Role of the Degree of Vascular Invasion in Predicting Prognosis of Follicular Thyroid Carcinoma.

OBJECTIVE: The present study investigated the prognostic factors for follicular thyroid carcinoma (FTC) with the incorporation of the histologic subtype and degree of vascular invasion (VI). PATIENTS: The records of 474 patients with FTC confirmed by surgical specimens at Ito Hospital from January 2005 to December 2014 were reviewed in this retrospective cohort study. The Cox proportional hazard model was used to determine factors associated with disease-free survival (DFS) and distant metastasis-free survival. RESULTS: Of the 474 patients, 140 (30%) had minimally invasive FTC, 260 (55%) had encapsulated angio-invasive FTC, and 74 (16%) had widely invasive FTC. Among the 428 patients with M0 FTC, the 10-year DFS rates of patients with minimally invasive FTC (n = 133), encapsulated angio-invasive FTC (n = 247), and widely invasive FTC (n = 48) were 97.3%, 84.2%, and 69.9% (P < .001), respectively. A multivariate analysis identified aged ≥55 years (hazard ratio [HR], 2.204; 95% CI, 1.223-3.969; P = .009), histologic subtype (HR, 2.068; 95% CI, 1.064-4.021; P = .032), VI of ≥2 (HR, 6.814; 95% CI, 3.157-14.710; P < .001), and tumor size >40 mm (HR, 2.014; 95% CI, 1.089-3.727; P = .026) as independent negative prognostic factors for DFS. CONCLUSION: Our study results may enable us to stratify the prognosis of FTC more accurately by combining the histologic subtype with the degree of VI ≥2, aged ≥55 years, and tumor size >40 mm.

Transcriptional Regulation of Methanol Dehydrogenases in the Methanotrophic Bacterium Methylococcus capsulatus Bath by Soluble and Insoluble Lanthanides.

The effects of soluble and insoluble lanthanides on gene expression in Methylococcus capsulatus Bath were investigated. Genes for lanthanide-containing methanol dehydrogenases (XoxF-MDHs) and their calcium-containing counterparts (MxaFI-MDHs) were up- and down-regulated, respectively, by supplementation with soluble lanthanide chlorides, indicating that M. capsulatus has the "lanthanide switch" observed in other methanotrophs. Insoluble lanthanide oxides also induced the lanthanide switch and were dissolved by the spent medium of M. capsulatus, suggesting the presence of lanthanide-chelating compounds. A transcriptome ana-lysis indicated that a gene cluster for the synthesis of an enterobactin-like metal chelator contributed to the dissolution of insoluble lanthanides.

The importance of early-stage blood pressure control in thyroid cancer patients treated with lenvatinib from the perspective of dose intensity.

PURPOSE: Lenvatinib (LEN) is a multikinase inhibitor that strongly inhibits tyrosine kinase receptors, especially VEGFR-2, which can cause hypertension, as well as strong tumor shrinkage. Though control of any side effects (SEs) is important for maintaining dose intensity (DI), hypertension is particularly important, because blood pressure (BP) can change quickly and respond to LEN administration and withdrawal, and it can be controlled with antihypertensive medications. Focusing on the early phase of treatment, the effect of BP 8 weeks after LEN initiation (BP8w) on DI at 8 weeks (DI8w) was investigated. METHODS: The subjects were 85 thyroid cancer patients who started LEN at 24 mg/day and continued for ≥8 weeks. The BP at the start of LEN (BPbase), BP8w grade, and DI8w were examined. RESULTS: Median (range) systolic BP changed significantly from BPbase of 117 (84-167) mmHg to BP8w of 134 (103-168) mmHg (p<0.001). Antihypertensive treatment at baseline, systolic BPbase, and male sex were related to higher DI8w on multivariate analysis. The median DI8w of the 23 patients who required dose modification due to hypertension was 20.2 mg/day (n=6) in grade 1, 15.8 mg/day (n=13) in grade 2, and 14.5 mg/day (n=4) in grade 3, showing a trend toward lower DI8w as the grade level increased. CONCLUSION: LEN can increase BP by 20 mmHg at 8 weeks even with intensive antihypertensive management. Baseline antihypertensive treatment and BPbase can affect DI8w. A higher DI8w may be achieved by aiming for a low 8-week BP with more intensive antihypertensive therapy after LEN initiation.

