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Background: Driver mutations at BRAF V600 are frequently identified in papillary thyroid cancer and anaplastic thyroid cancer (ATC), in which BRAF inhibitors have shown clinical effectiveness. This Japanese phase 2 study evaluated the efficacy and safety of a BRAF inhibitor, encorafenib, combined with an MEK inhibitor, binimetinib, in patients with BRAF V600-mutated thyroid cancer. Methods: This phase 2, open-label, uncontrolled study was conducted at 10 institutions targeted patients with BRAF V600-mutated locally advanced or distant metastatic thyroid cancer not amenable to curative treatment who became refractory/intolerant to ≥1 previous vascular endothelial growth factor receptor-targeted regimen(s) or were considered ineligible for those. The primary endpoint was centrally assessed objective response rate (ORR). The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: We enrolled 22 patients with BRAFV600E-mutated thyroid cancer: 17 had differentiated thyroid cancer (DTC), and 5 had ATC. At data cutoff (October 26, 2022), the median follow-up was 11.5 (range = 3.4–19.0) months. The primary endpoint of centrally assessed ORR was 54.5% (95% confidence interval [CI] 32.2–75.6; partial response in 12 patients and stable disease in 10). The ORRs in patients with DTC and ATC were 47.1% (8 of 17) and 80.0% (4 of 5), respectively. The medians for DOR and PFS by central assessment and for OS were not reached in the overall population, the DTC subgroup, or the ATC subgroup. At 12 months, the rate of ongoing response was 90.9%, and the PFS and OS rates were 78.8% and 81.8%, respectively. All patients developed ≥1 adverse events (AEs): grade 3 AEs in 6 patients (27.3%). No patients developed grade 4–5 AEs. The most common grade 3 AE was lipase increased (4 patients [18.2%]). Those toxicities were mostly manageable with appropriate monitoring and dose adjustment. Conclusions: Treatment with encorafenib plus binimetinib met the primary endpoint criteria and demonstrated clinical benefit in patients with BRAFV600E-mutated thyroid cancer regardless of its histological type, such as DTC or ATC, with no new safety concerns identified. Encorafenib plus binimetinib could thus be a new treatment option for BRAF V600-mutated thyroid cancer. Clinical Trial Registration number: Japan Registry of Clinical Trials: jRCT2011200018 [ABSTRACT FROM AUTHOR]

Outpatient ablation therapy with low-dose radioactive iodine (RAI) is applied to non-low-risk papillary thyroid cancer patients due to a chronic shortage of inpatient RAI treatment wards in Japan. We used the maximum dosage available for outpatient therapy of 30 mCi of RAI for ablation and diagnostic (Dx) whole-body scintigraphy (WBS). This study aimed to examine the significance of the second dose of 30 mCi. DxWBS was performed 6 months after ablation, and assessment of success or failure was performed 12 months after ablation. A second WBS was performed in the remaining RAI accumulation cases in the neck on DxWBS. The criteria for successful ablation was negative cervical accumulation on WBS, thyroid stimulating hormone-suppressed thyroglobulin (sup-Tg) below 1.0 ng/mL, and no increase in thyroglobulin antibody (TgAb) level. At the time of DxWBS, 35/68 cases met the successful criteria, and 45 cases achieved success at assessment. Sup-Tg values decreased significantly after ablation and decreased further after DxWBS in successful ablation cases, whereas those were not changed in ablation failure cases. Findings indicated that RAI used in DxWBS had therapeutic effects. It makes sense to use 30 mCi for DxWBS, given the current difficulty of inpatient ablation therapy with high-dose RAI. [ABSTRACT FROM AUTHOR]

