Abstract Objective To define somatic variants of parathyroid adenoma (PA) and to provide novel insights into the underlying molecular mechanism of sporadic PA. Methods Basic clinical characteristics and biochemical indices of 73 patients with PA were collected. Whole-exome sequencing was performed on matched tumor-constitutional DNA pairs to detect somatic alterations. Functional annotation was carried out by ingenuity pathway analysis afterward. The protein expression of the variant gene was confirmed by immunohistochemistry, and the relationship between genotype and phenotype was analyzed. Results Somatic variants were identified in 1549 genes, with an average of 69 variants per tumor (range, 13-2109; total, 9083). Several novel recurrent somatic variants were detected, such as KMT2D (15/73), MUC4 (14/73), POTEH (13/73), CD22 (12/73), HSPA2 (12/73), HCFC1 (11/73), MAGEA1 (11/73), and SLC4A3 (11/73), besides the previously reported PA-related genes, including MEN1 (11/73), CASR (6/73), MTOR (4/73), ASXL3 (3/73), FAT1 (3/73), ZFX (5/73), EZH1 (2/73), POT1 (2/73), and EZH2 (1/73). Among them, KMT2D might be the candidate driver gene of PA. Crucially, 5 patients carried somatic mutations in CDC73, showed an aggressive phenotype similar to that of parathyroid carcinoma (PC), and had a decreased expression of parafibromin. Pathway analysis of recurrent potential PA-associated driver variant genes revealed functional enrichments in the signaling pathway of Notch. Conclusion Our study expanded the pathogenic variant spectrum of PA and indicated that KMT2D might be a novel candidate driver gene and be considered as a diagnostic biomarker for PA. Meanwhile, CDC73 mutations might be an early developmental event from PA to PC. The results provided insights into elucidating the pathogenesis of parathyroid tumorigenesis and a certain basis for clinical diagnosis and treatment.
Abstract Background Chondromyxoid fibroma-like osteosarcoma (CMF-OS) is an exceedingly rare subtype of low-grade central osteosarcoma (LGCO), accounting for up to 10% of cases and making it difficult to diagnose. CMF-OS is frequently misdiagnosed on a radiological examination and biopsy, even after the initial operation. Its treatment is a controversial issue due to its low-grade classification and actual high-grade behavior. Case presentation We retrospectively reviewed the medical charts of more than 2000 osteosarcoma patients between 2008 and 2019; 11 patients with CMF-OS were identified, of which six patients were treated by our institution with complete clinical characteristics, including treatment and prognosis, radiological and pathological features were reviewed. Three males and three females with a median age of 46 (range 22–56) years were pathologically proven to have CMF-OS. The radiological presentation of CMF-OS is variable, thus radiological misdiagnoses are common. However, one must not ignore a malignant radiologic appearance. The most distinctive pathological feature conferring the diagnosis of CMF-OS is the presence of osteoid production directly by the tumor cells under a chondromyxoid fibroma (CMF)-like background. Differential diagnoses based on comprehensive data from CMF, LGCO, chondrosarcoma (CHS), conventional osteosarcoma (COS), etc., are needed. All patients were treated with an operation and chemotherapy, and one patient received additional radiotherapy. Nevertheless, recurrence and metastasis are common in CMF-OS patients. Relatively invasive biological behavior of CMF-OS is against the low-grade classification of this disease. Conclusions It is important to recognize CMF-OS and distinguish it from CMF, CHS, COS and other LGCOs. CMF-OS has a relatively poor prognosis despite its low-grade classification.
Based on the changes of the classification and nomenclature in the fifth edition of the World Health Organization (WHO) classification of thyroid neoplasms, the third edition Bethesda system for reporting thyroid cytopathology (TBSRTC) was revised in June 2023. Two new chapters have been added: one addressing the clinical perspectives and imaging findings in thyroid disease and another summarizing the molecular test for thyroid cytology. A discussion of risk of malignancy (ROM) and clinical management algorithms for pediatric thyroid carcinoma have been added. The third edition provides an average ROM for each category, in addition to the expected range of cancer risk. This paper aims to interpret the main changes in the third edition TBSRTC and to provide guidelines for the clinical management of thyroid nodules.基于第5版世界卫生组织（WHO）甲状腺肿瘤分类及命名的更新，第3版甲状腺细胞病理Bethesda报告系统（TBSRTC）于2023年6月修订再版，新增了甲状腺结节临床与超声特征、甲状腺细胞分子检测两个章节、儿童甲状腺癌恶性风险（ROM）和临床处理原则等相关内容。同时更新了TBSRTC报告中每个分类的ROM范围，并在原有ROM范围基础上新增其平均值。本文就第3版TBSRTC的更新要点进行阐述，为甲状腺结节的规范化诊疗提供依据。.
