[Evaluation of accuracy of pathological diagnosis based on thyroid core needle biopsy].

OBJECTIVE: To explore the protocol for diagnosing thyroid nodules based on core needle biopsy (CNB) and study the biomarkers' application in distinguishing indeterminate samples. METHODS: Patients with thyroid nodules treated at Peking University First Hospital from 2015 to 2020 were reviewed. In the study, 598 cases with CNB and matched resected specimens were retrieved. According to "diagnostic categories of thyroid CNB" proposed by the Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group, the CNB samples were diagnosed as follows: Ⅰ, unsatisfactory; Ⅱ, benign; Ⅲ, indeterminate; Ⅳ, follicular neoplasm; Ⅴ, suspicious for malignancy; and Ⅵ, malignant. The samples of CNB Ⅲ were stained by immunohistochemistry (IHC) using antibodies against CK19, Galectin-3, HBME-1, and CD56, and detected by next-generation sequencing (NGS) using an OncoAim® thyroid cancer multigene assay kit (Singlera Genomics) that detected 26 genes. Taking the resected specimens' classification as the gold standard, the predictive value of CNB for determining the malignancy of thyroid nodules and the biomarkers for distinguishing the samples of CNB Ⅲ was calculated. RESULTS: The study included 598 patients, of which none were CNB Ⅰ, 40 cases were CNB Ⅱ, 40 cases were CNB Ⅲ, 32 cases were CNB Ⅳ, 35 cases were CNB Ⅴ, and 451 cases were CNB Ⅵ. The predictive value of CNB Ⅳ for determining follicular neoplasm was sensitivity (Sen) 100.00% and specificity (Sep) 100.00%, CNB Ⅴ-Ⅵ for determining malignancy was Sen 94.55% and Sep 100.00%, CNB Ⅱ for determining benign lesions was Sen 75.00% and Sep 99.80%. The predictive value of biomarkers for determining malignancy in cases of CNB Ⅲ was Sen 96.30% and Sep 92.31% by NGS, and Sen 81.48% and Sep 92.30% by IHC. CONCLUSION: The Korean "diagnostic categories of thyroid CNB", which considers the histological specificity of CNB samples and the habits of clinicians, have strong operability, high diagnosis rate, and high clinical value. Under this framework, the cases of CNB Ⅵ should be treated with surgical operation, the cases of CNB Ⅴ-Ⅵ are recommended to be treated as malignant neoplasms, and the major cases of CNB Ⅱ could be followed up without worrisome except the one considered malignant by ultrasound. The value of biomarkers in distinguishing the cases of CNB Ⅲ is significant.

[Clinicopathological features of lung salivary gland-type tumors].

Objective: To study the clinicopathological characteristics of lung salivary gland-type tumors (SGT), and to compare with the corresponding primary SGT in salivary glands. Methods: Twenty-three cases of lung SGT were retrieved from the files of Peking University First Hospital from January 2004 to September 2018. The morphology, immunophenotype, genotype and outcome of these cases were analyzed. Results: The 23 patients included 13 males and 10 females, with age range of 13-79 years (median 54 years). There were 11 cases of adenoid cystic carcinoma, 10 cases of mucoepidermoid carcinoma (MEC), one case each of clear cell carcinoma and myoepithelioma. The morphology and immunophenotype of lung SGT were very similar to their counterparts in salivary gland. MYB rearrangement was detected in one of 11 adenoid cystic carcinomas. MAML2 rearrangement was detected in all the MECs. EWSR1 rearrangement was detected in the one case of clear cell carcinoma. Of patients with adenoid cystic carcinoma, the survival time was more than 60 months (three cases), 52 months (one case), and 12-36 months (three cases). There was no recurrence and death in seven cases of MEC with follow-up results. One case of clear cell carcinoma recurred after 52 months of follow-up. Conclusions: Although the SGT of lung and their counterparts in salivary gland are very similar in their morphology, immunophenotype, genotype and prognosis, there are also some differences between each other. MYB rearrangement can be detected in most adenoid cystic carcinomas of salivary gland, but rarely in lung adenoid cystic carcinoma. The prognosis of patients with lung MEC is better than that of patients with salivary gland MEC, while the prognosis of patients with lung adenoid cystic carcinoma is worse than that of patients with salivary gland adenoid cystic carcinoma.

