Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. METHODS: This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. FINDINGS: Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). INTERPRETATION: Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. FUNDING: Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Comparative effectiveness of prophylactic strategies for preeclampsia: a network meta-analysis of randomized controlled trials.

OBJECTIVE: Preeclampsia is a common disease during pregnancy that leads to fetal and maternal adverse events. Few head-to-head clinical trials are currently comparing the effectiveness of prophylactic strategies for preeclampsia. In this network meta-analysis, we aimed to compare the efficacy of prophylactic strategies for preventing preeclampsia in pregnant women at risk. DATA SOURCES: Articles published in or before September 2021 from PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov, references of key articles, and previous meta-analyses were manually searched. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing prophylactic strategies preventing preeclampsia with each other or with negative controls were included. METHODS: Two reviewers independently extracted data, assessed the risk of bias, and assessed evidence certainty. The efficacy of prophylactic strategies was estimated by frequentist and Bayesian network meta-analysis models. The primary composite outcome was preeclampsia/ pregnancy-induced hypertension. RESULTS: In total, 130 trials with a total of 112,916 patients were included to assess 13 prophylactic strategies. Low-molecular-weight heparin (0.60; 95% confidence interval, 0.42-0.87), vitamin D supplementation (0.65; 95% confidence interval, 0.45-0.95), and exercise (0.68; 95% confidence interval, 0.50-0.92) were as efficacious as calcium supplementation (0.71; 95% confidence interval, 0.62-0.82) and aspirin (0.79; 95% confidence interval, 0.72-0.86) in preventing preeclampsia/pregnancy-induced hypertension, with a P score ranking of 85%, 79%, 76%, 74%, and 61%, respectively. In the head-to-head comparison, no differences were found between these effective prophylactic strategies for preventing preeclampsia and pregnancy-induced hypertension, except with regard to exercise, which tended to be superior to aspirin and calcium supplementation in preventing pregnancy-induced hypertension. Furthermore, the prophylactic effects of aspirin and calcium supplementation were robust across subgroups. However, the prophylactic effects of low-molecular-weight heparin, exercise, and vitamin D supplementation on preeclampsia and pregnancy-induced hypertension varied with different risk populations, dosages, areas, etc. The certainty of the evidence was moderate to very low. CONCLUSION: Low-molecular-weight heparin, vitamin D supplementation, exercise, calcium supplementation, and aspirin reduce the risk of preeclampsia/pregnancy-induced hypertension. No significant differences between effective prophylactic strategies were found in preventing preeclampsia. These findings raise the necessity to reevaluate the prophylactic effects of low-molecular-weight heparin, vitamin D supplementation, and exercise on preeclampsia.

The association of baseline N-terminal pro-B-type natriuretic peptide with short and long-term prognosis following percutaneous coronary intervention in non-ST segment elevation acute coronary syndrome with multivessel coronary artery disease: a retrospective cohort study.

BACKGROUND: Several studies have shown that N-terminal pro-B-type natriuretic peptide (NT-proBNP) is strongly correlated with the complexity of coronary artery disease and the prognosis of patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS), However, it remains unclear about the prognostic value of NT-proBNP in patients with NSTE-ACS and multivessel coronary artery disease (MCAD) undergoing percutaneous coronary intervention (PCI). Therefore, this study aimed to reveal the relationship between NT-proBNP levels and the prognosis for NSTE-ACS patients with MCAD undergoing successful PCI. METHODS: This study enrolled 1022 consecutive NSTE-ACS patients with MCAD from January 2010 to December 2014. The information of NT-proBNP levels was available from these patients. The primary outcome was in-hospital all-cause death. In addition, the 3-year follow-up all-cause death was also ascertained. RESULTS: A total of 12 (1.2%) deaths were reported during hospitalization. The 4th quartile group of NT-proBNP (> 1287 pg/ml) showed the highest in-hospital all-cause death rate (4.3%) (P < 0.001). Besides, logistic analyses revealed that the increasing NT-proBNP level was robustly associated with an increased risk of in-hospital all-cause death (adjusted odds ratio (OR): 2.86, 95% confidence interval (CI) = 1.16-7.03, P = 0.022). NT-proBNP was able to predict the in-hospital all-cause death (area under the curve (AUC) = 0.888, 95% CI = 0.834-0.941, P < 0.001; cutoff: 1568 pg/ml). Moreover, as revealed by cumulative event analyses, a higher NT-proBNP level was significantly related to a higher long-term all-cause death rate compared with a lower NT-proBNP level (P < 0.0001). CONCLUSIONS: The increasing NT-proBNP level is significantly associated with the increased risks of in-hospital and long-term all-cause deaths among NSTE-ACS patients with MCAD undergoing PCI. Typically, NT-proBN P > 1568 pg/ml is related to the all-cause and in-hospital deaths.

