A high Ki-67 labeling index and high thyroglobulin doubling rate are significant predictors of excision-site recurrence of papillary thyroid carcinoma following airway resection for locally curative surgery.

BACKGROUND: Papillary thyroid carcinoma (PTC) occasionally invades the trachea and requires airway resection. Tracheal excision site recurrence (ESR) is a serious problem. We investigated predictors of ESR in patients with PTC who underwent airway resection for locally curative surgery. METHODS: We enrolled 149 patients with PTC who underwent airway resection (median age at the initial surgery: 67 years), including partial-thickness resection (n = 73) or full-thickness resection (n = 76), for grossly curative surgery. The median postoperative follow-up period was 93 months. RESULTS: To date, 11 patients (6.7%) underwent ESR: 6 underwent full-thickness resection and 5 underwent partial-thickness resection. The time to ESR ranged from 14 to 113 months (median: 57 months) after the initial surgery. None of the 11 ESR patients underwent adjuvant external beam radiotherapy (EBRT) and none of the 4 airway resection patients who underwent EBRT developed ESR. The 5- and 10-year ESR rates were 4.3% and 11.3%, respectively. In the multivariate analysis (forward-backward stepwise selection method), a Ki-67 labeling index (LI) ≥5% (p = 0.048) and the thyroglobulin doubling rate (Tg-DR) >0.33/year (p = 0.009) (for Tg-antibody negative cases) were independent predictors of ESR. Nine of the 11 patients underwent ESR resection and only one developed a second recurrence. CONCLUSIONS: A high Ki-67 LI was a static predictor, and high Tg-DR was a dynamic predictor, of ESR in patients with PTC following airway resection. In such patients, careful postoperative monitoring for ESR is necessary and adjuvant therapies, such as EBRT, may be considered.

Prognostic significance of T3b in papillary thyroid carcinoma: Appropriateness of classifying T3bN0M0 in patients aged 55 years or older into stage II.

BACKGROUND: Papillary thyroid carcinoma (PTC) often extends to adjacent organs. According to the 8th Tumor-Node-Metastasis Classification, extension to the strap muscles was graded as T3b. We investigated the prognostic impact of T3b and the appropriateness of T3b in patients aged ≥55 years who were classified as stage II. METHODS: We enrolled 7811 patients with M0 PTC who underwent initial surgery at the Kuma Hospital (Kobe, Japan) between January 2007 and December 2016. Tumor extension was divided into T3b, T4a1 (extension to the tracheal adventitia, tracheal cartilage, esophageal muscle layer, recurrent laryngeal nerve, cricothyroid, and inferior constrictor muscles), and sT4a2 (extension to the subcutaneous soft tissues, tracheal mucosa, esophageal mucosa, internal jugular vein, brachiocephalic vein, larynx, pharynx, and sternocleidomastoid muscle). RESULTS: In patients ≥55 years, the local recurrence-free survival (LR-FS), distant recurrence-free survival (DR-FS), and cause-specific survival (CSS) rates of T3bN0M0 were significantly poorer than those of T1/T2N0M0 but did not significantly differ from those of T3aN0M0. The LR-FS, DR-FS, and CSS rates of T3b stage II patients did not differ from those of T4a1 stage III patients but were significantly better than those of T4a2 stage III patients. T3b was an independent predictor of local recurrence and distant recurrence but not of death due to carcinoma in the multivariate analysis. In patients aged <55 years with M0 PTC, T3b had no prognostic value in both analyses. CONCLUSIONS: T3bM0 patients are appropriate to be classified as stage II in patients ≥55 years but be kept in stage I in patients <55 years.

Clinicopathological characteristics of methotrexate-related lymphoproliferative disorder of the thyroid: A study of 11 patients.

Methotrexate (MTX) is a well-known agent that can potentially cause lymphoproliferative disorder (LPD), known as MTX-related LPD (MTX-LPD). Only two cases of thyroid MTX-LPD have been reported to date. This study aimed to report 11 cases of MTX-LPDs arising in the thyroid gland and discuss their clinicopathological characteristics. Of the 747 patients with cytologically suspected lymphoma, 11 had received MTX. The mean age of the patients with MTX-LPD was 70.2 years (range: 51-82 years), and all were female. The duration of MTX administration ranged from 5 to 31 years (mean: 19.5 years). Nine patients (81.8 %) tested positive for anti-thyroglobulin antibody and/or anti-thyroid peroxidase antibody. In three patients, the tumor decreased in size or disappeared without surgery or chemotherapy after withdrawal of MTX therapy. Histologically, all eight nodules examined were B-cell lymphomas, and seven were mucosa-associated lymphoid tissue (MALT) lymphomas. Epstein-Barr virus-encoded small RNA in situ hybridization showed negative results for all six nodules examined. All five patients who were followed-up at our hospital exhibited progression-free survival for >3 years without chemotherapy. Six patients were transferred to other hospitals, and their follow-up details are unknown. MTX-LPDs occurring in the thyroid are characterized by a high female predominance, positivity for anti-thyroid autoantibodies, high prevalence of MALT lymphomas, negativity for Epstein-Barr virus, and good outcomes without chemotherapy. We recommend that patients with thyroid lymphoma should be checked for a history of MTX.