Clinical classification of recurrent laryngeal nerve palsy.

Background: The application of intraoperative neurophysiological monitoring (IONM) has been accepted to avoid injury of a recurrent laryngeal nerve (RLN). Loss of the neuromonitoring signal indicates nerve injury and is subdivided into segmental type and global type nerve paralysis. This study aimed to determine the course of vocal cord function recovery after definitive loss of signal (LOS) types. Methods: This retrospective study included 1,442 patients (with 2,752 nerves at risk) who had thyroidectomies between January 2018 and December 2021. Preoperative and postoperative vocal cord functions were evaluated by laryngoscopic examination. Results: LOS occurred in 168 of 1,442 (11.7%) patients and 171 of 2,748 (6.2%) nerves at risk during surgery. Of LOS nerves of benign tumors, 74.2% showed global type. In cancer cases, segmental paralysis was more common, accounting for 51.3% of LOS nerves. Of nerves with segmental LOS in cancer patients, 55.3% needed partial layer resection for RLN invasion. Intraoperative recovery was seen in 9 of 62 nerves (14.5%) with segmental LOS and 32 of 109 (29.4%) nerves with global type LOS. The vocal cord palsy rate on postoperative days (PODs) 2-3 was lower after global type nerve paralysis (63.6%) than after segmental loss (84.9%). At 6 months postoperatively, the rate of vocal cord paralysis in benign tumors was not significantly different between segmental type and global type (P=0.586). However, cancer patients with segmental LOS significantly more often had vocal cord dysfunction than those with global LOS at 6 months postoperatively (rate of nerve palsy: segmental 40.0% vs. global 3.4%) (P<0.001). Conclusions: The intraoperative recovery rate and early nerve recovery rate are significantly higher for patients with global LOS than for patients with segmental LOS. Cancer patients with segmental LOS significantly more often had vocal cord dysfunction than those with global LOS at 6 months postoperatively.

New Insights on the Importance of the Extent of Vascular Invasion in Widely Invasive Follicular Thyroid Carcinoma.

BACKGROUND: This study aimed to investigate the association between the extent of vascular invasion (VI) and the outcome of widely invasive follicular thyroid carcinoma (WI-FTC). METHODS: The records of 107 patients with WI-FTC confirmed by surgical specimens from January 2005 to December 2016 were retrospectively reviewed. RESULTS: Among the 107 patients with WI-FTC, those with a VI of < 4 (n = 62) and ≥ 4 (n = 45) had a 10 year cause-specific survival (CSS) rate of 97.7% and 89.4% (p = 0.008), respectively. Univariate analysis identified M1 (p = 0.001), and the number of VI of ≥ 4 as significant negative prognostic factors for CSS. Multivariate analysis identified M1 (hazard ratio [HR] = 9.366) as independent negative prognostic factor for CSS. Among the 72 patients with M0 WI-FTC, those with a VI of < 2 (n = 33) and ≥ 2 (n = 39) had a 10-year distant metastasis-free survival (DMFS) rate of 96.8% and 56.8% (p = 0.001), respectively. Univariate analysis identified age ≥ 55 years (p = 0.011), presence of VI, the number of VI of ≥ 2, and resection margin status (p < 0.001) as significant negative prognostic factors for DMFS. Multivariate analysis identified the number of VI ≥ 2 (HR = 9.137), and resection margin status (HR = 5.853) as independent negative prognostic factors for DMFS. CONCLUSIONS: It may be unnecessary that WI-FTC with curative resection margin status and a VI of < 2, especially in capsular invasion only, routinely undergo completion thyroidectomy and postoperative ablation.

Self-cloning of the Catalase Gene in Environmental Isolates Improves Their Colony-forming Abilities on Agar Media.