Incidence, Risk Factors and Subsequent Prognostic Impact of New-Onset Atrial Fibrillation in Infective Endocarditis.

BACKGROUND: Few studies with a large sample size have been performed to evaluate the incidence, risk factors and prognostic value of new-onset atrial fibrillation (AF) in patients with infective endocarditis (IE).Methods and Results:A total of 1,063 IE patients were included and 83 developed new AF. Compared with no-AF, the incidence of in-hospital death (6.0% vs. 22.9%, P<0.001) was higher in patients with new-onset AF. New-onset AF was independently associated with increased risk of in-hospital (adjusted odds ratio [OR]=3.92, P=0.001) and 1-year death (adjusted hazard ratio=2.91, P=0.001), while prior AF was not an independent factor. Kaplan-Meier curve analysis demonstrated new-onset AF mainly affected short-term death (180 days). Age (OR=1.04, P<0.001), rheumatic heart disease (OR=1.88, P=0.022), NYHA Class III or IV (OR=2.09, P=0.003), and left atrial diameter (LAD; OR=1.05, P=0.006) were independent risk factors for development of new AF. CONCLUSIONS: New-onset AF, not prior AF, was a prognostic factor in IE patients, which was mainly associated with increased risk of short-term death. Patients with concomitant rheumatic heart disease, poor cardiac function, and larger LAD had higher risk of developing new AF.

Association of in-hospital intensive statins dosage and death in arteriosclerotic cardiovascular disease with percutaneous coronary intervention: insights of multicentre cohort from China.

PURPOSE: In-hospital statin dosage-related effect remains unknown for patients with arteriosclerotic cardiovascular disease (ASCVD). This study aimed to determine the associations of different in-hospital intensive statins dosages with the prognosis for patients in the era of percutaneous coronary intervention (PCI). METHODS: From January 2010 to December 2014, consecutive ASCVD patients receiving PCI were enrolled from five centres in China. All the enrolled patients were classified into high-dose (40 mg atorvastatin or 20 mg rosuvastatin) or low-dose (20 mg atorvastatin or 10 mg rosuvastatin) intensive statin group. In-hospital all-cause death was the primary outcome. RESULTS: Of the 7008 patients included in this study, 5248 received low-dose intensive statins (mean age, 64.28 ± 10.39; female, 25.2%), whereas 1760 received high-dose intensive statins (mean age, 63.68 ± 10.59; female, 23.1%). There was no significant difference in the in-hospital all-cause death between the two groups (adjusted OR, 1.27; 95% CI, 0.43-3.72; P = 0.665). All-cause death was similar between the two groups during the 30-day follow-up period (adjusted HR, 1.28; 95% CI, 0.55-2.97; P = 0.571). However, the high-dose intensive statins were tightly associated with the reduction in in-hospital dialysis (adjusted OR, 0.11; 95% CI, 0.01-0.81; P = 0.030). Besides, primary analyses were confirmed by subgroup analyses. CONCLUSIONS: The in-hospital high-dose intensive statins are not associated with the lower risk of in-hospital or 30-day all-cause death among ASCVD patients undergoing PCI. Given the robust beneficial effect of high-dose intensive statins with in-hospital dialysis, an individualized high-dose intensive statin therapy can be rational in specified populations.

Pre-Procedural Risk Score of Contrast-Induced Nephropathy in Elderly Patients Undergoing Elective Coronary Angiography.

To establish a scoring model to predict the risk of contrast-induced nephropathy (CIN) in elderly patients undergoing elective coronary angiography (CAG).A total of 1286 patients aged > 65 years who had undergone elective CAG between August 2009 and February 2013 were enrolled in this study. They were randomly (3:2) assigned to a development (n = 756) or validation dataset (n = 530). Independent predictors of CIN were identified by using logistic regression and were assigned a weighted integer, which was used to establish a score model.CIN incidence in the development set was 6.3%. The risk score model contained 3 variables (with the weighted integer): age > 75 years (1.5), creatinine clearance (CrCl) < 60 mL/minute (1), and congestive heart failure (CHF) (1.5). CIN incidence was 3.1%, 9.1%, and 29.0% in the low-risk group (≤ 1), moderate risk group (1 - 3), and high-risk group (≥ 3), respectively. The risk model demonstrated good prediction value in the development (c-statistic = 0.727) and validation (c-statistic = 0.695) datasets. Compared to the non-CIN group, the CIN group had a significantly higher rate of inhospital major adverse cardiac events (P < 0.01).The risk score model with 3 variables, namely age > 75 years, CrCl < 60 mL/minute, and CHF, is a clinical prediction tool for CIN in elderly patients before elective CAG. CIN is one of the independent risk factors of major adverse cardiac events (MACE).