Screening of a Panel of Low Molecular Weight Compounds That Inhibit Synovial Fibroblast Invasion in Rheumatoid Arthritis.

Increased invasion of synovial fibroblasts and their involvement in cartilage damage are characteristic phenotypes of rheumatoid arthritis (RA). To identify low molecular weight compounds that suppress synovial fibroblast invasion, a panel of inhibitors (n = 330) was initially screened using a real-time cell analysis system for human synovial fibroblasts that were enzymatically isolated from surgical samples of RA patients. To evaluate the effects of the inhibitors identified in the screen, synovial fibroblast migration was measured using a wound-healing assay, and phosphorylation of intracellular signaling molecules was determined by immunoblots. Several candidate inhibitors were identified in the screen, including inhibitors against platelet-derived growth factor receptor (PDGFR), Akt, PI3K, and glycogen kinase synthetase 3 (GSK-3). These inhibitors strongly suppressed synovial fibroblast migration after 72 h and downregulated phosphorylation of Akt (Ser473) at 48 h. When the inhibitors were removed from the culture conditions, both migration and phosphorylated Akt (Ser473) levels were restored. Furthermore, all the categories of inhibitors except for PDGFR inhibitor IV decreased cell proliferation as well as IL-6 production in synovial fibroblasts. Interestingly, GSK-3 inhibitors increased anti-inflammatory cytokine IL-10 production but suppressed IL-23 production from LPS-primed macrophages obtained from healthy donors. In conclusion, blocking PDGFR, PI3K, or GSK-3 could have therapeutic value as an RA treatment that targets the invasion/migration of synovial fibroblasts.

Criteria for follow-up of thyroid nodules diagnosed as follicular neoplasm without molecular testing - The experience of a high-volume thyroid centre in Japan.

BACKGROUND: Clinical management of follicular neoplasms (FNs) using molecular testing of thyroid-aspirated materials is not routinely performed in Japan. This article aims to identify low-risk FN nodules that can be followed up without molecular testing. METHODS: The relationship between preoperative findings, factors influencing surgical decision, and the risk of malignancy (ROM) was examined in 356 thyroid nodules with cytological diagnosis of FN at Kuma Hospital from January to December 2020. RESULTS: ROMs of FN with cytology results favouring malignancy (41.2%) were significantly higher than those favouring benign (7.7%) or borderline (8.2%) (p < .001). Moreover, ROMs of FN with ultrasonography results of high suspicion (54.5%) were significantly higher than those with low (4.5%) or intermediate suspicion (0%) (p < .0001). There was a large difference in overall ROM in tumours bordering 30 mm in size (<30 mm; 3.6%, ≥30 mm; 20.0%). ROMs of FNs with a tumour volume doubling rate (TVDR) of 1.0/year or more (28.6%) were higher than those of FNs with a lower TVDR (9.9%) (p < .05). The ROMs of FNs with or without one or more of the following four findings suggestive of malignancy: cytological findings favouring malignancy, ultrasonography findings of high suspicion, tumour size ≥30 mm, and TV-DR ≥1.0/year, were 14.6% and 1.0%, respectively. CONCLUSION: FNs with no cytological findings favouring malignancy, no ultrasonography findings of high suspicion, tumour size <30 mm and TV-DR <1.0/year, are considered low risk and can be followed up without the need for molecular testing.

Design and performance from an integrated PET/MRI system for small animals.