Hydrogen peroxide (H2O2) inhibits microbial growth at a specific concentration. However, we previously isolated two environmental bacterial strains that exhibited sensitivity to a lower H2O2 concentration in agar plates. Putative catalase genes, which degrade H2O2, were detected in their genomes. We herein elucidated the characteristics of these putative genes and their products using a self-cloning technique. The products of the cloned genes were identified as functional catalases. The up-regulation of their expression increased the colony-forming ability of host cells under H2O2 pressure. The present results demonstrated high sensitivity to H2O2 even in microbes possessing functional catalase genes.

Role of Surgery in Patients with Stage IE Primary Thyroid MALT Lymphoma Staged by a Modified Classification System: The Tokyo Classification.

PURPOSES: To establish the appropriate staging system and assess the role of curative thyroidectomy alone (Surgery) vs. involved-site radiation therapy after open biopsy (OB-ISRT) in stage IE mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS: We examined the Tokyo Classification as a modified classification. This retrospective cohort study included 256 patients with thyroid MALT lymphoma; 137 underwent standard therapy (i.e., OB-ISRT) and were enrolled for the Tokyo classification. Sixty stage IE patients with the same diagnosis were examined to compare Surgery with OB-ISRT. RESULTS: Overall survival (p = 0.0092) and relapse-free survival (0.00113) were significantly better in stage IE vs. stage IIE under the Tokyo classification. No OB-ISRT and Surgery patients died, but three OB-ISRT patients relapsed. The incidence of permanent complications was 28% in OB-ISRT (mainly dry mouth) and 0% in Surgery (p = 0.027). The number of painkiller prescription days was significantly greater in OB-ISRT (p < 0.001). During follow-up, the rate of the new appearance/change of the low-density area in the thyroid gland was significantly higher in OB-ISRT (p = 0.031). CONCLUSIONS: The Tokyo classification allows an appropriate discrimination between stages IE and IIE MALT lymphoma. Surgery can provide a good prognosis in stage IE cases; it also avoids complications, shortens painful periods during treatment, and simplifies ultrasound follow-up.

Genome Sequences of Comamonadaceae Bacteria OS-1 and OS-4, Two Highly H2O2-Sensitive Strains Isolated from Pond Water.

The Comamonadaceae bacterial strains OS-1 and OS-4 were isolated from pond water and were found to be highly sensitive to hydrogen peroxide in the agar plates. Here, we report the nearly complete and complete genome sequences, respectively, of these two strains.

Development of Efficient Genome-Reduction Tool Based on Cre/loxP System in Rhodococcus erythropolis.

Rhodococcus has been extensively studied for its excellent ability to degrade artificial chemicals and its capability to synthesize biosurfactants and antibiotics. In recent years, studies have attempted to use Rhodococcus as a gene expression host. Various genetic tools, such as plasmid vectors, transposon mutagenesis, and gene disruption methods have been developed for use in Rhodococcus; however, no effective method has been reported for performing large-size genome reduction. Therefore, the present study developed an effective plasmid-curing method using the levansucrase-encoding sacB gene and a simple two-step genome-reduction method using a modified Cre/loxP system. For the results, R. erythropolis JCM 2895 was used as the model; a mutant strain that cured all four plasmids and deleted seven chromosomal regions was successfully obtained in this study. The total DNA deletion size was >600 kb, which corresponds mostly to 10% of the genome size. Using this method, a genome-structure-stabilized and unfavorable gene/function-lacking host strain can be created in Rhodococcus. This genetic tool will help develop and improve Rhodococcus strains for various industrial and environmental applications.

Evaluation of factors predicting postoperative recurrence and metastasis of parathyroid cancer: a single-center study.

PURPOSE: The purpose of this study was to examine the postoperative clinical course of parathyroid carcinoma to determine factors that predict postoperative recurrence and distant metastasis. METHODS: In this retrospective study, we included 38 patients with parathyroid carcinoma who received surgical intervention at Itoh Hospital between 1979 and 2020. Clinicopathologic characteristics (age, sex, intact PTH, serum Ca level, operation type, parathyroid weight, parathyroid size, histopathologic findings: vascular invasion, capsular invasion, necrosis, histological type, and Ki-67 staining) were used. The median follow-up observation period was 63.7 months. RESULTS: Postoperatively, 5 patients (13.2%) developed distant metastasis or had localized recurrence, and 3 patients died (7.9%). The results of the univariate analysis revealed three factors affecting distant metastasis and recurrence, which were Ki-67 (p = 0.0041), the presence or absence of necrosis (p = 0.0163), and tumor weight (p = 00,189). Using the cutoff values obtained by ROC analysis, which were 4.1 for Ki-67 (sensitivity of 80% and specificity of 96.9%) and 4890 mg for tumor weight (sensitivity of 100% and specificity of 60.9%), we calculated the cumulative incidence of recurrence and distant metastasis by the three factors retained. We found that the presence of the three factors was associated with a high possibility of distant metastasis or recurrence during the 5-year follow-up period. CONCLUSIONS: Three factors, Ki-67, necrosis, and tumor weight in parathyroid carcinoma, may predict outcomes of postoperative recurrence and distant metastasis.