Aggressive hydraTion in patients with ST-Elevation Myocardial infarction undergoing Primary percutaneous coronary intervention to prevenT contrast-induced nephropathy (ATTEMPT): Study design and protocol for the randomized, controlled trial, the ATTEMPT, RESCIND 1 (First study for REduction of contraSt-induCed nephropathy followINg carDiac catheterization) trial.

Adequate hydration is recommended for acute ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) to prevent contrast-induced nephropathy (CIN). However, the optimal hydration regimen has not been well established in these high-risk patients. The objective of this study is to evaluate the efficacy of a preprocedural loading dose plus postprocedural aggressive hydration with normal saline guided by the left ventricular end-diastolic pressure (LVEDP) compared with general hydration for CIN prevention. The ATTEMPT study is a multicenter, open-label, investigator-driven, randomized controlled trial in China. Approximately 560 patients with STEMI undergoing primary PCI will be randomized (1:1) to receive either periprocedural general hydration (control group) or aggressive hydration (treatment group). Patients in the control group receive periprocedural general hydration with ≤500 mL normal saline (within 6 hours) at a normal rate (0.5 or 1 mL/kg · h). Patients in the treatment group receive a preprocedural loading dose (125/250 mL) of normal saline within 30 minutes and intravenous hydration at a normal rate until LVEDP is available, followed by postprocedural aggressive hydration guided by LVEDP for 4 hours and then continuous intravascular hydration at the normal rate until 24 hours after PCI. The primary end point is CIN, defined as a >25% or 0.5-mg/dL increase in serum creatinine from baseline during the first 48 to 72 hours after procedure. The ATTEMPT study has the potential to identify optimal hydration regimens for STEMI patients undergoing PCI.

N-terminal pro-brain natriuretic peptide improves the C-ACS risk score prediction of clinical outcomes in patients with ST-elevation myocardial infarction.

BACKGROUND: It remained unclear whether the combination of the Canada Acute Coronary Syndrome Risk Score (CACS-RS) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) could have a better performance in predicting clinical outcomes in acute ST-elevation myocardial infarction (STEMI) patients with primary percutaneous coronary intervention. METHODS: A total of 589 consecutive STEMI patients were enrolled. The potential additional predictive value of NT-pro-BNP with the CACS-RS was estimated. Primary endpoint was in-hospital mortality and long-term poor outcomes. RESULTS: The incidence of in-hospital death was 3.1%. Patients with higher NT-pro-BNP and CACS-RS had a greater incidence of in hospital death. After adjustment for the CACS-RS, elevated NT-pro-BNP (defined as the best cutoff point based on the Youden's index) was significantly associated with in hospital death (odd ratio = 4.55, 95%CI = 1.52-13.65, p = 0.007). Elevated NT-pro-BNP added to CACS-RS significantly improved the C-statistics for in-hospital death, as compared with the original score (0.762 vs. 0.683, p = 0.032). Furthermore, the addition of NT-pro-BNP to CACS-RS enhanced net reclassification improvement (0.901, p < 0.001) and integrated discrimination improvement (0.021, p = 0.033), suggesting effective discrimination and reclassification. In addition, the similar result was also demonstrated for in-hospital major adverse clinical events (C-statistics: 0.736 vs. 0.695, p = 0.017) or 3-year mortality (0.699 vs. 0.604, p = 0.004). CONCLUSIONS: Both NT-pro-BNP and CACS-RS are risk predictors for in hospital poor outcomes in patients with STEMI. A combination of them could derive a more accurate prediction for clinical outcome s in these patients.

Endobronchial optical coherence tomography or computed tomography for evaluating progression of bronchiectasis.

