A prospective cross-sectional study on hypocalcemia after total thyroidectomy in patients with Graves' disease: insights on secondary hyperparathyroidism.

PURPOSE: To investigate the parathyroid function and calcium (Ca) levels in the secondary hyperparathyroidism (SHPT) state in patients with Graves' disease. METHODS: We examined 31 consecutive patients with Graves' disease without chronic kidney disease, who were treated with total thyroidectomy. The patients were divided into a normal parathyroid hormone (PTH) group (NPTH group; n = 19) with a PTH level ≤ 65 pg/mL, and a secondary hyperparathyroidism group (SHPT group; n = 12), with a PTH level > 65 pg/mL. The PTH and Ca-related parameters were examined and the risk factors for postoperative hypocalcemia were analyzed. RESULTS: The preoperative Ca level was significantly lower (2.24 ± 0.06 vs. 2.31 ± 0.07 mmol/L, p < 0.05) in the SHPT group than in the NPTH group. The reduction in PTH, 1,25-dihydroxyvitamin D (1,25(OH)2D), and Ca levels from the preoperative day to the next morning was significantly greater in the SHPT group than in the NPTH group (p < 0.05). When intraoperative factors were included, the decrease in the PTH level alone was significant. SHPT was a significant factor in determining the extent of PTH reduction. CONCLUSIONS: Hyperfunctioning parathyroid glands in the SHPT state were more susceptible to postoperative PTH reduction, which, combined with low preoperative Ca levels, increased the risk of postoperative hypocalcemia in patients with Graves' disease.

Intraoperative parathyroid hormone measurement pitfalls: parathyroid hormone spikes with carboxyl-terminal parathyroid hormone fragments in primary hyperparathyroidism-a case report.

BACKGROUND: Intraoperative parathyroid hormone (IOPTH) monitoring is a critical surgical adjunct for determining the extent of surgery for primary hyperparathyroidism (PHPT), with reported false-positive and false-negative rates of up to 10%. Surgeons must understand the parathyroid hormone (PTH) dynamics and select the appropriate IOPTH protocol and interpretation criteria for curative surgery. CASE PRESENTATION: We present the case of a 64-year-old woman with a large cystic parathyroid tumor and PHPT who experienced a significant delay in IOPTH decrease but was cured without additional surgery. The patient's basal intact PTH was 96.2 pg/mL, which decreased to 93.3 pg/mL at 25 min and 72.4 pg/mL at 55 min after removal of the parathyroid tumor. In an attempt to elucidate its pathophysiology, 1-84 PTH levels were measured in stored serum. These results can also be attributed to the relatively low basal PTH levels, intact PTH spike, and high ratio of large carboxyl-terminal PTH fragments present. The patient had normal intact PTH and calcium levels at the 9-month postoperative visit. CONCLUSIONS: As detailed reports on these phenomena are scarce, we discuss the causes of false-negative IOPTH results in terms of PTH production, secretion, metabolism, and differences in measurement methods to avoid unnecessary surgery.

A Prospective Cohort Study Exploring the Effect of Lenvatinib Planned Drug Holidays in Treatment of Differentiated Thyroid Cancer.

Background: Although lenvatinib is the preferred treatment for unresectable radioactive iodine-refractory differentiated thyroid cancer (RR-DTC), this agent exerts considerable toxicities, which can lead to frequent dose interruptions and modifications. The adoption of planned drug holidays has been recently suggested as one means of minimizing or avoiding these severe adverse events. Our retrospective study demonstrated that planned drug holidays appear to be a promising strategy for continuing of lenvatinib. However, the benefits of planned drug holidays in a prospective study have yet to be clarified. Here, we investigated the impact of planned drug holidays on clinical outcomes in patients treated with lenvatinib in the COLLECT study. Methods: In COLLECT, a prospective observational study, patients with RR-DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities was permitted. Furthermore, planned drug holidays were allowed to avoid severe or intolerable toxicities. The present post hoc analysis focused on evaluating the impact of planned drug holidays on clinical outcomes, including overall survival (OS), time to treatment failure (TTF), time to failure strategy (TFS), and progression-free survival (PFS), in patients in the COLLECT study who were treated with lenvatinib. Results: In total, 262 patients were included. Of the 253 patients evaluable for efficacy, 73 undertook a planned drug holiday at the discretion of the attending physician. OS, TTF, TFS, and PFS were significantly longer in patients who used a planned drug holiday than in those who did not. The planned drug holiday group demonstrated notable clinical outcomes, with a 1-year OS of 95.8% and a 1-year PFS of 94.5%. Moreover, planned drug holidays demonstrated a clinically meaningful advantage in clinical outcomes. The planned drug holiday group had a significantly longer duration of administration at a dose of ≥10 mg. Conclusions: Planned drug holidays for lenvatinib were associated with significantly improved clinical outcomes compared to daily oral administration. Further investigation of the optimal treatment schedule for lenvatinib is warranted. Clinical Trial Registration: UMIN000022243.

