Search

Xiying Chi,1 Tao Ji,1 Junying Li,2 Jie Xu,1 Xiaodong Tang,1 Lu Xie,1 Fanfei Meng,2 Wei Guo1 1Musculoskeletal Tumor Center, Peking University, People’s Hospital, Beijing, 100044, People’s Republic of China; 2Department of Medicine, OrigiMed, Shanghai, 201114, People’s Republic of ChinaCorrespondence: Wei Guo; Tao JiMusculoskeletal Tumor Center, Peking University, People’s Hospital, Beijing, 100044, People’s Republic of ChinaEmail bonetumor@163.com; jitaomd@163.comObjective: The limited understanding of correlation between genomic features and biological behaviors has impeded the therapeutic breakthrough in osteosarcoma (OS). This study aimed to reveal the correlation of mutational and evolutionary traits with clinical outcomes.Methods: We applied a case-based targeted and whole exome sequencing of eleven matched primary, recurrent and metastatic samples from three OS patients characterized by different clinical behaviors in local recurrence or systematic progression pattern.Results: Extensive OS-associated driver genes were detected including TP53, RB1, NF1, PTEN, SPEN, CDKN2A. Oncogenic signaling pathways including cell cycle, TP53, MYC, Notch, WNT, RTK-RAS and PI3K were determined. MYC amplification was observed in the patient with shortest disease-free interval. Linear, branched or mixed evolutionary models were constructed in the three OS cases. A branched evolution with limited root mutation was detected in patient with shorter survival interval. ADAM17 mutation and HEY1 amplification were identified in OS happening dedifferentiation. Signatures 21 associated with microsatellite instability (MSI) was identified in OS patient with extra-pulmonary metastases.Conclusion: OS was characterized by complex genomic alterations. MYC aberration, limited root mutations, and a branched evolutionary model were observed in OS patient with relatively aggressive course. Extra-pulmonary metastases of OS might attribute to distinct mutational process pertaining to MSI. Further research in a larger number of people is needed to confirm these findings.Keywords: osteosarcoma, clinical behavior, root mutation, evolution, extra-pulmonary metastase, microsatellite instability

IgG4-related disease (IgG4-RD) is an autoimmune disorder and frequently involves multiple organs. The respiratory tract is one of the most frequently affected sites. In this study, we aimed to compare the demographic and clinical characteristics between IgG4 related respiratory disease (IgG4-RRD+) and extra-thoracic IgG4-related disease (IgG4-RRD-) in a large cohort.A total of 448 cases of IgG4-RD (104 IgG4-RRD+ patients and 344 IgG4-RRD- patients) diagnosed at Peking University People's Hospital during 2003 to 2020 were included in our study. Patients' demographic data, clinical characteristics, laboratory parameters and imaging features were analysed.IgG4-RRD+ patients had an older age at disease onset and diagnosis. Multiorgan involvement and hypocomplementaemia were more common in IgG4-RRD+. Besides, the level of ESR, IgG and IgG4 were higher in IgG4-RRD+ patients. In IgG4-RRD+ group, salivary gland, lacrimal gland, lymph nodes, biliary system and kidney were more commonly involved than those in the IgG4-RRD- group. Also, more organ involvement eosinophilia and biliary involvement were independent risk factors for the development of IgG4-RRD+.Our study revealed demographic, clinical and laboratory differences between the two phenotypes, in addition to describing the imaging features of IgG4-RRD+, which will be helpful for understanding of the disease.

We aimed to compare the demographic, clinical and laboratory characteristics between IgG4-related kidney disease (IgG4-RKD+) and extrarenal IgG4-related disease (IgG4-RKD−) in a large Chinese cohort, as well as describing the radiological and pathological features of IgG4-RKD+. We retrospectively analyzed the medical records of 470 IgG4-related disease (IgG4-RD) patients at Peking University People’s Hospital from January 2004 to January 2020. The demographic, clinical, laboratory, radiological and pathological characteristics between IgG4-RKD+ and IgG4-RKD− were compared. Twenty IgG4-RD patients who had definite etiology of renal impairment including diabetes, hypertension and etc. were excluded. Among the remained 450 IgG4-RD patients, 53 were diagnosed with IgG4-RKD+ . IgG4-RKD+ patients had older age at onset and at diagnosis. Male to female ratio of IgG4-RKD+ patients is significantly higher. In the IgG4-RKD+ group, the most commonly involved organs were salivary gland, lymph nodes and pancreas. It was found that renal function was impaired in approximately 40% of IgG4-RKD+ patients. The most common imaging finding is multiple, often bilateral, hypodense lesions. Male sex, more than three organs involved, and low serum C3 level were risk factors for IgG4-RKD+ in IgG4-RD patients. These findings indicate potential differences in pathogenesis of these two phenotypes.

