Immune checkpoint inhibitors (ICIs) cause fewer toxicities than conventional chemotherapy. Although most of the immune-related adverse events (irAEs) are mild, reversible, and manageable, potentially severe and rare irAEs remain relevant. We present a 24-year-old man with advanced hereditary renal cancer who developed bilateral posterior uveitis and retinal detachment after systematic treatment of ICI and an anti-angiogenic drug. Axitinib and pembrolizumab were administered with a partial response and following the severe ocular irAE and systemic corticosteroid treatment was initiated. Our case indicates that ocular irAEs may occur rapidly. To the best of our knowledge, this is the first case of posterior uveitis and retinal detachment in hereditary renal cancer patients treated with ICI and anti-angiogenic drugs.
Objective: To investigate the inactivation of PMS2 gene mediated by promoter methylation and its regulatory mechanism in nasopharyngeal carcinoma (NPC). Methods: Fifty-four NPC tissues, 16 normal nasopharyngeal epithelia (NNE), 5 NPC cell lines (CNE1, CNE2, TWO3, HNE1 and HONE1) and 1 normal nasopharyngeal epithelial cell line (NP69) were collected.Methylation-specific PCR (MSP) was used to detect the PMS2 promoter methylation, semi-quantitative reverse transcription PCR (qRT-PCR) was applied to determine its mRNA expression, and immunohistochemistry (IHC) was used to detect the protein expression of PMS2. The expressions of PMS2 mRNA in CNE1 and CNE2 cells before and after treated with methyltransferase inhibitor 5-aza-2-deoxycytidine were analyzed by qRT-PCR. The impact of methylation and demethylation on the mRNA expression of PMS2, and the association of mRNA and protein expression of PMS2 with clinicopathological features of nasopharyngeal cancer were analyzed. Results: Methylation of PMS2 gene was detected in all of the five NPC cell lines, but not in normal nasopharyngeal epithelial NP69 cells. The methylation rate of PMS2 gene in NPC tissues was 63% (34/54), significantly higher than that of the normal nasopharyngeal epithelia (0/16, P<0.001). The expression levels of PMS2 mRNA and protein were significantly down-regulated in the 54 NPC tissues when compared with those in the 16 NNE tissues (P<0.001), and were also significantly lower in the 34 methylated NPC tissues than those in the 20 unmethylated NPC tissues (P<0.001). After treatment with 5-aza-2-deoxycytidine, the expression of PMS2 mRNA was restored in the CNE1 and CNE2 cells.However, the expressions of PMS2 mRNA and protein were not significantly correlated with patients' age, gender, TNM stage, histopathologic type or lymph node metastasis (P>0.05 for all). Conclusions: Promoter methylation-mediated inactivation of PMS2 gene participates in carcinogenesis and development of NPC. PMS2 may be a candidate tumor suppressor in the treatment for patients with inactivation of PMS2 promoter methylation.
Abnormal glucose metabolism brings out joint inflammation and destruction in rheumatoid arthritis (RA). The aim of this study was to evaluate the potential of circulating hexokinase-2 (HK2) in peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients.PBMCs were obtained from patients with RA or osteoarthritis (OA) and healthy controls (HCs). The expression of HK2 was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), Calprotectin, rheumatoid factor (RF), anti-cyclic citrullinated peptides (anti-CCP) antibody level and 28-joint Disease Activity Score (DAS28), Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) were measured. Spearman's analysis was performed to determine the association between the level of HK2 and clinical characteristics. A receiver operating characteristic (ROC) curve was employed to evaluate the diagnostic value of HK2 in PBMCs. Logistic regression was used to identify risk factors. Sixty-five RA patients, 35 OA patients, and 40 HCs were included in the study.HK2 was upregulated in RA and OA patients compared with that in HCs (P < .05). The area under the ROC of HK2 for diagnosing RA and OA was 0.808 and 0.640, respectively. In addition, HK2 levels were increased in active RA compared with those in remittent RA (P = .03). Furthermore, HK2 correlated positively with the DAS28-ESR (P < .001), CDAI (P = .02) and SDAI scores (P = .02). Moreover, HK2 was independently associated with an increased risk of disease activity (DAS28-ESR>3.2, P = .02; CDAI score>10, P = .03; SDAI score>11, P = .04). Additionally, HK2 positivity was more frequently detected in patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs) than in those not treated with bDMARDs.HK2 levels in PBMCs can be considered an ideal biomarker for diagnosing RA and involved in disease activity in RA. Dysregulation of HK2 may participate in the molecular mechanism of RA and could be an attractive selective metabolic target for RA treatment.
Introduction: Recently, the usesfulness of endoscopic submucosal tunnel dissection (ESTD) in the management of upper gastrointestinal submucosal tumors (SMTs) have gained popularity in the world. The aim of this study was to evaluate the safety and efficacy of ESTD for treating upper gastrointestinal SMTs in a large-volume endoscopic center. Methods: Between January 2012 and January 2015, patients with SMTs were prospectively included in this study. Demographic data, clinical data, outcome of treatment were collected. Long-term outcome for patients was also investigated. Results: 71 SMTs originating from the muscularis propria (MP) layer was identified in 70 patients, with a mean age of 47.9 ± 11.2 years. The ratio between female and male was 24/46 (Table 1). All patients underwent ESTD procedure successfully (Figure 1 and 2). The mean procedure time was 49.1 ± 29.3 minutes, and the mean tumor size was 18.8 ± 7.2 mm. Among all lesions, the majority (69.0%) located in the esophagus, 12.7% in the cardia and 13% in the stomach. Complete resection was achieved in all patients (100%). Perforation occurred in 3 patient (4.3%), which was treated by endoclips. Pneumothorax occurred in 2 patients (2.9%) and was managed conservatively. During a median follow-up of 17.2 months, patients were free of local recurrence or distant metastasis (Table 2).Figure 1Figure 2Table 1: Baseline characteristics of patientsTable 2: Clinical outcome of endoscopic submucosal tunnel dissection for patients with submucosal tumorsConclusion: Our results demonstrated that the feasibility and safety of ESTD in the treatment of upper GI SMTs originating from the MP layer. Further large-scale comparative studies with other treatment methods should be conducted in the future.
The aim of this study was to investigate the inactivation of the MutS homolog human 3 (MSH3) gene by promoter methylation in nasopharyngeal carcinoma (NPC). Methylation‑specific PCR, semi‑quantitative reverse transcription PCR and immunohistochemical analysis were used to detect methylation and the mRNA and protein expression levels of MSH3 in 54 cases of NPC tissues and 16 cases of normal nasopharyngeal epithelial (NNE) tissues. The association between promoter methylation and mRNA expression, and the mRNA and protein expression of the gene and clinical factors was analyzed. The promoter methylation of MSH3 was detected in 50% (27/54) of the primary tumors, but not in the 16 NNE tissues. The mRNA and protein expression levels were significantly decreased in the 54 cases of human NPC as compared to the 16 NNE tissues (P<0.05). The MSH3‑methylated cases exhibited significantly lower mRNA and protein expression levels than the unmethylated cases (P<0.05). The MSH3 mRNA and protein expression levels were significantly associated with the variable T stage (P<0.05); however, they did not correlate with the age and sex of the patients, or with the N stage, TNM classification or histopathological subtype (P>0.05). On the whole, MSH3 was frequently inactivated by promoter methylation and its mRNA and protein expression correlated with the primary tumor stage in NPC.
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