Background: The early radiological signs of progression in bronchiectasis remain unclear. The objective of the present study was to compare endobronchial optical coherence tomography (EB-OCT) and chest computed tomography (CT) for the evaluation of radiological progression of bronchiectasis via stratification of the presence (TW+) or absence (TW-) of thickened-walled bronchioles surrounding dilated bronchi in patients with bronchiectasis based on CT, and determine the risk factors. Methods: In this prospective cohort study, we performed both chest CT and EB-OCT at baseline and 5-year follow-up, to compare changes in airway calibre metrics. We evaluated bacterial microbiology, sputum matrix metalloproteinase-9 levels and free neutrophil elastase activity at baseline. We compared clinical characteristics and airway calibre metrics between the TW+ and TW- groups. We ascertained radiological progression at 5 years via CT and EB-OCT. Results: We recruited 75 patients between 2014 and 2017. At baseline, EB-OCT metrics (mean luminal diameter (p=0.017), inner airway area (p=0.005) and airway wall area (p=0.009) of seventh- to ninth-generation bronchioles) were significantly greater in the TW+ group than in the TW-group. Meanwhile, EB-OCT did not reveal bronchiole dilatation (compared with the same segment of normal bronchioles) surrounding nondilated bronchi on CT in the TW- group. At 5 years, 53.1% of patients in the TW+ group progressed to have bronchiectasis measured with EB-OCT, compared with only 3.3% in TW- group (p<0.05). 34 patients in the TW+ group demonstrated marked dilatation of medium-sized and small airways. Higher baseline neutrophil elastase activity and TW+ bronchioles on CT predicted progression of bronchiectasis. Conclusion: Thickened-walled bronchioles surrounding the dilated bronchi, identified with EB-OCT, indicates progression of bronchiectasis.

Fosaprepitant Weekly vs Every 3 Weeks for the Prevention of Concurrent Chemoradiotherapy-Induced Nausea and Vomiting: A Pilot Randomized Clinical Trial.

Importance: Unlike substantial evidence in the prevention of chemotherapy-induced nausea and vomiting (CINV), research in the prevention of nausea and vomiting caused by concurrent chemoradiotherapy (CCRT) is currently lacking. Objective: To compare the efficacy and safety of fosaprepitant weekly vs every 3 weeks for the prevention of nausea and emesis caused by CCRT among patients with nasopharyngeal carcinoma. Design, Setting, and Participants: This pilot randomized clinical trial was conducted at a single cancer center from November 24, 2020, to July 26, 2021, among patients with nasopharyngeal carcinoma who had achieved CINV control after 2 to 3 cycles of induction chemotherapy. Efficacy analyses were performed in the intention-to-treat population. Data were analyzed on November 4, 2022. Interventions: Eligible patients were randomly assigned (1:1) to receive fosaprepitant either weekly or every 3 weeks. Main Outcomes and Measures: The primary end point was the proportion of patients with sustained complete response (defined as no emesis and no rescue therapy) during CCRT. Secondary end points were sustained no emesis, no nausea, no significant nausea, mean time to first emetic episode, quality of life, and 1-year progression-free survival (PFS). Results: A total of 100 patients (mean [SD] age, 46.6 [10.9] years; 83 [83.0%] male) who had achieved CINV control after induction chemotherapy were randomly assigned to receive fosaprepitant weekly (50 patients) or every 3 weeks (50 patients). There was no significantly significant difference in cumulative risk of emesis or rescue therapy in the group that received weekly fosaprepitant compared with those who received fosaprepitant every 3 weeks (subhazard ratio, 0.66 [95% CI, 0.43-1.02]; P = .06). The proportion of patients with sustained no emesis (38% vs 14%; P = .003) or no significant nausea (92% vs 72%; P = .002) was significantly higher in the group that received fosaprepitant weekly vs those who received fosaprepitant every 3 weeks. Treatments were well tolerated. Patients in the weekly group had improved scores for multiple quality-of-life measures. There was no significant difference in survival outcomes between groups (91.8% vs 93.7%; P = .99). In the mean brainstem dose subgroups, a possible treatment interaction effect was observed in sustained complete response (mean brainstem dose ≥36 Gy: hazard ratio [HR], 0.32 [95% CI, 0.15-0.69]; mean brainstem dose <36 Gy: HR, 0.95 [95% CI, 0.55-1.63]) and sustained no emesis (mean brainstem dose ≥36 Gy: HR, 0.21 [95% CI, 0.08-0.53]; mean brainstem dose <36 Gy: HR, 0.73 [95% CI, 0.41-1.28]). Conclusions and Relevance: In this pilot randomized clinical trial, there was no statistically significant difference in the complete response primary end point, but patients receiving weekly fosaprepitant were less likely to experience emesis compared with those who received fosaprepitant every 3 weeks, especially in the subgroup with a mean brainstem dose of 36 Gy or more. Weekly fosaprepitant was well tolerated and improved quality of life of patients without compromising survival. Trial Registration: ClinicalTrials.gov Identifier: NCT04636632.

Sputum pathogen spectrum and clinical outcomes of upper respiratory tract infection in bronchiectasis exacerbation: a prospective cohort study.