Background: The increasing prevalence of thyroid cancer among the survivors of atomic bomb attacks in Japan, nuclear fallout in the Marshall Islands, and Chernobyl nuclear power plant accident indicate a strong relationship between nuclear radiation and the occurrence of thyroid cancer. Materials and Methods: Systematic researches were conducted in the medical database of the American National Library of Congress, PubMed, using keywords of thyroid cancer, radiation, papillary thyroid cancer. After screening the titles and abstracts of 1791 citations, a total of 77 citations were identified to include in the current study. Results: The latency period for developing nuclear radiation-induced thyroid cancers was 5 to 10 years to decades after exposure. The most important risk factor for developing radiation-induced thyroid cancer was the received radiation dose. A strong dose-response relationship between radiation dose and the incidence of thyroid cancer has been reported (P value<0.001). Also, a strong relationship between the age of exposure to nuclear radiation and the incidence of thyroid cancer has been reported among the survivors of atomic accidents. Although the incidence rate of thyroid cancer in girls was 2-3 times more than boys in some studies, in other studies from the Chernobyl accident, no gender effect was observed. The risk of radiation-induced thyroid cancer was estimated to be higher in areas with iodine deficiency. The most common route of internal radiation was through absorption of radioactive iodine isotopes via consumption of the contaminated milk. The main mechanism in the pathogenesis of radiation-induced thyroid cancer was activation of the MAPK pathway through genetic alterations (e.g., gene rearrangements in RET family and NTRK1) or point mutations (e.g., in BRAF). Among these genetic alteration, RET/PTC3 and RET/PTC1 rearrangements were more common in radiation--induced thyroid cancer. The clinical behavior of radiation-induced thyroid cancer was a non-invasive type similar to the sporadic one at the same age Conclusion: Nuclear radiation, especially at a young age (under 20 years old), directly or indirectly in a dose-dependent manner via reactive oxygen species production induces gene alterations that underlie the increasing incidence of thyroid cancer after radiation exposure. Preparedness to deal with nuclear radiation including prescription of stable iodine prophylaxis, evacuation of the contaminated regions and restriction of access to contaminated foods are recommended in power plant accidents or atomic bomb explosions. [ABSTRACT FROM AUTHOR]

Objective: To investigate how birthplace influences the incidence of papillary thyroid cancer among Asian American women.Methods: Birthplace- and ethnic-specific age-adjusted and age-specific incidence rates were calculated using data from the California Cancer Registry for the period 1988-2004. Birthplace was statistically imputed for 30% of cases using a validated imputation method based on age at Social Security number issuance. Population estimates were obtained from the US Census. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were estimated for foreign-born vs. US-born women.Results: Age-adjusted incidence rates of papillary thyroid cancer among Filipina (13.7 per 100,000) and Vietnamese (12.7) women were more than double those of Japanese women (6.2). US-born Chinese (IRR = 0.48, 95% CI: 0.40-0.59) and Filipina women (IRR = 0.74, 95% CI: 0.58-0.96) had significantly higher rates than those who were foreign-born; the opposite was observed for Japanese women (IRR = 1.55, 95% CI: 1.17-2.08). The age-specific patterns among all foreign-born Asian women and US-born Japanese women showed a slow steady increase in incidence until age 70. However, among US-born Asian women (except Japanese), substantially elevated incidence rates during the reproductive and menopausal years were evident.Conclusions: Ethnic- and birthplace-variation in papillary thyroid cancer incidence can provide insight into the etiology of this increasingly common and understudied cancer. [ABSTRACT FROM AUTHOR]

Purpose: Thyroid cancer of papillary histology (PTC) is the dominant type in radio-epidemiological cohorts established after nuclear accidents or warfare. Studies on post-Chernobyl PTC and on thyroid cancer in the life span study (LSS) of Japanese a-bomb survivors consistently revealed high radiation risk after exposure during childhood and adolescence. For post-Chernobyl risk assessment overexpression of the CLIP2 gene was proposed as molecular biomarker to separate radiogenic from sporadic PTC. Based on such binary marker a biologically-based risk model of PTC carcinogenesis has been developed for observational Chernobyl data. The model featured two independent molecular pathways of disease development, of which one was associated with radiation exposure. To gain credibility the concept for a mechanistic risk model must be based on general biological features which transcend findings in a single cohort. The purpose of the present study is therefore to demonstrate portability of the model concept by application to PTC incidence data in the LSS. By exploiting the molecular two-path concept we improve the determination of the probability of radiation causing cancer (POC)., Materials and Methods: The current analysis uses thyroid cancer incidence data of the LSS with thyroid cancer diagnoses and papillary histology ( n  = 292) from the follow-up period between 1958 and 2005. Risk analysis was performed with both descriptive and biologically-based models., Results: Judged by goodness-of-fit all applied models described the data almost equally well. They yielded similar risk estimates in cohorts post-Chernobyl and LSS. The preferred mechanistic model was selected by biological plausibility. It reflected important features of an imperfect radiation marker which are not easily addressed by descriptive models. Precise model predictions of marker prevalence in strata of epidemiological covariables can be tested by molecular measurements. Application of the radiation-related molecular pathway from our preferred model in retrospective risk assessment decreases the threshold dose for 50% POC from 0.33 (95% confidence interval (CI) 0.18; 0.64) Gy to 0.04 (95% CI 0.01; 0.19) Gy for females and from 0.43 (95% CI 0.17; 1.84) Gy to 0.19 (95% CI 0.05; 1.00) Gy for males. These improvements are still not sufficient to separate radiation-induced from sporadic PTC cases at very low doses <0.015 Gy typical for the Fukushima accident., Conclusions: Successful application of our preferred mechanistic model to LSS incidence data confirms and improves the biological two-path concept of radiation-induced PTC. Model predictions suggest further molecular validation studies to consolidate the basis of biologically-based risk estimation.