Additional file 1:. Supplementary Table 1. 2011 Comprehensive clinical diagnostic criteria. Supplementary Table 2. 2011 pathology consensus. Supplementary Table 3. Histological Characteristics in 4 biopsy organs of classified as IgG4-RD. Supplementary Table 4. Comparison of Needle Biopsy and Surgical Biopsy in 72 diagnosed IgG4-RD samples.

Objective The growing utilization of needle biopsy has challenged the current pathology consensus of IgG4-related disease (IgG4-RD). The aims of this study were to identify the histological characteristics of needle biopsy and surgical specimens and evaluate the ability of needle biopsy in histological diagnosis of IgG4-RD. Methods Biopsies from patients who were referred to as IgG4-RD by the 2019 ACR/EULAR IgG4-RD classification criteria in Peking University People’s Hospital from 2012 to 2019 were re-evaluated. Typical histological features and diagnostic categories were compared between needle biopsy and surgical biopsy. Results In total, 69 patients met the 2019 ACR/EULAR classification criteria and 72 biopsies of them were re-evaluated. All cases showed lymphoplasmacytic infiltrate, while storiform fibrosis and obliterative phlebitis were only present in 35 (48.6%) and 23 (31.9%) specimens, respectively. Storiform fibrosis was more likely to be seen in retroperitoneum lesion (P = 0.033). Surgical biopsy showed significantly higher IgG4+ plasma cells/high-power field (IgG4/HPF) count (P 10 (P P = 0.399), storiform fibrosis (P = 0.739), and obliterative phletibis (P = 0.153). According to the 2011 comprehensive diagnostic criteria, patients who performed a needle biopsy were less likely to be probable IgG4-RD (P = 0.045). Based on the 2011 pathology consensus, needle biopsy was less likely to be diagnosed as IgG4-RD (P P 100, which was significantly less than 15/23 (65.2%) of surgical ones (P Conclusions Needle biopsy shows an inferiority in detecting IgG4/HPF count but not in IgG4/IgG ratio, storiform fibrosis, and obliterative phlebitis. Compared with surgical samples, needle biopsy is less likely to obtain a histological diagnosis of IgG4-RD. A different IgG4/HPF threshold for needle biopsy of the salivary glands may be considered.

Background We aimed to compare the demographic, clinical and laboratory characteristics between IgG4-related kidney disease (IgG4-RKD+) and extrarenal IgG4-related disease (IgG4-RKD-) in a large Chinese cohort, as well as describing the radiological and pathological features of IgG4-RKD+.Methods We retrospectively analyzed the medical records of 450 IgG4-RD patients at Peking University People’s Hospital from January 2004 to January 2020.Results Among the 450 IgG4-RD patients, 66 were diagnosed with IgG4-RKD+. Compared with IgG4-RKD- patients, IgG4-RKD+ patients had older age at onset and at diagnosis (59 vs 54, P=0.007; 61 vs 56, P=0.002, respectively). Male to female ratio of IgG4-RKD+ patients is significantly higher (2.5:1 vs 1.2:1, P=0.015). In the IgG4-RKD+ group, the most commonly involved organs were salivary gland (54.6%), lymph nodes (47.0%) and pancreas (40.9%). More than three organs involved (OR=6.212), retroperitoneal fibrosis involvement (RPF) (OR=12.460) and low serum C3 level (OR=0.202) were risk factors for the kidney disease in IgG4-RD patients. It was found that renal function was impaired in more than 50% of IgG4-RKD+ patients. The most common imaging finding is multiple, often bilateral, hypodense lesions, followed by ureteric obstruction and hydronephrosis related to RPF, and thickening of the renal pelvic wall. Conclusions Involvement of three or more organs, retroperitoneal fibrosis and low serum C3 level were risk factors for the kidney disease in IgG4-RD patients. These findings indicate potential differences in pathogenesis of these two phenotypes.

Immunoglobulins emerging from B lymphocytes and capable of recognizing almost all kinds of antigens owing to the extreme diversity of their antigen-binding portions, known as variable (V) regions, play an important role in immune responses. The exons encoding the V regions are known as V (variable), D (diversity), or J (joining) genes. V, D, J segments exist as multiple copy arrays on the chromosome. The recombination of the V(D)J gene is the key mechanism to produce antibody diversity. The recombinational process, including randomly choosing a pair of V, D, J segments, introducing double-strand breaks adjacent to each segment, deleting (or inverting in some cases) the intervening DNA and ligating the segments together, is defined as V(D)J recombination, which contributes to surprising immunoglobulin diversity in vertebrate immune systems. To enhance both the ability of immunoglobulins to recognize and bind to foreign antigens and the effector capacities of the expressed antibodies, naive B cells will undergo class switching recombination (CSR) and somatic hypermutation (SHM). However, the genetics mechanisms of V(D)J recombination, CSR and SHM are not clear. In this review, we summarize the major progress in mechanism studies of immunoglobulin V(D)J gene recombination and CSR as well as SHM, and their regulatory mechanisms.