Impact of Age on Prognosis in Papillary Thyroid Carcinoma: How Should Age be Incorporated into the Treatment Strategy?

BACKGROUND: Age has been recognized as one of the strong prognostic indicators for thyroid cancer. However, treatment strategies for papillary thyroid cancer (PTC) are usually determined only by the extent of disease progression, without considering the patient's age. The aim of this study was to investigate how the surgical strategy for PTC should take into account patient age. METHODS: To exclude the effect of treatment strategy, 837 patients treated with uniform treatment strategies (hemithyroidectomy without radioiodine therapy) between 1986 and 1995 were the subjects of this study. Using a Cox proportional hazard model, clinical risk factors related to disease-specific survival (DSS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) were analyzed. A receiver-operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff points. RESULTS: Significant risk factors related to DSS and DMFS were age, extrathyroidal extension (ETE), and numbers of metastatic lymph nodes (NMLNs), but age was not significantly related to DFS. The 20-year DSS and DMFS rates were fair in patients without ETE regardless of age or NMLNs. However, in patients with ETE, DSS and DMFS rates were significantly worse in elderly patients than in young patients. ROC curve analysis showed that the optimal cutoff age was 48 years for discriminating DSS in patients with ETE. CONCLUSION: Regardless of age, PTC patients without ETE are candidates for a treatment strategy not using RAI, and more aggressive treatment may be recommended for elderly PTC patients with ETE.

Response to neoadjuvant paclitaxel predicts survival in anaplastic thyroid carcinoma.

The clinical utilities of paclitaxel in anaplastic thyroid carcinoma (ATC) have been reported. The current study investigated the outcomes in ATC patients treated by paclitaxel as neoadjuvant setting. Furthermore, the prognostic factor for overall survival (OS) and predictive marker for response to paclitaxel were investigated. Records of ATC patients treated by paclitaxel as neoadjuvant setting in our hospital were reviewed. The median OS for the patients with (n = 43) and without (n = 23) resection were 14.7 (95% CI, 11.0-21.7) and 4.2 (95% CI, 3.0-5.4) months, respectively (p < 0.001). Univariate analysis identified the factors of stage (p = 0.028), prognostic index (PI) ≥2 (p < 0.001), response to paclitaxel (p = 0.007), resection (p < 0.001), and radiotherapy (p < 0.001) to be associated with OS, and multivariate analysis revealed that the factors of PI ≥2 [hazard ratio (HR), 2.406 (95% CI, 1.096-5.281), p = 0.029], response to paclitaxel [HR, 0.423 (95% CI, 0.193-0.930), p = 0.032], resection [HR, 0.316 (95% CI, 0.129-0.773), p = 0.012], and radiotherapy [HR, 0.229 (95% CI, 0.100-0.526), p < 0.001] were independent prognostic factors of OS. There were no significant predictive factors for response to paclitaxel in baseline characteristics. PI ≥2, response to paclitaxel, resection, and radiotherapy were independent prognostic factors in ATC patients treated with paclitaxel as neoadjuvant setting. It is important to investigate predictor for response to paclitaxel for improving resectability and prognosis in ATC.

Complete Genome Sequence of Rhodococcus erythropolis JCM 2895, an Antibiotic Protein-Producing Strain.

