mutations associated with hereditary tumor syndromes (HTS) are at high risk of developing tumors in childhood and young age and synchronous and metachronous multiple tumors. At the same time, this group of diseases remains mainly an oncological problem, and clinical decisions are made only when MNs are detected in carriers of pathogenic mutations.Individual recommendations for cancer screening, treatment, and prevention should be developed for carriers of mutations associated with HTS to prevent an adverse outcome of the disease. It is essential to identify patients at risk by doctors of all specialties for further referral to medical and genetic counseling with molecular genetic testing (in case of indications). The problems of standardization of enrollment criteria for genetic tests, further tactics of prevention, screening, and treatment of many hereditary oncological diseases remain unsolved.This review was created to inform doctors of various specialties, including endocrinologists, about the HTS. This allows them to get acquainted with main clinical features of specific syndromes, helps to understand the difference between hereditary and non-hereditary cancer, recognize signs of hereditary cancer, and introduce the indications for genetic examination and genetic counseling of the patient. Also, significant differences between international and domestic recommendations on screening measures, diagnosis, and treatment of HTS underline the need to review the existing and develop new algorithms for medical support of patients with HTS.

[Predictors of the efficacy of radioiodine therapy of Graves' disease in children and adolescents].

RATIONALE: Insufficient world-wide clinical experience in radioiodine therapy (RIT) for Graves' disease (GD) in children and adolescents, and limited knowledge of the predictors of RIT efficacy. AIMS: Analysis and identification of the most significant predictors of the efficacy of RIT in children and adolescents with Graves' disease. MATERIALS AND METHODS: A total of 55 patients (48 females and 7 males) aged from 8 to 18 years receiving primary RIT for GD were enrolled. RIT planning was based on the dosimetric method. Analyzed parameters included gender, age, ultrasound thyroid volume before and 6 months after treatment, the presence of endocrine ophthalmopathy, duration of antithyroid drug (ATD) therapy, relapse of thyrotoxicosis after ATD dose reduction, blood fT3, fT4 and TSH levels initially and at 1, 3, 6 months after treatment, TSH receptor Ab initially and at 3 and 6 months after treatment, thyroid 99mTc-pertechnetate uptake at 10-20 minutes (%), maximum thyroid 131I uptake (%), specific 131I uptake (MBq/g) and therapeutic 131I activity (MBq). Fisher exact test, non-parametric Mann-Whitney test, Wilcoxon signed-rank test, logistic regression modelling, ROC-analysis, proportional hazard model (the Cox regression), the Kaplan-Meier method and log-rank test were used for statistical analysis as appropriate. RESULTS: Six months after RIT, hypothyroidism was achieved in 45 (81.8%), euthyroid state - in 2 (3.6%), and in 8 (14.6%) patients thyrotoxicosis persisted. On univariate statistical analysis, the smaller thyroid volume, higher fT4 and lower TSH receptor Ab levels, lower 99mTc-pertechnetate uptake and higher specific 131I uptake were associated with hypothyroidism. On multivariate logistic regression analysis, the older patient's age (p=0.011), smaller thyroid volume (p=0.003) and higher fT4 (p=0.024) were independent predictors of RIT efficacy. Thyroid volume was also the only variable associated with achievement of hypothyroidism in time after RIT (p=0.011). CONCLUSION: The efficacy of dosimetry-based RIT in children and adolescents with GD 6 months after treatment was 81.2%. Older patients' age, smaller thyroid volume and higher fT4 level were independent predictors of therapy success. Smaller thyroid volume was also a predictor of the favorable time-related outcome. Statistical models obtained in this work may be used to prospectively estimate the chance of efficient RIT for GD in pediatric patients.

Radiation exposure does not significantly contribute to the risk of recurrence of Chernobyl thyroid cancer.

CONTEXT: Papillary thyroid carcinoma (PTC) in patients exposed to environmental radioiodine after the Chernobyl accident is thought to have a relatively aggressive clinical course. Long-term results of treatment are not well known, especially in comparison with sporadic PTC. OBJECTIVE: The determination of risk factors for PTC recurrence in a controlled for baseline factors group of patients with radiation-related and sporadic PTC. DESIGN: Retrospective cohort study involving patients treated for PTC and followed-up in 1991-2008. Risk factors were assessed by stratified analysis using the proportional hazard model. SETTING: Referral center-based. PATIENTS: A total of 497 patients were enrolled. Patients exposed to radioiodine were 172 individuals with reconstructed individual radiation thyroid doses ranging 51-3170 mGy. Patients with sporadic PTC included 325 individuals matched to exposed patients for sex, age ± 5 yr and time to treatment ± 2 yr. MAIN OUTCOME MEASURE: Cancer recurrence. RESULTS: Nodal disease increased the recurrence rate (HR = 5.21; 95% CI = 1.63-16.7) while the presence of tumor capsule (HR = 0.17; 95% CI = 0.06-0.45) and, particularly, treatment according to the Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer significantly reduced it (HR = 0.16; 95% CI = 0.06-0.42). None of the tested variables interacted with radiation factor. CONCLUSIONS: PTC developing after internal exposure to radioiodine does not display specific risk factors for recurrence different from those in sporadic PTC. Common treatment approaches for patients with PTC should be recommended regardless of a history of radiation exposure.

Mutation analysis of RAP1 gene in papillary thyroid carcinomas.

In human papillary thyroid carcinomas (PTCs), the genetic alterations of RET/PTC, RAS or BRAF account for about 60-70% of cases with practically no overlap, providing strong genetic evidence that constitutive active signaling along MAPK pathway is critical for PTC development. In the remaining 30-40% of the cases, the oncogenes are still unknown. RAP1 is a member of the RAS family of small G proteins transmitting signals from the TSH-R to MAPK pathway using cAMP-dependent mechanism in thyroid cells. RAP1 was shown to have both mitogenic and tumorigenic properties in certain systems; however, the potential role of RAP1 mutation in thyroid carcinogenesis has yet to be elucidated. In this study, we analyzed the mutational status of RAP1 gene in 36 Russian patients with PTCs without RET/PTC rearrangement, BRAF mutation or RAS mutation. No mutations in either RAP1A or RAP1B genes were found. These results suggest that RAP1 mutation does not play an important role in PTC pathogenesis.