Novel mutations and phenotypes of epilepsy-associated genes in epileptic encephalopathies.

Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next-generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty-three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance. Twelve variants were initially assessed as uncertain significance by ACMG, among which 3 were considered causative and 3 others were considered possibly causative after analysis of clinical concordance. In total, 24 variants were identified as putatively causative, among which 19 were novel findings. SCN1A mutations were identified in 50% of patients with Dravet syndrome. TSC1/TSC2 mutations were detected in 66.7% of patients with tuberous sclerosis. STXBP1 mutations were the main findings in patients with West syndrome. Mutations in SCN2A, KCNT1, KCNQ2 and CLCN4 were identified in patients with epileptic infantile with migrating focal seizures; among them, KCNQ2 and CLCN4 were first identified as potential causative genes. Only one CHD2 mutation was detected in patients with Lennox-Gastaut syndrome. This study highlighted the utility of targeted NGS in genetic diagnoses of epileptic encephalopathies and a comprehensive evaluation of the pathogenicity of variants based on ACMG scoring and assessment of clinical concordance. Epileptic encephalopathies differ in genetic causes, and the genotype-phenotype correlations would provide insights into the underlying pathogenic mechanisms.

A comparison of the cost-utility of ultrasound-guided high-intensity focused ultrasound and hysterectomy for adenomyosis: a retrospective study.

OBJECTIVE: To evaluate cost-effectiveness of ultrasound-guided high-intensity focused ultrasound (USgHIFU) and open hysterectomy for adenomyosis. DESIGN: A retrospective analysis. SETTING: Gynaecological department in a single centre in China. POPULATION: Patients with symptomatic adenomyosis. MAIN OUTCOME MEASURES: Cost difference between patients with adenomyosis treated with USgHIFU and open hysterectomy. METHODS: Three hundred and sixty-eight patients with adenomyosis were retrospectively reviewed. Among them, 302 patients were treated with USgHIFU and 66 patients with open hysterectomy. All of them had 1-, 3-, 6- and 12-month follow ups. The patients' quality of life (QOL) was evaluated and the utility scores were obtained from a rating scale to conduct a cost-utility analysis (CUA). RESULTS: No significant differences were found at any follow-up time point in the QOL between the two groups (P > 0.05). After treatment, the QOL scores significantly increased in both groups (P < 0.05): the quality adjusted life year (QALY) for patients treated with USgHIFU was USUS$5256.48, whereas it was USUS$7510.03 for patients treated with open hysterectomy. Both incremental cost and sensitivity analysis showed that USgHIFU was less costly than open hysterectomy. CONCLUSIONS: The QOL of patients with adenomyosis can be significantly improved by either USgHIFU or open hysterectomy, but USgHIFU is less costly. TWEETABLE ABSTRACT: USgHIFU can safely be used to treat patients with adenomyosis and significantly improved the quality of life of patients after treatment. The cost of USgHIFU is less than that of surgical treatment.

Inhibitory effect of microRNA-24 on fatty acid-binding protein expression on 3T3-L1 adipocyte differentiation.

We examined the effect of microRNAs on 3T3-L1 adipocyte differentiation and expression of adipocyte-specific gene fatty acid-binding protein 4 (FABP4). We screened and identified adipo-related microRNAs during 3T3-L1 adipocyte differentiation with a microRNA microarray. High expression plasmids of miR-24 and miR-21 were constructed and transfected into 3T3-L1 preadipocytes by lipofectamine. The effects of miR-24 and miR-21 on 3T3-L1 adipocyte differentiation were observed, and the protein and mRNA expression levels of FABP4 and AP-1 were determined. The expression profiles of microRNAs significantly changed during 3T3-L1 adipocyte differentiation. The expression of 33 microRNAs was downregulated, among which downregulation of miR-24 was the most extensive. There were 17 microRNAs with upregulated expression; the highest levels were found for miR-21. miR-24 significantly inhibited 3T3-L1 adipocyte differentiation and maturity, while miR-21 had no significant effect. In addition, miR-24 significantly inhibited the expression of FABP4, while it upregulated AP-1 expression, but had no effect on the level of FABP4 mRNA. miR-21 had no effect on FABP4 protein and mRNA expression. AP-1 silencing could, at least partially, reverse the inhibitory effect of miR-24 on FABP4 expression. We conclude that microRNA expression profiles change significantly during 3T3- L1 adipocyte differentiation and that miR-24 plays an important role in regulating adipocyte differentiation and FABP4 expression. The mechanism involved may be the upregulation of AP-1.