Usefulness of preoperative ice cream consumption and novel postoperative drainage management in patients undergoing left-sided neck dissection for thyroid cancer: a nonrandomized prospective study.

PURPOSE: This study investigated the effects of ice cream consumption on chyle leakage after left lateral neck dissection in patients with thyroid cancer. METHODS: A total of 491 patients with thyroid cancer underwent left lateral neck dissection with identification of the thoracic duct following ice cream consumption. Before closing the wound, the anesthesiologist increased the intrathoracic pressure to observe chyle leakage. If chyle leakage occurred postoperatively, the drain was removed using the drain negative pressure release test. RESULTS: Postoperative chyle leakage was observed in 18 of the 491 patients who underwent left lateral neck dissection. We treated 17 patients conservatively and 1 patient surgically. Drains were removed within five days in all patients. After the drain negative pressure release test had been performed in eight patients, the drainage volume significantly decreased from an average of 175 ml to 31 ml per day. The average number of days until the removal of the drainage tube was 3.2 days. No perioperative complications were associated with ice cream consumption. CONCLUSIONS: In left lateral neck dissection for thyroid cancer, performing surgery following ice cream consumption does not completely prevent chyle leakage; however, early drain removal is possible because there is only mild leakage.

Clinical Characteristics and Predictors of the Recurrence of Organizing Pneumonia Associated With Rheumatoid Arthritis.

OBJECTIVE: To clarify the clinical characteristics of organizing pneumonia (OP) in rheumatoid arthritis (RA; RA-OP) and the association of OP development with RA exacerbation, and to identify OP recurrence predictors. METHODS: Data from 33 patients with RA-OP admitted to our hospital were retrospectively analyzed (2006-2016). RESULTS: RA onset preceded OP onset in 82% of patients, whereas OP onset preceded (OP-preceding) or co-occurred with RA in 9% of patients each. Median age at first OP onset was 64.0 years, and the period from RA onset to first OP onset was 5.5 years. At OP onset, 42% of events exhibited unilateral involvement and 76% had normal Krebs von den Lungen-6. RA disease control remained optimal in 52% of events and was exacerbated in 18% of events. Ten patients (30%) experienced OP recurrence with an interval of 13.0 months between events, and the first OP recurrence rate was 127/1000 person-years. Compared with nonrecurrent cases (n = 14), recurrent cases (n = 10) showed lower age at first OP onset (59.5 vs 67.1 yrs; P = 0.04) and a shorter period from RA onset to first OP onset (6.4 vs 14.2 yrs; P = 0.047); moreover, these cases included a higher number of OP-preceding patients (30% vs 0%; P = 0.03) and ever smokers (80% vs 36%; P = 0.03). OP-preceding patients showed shorter median recurrence-free survival time (15 vs 136 months; P = 0.01) and higher recurrence risk (hazard ratio 5.45; P = 0.02). CONCLUSION: RA-OP showed a high recurrence rate and was not associated with RA exacerbation. Four RA-OP recurrence predictors were identified.

Extracellular aaRSs drive autoimmune and inflammatory responses in rheumatoid arthritis via the release of cytokines and PAD4.

OBJECTIVES: Recent studies demonstrate that extracellular-released aminoacyl-tRNA synthetases (aaRSs) play unique roles in immune responses and diseases. This study aimed to understand the role of extracellular aaRSs in the pathogenesis of rheumatoid arthritis (RA). METHODS: Primary macrophages and fibroblast-like synoviocytes were cultured with aaRSs. aaRS-induced cytokine production including IL-6 and TNF-α was detected by ELISA. Transcriptomic features of aaRS-stimulated macrophages were examined using RNA-sequencing. Serum and synovial fluid (SF) aaRS levels in patients with RA were assessed using ELISA. Peptidyl arginine deiminase (PAD) 4 release from macrophages stimulated with aaRSs was detected by ELISA. Citrullination of aaRSs by themselves was examined by immunoprecipitation and western blotting. Furthermore, aaRS inhibitory peptides were used for inhibition of arthritis in two mouse RA models, collagen-induced arthritis and collagen antibody-induced arthritis. RESULTS: All 20 aaRSs functioned as alarmin; they induced pro-inflammatory cytokines through the CD14-MD2-TLR4 axis. Stimulation of macrophages with aaRSs displayed persistent innate inflammatory responses. Serum and SF levels of many aaRSs increased in patients with RA compared with control subjects. Furthermore, aaRSs released PAD4 from living macrophages, leading to their citrullination. We demonstrate that aaRS inhibitory peptides suppress cytokine production and PAD4 release by aaRSs and alleviate arthritic symptoms in a mouse RA model. CONCLUSIONS: Our findings uncovered the significant role of aaRSs as a novel alarmin in RA pathogenesis, indicating that their blocking agents are potent antirheumatic drugs.