Background: Little is known about annual hazard rates of cancer mortality and recurrence for papillary thyroid cancer (PTC). This study investigated the time-varying pattern of cancer death and recurrence from PTC and independent prognostic factors for cause-specific mortality (CSM) and recurrence of PTC. Methods: This retrospective chart review enrolled 466 patients diagnosed with PTC who underwent curative initial surgery between April 1981 and December 1991 with a median follow-up of 18.4 years. Clinical characteristics, cancer mortality (primary endpoint), and recurrence (secondary endpoint) were ascertained. The failure rates of either death or recurrence were estimated using the Kaplan-Meier methods, and annual death/recurrence hazard was depicted using hazard function. Results: In this Japanese cohort where only 1.5% of patients received radioactive iodine therapy, the 10-, 20-, and 30-year CSM rates were 2.7%, 6.2%, and 8.6%, respectively. Eleven (44.0%) cases of death occurred within the first 10 years, whereas 10 (40.0%) and 4 (16.0%) cases occurred within 10-20 and 20-30 years after surgery, respectively. The 10-, 20-, and 30-year recurrence rates were 11.3%, 21.8%, and 29.4%, respectively. Forty-six (54.8%) cases of recurrence occurred within the first 10 years, predominantly within the first five years (31 cases; 36.9%), whereas 29 (34.5%), 7 (8.3%), and 2 (2.4%) cases occurred within 10-20, 20-30, and ≥30 years after surgery, respectively. Age ≥55 years was the only independent prognostic factor for CSM. Age ≥55 years, male, tumor size > 4 cm, extranodal extension, and positive pathological lymph node metastasis were independent prognostic factors for recurrence. The annual hazard curve of cancer mortality presented a double-peaked distribution, with a first peak at the 10th year, and the second peak reaching the maximum at the 20th year after surgery for the entire population. The annual hazard curve of recurrence showed a triple-peaked pattern, with surges at about 12, 22, and 29 years after surgery. Conclusions: Patients with PTC harboring at least one of the prognostic characteristics may be at persistent risk of cancer mortality and recurrence even 10 or more years after initial treatment. Understanding the hazard rate of PTC is key to creating more tailored treatment and surveillance.

Background: In patients with papillary thyroid carcinoma (PTC), the role of total thyroidectomy (TT) versus that of thyroid lobectomy (TL) has been controversial., Methods: This retrospective study was approved by our institutional review board, and the requirement to obtain informed consent was waived. In total, 173 patients with 1- to 5-cm stage cN0 and cM0 PTC tumors treated by curative surgery from 1994 to 2008 were evaluated. Clinicopathologic features and adverse events were compared between patients who underwent TT and those who underwent TL. After adjustment for differences in baseline clinicopathologic factors using propensity score matching, we compared recurrence-free survival (RFS) and OS., Results: TL was performed in 120 patients and TT in 53 patients. Patients who underwent TT were older; had larger tumors; more frequently had nodal metastasis, multifocal tumors, and extracapsular invasion; and more frequently underwent radioactive iodine ablation than patients who underwent TL. Hypocalcemia requiring medication and recurrent laryngeal nerve paralysis were more frequent in TT than TL. The 10-year RFS and OS of all patients were 93.3% and 96.7%, respectively. There was no significant difference in RFS (90.6% vs 93.0% in TT and TL groups, respectively) or OS (96.2% vs 96.9% in TT and TL groups, respectively) according to the extent of surgical resection after propensity score matching., Conclusion: Equivalent prognoses were observed for patients with 1- to 5-cm stage cN0 and cM0 PTC tumors treated by TL or TT after propensity score matching. Adverse events occurred less frequently in patients who underwent TL than TT., (Copyright © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)