The complete genome sequence of Rhodococcus erythropolis JCM 2895, an antibiotic protein-producing strain, was determined. It consists of a 6,455,263-bp chromosome, one linear plasmid (pR09L01 [227,989 bp]), and three circular plasmids (pR09C01 [79,600 bp], pREC01 [5,420 bp], and pREC02 [5,444 bp]).

Critical Effect of H2O2 in the Agar Plate on the Growth of Laboratory and Environmental Strains.

We previously showed that autoclaving in preparing agar media is one of the sources of hydrogen peroxide (H2O2) in the medium. This medium-embedded H2O2 was shown to lower the total colony count of environmental microorganisms. However, the critical concentrations of H2O2 detrimental to colony formation on the agar plate remain largely undetermined. Herein, we elucidated the specific effect of H2O2 on microbial colony formation on solid agar medium by external supplementation of varying amounts of H2O2. While common laboratory strains (often called domesticated microbes) formed colonies in the presence of high H2O2 concentrations (48.8 µM or higher), microbes from a freshwater sample demonstrated greatly decreased colony counts in the presence of 8.3 µM H2O2. This implies that environmental microbes are susceptible to much lower concentrations of H2O2 than laboratory strains. Among the emergent colonies on agar plates supplemented with different H2O2 concentrations, the relative abundance of betaproteobacterial colonies was found to be lower on plates containing higher amounts of H2O2. Further, the growth of the representative betaproteobacterial isolates was completely inhibited in the presence of 7.2 µM H2O2. Therefore, our study clearly demonstrates that low micromolar levels of H2O2 in agar plates critically affect growth of environmental microbes, and large portions of those are far more susceptible to the same than laboratory strains. IMPORTANCE It is well-known that most of environmental microorganisms do not form colonies on agar medium despite that agar medium is the commonly used solidified medium. We previously demonstrated the negative effects of H2O2 generation during agar medium preparation on colony formation. In the present study, we investigated the independent effect of H2O2 on microbial growth by adding different concentrations of H2O2 to agar medium. Our results demonstrate for the first time that even low micromolar levels of H2O2 in agar plates, that are far lower than previously recognized as significant, adversely affect colony number obtained from freshwater inoculum.

Impact of Local Control on Clinical Course in Stage IVC Anaplastic Thyroid Carcinoma.

BACKGROUND: The present study investigated the association between local resection and cause of death in anaplastic thyroid carcinoma (ATC) patients with stage IVC disease. METHODS: A total of 54 ATC patients with stage IVC disease were included in the study. Information including patient characteristics, laboratory data including complete blood count, treatment, and death were collected for analysis. RESULTS: The median overall survival (OS) for patients with or without resection was 8.4 [95% confidence interval (CI) 5.9-14.4)] and 4.2 (95% CI 2.5-6.2) months, respectively (p < 0.001). No patients survived without resection at 1 year. Univariate analysis revealed that resection (p < 0.001) and radiotherapy (p = 0.018) were significantly associated with OS. Multivariate analysis revealed that resection (hazard ratio 0.257; 95% CI 0.115-0.575; p < 0.001) was the only independent prognostic factor of OS. In ATC patients with known resection status, the median OS for the patients with a resection status of R0/1 (n = 28) and R2 (n = 7) were 13.0 (95% CI 7.5-18.7) and 1.7 (95% CI 0.1-6.2) months, respectively (p < 0.001). The most common specific cause of death was respiratory insufficiency (35%), followed by airway obstruction (25%) and cerebral cardiovascular-related death (5%). The frequency of airway obstruction was significantly lower in patients with resection (p = 0.018). CONCLUSIONS: Resection probably impacts on clinical course in ATC patients despite the presence of distant metastasis. However, R2 resection is likely to be harmful and surgeons should carefully consider the resectability of thyroid tumors.

Preoperative inflammatory markers for predicting parathyroid carcinoma.

