Effect of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer: A randomized clinical trial.

Neoadjuvant chemoradiotherapy (NACRT) was the standard treatment for patients with locally advanced rectal cancer (LARC) with proficient mismatch repair (pMMR) proteins. In this randomized phase 2 trial (ClinicalTrial.gov: NCT04304209), 134 pMMR LARC patients were randomly (1:1) assigned to receive NACRT or NACRT and the programmed cell death protein 1 (PD-1) antibody sintilimab. As the primary endpoint, the total complete response (CR) rate is 26.9% (18/67, 95% confidence interval [CI] 16.0%-37.8%) and 44.8% (30/67, 95% CI 32.6%-57.0%) in the control and experimental arm, respectively, with significant difference (p = 0.031 for chi-squared test). Response ratio is 1.667 (95% CI 1.035-2.683). Immunohistochemistry shows PD-1 ligand 1 (PD-L1) combined positive score is associated with the synergistic effect. The safety profile is similar between the arms. Adding the PD-1 antibody sintilimab to NACRT significantly increases the CR rate in pMMR LARC, with a manageable safety profile. PD-L1 positivity may help identify patients who might benefit most from the combination therapy.

Longitudinal on-treatment circulating tumor DNA as a biomarker for real-time dynamic risk monitoring in cancer patients: The EP-SEASON study.

Recurrence risks of cancer patient can change during treatment as a result of treatment-related tumor evolution. However, biomarkers that can monitor these changes are lacking. Here, we investigated whether tracking circulating tumor DNA (ctDNA) dynamics through liquid biopsy can inform real-time recurrence risk. Nasopharyngeal carcinoma (NPC) provides an ideal model where cell-free Epstein-Barr virus (EBV) DNA (cfEBV DNA), a ctDNA, can be sensitively detected. We conducted the EP-SEASON study (NCT03855020) and prospectively recruited 1,000 NPC patients undergoing per-protocol cfEBV DNA assessments at 11 time points and receiving sequential chemo-radiotherapy. Longitudinal cfEBV DNA displayed distinct patterns during neoadjuvant chemotherapy and radiotherapy. Despite the prognostic significance of cfEBV DNA at each time point, real-time recurrence risks changed in sync with cfEBV DNA dynamics. Furthermore, we identified phenotypes of whole-course ctDNA changing dynamics associated with different survival outcomes. In conclusion, tracking longitudinal on-treatment ctDNA can forecast real-time recurrence risk, facilitating risk-adapted, individualized patient management.

A novel Saclayvirus Acinetobacter baumannii phage genomic analysis and effectiveness in preventing pneumonia.

Acinetobacter baumannii, which is resistant to multiple drugs, is an opportunistic pathogen responsible for severe nosocomial infections. With no antibiotics available, phages have obtained clinical attention. However, since immunocompromised patients are often susceptible to infection, the appropriate timing of administration is particularly important. During this research, we obtained a lytic phage vB_AbaM_P1 that specifically targets A. baumannii. We then assessed its potential as a prophylactic treatment for lung infections caused by clinical strains. The virus experiences a period of inactivity lasting 30 min and produces approximately 788 particles during an outbreak. Transmission electron microscopy shows that vB_AbaM_P1 was similar to the Saclayvirus. Based on the analysis of high-throughput sequencing and bioinformatics, vB_AbaM_P1 consists of 107537 bases with a G + C content of 37.68%. It contains a total of 177 open reading frames and 14 tRNAs. No antibiotic genes were detected. In vivo experiments, using a cyclophosphamide-induced neutrophil deficiency model, tested the protective effect of phage on neutrophil-deficient rats by prophylactic application of phage. The use of phages resulted in a decrease in rat mortality caused by A. baumannii and a reduction in the bacterial burden in the lungs. Histologic examination of lung tissue revealed a decrease in the presence of immune cells. The presence of phage vB_AbaM_P1 had a notable impact on preventing A. baumannii infection, as evidenced by the decrease in oxidative stress in lung tissue and cytokine levels in serum. Our research offers more robust evidence for the early utilization of bacteriophages to mitigate A. baumannii infection. KEY POINTS: •A novel Saclayvirus phage infecting A. baumannii was isolated from sewage. •The whole genome was determined, analyzed, and compared to other phages. •Assaying the effect of phage in preventing infection in neutrophil-deficient models.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

In vivo efficacy of phage cocktails against carbapenem resistance Acinetobacter baumannii in the rat pneumonia model.