A novel protocol for de-isolating moderately and severely immunocompromised COVID-19 patients.

Immunocompromised coronavirus disease 2019 patients are at a higher risk of prolonged viral shedding than immunocompetent patients. However, as of August 2023, there is no clear international standard for de-isolating vulnerable patients. A comprehensive assessment is advisable based on various information, such as the increase in immune escape of specific mutant strains as well as the patient's innate immunity and vaccination status; therefore, consultation with an infectious disease specialist is recommended. The patient population defined as moderately or severely immunocompromised by the Centers for Disease Control and Prevention and the European Centre for Disease Prevention and Control is significantly broad. A boundary between the two remains to be delineated, and the existing protocols allow the release of patients based on their symptoms alone. This may lead to an unnecessary extension or premature termination of isolation. In this study, we searched for studies, particularly those that used real-world data, discussed the results with experts in our hospital, and proposed new isolation criteria based on both testing and clinical symptoms. We classified patients into three groups namely severely, moderately, and mildly immunocompromised, defined by their background and the administration of immunosuppressive drugs. A separate flowchart for ending isolation is indicated for each group. This standard may be a useful support material, especially for non-specialists. Nevertheless, our criteria must be revised and added continuously; accumulating real-world data to support revision of and addition to the list is becoming increasingly important.

Gestational Outcomes and Birth Weight in Japanese Women at the Upper and Lower limits of the Normal BMI range.

To examine the outcome of gestational blood pressure and birth weight in women with normal pre-pregnancy BMI (18.5-25 kg/m2) who are at the lower and upper limits of this range, i.e., slightly underweight or slightly overweight. Overall, 2,038 Japanese women with low -risk who had delivered during January 2014-December 2016 were classified according to their pre-pregnancy BMI: underweight (< 18.5 kg/m2), slightly underweight (18.5≤BMI<21 kg/m2), normal (21≤BMI<23 kg/m2), slightly overweight (23≤BMI<25 kg/m2) and overweight (≤ 25 kg/m2). Their blood pressure during each trimester and birth weight was evaluated. The slightly overweight group showed a significantly higher blood pressure than the underweight and slightly underweight groups. Birth weight was lower in the slightly underweight than in the slightly overweight group (p<0.01). The incidence rate of "heavy for dates" (HFD) infants was significantly higher in the slightly overweight and overweight groups than in the other groups (p<0.05 and p<0.01, respectively). Weight gain of < 7 kg significantly increased the rate of "light for dates" (LFD) infants, while a weight gain of ≥13 kg significantly increased the rate of HFD infants (p<0.05 and p<0.01, respectively). Blood pressure during pregnancy was ssociated with pre-pregnancy BMI. The birth weight of infants of low-risk pregnant women is affected by both pre-pregnancy BMI and gestational weight gain.

Molecular Pathological Characteristics of Thyroid Follicular-Patterned Tumors Showing Nodule-in-Nodule Appearance with Poorly Differentiated Component.

Thyroid follicular-patterned tumors (TFTs) showing nodule-in-nodule (NN) appearance with poorly differentiated component (PDc) but neither invasion nor metastasis are diagnosed as benign nodules. Although PDc exhibits histologically aggressive features relative to the outer nodule (Out-N), its pathological significance remains unclear. TP53 binding protein-1 (53BP1) is a DNA damage response (DDR) molecule that rapidly localizes at DNA double-strand breaks. Using dual-color immunofluorescence with Ki-67, the profile of 53BP1 expression is shown to be significantly altered during diverse tumorigenesis. In this study, we aimed to elucidate the malignant potential of PDc at the molecular level. We analyzed the profile of 53BP1 expression and NRAS codon 61 and TERT-promoter (TERT-p) mutations in 16 cases of TFTs showing NN with PDc compared to 30 adenomatous goiters, 31 follicular adenomas, 15 minimally invasive follicular carcinomas (FCs), and 11 widely invasive FC cases. Our results revealed that the expression level of abnormal type 53BP1 and incidence of NRAS and TERT-p mutations in PDc were comparable to FCs, suggesting a malignant potential. Because co-expression of 53BP1 and Ki-67 can be an indicator of altered DDR, the development of PDc in NN may be associated with DDR impairments after harboring NRAS and TERT-p mutations.