Small cell osteosarcoma (SCOS) is a rare subtype of osteosarcoma, with limited studies mainly focusing on histological features. Our study aims to analyze our own patients and those reported in the literature to increase the recognition of this rare disease, to evaluate patient survival and to further determine potential prognostic factors.Twenty patients with SCOS were treated in our hospital between 2010 and 2019. Their follow-up data were collected retrospectively. A total of 336 literature cases from 58 manuscripts were retrieved by means of a PubMed search with the key word "small cell osteosarcoma". Data pertaining to treatment and follow-up were extracted. We performed a pooled analysis for the survival of patients and the risk factors for local recurrence (LR), as well as metastatic disease (MD), in a total of 160 patients using the Kaplan-Meier method and Cox regression method.We reported our experience in diagnosing and treating SCOS. In our cases, elevated alkaline phosphatase (P = 0.013) and lactate dehydrogenase (P = 0.001) significantly impaired overall survival. In the pooled analysis, SCOS was diagnosed at the median age of 17 years and affected both sexes almost equally. The median follow-up duration was 19.5 months. In the pooled analysis cases, the 5-year overall survival rate was 38.6%, and 36.4% of patients survived 10 years. However, an increasing trend was detected, indicating recent improvements in management. The surgical margin status (P = 0.024) and metastases (P = 0.008) significantly impaired overall survival, and the response to chemotherapy was related to disease-free survival (P = 0.012). LR and MD were significantly correlated (P = 0.002) and could be observed after 5 years of follow-up. LR was significantly dependent on response to chemotherapy (P = 0.020). The development of MD seemed to be affected by response to chemotherapy (P = 0.060). Correlations between imaging features and prognosis were not detected.This study suggested that positive margins, poor response to chemotherapy and MD are negative prognostic factors for SCOS, implied the potential role of laboratory examinations in the survival prediction and supported the need for prolonged or more intensive surveillance in patients with MD or LR. More well-documented literatures are encouraged to allow further confirmations.
Abstract: Preclinical studies have demonstrated that Apatinib, major targeting vascular endothelial growth factor receptor-2 (VEGFR-2), could inhibit the proliferation of anaplastic thyroid carcinoma (ATC) cells in vitro and in vivo. The efficacy and safety in ATC patients, however, remains unknown. Here, we report the case of a 93-year-old female with advanced ATC who initially treated with Apatinib. The tumor shrank notably 4 weeks after the initiation of therapy, which sustained for more than 30 weeks. The cervical CT illuminated a stable disease with a best response of 19.7% of the primary lesion and shrinkage of the metastatic lymph node. Adverse events, including hypertension, dental ulcer, hand-foot syndrome, fatigue, and anorexia, were observed and lightened with supportive treatment and dose reductions. The overall survival of the patient was 41 weeks. This is the first report describing the effectiveness of the VEGFR-2 inhibitor for the treatment of advanced ATC, warranting clinical trials to further ascertain its utility in this challenging setting. Keywords: anaplastic thyroid carcinoma, vascular endothelial growth factor receptor, Apatinib
Background: Despite marked improvements in pancreatic surgery, the high incidence and morbidity of pancreatic leak after resection has remained unchanged. The current study investigated the safety and efficacy of bovine pericardium wrapping stump after distal pancreatectomy in a porcine model. Methods: Thirty-two swine were randomly assigned to control and experiment groups to undergo conventional scalpel transection with single hand-sewn closure of the pancreatic remnant (control) or bovine pericardium wrapping stump combined with hand-sewn closure (experiment). Closed-suction drainage was collected and measured daily. Animals were necropsied at 3 weeks postoperatively, and the pancreatic remnants were examined for histology. Primary end points were the development of a pancreatic fistula defined as greater than threefold drain/serum amylase after the 3rd postoperative day, and the presence of undrained amylase-rich fluid collections/abscess. Results: The incidence of pancreatic leak in the wrapping group was 6.3 versus 46.7% in the control group (p < 0.05). The amount of drainage fluid was higher in the control group than the experiment group during the postoperative days. There were no differences in operative time or other clinical parameters measured. No other significant differences were found in macroscopic changes between groups at reexploration. Histological examination demonstrated focal, chronic inflammation with necrosis in all animals. Conclusions: Bovine pericardium wrapping stump effectively reduced the incidence of pancreatic leakage after the distal pancreatectomy.
