Retrospective case-control study examining the relationship between recurrence-free survival and changes in pre- and post-radioiodine therapy serum thyroglobulin levels in patients with differentiated thyroid cancer.

PURPOSE: Thyroglobulin assay is important to assess the residual or recurrence of differentiated thyroid cancer (DTC). Patients with positive serum thyroglobulin levels after radioactive iodine (RAI) adjuvant therapy could achieve long-term recurrence-free survival (RFS). The patient's prognosis could not be confidently estimated based solely on the evaluation of thyroglobulin levels. We investigated the recurrence rate and RFS of patients who received adjuvant RAI therapy after surgery for DTC to clarify the relationship between changes in pre- and post-therapy serum thyroglobulin levels and RFS. MATERIALS AND METHODS: Patients who underwent adjuvant RAI therapy between May 2007 and March 2021 were included in this study, whereas those with positive anti-thyroglobulin antibodies, distant metastases, or gross residual tumors were excluded. The change in pre- and post-treatment serum thyroglobulin levels under thyroid-stimulating hormone stimulation was calculated and classified as follows: group A, thyroglobulin levels decreased by ˃10%; group B, thyroglobulin levels within a range of 10% or less; and group C, thyroglobulin levels increased by ˃10%. RFS outcomes were analyzed using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test, and multivariate analysis was performed using the Cox proportional hazard model. RESULTS: A total of 74 patients were included. Relapse was seen in 13 of 46 patients in group A, 9 of 15 in group B, and 10 of 13 in group C. Median RFS was 129.00 (95% confidence interval CI 77.79-180.21), 113.00 (95% CI 86.83-139.17), and 33 months (95% CI 6.026-59.974) in groups A, B, and C, respectively. Patients in group C exhibited significantly shorter RFS than those in groups A and B (P = 0.001). CONCLUSIONS: Changes in thyroglobulin levels pre- and post-therapy were associated with RFS. Patients with decreased post-therapy thyroglobulin levels had a favorable prognosis, even if their thyroglobulin levels were positive after RAI therapy.

Relapse-free survival after adjuvant radioactive iodine therapy in patients with differentiated thyroid carcinoma with a microscopically positive tumor margin.

OBJECTIVE: In patients with differentiated thyroid carcinoma (DTC) with a microscopically positive tumor margin, the optimal first dose of I-131 during adjuvant radioactive iodine (RAI) therapy to improve relapse-free survival (RFS) is unclear. Due to the limited number of hospital beds, 1110 MBq of I-131 is administered to such patients in Japan. This study primarily aimed to retrospectively determine the difference in RFS between high-dose (3700 MBq) and low-dose (1110 MBq) adjuvant RAI therapies in DTC patients with a microscopically positive tumor margin. The secondary aim was to investigate the background factors affecting RFS. METHODS: Forty-eight consecutive patients (15 men and 33 women) who underwent total thyroidectomy between April 2007 and December 2017 for DTC without gross residual tumors and distant metastasis, and who were diagnosed with a positive margin histopathologically, followed by RAI therapy, were enrolled. We retrospectively investigated initial I-131 dose, classifying it into high-dose and low-dose groups. The primary endpoint was RFS. Relapse was considered in the following cases: patients with visible recurrent tumor and/or metastasis on neck ultrasound and/or computed tomography, and patients without visible tumor, but with clearly increasing thyroglobulin levels on follow-up every 3-6 months. RFS outcomes were analyzed using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test, and multivariate analysis was undertaken using the Cox proportional hazard model. RESULTS: There were nine cases of recurrence (52.9%) in the low-dose group and seven in the high-dose group (22.5%) during follow-up. The estimated median RFS was 69.4 months in the low-dose group and 120.7 months in the high-dose group. High-dose administration was associated with improved RFS, as demonstrated by Kaplan-Meier survival curves (log-rank test [P = 0.009]). Patient factors associated with worse RFS included low-dose administration (hazard ratio [HR] = 91.9; 95% confidence interval [CI] = 7.66-1102.79); P < 0.001), T4 stage (HR = 1.88; 95% CI = 0.44-8.10; P = 0.015), and presence of central lymph node metastases (HR = 190; 95% CI = 3.80-9496; P = 0.009). The most common type of recurrence was lymph node metastasis. CONCLUSION: Patients with microscopically positive tumor margins could benefit from RAI with high activities.

Outer sphere mutagenesis of Lactobacillus plantarum manganese catalase disrupts the cluster core. Mechanistic implications.

X-ray crystallography of the nonheme manganese catalase from Lactobacillus plantarum (LPC) [Barynin, V.V., Whittaker, M.M., Antonyuk, S.V., Lamzin, V.S., Harrison, P.M., Artymiuk, P.J. & Whittaker, J.W. (2001) Structure9, 725-738] has revealed the structure of the dimanganese redox cluster together with its protein environment. The oxidized [Mn(III)Mn(III)] cluster is bridged by two solvent molecules (oxo and hydroxo, respectively) together with a micro 1,3 bridging glutamate carboxylate and is embedded in a web of hydrogen bonds involving an outer sphere tyrosine residue (Tyr42). A novel homologous expression system has been developed for production of active recombinant LPC and Tyr42 has been replaced by phenylalanine using site-directed mutagenesis. Spectroscopic and structural studies indicate that disruption of the hydrogen-bonded web significantly perturbs the active site in Y42F LPC, breaking one of the solvent bridges and generating an 'open' form of the dimanganese cluster. Two of the metal ligands adopt alternate conformations in the crystal structure, both conformers having a broken solvent bridge in the dimanganese core. The oxidized Y42F LPC exhibits strong optical absorption characteristic of high spin Mn(III) in low symmetry and lower coordination number. MCD and EPR measurements provide complementary information defining a ferromagnetically coupled electronic ground state for a cluster containing a single solvent bridge, in contrast to the diamagnetic ground state found for the native cluster containing a pair of solvent bridges. Y42F LPC has less than 5% of the catalase activity and much higher Km for H2O2 ( approximately 1.4 m) at neutral pH than WT LPC, although the activity is slightly restored at high pH where the cluster is converted to a diamagnetic form. These studies provide new insight into the contribution of the outer sphere tyrosine to the stability of the dimanganese cluster and the role of the solvent bridges in catalysis by dimanganese catalases.