[The role of endogenous CO in the regulation of endothelin-induced VSMC proliferation and MAPK activity].

Heme oxygenase (HO) is a rate-limiting enzyme of heme degradation, which converts the cellular heme to bilirubin and carbon monoxide (CO). Recently it is suggested that endogenous CO plays an important role in regulating vascular tone under both physiological and pathological conditions, but it is not clear whether endogenous HO/CO system regulates vascular smooth muscle cell (VSMC) proliferation. In the present study, VMSC 3H-TdR incorporation, mitogen-activated protein kinase (MAPK) activity, HO activity and CO release were determined to study the role of endogenous HO/CO system in regulating the VSMC proliferation induced by endothelin-1 (ET-1) in a cultured system. The results showed that ET-1 increased VSMC 3H-TdR incorporation, MAPK activity, HO activity, and CO release were up-regulated. Pretreatment of HO inhibitor, zinc protoporphyrin-9 (ZnPP-9), increased the ET-1-induced VSMC 3H-TdR incorporation and MAPK activity by 31.8% and 36.6% (P < 0.01, respectively), whereas pretreatment of heme-L-lysinate (HLL), a HO substrate, inhibited these activities. This study demonstrated that up-regulation of VSMC endogenous HO represents a cellular protective response to stress or injury. Inhibition of HO may enhance VSMC proliferation induced by ET-1 in vitro, suggesting that endogenous HO/CO system may be directly involved in the regulation of VSMC proliferation through MAPK signaling pathway.

Prostaglandin E and F2 alpha levels in plasma and amniotic fluid during mid-trimester abortion induced by trichosanthin.

This paper gives a brief account concerning the estimation of PGE and PGF2 alpha concentrations in both plasma and amniotic fluid by radioimmunoassay in mid-trimester abortion induced by Trichosanthin. The significant change in amniotic fluids as compared with that in plasma is brought out for discussion as an aid to the study of mechanism of abortion by Trichosanthin.

PIP: Trichosanthin, an abortifacient plant protein isolated from Radix Trichosanthes, has a success rate of approximately 98%. This paper examines changes in prostaglandin (PG) E and F2alpha levels in both plasma and amniotic fluid by radioimmunoassay in midtrimester abortion induced by Trichosanthin. Trichosanthin was given by transabdominal amniotic injection (average dosage, 8-11 mg) in 8 women (7 primigravidae and 1 secundigravida) of 17-24 weeks gestation. Venous blood and amniotic fluid samples were collected both before and after drug administration. PGE and F2alpha in plasma and amniotic fluid were measured by radioimmunoassay based upon a method described by the Pekin Institute of Zoology. Injection-abortion time ranged from 72-168 hours with a mean of 100 hours. No significant change was observed between concentrations of PGE and PGF2alpha in the plasma before and after drug administration, probably due to the fact that the 2 PGs were released in pulsatile fashion instead of continuous, and because PGs have short half-life in the circulating blood. In contrast, both PGE and PGF2alpha levels in the amniotic fluid were markedly increased after Trichosanthin administration, the increments amounting to 12.8 and 23.8 times the preinjection value respectively (p0.001). In midtrimester abortion, Trichosanthin exerts a selective action on the syncytiotrophoblasts as demonstrated by their degenerative and necrotic changes and simultaneous deciduitis. These injuries are followed by impairment of the endocrine functions of the placenta, a disintegration of lysosomes inside the decidual cells, and a decreased stability of the lysosomal membrane, an increase of synthesis of PGE and PGF2alpha both in the fetal membrane and decidua, and finally, complete abortion.