Background and Objective: Propofol is the most commonly used sedative in gastrointestinal endoscopic procedures, but is associated with cardiorespiratory suppression, particularly in elderly patients. Remimazolam is a new short-acting GABA(A) receptor agonist with minimal impact on cardiorespiratory suppression, and may be a viable alternative in elderly patients undergoing endoscopic procedures.Methods: This multicenter, randomized controlled trial was conducted between September 2020 and September 2021. Elderly patients (65-85 years of age) scheduled to undergo upper gastrointestinal endoscopy were randomized in 1:1 ratio to receive remimazolam tosilate (300 mg/h) or propofol (3 g/h) in addition to 50-μg fentanyl, until the Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) reached ≤1. MOAA/S was maintained at 0 or 1 throughout the procedure using 2.5 mg remimazolam or 0.5 mg/kg propofol boluses in the two groups, respectively. The primary outcome was the rate of hypotension (defined as systolic blood pressure at ≤90 mmHg or > 30% decline vs. the baseline). Bradycardia was defined as heart rate ≤50 per minute; respiratory depression was defined as respiratory rate <8 per minute and/or SpO 2 < 90%.Results: A total of 400 patients (161 men and 239 women; 70.4 ± 4.6 years of age) were enrolled (200 patients per group). Average body mass index was 22.2 ± 2.4 kg/m 2 . The rate of hypotension was 36.5% in the remimazolam group and 69.6% in the propofol group (p < 0.001). The remimazolam group also had a lower Kejian Lu, Shanshan Wei and Wenwen Ling contributed equally to this work.
Background
Radioresistance is the primary cause of nasopharyngeal carcinoma (NPC) treatment failure. Previous studies have focused on the deficits in cellular apoptosis as a mechanism for radioresistance; however, additional potential death modes involved in modulating radiosensitivity of NPC have not been explored.
Methods
Pyroptosis was assessed by phase-contrast imaging, LDH release assays, live cell imaging, and Western blotting. In vitro and in vivo assays were used to investigate the function of gasdermin E (GSDME) and ovarian tumor family deubiquitinase 4 (OTUD4). NPC tissues were analyzed using Western blotting, immunohistochemistry, and real-time PCR. The molecular mechanism was determined using immunoprecipitation assays and mass spectrometry.
Results
Live cell imaging revealed that 40—75% of irradiation-induced dead NPC cells were pyroptotic cells. Furthermore, irradiation-induced pyroptosis is triggered by GSDME, which are cleaved by activated caspase-3 in the intrinsic mitochondrial pathway. Additionally, GSDME was significantly downregulated in radioresistant NPC specimens. Low GSDME expression was a predictor of worse prognosis and conferred NPC radioresistance both in vitro and in vivo. Mechanistically, OTUD4 deubiquitinated and stabilized GSDME, enhancing radiosensitivity of NPC cells by promoting pyroptosis. Clinically, OTUD4 was significantly correlated with GSDME in NPC biopsies, and patients with low expression of both OTUD4 and GSDME suffered the worst radiotherapy response and survival.
Conclusions
GSDME-dependent pyroptosis is a critical determinant of radiosensitivity in NPC, and is modulated by OTUD4 via deubiquitinating and stabilizing GSDME. These findings reveal a promising novel direction to investigate radioresistance and suggest potential therapeutic targets for sensitizing NPC to radiotherapy.
To investigate long-term survivals and toxicities of early-stage nasopharyngeal carcinoma (NPC) in endemic area, evaluating the role of chemotherapy in stage II patients.
Materials and MethodsTotally 187 patients with newly diagnosed NPC and restaged AJCC/UICC 8th T1-2N0-1M0 were retrospectively recruited. All received intensity-modulated radiotherapy (IMRT) ± chemotherapy (CT) from 2001 to 2010.
ResultsWith 15.7-year median follow-up, 10-year locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), disease specific survival (DSS) and overall survival (OS) were 93.3%, 93.5%, 92.9% and 88.2%, respectively. Multivariable analyses showed cervical lymph nodes positive and pre-treatment prognostic nutritional index ≥52.0 could independently predict DMFS (p=0.036 and 0.011), DSS (p=0.014 and 0.026) and OS (p=0.002 and <0.001); Charlson comorbidity index <3 points could predict DSS (p=0.011); age >45 years (p=0.002) and pretreatment lactate dehydrogenase ≥240 U/L (p<0.001) predicted OS. No grade 4 late toxicity happened; grade 3 late toxicities included subcutaneous fibrosis (4.3%), deafness or otitis (4.8%), skin dystrophy (2.1%) and xerostomia (1.1%). No differences on survivals were shown between IMRT+CT vs. IMRT alone in stage II patients, even in T2N1M0 (p>0.05). Unsurprising, patients in IMRT+CT had more acute gastrointestinal reaction, myelosuppression, mucositis, late ear toxicity and cranial nerve injury (all p < 0.05) than IMRT alone group.
ConclusionSuperior tumor control and satisfying long-term outcomes could be achieved with IMRT in early-stage NPC with mild late toxicities. As chemotherapy would bring more toxicities, it should be carefully performed to stage II patients.
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