Objective: Parathyroid carcinoma is a rare tumor among parathyroid tumors. Aspiration cytology and needle biopsy are generally not recommended for diagnostic purposes because they cause dissemination. Therefore, it is commonly diagnosed by postoperative histopathological examination. In this study, we investigated whether preoperative inflammatory markers can be used as predictors of cancer in patients with primary hyperparathyroidism. Design: This was a retrospective study. Methods: Thirty-six cases of parathyroid carcinoma and 50 cases of parathyroid adenoma (PA) operated with the diagnosis of primary hyperparathyroidism and confirmed histopathologically at Ito Hospital were included in this study. Preoperative clinical characteristics and inflammatory markers (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio (LMR)) were compared and their values in preoperative prediction were evaluated and analyzed. Results: Preoperative intact-parathyroid hormone (P = 0.0003), serum calcium (P = 0.0048), and tumor diameter (P = 0.0002) were significantly higher in parathyroid carcinoma than in PA. LMR showed a significant decrease in parathyroid carcinoma (P = 0.0062). In multivariate analysis, LMR and tumor length diameter were independent predictors. In the receiver operating characteristics analysis, the cut-off values for LMR and tumor length diameter were 4.85 and 28.0 mm, respectively, for parathyroid cancer prediction. When the two extracted factors were stratified by the number of factors held, the predictive ability improved as the number of factors increased. Conclusion: In the preoperative evaluation, a combination of tumor length diameter of more than 28 mm and LMR of less than 4.85 was considered to have a high probability of cancer.

Prevalence and Characterization of Gentamicin Resistance Genes in Escherichia coli Isolates from Beef Cattle Feces in Japan.

Gentamicin is an important antibiotic for the treatment of opportunistic infections in the clinical field. Gentamicin-resistant bacteria have been detected in livestock animals and can be transmitted to humans through the food supply or direct contact. We have previously revealed that gentamicin-resistant Escherichia coli are distributed at a comparatively high rate from beef cattle in Japan, but few studies have focused on the molecular epidemiology of gentamicin-resistant bacteria. To understand these bacteria, this study examined the prevalence of various gentamicin resistance genes in gentamicin-resistant E. coli isolates from beef cattle feces. Of the 239 gentamicin-resistant E. coli isolates, the presence of the aacC2, aadB, or aac(3)-VIa genes was confirmed in 147, 84, and 8 isolates, respectively. All aac(3)-VIa-harboring isolates had an MIC value of 64 µg/mL for gentamicin and exhibited resistance to 11 antibiotic agents. An analysis of the representative aac(3)-VIa-harboring E. coli strain GC1-3-GR-4 revealed that the aac(3)-VIa gene was present on the IncA/C plasmid together with the aadA and blaCMY genes. Furthermore, the upstream region of the aac(3)-VIa gene contained the aadA gene and the class 1 integron-integrase gene (intI1). The aac(3)-VIa gene was detected for the first time in Japan and is expected to be able to transfer between bacteria via the IncA/C plasmid and integron. These results reveal the expansion of the distribution or diversity of gentamicin resistance genes in Japan.

Successful dose escalation of lenvatinib for thyroid cancer after disease progression.

PURPOSE: Lenvatinib is started at a standard dose, continuing with dose reduction and interruption, balancing between efficacy and adverse events (AEs). Because few drugs are available for thyroid cancer, efforts for continuing treatment with one agent, such as "dose escalation (DE)", are made. The dose is increased, aiming to regain the anti-tumor effect after dose reduction. The effects of lenvatinib DE in differentiated thyroid carcinoma (DTC) patients are reported. PATIENTS AND METHODS: The efficacy of lenvatinib DE in DTC patients using the serum thyroglobulin (Tg) level and management of AEs was investigated. RESULTS: A total of 70 DE episodes in 33 patients were investigated. The median increased dose was 2.0 (1.0-14.0) mg, increased from 8.6 (2-16) mg to 10.1 (6-24) mg. The serum Tg level decreased in 53 DE episodes. Though the serum Tg level in 17 DE episodes was not decreased, the Tg rate of increase was decreased in 7 of these DE episodes using the Tg-doubling rate. Overall, clinical benefit was seen in 60 (86%) DE episodes. AEs that could not be controlled after DEs were seen in only 16% of cases. No intolerable AEs were observed in patients who received more drug holidays at the time of DEs compared to two times before the DEs. CONCLUSION: DE may become one of the standard treatment strategies after disease progression if AEs are well managed. Drug holidays may be a key for successfully controlling AEs with DE. DE can be useful for controlling progressive disease with increasing Tg levels.