Acinetobacter baumannii, an opportunistic pathogen, poses a significant threat in intensive care units, leading to severe nosocomial infections. The rise of multi-drug-resistant strains, particularly carbapenem-resistant A. baumannii, has created formidable challenges for effective treatment. Given the prolonged development cycle and high costs associated with antibiotics, phages have garnered clinical attention as an alternative for combating infections caused by drug-resistant bacteria. However, the utilization of phage therapy encounters notable challenges, including the narrow host spectrum, where each phage targets a limited subset of bacteria, increasing the risk of phage resistance development. Additionally, uncertainties in immune system dynamics during treatment hinder tailoring symptomatic interventions based on patient-specific states. In this study, we isolated two A. baumannii phages from wastewater and conducted a comprehensive assessment of their potential applications. This evaluation included sequencing analysis, genome classification, pH and temperature stability assessments, and in vitro bacterial inhibition assays. Further investigations involved analyzing histological and cytokine alterations in rats undergoing phage cocktail treatment for pneumonia. The therapeutic efficacy of the phages was validated, and transcriptomic studies of rat lung tissue during phage treatment revealed crucial changes in the immune system. The findings from our study underscore the potential of phages for future development as a treatment strategy and offer compelling evidence regarding immune system dynamics throughout the treatment process.IMPORTANCEDue to the growing problem of multi-drug-resistant bacteria, the use of phages is being considered as an alternative to antibiotics, and the genetic safety and application stability of phages determine the potential of phage application. The absence of drug resistance genes and virulence genes in the phage genome can ensure the safety of phage application, and the fact that phage can remain active in a wide range of temperatures and pH is also necessary for application. In addition, the effect evaluation of preclinical studies is especially important for clinical application. By simulating the immune response situation during the treatment process through mammalian models, the changes in animal immunity can be observed, and the effect of phage therapy can be further evaluated. Our study provides compelling evidence that phages hold promise for further development as therapeutic agents for Acinetobacter baumannii infections.

A landscape of methodology and implementation of adaptive designs in cancer clinical trials.

BACKGROUND: The use of adaptive designs in cancer trials has considerably increased worldwide in recent years, along with the release of various guidelines for their application. This systematic review aims to comprehensively summarize the key methodological and executive features of adaptive designs in cancer clinical trials. METHODS: A comprehensive search from PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials was conducted to screen eligible clinical trials that employed adaptive designs and were conducted in cancer patients. The methodological and executive characteristics of adaptive designs were the main measurements extracted. Descriptive analyses, primarily consisting of frequency and percentage, were employed to analyzed and reported the data. RESULTS: A total of 180 cancer clinical trials with adaptive designs were identified. The first three most common type of adaptive design was the group sequential design (n=114, 63.3 %), adaptive dose-finding design (n=22, 12.2 %), and adaptive platform design (n=16, 8.9 %). The results showed that 4.4 % (n=8) of trials conducted post hoc modifications, and around 29.4 % (n=53) did not provide the methods for controlling type I errors. Among phase II or above trials, 79.9 % (112/140) applied the surrogate endpoint as the primary outcome in these trials. Importantly, 27.2 % (49/180) of trials did not report clear information on the independent data monitoring committee (iDMC), and 13.3 % (n=24) without clear information on interim analyses. Interim analyses suggested 34.4 % (62/180) of trials being stopped for futility, 10.6 % (n=19) for efficacy, and 2.2 % (n=4) for safety concerns in the early stage. CONCLUSIONS: This study emphasizes adaptive designs in cancer trials face significant challenges in their design or strict implementation according to protocol, which might significantly compromise the validity and integrity of trials. It is thus important for researchers, sponsors, and policymakers to actively oversee and guide their application.

Noteworthy impacts of COVID-19 pandemic on cancer screening: A systematic review.

The sudden onset of the coronavirus disease 2019 (COVID-19) in January 2020 has affected essential global health services. Cancer-screening services that can reduce cancer mortality are strongly affected. However, the specific role of COVID-19 in cancer screening is not fully understood. This study aimed to assess the efficiency of global cancer screening programs before and during the COVID-19 pandemic and to promote potential cancer-screening strategies for the next pandemic. Electronic searches in PubMed, Embase, and Web of Science, and manual searches were performed between January 1, 2020 and March 1, 2023. Cohort studies that reported the number of participants who underwent cancer screening before and during the COVID-19 pandemic were included. The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Differences in cancer-screening rates were estimated using the incidence rate ratio (IRR). Fifty-five cohort studies were included in this meta-analysis. The screening rates of colorectal cancer using invasive screening methods (Pooled IRR = 0.52, 95% CI: 0.42 to 0.65, p < 0.01), cervical cancer (Pooled IRR = 0.56, 95% CI: 0.47 to 0.67, p < 0.01), breast cancer (Pooled IRR = 0.57, 95% CI: 0.49 to 0.66, p < 0.01) and prostate cancer (Pooled IRR = 0.71, 95% CI: 0.56 to 0.90, p < 0.01) during the COVID-19 pandemic were significantly lower than those before the COVID-19 pandemic. The screening rates of lung cancer (Pooled IRR = 0.77, 95% CI: 0.58 to 1.03, p = 0.08) and colorectal cancer using noninvasive screening methods (Pooled IRR = 0.74, 95% CI: 0.50 to 1.09, p = 0.13) were reduced with no statistical differences. The subgroup analyses revealed that the reduction in cancer-screening rates varied across economies. Our results suggest that the COVID-19 pandemic has had a noteworthy impact on colorectal, cervical, breast, and prostate cancer screening. Developing innovative cancer-screening technologies is important to promote the efficiency of cancer-screening services in the post-COVID-19 era and prepare for the next pandemic.