To evaluate the diagnostic criteria and morphologic difference of primary schwannoma from that of soft tissue schwannoma.All neurogenic tumors of the bone in this hospital from 2002 to 2013 were reviewed, four cases of primary schwannoma arising from bone were selected. Their clinical features, radiologic appearance and pathologic findings were evaluated. Immunophenotyping was performed using EnVision method.All four cases had classic morphologic features and immunophenotype of conventional schwannoma. Compared with schwannoma of the soft tissue, primary bone schwannoma had the following features: benign radiological appearance, absence of capsule under light microscope, local infiltration of bone or destruction of bone cortex, occasionally involving extra-osseous soft tissue. Most tumors were solid, with less cystic degeneration. Histologically, the tumors were mainly composed of compact areas of spindle cells (Antoni A), and areas of hypercellularity could often be observed.Primary schwannoma of the bone is rare, usually arises within the long bones and flat bones. Compared to conventional soft tissue schwannoma, it shows different growth pattern, imaging and pathologic features; thus care should be exercised not to misdiagnose schwannoma of the bone as other primary low-grade malignant spindle cell sarcoma of the bone and to avoid unnecessary over-treatment.
Following acute kidney injury (AKI), renal tubular cells may stimulate fibroblasts in a paracrine fashion leading to interstitial fibrosis, but the paracrine factors and their regulation under this condition remain elusive. Here we identify a macroautophagy/autophagy-dependent FGF2 (fibroblast growth factor 2) production in tubular cells. Upon induction, FGF2 acts as a key paracrine factor to activate fibroblasts for renal fibrosis. After ischemic AKI in mice, autophagy activation persisted for weeks in renal tubular cells. In inducible, renal tubule-specific atg7 (autophagy related 7) knockout (iRT-atg7-KO) mice, autophagy deficiency induced after AKI suppressed the pro-fibrotic phenotype in tubular cells and reduced fibrosis. Among the major cytokines, tubular autophagy deficiency in iRT-atg7-KO mice specifically diminished FGF2. Autophagy inhibition also attenuated FGF2 expression in TGFB1/TGF-β1 (transforming growth factor, beta 1)-treated renal tubular cells. Consistent with a paracrine action, the culture medium of TGFB1-treated tubular cells stimulated renal fibroblasts, and this effect was suppressed by FGF2 neutralizing antibody and also by fgf2- or atg7-deletion in tubular cells. In human, compared with non-AKI, the renal biopsies from post-AKI patients had higher levels of autophagy and FGF2 in tubular cells, which showed significant correlations with renal fibrosis. These results indicate that persistent autophagy after AKI induces pro-fibrotic phenotype transformation in tubular cells leading to the expression and secretion of FGF2, which activates fibroblasts for renal fibrosis during maladaptive kidney repair.Abbreviations: 3-MA: 3-methyladnine; ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ACTB/β-actin: actin, beta; AKI: acute kidney injury; ATG/Atg: autophagy related; BUN: blood urea nitrogen; CCN2/CTGF: cellular communication network factor 2; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CKD: chronic kidney disease; CM: conditioned medium; COL1A1: collagen, type I, alpha 1; COL4A1: collagen, type IV, alpha 1; CQ: chloroquine; ECM: extracellular matrix; eGFR: estimated glomerular filtration rate; ELISA: enzyme-linked immunosorbent assay; FGF2: fibroblast growth factor 2; FN1: fibronectin 1; FOXO3: forkhead box O3; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAVCR1/KIM-1: hepatitis A virus cellular receptor 1; IHC: immunohistochemistry; IRI: ischemia-reperfusion injury; ISH: in situ hybridization; LTL: lotus tetragonolobus lectin; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PDGFB: platelet derived growth factor, B polypeptide; PPIB/cyclophilin B: peptidylprolyl isomerase B; RT-qPCR: real time-quantitative PCR; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; SASP: senescence-associated secretory phenotype; sCr: serum creatinine; SQSTM1/p62: sequestosome 1; TASCC: TOR-autophagy spatial coupling compartment; TGFB1/TGF-β1: transforming growth factor, beta 1; VIM: vimentin.
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