Subclinical giant cell arteritis in new onset polymyalgia rheumatica A systematic review and meta-analysis of individual patient data.

OBJECTIVES: To determine the prevalence and predictors of subclinical giant cell arteritis (GCA) in patients with newly diagnosed polymyalgia rheumatica (PMR). METHODS: PubMed, Embase, and Web of Science Core Collection were systematically searched (date of last search July 14, 2021) for any published information on any consecutively recruited cohort reporting the prevalence of GCA in steroid-naïve patients with PMR without cranial or ischemic symptoms. We combined prevalences across populations in a random-effect meta-analysis. Potential predictors of subclinical GCA were identified by mixed-effect logistic regression using individual patient data (IPD) from cohorts screened with PET/(CT). RESULTS: We included 13 cohorts with 566 patients from studies published between 1965 to 2020. Subclinical GCA was diagnosed by temporal artery biopsy in three studies, ultrasound in three studies, and PET/(CT) in seven studies. The pooled prevalence of subclinical GCA across all studies was 23% (95% CI 14%-36%, I2=84%) for any screening method and 29% in the studies using PET/(CT) (95% CI 13%-53%, I2=85%) (n=266 patients). For seven cohorts we obtained IPD for 243 patients screened with PET/(CT). Inflammatory back pain (OR 2.73, 1.32-5.64), absence of lower limb pain (OR 2.35, 1.05-5.26), female sex (OR 2.31, 1.17-4.58), temperature >37° (OR 1.83, 0.90-3.71), weight loss (OR 1.83, 0.96-3.51), thrombocyte count (OR 1.51, 1.05-2.18), and haemoglobin level (OR 0.80, 0.64-1.00) were most strongly associated with subclinical GCA in the univariable analysis but not C-reactive protein (OR 1.00, 1.00-1.01) or erythrocyte sedimentation rate (OR 1.01, 1.00-1.02). A prediction model calculated from these variables had an area under the curve of 0.66 (95% CI 0.55-0.75). CONCLUSION: More than a quarter of patients with PMR may have subclinical GCA. The prediction model from the most extensive IPD set has only modest diagnostic accuracy. Hence, a paradigm shift in the assessment of PMR patients in favour of implementing imaging studies should be discussed.

Anti-Zo antibodies in Japanese myositis patients detected by a newly developed ELISA.

OBJECTIVES: The myositis-specific autoantibodies that characterise certain forms of idiopathic inflammatory myopathy (IIM) are useful for diagnosing dermatomyositis (DM) / polymyositis (PM) and predicting its prognosis. The autoantibody to phenylalanyl-tRNA synthetase (anti-Zo) has been identified as a disease marker antibody for anti-synthetase syndrome only in a UK cohort. Here we aim to establish an ELISA for the measurement of anti-Zo and to characterise the clinical features of Japanese patients who have this autoantibody. METHODS: Anti-Zo was investigated by immunoprecipitation with recombinant phenylalanyl-tRNA synthetase α/ß proteins. The results were confirmed by immunoprecipitation-Western blotting with cell extract. Sera from patients with DM/PM (n=224) were screened by an ELISA with the recombinant proteins. Medical records were retrospectively reviewed to obtain detailed information on the clinical phenotypes of the anti-Zo-positive patients. RESULTS: Only two male patients were confirmed to have anti-Zo. Both patients had fever, myopathy, interstitial lung disease, and mechanic's hands, and these clinical features are consistent with those of anti-synthetase syndrome. Another patient's serum showed a higher level than the cut-off value for anti-phenylalanyl-tRNA synthetase α by our in-house ELISA, but was judged to be negative for anti-Zo by immunoprecipitation-Western blotting. CONCLUSIONS: This is the first report of anti-Zo-positive IIM patients from Asia. Although Japanese patients with anti-Zo have a clinical phenotype similar to that of Caucasian patients, further large cohort studies are necessary to confirm the frequency of anti-Zo in Japanese IIM patients. Our newly developed ELISA should be validated for sensitivity and specificity in large cohorts.

A New Indicator to Differentiate Thyroid Follicular Inclusions in Cervical Lymph Nodes from Patients with Thyroid Cancer.