OBJECTIVE: Although simultaneous measurements of PET and magnetic resonance imaging (MRI) can provide interesting results in molecular imaging research, most of the combined systems are huge and animal handling in the system is not easy. To minimize these problems, we developed a compact integrated PET/MRI (iPET/MRI) system for small animals. METHODS: For the iPET/MRI system, a new MR-compatible PET and a permanent magnet open MRI were designed. In the MRI, a tunnel is opened at the yoke of the magnet. The position-sensitive photo-multiplier tubes (PSPMTs) of the MR-compatible PET are positioned at the back of the yoke where the magnetic field is sufficiently low. The scintillators for the PET system are positioned at the center of the MRI magnets, and the direction of the scintillation photons is changed by slanted light guides, and they are fed to the PSPMTs by 75 cm long optical fiber bundles. The PET detectors employed two types of LGSO crystals (1.9 mm x 2.2 mm x 6 mm and 7 mm) with different decay times (33 and 43 ns) for depth of interaction detection. Sixteen optical fiber-based block detectors are arranged in a 112 mm diameter ring. RESULTS: The transaxial field-of-view (FOV) of the PET system is ~80 mm, and the axial FOV is 21 mm which can be enlarged by the axial motion of the PET detector ring during MRI acquisition. The transaxial and axial resolutions at the center of the PET system was 2.9 and 2.4 mm FWHM, respectively. The absolute sensitivity was 1.5% at the center of the axial FOV. Phantom images revealed no artifact in either the PET or MRI images. We successfully obtained simultaneously measured small animal images using the iPET/MRI system. CONCLUSION: The open geometry of the developed iPET/ MRI facilitates easy accessibility to the subject. The iPET/ MRI system appears to be a promising tool for molecular imaging research.

Simultaneous imaging of magnetic resonance imaging and positron emission tomography by means of MRI-compatible optic fiber-based PET: a validation study in ex vivo rat brain.

PURPOSE: We developed a new type of scintillation detector ring for positron emission tomography (PET). In this device the scintillation detectors were connected with 2.6 m length optic fibers to transport scintillation light to a photomultiplier (PMT) located apart from the detector rings. The present study aimed to test the possibility of simultaneous imaging with PET and magnetic resonance imaging (MRI) by means of the present PET device in ex vivo rat brain. MATERIALS AND METHODS: The scintillation detector ring of 4 cm diameter was located in a magnetic field of 0.15 T open MRI. Simultaneous measurements of PET and MRI were performed in ex vivo rat brain after injection of (18)F-fluorodeoxyglucose ((18)F-FDG) 37 MBq and (18)F-NaF 37 MBq. Simultaneous data acquisition was performed for 10 min for PET and 5 min for T1-weighted MRI. RESULTS: Simultaneous imaging of PET and MRI was possible without noticeable image distortion in the PET and MRI scans. In the fusion images, high uptake of (18)F-FDG was identified in the Harderian glands and striatum. High uptake of (18)F-NaF was found in the skull base and vault. CONCLUSIONS: The present study indicated the possibility of simultaneous imaging of PET and MRI by means of optic fiber-based scintillation detectors.

How does Pseudomonas fluorescens avoid suicide from its antibiotic pseudomonic acid?: Evidence for two evolutionarily distinct isoleucyl-tRNA synthetases conferring self-defense.

Two isoleucyl-tRNA synthetases (IleRSs) encoded by two distinct genes (ileS1 and ileS2) were identified in pseudomonic acid (mupirocin)-producing Pseudomonas fluorescens. The most striking difference between the two IleRSs (IleRS-R1 and IleRS-R2) is the difference in their abilities to resist pseudomonic acid. Purified IleRS-R2 showed no sensitivity to pseudomonic acid even at a concentration of 5 mm, 105 times higher than the Ki value of IleRS-R1. The amino acid sequence of IleRS-R2 exhibits eukaryotic features that are originally found in eukaryotic proteins. Escherichia coli cells transformed with the ileS2 gene exerted pseudomonic acid resistance more than did those transformed with ileS1. Cells transformed with both genes became almost as resistant as P. fluorescens. These results suggest that the presence of IleRS-R2 could be the major reason why P. fluorescens is intrinsically resistant to the antibiotic. Here we suggest that the evolutionary scenario of the eukaryotic ileS2 gene can be explained by gene acquisition and that the pseudomonic acid producer may have maintained the ileS2 gene to protect itself from pseudomonic acid.

Stimulated accumulation of lectin mRNA and stress response in Helianthus tuberosus callus by methyl jasmonate.

Callus from Helianthus tuberosus expresses a mannose-specific lectin (HTA). The level of HTA mRNA significantly increased one hour after treatment of the callus with 20 mg/l methyl jasmonate. Following this, fragmentation of the callus DNA at regular intervals was observed together with strong self-fluorescence emission in the callus cells.