Upper respiratory tract infection (URTI) is common in humans. We sought to profile sputum pathogen spectrum and impact of URTI on acute exacerbation of bronchiectasis (AE). Between March 2017 and December 2021, we prospectively collected sputum from adults with bronchiectasis. We stratified AEs into events related (URTI-AE) and unrelated to URTI (non-URTI-AE). We captured URTI without onset of AE (URTI-non-AE). We did bacterial culture and viral detection with polymerase chain reaction, and explored the pathogen spectrum and clinical impacts of URTI-AE via longitudinal follow-up. Finally, we collected 479 non-AE samples (113 collected at URTI-non-AE and 225 collected at clinically stable) and 170 AE samples (89 collected at URTI-AE and 81 collect at non-URTI-AE). The viral detection rate was significantly higher in URTI-AE (46.1%) than in non-URTI-AE (4.9%) and URTI-non-AE (11.5%) (both P < 0.01). Rhinovirus [odds ratio (OR): 5.00, 95% confidence interval (95%CI): 1.06-23.56, P = 0.03] detection was independently associated with URTI-AE compared with non-URTI-AE. URTI-AE tended to yield higher viral load and detection rate of rhinovirus, metapneumovirus and bacterial shifting compared with URTI-non-AE. URTI-AE was associated with higher initial viral loads (esp. rhinovirus, metapneumovirus), greater symptom burden (higher scores of three validated questionnaires) and prolonged recovery compared to those without. Having experienced URTI-AE predicted a greater risk of future URTI-AE (OR: 10.90, 95%CI: 3.60-33.05). In summary, URTI is associated with a distinct pathogen spectrum and aggravates bronchiectasis exacerbation, providing the scientific rationale for the prevention of URTI to hinder bronchiectasis progression.

Camrelizumab Plus Apatinib in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma: An Open-Label, Single-Arm, Phase II Study.

PURPOSE: Immune checkpoint inhibitors combined with antiangiogenic therapy reportedly have potential synergistic antitumor activity. We investigated the activity and safety of this regimen for recurrent/metastatic nasopharyngeal carcinoma (NPC). METHODS: This single-arm, Simon two-stage study enrolled patients with recurrent/metastatic NPC who were refractory to at least first-line systemic therapy and treatment-naive to immune checkpoint inhibitors. The patients received camrelizumab 200 mg once every 3 weeks and apatinib 250 mg once per day. The primary end point was the objective response rate. Key secondary end points included disease control rate, progression-free survival, duration of response, overall survival, and safety. RESULTS: Between October 14, 2020, and December 23, 2021, 58 patients were enrolled, and all were included in the efficacy and safety analysis set. The objective response rate was 65.5% (95% CI, 51.9 to 77.5), and the disease control rate was 86.2% (95% CI, 74.6 to 93.9). The median duration of response was not reached, and the median progression-free survival was 10.4 months (95% CI, 7.2 to 13.6), with a median follow-up duration of 12.4 months (range, 2.1-19.9 months). Treatment-related adverse events (TRAEs) of grade 3 or higher were reported in 34 (58.6%) patients, with the most common being hypertension (19.0%), nasopharyngeal necrosis (15.5%), headache (12.1%), AST elevation (10.3%), and creatine phosphokinase elevation (10.3%). Sixteen (27.6%) patients discontinued apatinib treatment before progression because of unbearable TRAEs, and the most common complication was nasopharyngeal necrosis (9/16; 56.3%). Recurrent nasopharyngeal lesions (odds ratio, 5.94 [95% CI, 1.45 to 24.24]) and reirradiation (odds ratio, 5.33 [95% CI, 1.15 to 24.79]) were significantly positively correlated with nasopharyngeal necrosis. CONCLUSION: Camrelizumab plus apatinib had promising antitumor activity in patients with refractory recurrent/metastatic NPC who failed first-line therapy. Moderate to severe TRAEs were experienced by 58.6%, including nasopharyngeal necrosis associated with local recurrence and a history of reirradiation.

Camrelizumab plus famitinib in patients with recurrent or metastatic nasopharyngeal carcinoma treated with PD-1 blockade: data from a multicohort phase 2 study.