Nodal metastasis is crucial for determining the stage of well-differentiated thyroid cancer (WTC) in patients older than 55. Well-formed thyroid follicular inclusions (TFIs) are occasionally encountered in the cervical lymph nodes (LNs) of patients with papillary thyroid carcinoma (PTC), and it is difficult to determine whether they are true nodal metastases or ectopic thyroid tissues (ETT). This study aimed to elucidate the impact of the expression of the DNA damage response molecule TP53-binding protein 1 (53BP1) using immunofluorescence (IF) as a biomarker to differentiate TFIs in cervical LN by comparing the mutation analyses of primary thyroid cancers. The data demonstrated the necessity for the differential diagnosis of true metastases from ETT among TFIs in cervical LNs. PTC-like nuclear features using hematoxylin-eosin staining combined with immunohistochemistry for conventional biomarkers of PTC, including BRAFV600E protein, were most helpful in identifying metastatic follicular-patterned carcinomas. In conclusion, IF analysis of 53BP1 expression could be an excellent ancillary technique to distinguish metastatic carcinoma or ETT from TFIs in LNs, particularly in cases other than BRAFV600E-mutated PTC.

Hypertrophic pachymeningitis in eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is one of the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), which is characterised by systemic small vessels vasculitis with associated eosinophilia. Hypertrophic pachymeningitis (HP) is an inflammatory disease in which the cerebral or spinal dura mater is thickened. AAV other than EGPA may sometimes develop HP; however, patients with EGPA rarely develop HP. This is the case of myeloperoxidase-ANCA-positive EGPA that presented with headache and blurred vision and was diagnosed with HP. It was successfully treated with pulsed steroid therapy and intravenous cyclophosphamide without any relapse for more than 4 years.

Adverse drug reactions to trimethoprim-sulfamethoxazole in systemic lupus erythematosus.

OBJECTIVES: Trimethoprim-sulfamethoxazole (TMP-SMX), a prophylactic agent against pneumocystis pneumonia (PCP), can cause adverse drug reactions (ADRs), particularly in patients with systemic lupus erythematosus (SLE). However, the risk factors for ADRs remain unclear. Thus, we sought to examine the prevalence of TMP-SMX-related ADRs in patients with SLE and identify specific risk factors for ADR development in these patients. METHODS: We retrospectively reviewed data from patients with connective tissue disease (CTD) who were administered TMP-SMX as a PCP prophylactic. The prevalence of ADRs was compared between patients with SLE and those with other CTDs. Univariate and multivariate analyses were conducted to identify risk factors for ADRs in patients with SLE. RESULTS: Of the 424 patients with CTD included in our study (SLE, n = 162; other CTDs, n = 262), 22 with SLE (13.6%) developed ADRs, and this rate was significantly higher than that observed in patients with non-SLE CTDs (n = 18 [6.9%], p = 0.033). In patients with SLE, univariate analyses revealed direct associations of ADRs with anti-Sm (p < 0.001), anti-RNP (p = 0.02), and anti-Ro/SS-A antibodies (p = 0.042). Multivariate analysis identified a significant association between anti-Sm antibody levels and the development of ADRs (adjusted odds ratio 5.27, 95% confidence interval 1.80-15.40, p = 0.002). CONCLUSIONS: Patients with SLE who are prophylactically administered TMP-SMX are at high risk of ADRs. Among these patients, those who display a positive anti-Sm antibody should be carefully monitored for ADRs.

Additional Tissue Sampling Trials Did Not Change Our Thyroid Practice.

This study aimed to determine whether additional tissue sampling of encapsulated thyroid nodules would increase the frequency of follicular thyroid carcinoma (FTC) diagnoses. We examined thyroid tissue specimens from 86 patients suspected of FTC (84.9% female; mean age, 49.0 ± 17.8 years). The number of tissue blocks created for pathological assessments ranged from 3 to 20 (mean, 9.1 ± 4.1); the numbers in the previous method recommended by the Japanese General Rules for the Description of Thyroid Cancer and additional blocks ranged from 1 to 12 (mean, 6.0 ± 2.8) and from 1 to 8 (mean, 3.1 ± 2.0), respectively. The additional blocks were subsequently examined to determine whether any diagnoses changed from those based on the previous method. Five patients were diagnosed with FTC using the previous method; however, additional tissue blocks led to the diagnosis of FTC in 6 patients, as 1 diagnosis was revised from follicular adenoma to FTC. It has been reported that increasing the number of tissue blocks used for pathological assessments can increase the frequency of FTC diagnoses; however, this was not clinically significant in thyroid carcinoma, which requires completion thyroidectomy and radioactive iodine treatment. It resulted in no benefits to the patient because all minimally invasive FTCs, follicular tumors of uncertain malignant potential (FT-UMP), and follicular adenomas are treated with lobectomy alone in Japan. Additional tissue sampling only had a slight impact on our thyroid practice; therefore, we decided to cease it.