Background: Treatment options for patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) are not clear after progression on previous treatment with PD-(L)1 inhibitor; critical gaps in evidence remain for such cases. Immunotherapy combined with antiangiogenic therapy has been reported to have synergistic antitumor activity. Therefore, we evaluated the efficacy and safety of camrelizumab plus famitinib in patients with RM-NPC who failed treatment with PD-1 inhibitor-containing regimens. Methods: This multicenter, adaptive Simon minimax two-stage, phase II study enrolled patients with RM-NPC refractory to at least one line of systemic platinum-containing chemotherapy and anti-PD-(L)1 immunotherapy. The patient received camrelizumab 200 mg every 3 weeks and famitinib 20 mg once per day. The primary endpoint was objective response rate (ORR), and the study could be stopped early as criterion for efficacy was met (>5 responses). Key secondary endpoints included time to response (TTR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. This trial was registered with ClinicalTrials.gov, NCT04346381. Findings: Between October 12, 2020, and December 6, 2021, a total of 18 patients were enrolled since six responses were observed. The ORR was 33.3% (90% CI, 15.6-55.4) and the DCR was 77.8% (90% CI, 56.1-92.0). The median TTR was 2.1 months, the median DoR was 4.2 months (90% CI, 3.0-not reach), and the median PFS was 7.2 months (90% CI, 4.4-13.3), with a median follow-up duration of 16.7 months. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in eight (44.4%) patients, with the most common being decreased platelet count and/or neutropenia (n = 4, 22.2%). Treatment-related serious AEs occurred in six (33.3%) patients, and no deaths occurred due to TRAEs. Four patients developed grade ≥3 nasopharyngeal necrosis; two of them developed grade 3-4 major epistaxis, and they were cured by nasal packing and vascular embolization. Interpretation: Camrelizumab plus famitinib exhibited encouraging efficacy and tolerable safety profiles in patients with RM-NPC who failed frontline immunotherapy. Further studies are needed to confirm and expand these findings. Funding: Jiangsu Hengrui Pharmaceutical Co., Ltd.

Efficacy of sequential chemoradiotherapy combined with toripalimab in de novo metastatic nasopharyngeal carcinoma: A phase II trial.

Locoregional radiotherapy added to chemotherapy has significantly improved survival in de novo metastatic nasopharyngeal carcinoma (mNPC). However, only 54% of de novo mNPC patients who received sequential chemoradiotherapy have complete or partial response 3 months after radiotherapy. This Simon's optimal two-stage design phase II study (NCT04398056) investigates whether PD-1 inhibitor could improve tumor control in combination with chemoradiation. The primary endpoint is objective response rate (ORR) at 3 months after radiotherapy. Twenty-two patients with primary mNPC are enrolled. The ORR at 3 months after radiotherapy is 81.8% (22.7% complete response, n = 5; 59.1% partial response, n = 13), and the disease control rate is 81.8%. The 3-year progression-free survival (PFS) rate is 44.9% (95% confidence interval 26.4%-76.3%). Fifteen patients (68.2%) experienced grade 3-4 adverse events. Patients with high baseline plasma Epstein-Barr virus DNA copy number (>104 cps/mL) show worse PFS. Addition of toripalimab to sequential chemoradiotherapy suggests promising tumor response in patients with primary mNPC.

Association of Proton Pump Inhibitor and Infection and Major Adverse Clinical Events in Patients With ST-Elevation Myocardial Infarction: A Propensity Score Matching Analysis.

Background: Infections are not common but important in patients with acute myocardial infarction, and are associated with worse outcomes. Infection was proved to be associated with the use of proton pump inhibitor (PPI) in several cohorts. It remains unclear whether PPI usage affects infection in patients with acute myocardial infarction. Methods: We consecutively enrolled patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) from January 2010 to June 2018. All patients were divided into the PPI group and non-PPI group according to whether the PPI was used. The primary endpoint was the development of infection during hospitalization. Results: A total of 3027 patients were finally enrolled, with a mean age of 62.2 ± 12.6 years. 310 (10.2%) patients were developed infection during hospitalization. Baseline characteristics were similar between the PPI and non-PPI groups (n = 584 for each group) after propensity score analysis. PPI usage was significantly associated with infection based on the propensity score matching analysis (adjusted OR = 1.62, 95% CI = 1.02-2.57, P = 0.041). Comparing to patients with non-PPI usage, PPI administration was positively associated with higher risk of in-hospital all-cause mortality (adjusted OR = 3.25, 95% CI = 1.06-9.97, P = 0.039) and in-hospital major adverse clinical events (adjusted OR = 3.71, 95% CI = 1.61-8.56, P = 0.002). Subgroup analysis demonstrated that the impact of PPI on infection was not significantly different among patients with or without diabetes and patients with age ≥65 years or age <65 years. Conclusion: PPI usage was related to a higher incidence of infection during hospitalization, in-hospital all-cause mortality, and in-hospital major adverse clinical events (MACE) in STEMI patients.

Association between DBP and major adverse cardiovascular events in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.

BACKGROUND: In patients with stable coronary artery disease, low DBP is associated with an increased risk of myocardial infarction and cardiovascular death, but its association with clinical outcomes in patients with acute myocardial infarction undergoing percutaneous coronary intervention (PCI) is unknown. METHODS: Consecutive patients with ST-segment elevation myocardial infarction (STEMI) undergoing PCI from January 2010 to June 2016 were enrolled. The patients were divided into five groups according to the quintiles of DBP at admission. The primary outcome was in-hospital major adverse cardiovascular events (MACE) including all-cause death, stroke, target vessel revascularization, and recurrent myocardial infarction. RESULTS: A total of 2198 patients were enrolled, of whom 157 (7.1%) developed in-hospital MACE. Patients with DBP lower than 60 mmHg was associated with a higher rate of in-hospital MACE (14.8, 7.8, 5.6, 6.1, and 3.8%, P < 0.001) and all-cause death (12.5, 6.4, 4.3, 3.9, and 1.9%, P < 0.001) compared with those with DBP 60-69, 70-79, 80-89, and at least 90 mmHg. Multivariate logistic regression analysis demonstrated that DBP higher than 90 mmHg was a significant predictor of lower risk of in-hospital MACE (OR = 0.16, 95% CI = 0.04-0.61, P = 0.007). Cubic spline models for the association between DBP and MACE did not demonstrate a U-type relationship after adjusting for potential risk factors. During the follow-up, lower DBP was associated with a higher risk of all-cause death (P < 0.0001). CONCLUSION: Lower DBP is independently associated with an elevated risk of in-hospital MACE and follow-up all-cause death.

Association of baseline hemoglobin A1c levels with bleeding in patients with non-ST-segment elevation acute coronary syndrome underwent percutaneous coronary intervention: insights of a multicenter cohort study from China.

OBJECTIVE: To investigate the association between baseline hemoglobin A1c (HbA1c) levels and bleeding in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) who underwent percutaneous coronary intervention (PCI). METHODS: This observational cohort study enrolled 6283 consecutive NSTE-ACS patients undergoing PCI from January 1, 2010 to December 31, 2014. Based on baseline HbA1c levels, the patients were divided into the group with HbA1c < 7% ( n = 4740) and the group with HbA1c ≥ 7% (n = 1543). The primary outcomes are major bleeding (BARC grades 3-5) and all-cause death during follow-up. RESULTS: Of patients enrolled, 4705 (74.9%) were male, and 2143 (34.1%) had a history of diabetes mellitus, with a mean (SD) age of 64.13 (10.32) years. The median follow-up duration was 3.21 years. Compared with the patients with HbA1c < 7%, the risk of major bleeding events during follow-up was higher in patients with HbA1c ≥ 7% (adjusted hazard ratio [HR] = 1.57; 95% confidence interval [CI]: 1.01-2.44; P = 0.044), while the risk of all-cause death during follow-up was not associated with the higher HbA1c levels (adjusted HR = 0.88; 95% CI: 0.66-1.18; P = 0.398). CONCLUSIONS: Compared with the lower baseline HbA1c levels, the higher baseline HbA1c levels were associated with an increase in long-term bleeding risk in NSTE-ACS patients undergoing PCI, though higher baseline HbA1c levels were not associated with the higher risk in all-cause death.

Gemcitabine combined with apatinib and toripalimab in recurrent or metastatic nasopharyngeal carcinoma.

BACKGROUND: The role of a triple combination of gemcitabine (chemotherapy) plus apatinib (anti-vascular endothelial growth factor [VEGFR]) and toripalimab (anti-PD-1) (GAT) in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) is unclear. METHODS: Between August 2019 and April 2020, 41 patients with RM-NPC were enrolled and received GAT for up to 6 cycles followed by apatinib and toripalimab. The primary endpoint was the safety. The secondary endpoints included the objective response rate (ORR) and progression-free survival (PFS). Integrated genomic and transcriptional analyses were conducted to identify the patients who benefited in response to this novel combination therapy. FINDINGS: As of April 1, 2022, treatment-related grade 3 or 4 adverse events (AEs) occurred in 23 of 41 patients (56.1%, 95% confidence interval [CI] 41%-70.1%). G3-4 nasopharyngeal necrosis was observed in 9 (9/41, 21.9%) patients. High-risk factors for necrosis included repeated radiotherapy and an interval of less than 12 months from the last radiotherapy. The ORR was 90.2% (95% CI: 76.9%-97.2%). The median PFS was 25.8 months (95% CI: not reached (NR)-NR), and the 24-month PFS rate was 50.7% (95% CI: 34.0%-67.4%). MAS-related GPR family member F (MRGPRF) high expression in tumors correlated with poor PFS from the GAT therapy, characterized by high epithelial mesenchymal transition signatures. Serial circulating tumor DNA (ctDNA) sequencing could predict PFS outcomes to combination therapy. CONCLUSIONS: GAT therapy exhibits a promising antitumor activity and manageable toxicities in patients with RM-NPC. Patients with repeated radiotherapy and an interval of less than 12 months from the last radiotherapy should be carefully selected for antiangiogenic therapies. MRGPRF expression and serial ctDNA monitoring could identify patients that derive benefits from the combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04073784. FUNDING: This research was funded by the National Natural Science Foundation of China (nos. 81772895 and 82002857), the Key-Area Research and Development of Guangdong Province (2020B1111190001), the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project (202103010001), and the National "Ten Thousand Talents Program" Science and Technology Innovation Leading Talents (84000-41180005).

Efficacy of local therapy to metastatic foci in nasopharyngeal carcinoma: large-cohort strictly-matched retrospective study.

Background: Studies of local therapy (LT) to metastatic foci from nasopharyngeal carcinoma (NPC) are inconsistent and controversial. Here, we aimed to explore the survival benefit of LT directed at metastatic foci from NPC. Methods: A retrospective analysis was conducted in NPC patients with liver, lung, and/or bone metastases. The postmetastatic overall survival (OS) rate was analyzed using the Kaplan-Meier method and compared by the log-rank test. Multivariate analysis was performed using the Cox hazard model. Subgroup analyses evaluating the effect of LT were performed for prespecified covariates. Propensity score matching was applied to homogenize the compared arms. Results: Overall, 2041 of 2962 patients were eligible for analysis. At a median follow-up of 43.4 months, the 5-year OS improved by an absolute difference of 14.6%, from 46.2% in the LT group versus 31.6% in the non-LT group, which led to a hazard ratio of 0.634 for death (p < 0.001). Matched-pair analyses confirmed that LT was associated with improved OS (p = 0.003), and the survival benefits of LT remained consistent in the subcohorts of liver and lung metastasis (p = 0.009 and p = 0.007, respectively) but not of bone metastasis (BoM; p = 0.614). Radiotherapy was predominantly used for BoM and biological effective dose (BED) >60 Gy was found to yield more survival benefit than that of BED ⩽ 60 Gy. Conclusions: The addition of LT directed at metastasis has demonstrated an improvement to OS compared with non-LT group in the present matched-pair study, especially for patients with liver and/or lung metastases.

Hydration for prevention of kidney injury after primary coronary intervention for acute myocardial infarction: a randomised clinical trial.

OBJECTIVE: To evaluate the efficacy of aggressive hydration compared with general hydration for contrast-induced acute kidney injury (CI-AKI) prevention among patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). METHODS: The Aggressive hydraTion in patients with STEMI undergoing pPCI to prevenT Contrast-Induced Acute Kidney Injury study is an open-label, randomised controlled study at 15 teaching hospitals in China. A total of 560 adult patients were randomly assigned (1:1) to receive aggressive hydration or general hydration treatment. Aggressive hydration group received preprocedural loading dose of 125/250 mL normal saline within 30 min, followed by postprocedural hydration performed for 4 hours under left ventricular end-diastolic pressure guidance and additional hydration until 24 hours after pPCI. General hydration group received ≤500 mL 0.9% saline at 1 mL/kg/hour for 6 hours after randomisation. The primary end point is CI-AKI, defined as a >25% or 0.5 mg/dL increased in serum creatinine from baseline during the first 48-72 hours after primary angioplasty. The safety end point is acute heart failure. RESULTS: From July 2014 to May 2018, 469 patients were enrolled in the final analysis. CI-AKI occurred less frequently in aggressive hydration group than in general hydration group (21.8% vs 31.1%; risk ratio (RR) 0.70, 95% CI 0.52 to 0.96). Acute heart failure did not significantly differ between the aggressive hydration group and the general hydration group (8.1% vs 6.4%, RR 1.13, 95% CI 0.66 to 2.44). Several subgroup analysis showed the better effect of aggressive hydration in CI-AKI prevention in male, renal insufficient and non-anterior myocardial infarction participants. CONCLUSIONS: Comparing with general hydration, the peri-operative aggressive hydration seems to be safe and effective in preventing CI-AKI among patients with STEMI undergoing pPCI.