The optimal threshold of PD-L1 combined positive score to predict the benefit of PD-1 antibody plus chemotherapy for patients with HER2-negative gastric adenocarcinoma: a meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line treatment of metastatic gastric and gastroesophageal adenocarcinomas (GEACs). This study aims to figure out the optimal combined positive score (CPS) cutoff value. METHODS: We searched for randomized phase III trials to investigate the efficacy of ICIs plus chemotherapy for metastatic GEACs compared with chemotherapy alone. Pooled analyses of hazard ratios (HRs) based on PD-L1 expression were performed. RESULTS: A total of six trials (KEYNOTE-062, KEYNOTE-590, KEYNOTE-859, ATTRACTION-04, CheckMate 649, and ORIENT-16) were included, comprising 5,242 patients. ICIs plus chemotherapy significantly improved OS (HR: 0.79, 95% CI 0.72-0.86 in global patients; HR: 0.75, 95% CI 0.57-0.98 in Asian patients) and PFS (HR: 0.74, 95% CI 0.68-0.82 in global patients; HR: 0.64, 95% CI 0.56-0.73 in Asian patients) compared with chemotherapy alone. The differences in OS (ratio of HR: 1.05, 95% CI 0.79-1.40; predictive value: - 5.1%) and PFS (ratio of HR: 1.16, 95% CI 0.98-1.36; predictive value: - 13.5%) were not statistically significant between the global and Asian patients. Subgroup analyses indicated that the optimal CPS threshold was at ≥ 5 for OS and ≥ 10 for PFS with the highest predictive values. CONCLUSIONS: The benefit derived from ICIs plus chemotherapy is similar between Asian and global GEAC patients. However, those with a PD-L1 CPS < 5 or CPS < 10 may not have significant benefits from ICIs therapy. Therefore, it is advisable to routinely assess PD-L1 expression in GEAC patients considered for ICIs treatment.

Sintilimab (anti-PD-1 antibody) plus chidamide (histone deacetylase inhibitor) in relapsed or refractory extranodal natural killer T-cell lymphoma (SCENT): a phase Ib/II study.

Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.

Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Radiotherapy alone versus concurrent chemoradiotherapy in patients with stage II and T3N0 nasopharyngeal carcinoma with adverse features: A propensity score-matched cohort study.

BACKGROUND AND PURPOSE: Whether concurrent chemoradiotherapy would provide survival benefits in patients with stage II and T3N0 NPC with adverse factors remains unclear in IMRT era. We aimed to assess the value of concurrent chemotherapy compared to IMRT alone in stage II and T3N0 NPC with adverse features. MATERIALS AND METHODS: 287 patients with stage II and T3N0 NPC with adverse factors were retrospectively analyzed, including 98 patients who received IMRT alone (IMRT alone group) and 189 patients who received cisplatin-based concurrent chemotherapy (CCRT group). The possible prognostic factors were balanced using propensity score matching (PSM). Kaplan-Meier analysis was used to evaluate the survival rates, and log-rank tests were employed to compare differences between groups. RESULTS: The median follow-up duration was 90.8 months (interquartile range = 75.6-114.7 months). The IMRT alone and the CCRT group were well matched; however, for all survival-related endpoints, there were no significant differences between them (5-year failure-free survival: 84.3% vs. 82.7%, P value = 0.68; 5-year overall survival: 87.3% vs. 90.6%, P value = 0.11; 5-year distant metastasis-free survival: 92.8% vs. 92.5%, P value = 0.97; 5-year locoregional relapse-free survival: 93.4% vs. 89.9%, P value = 0.30). The incidence of acute toxicities in the IMRT alone group was significantly lower than that in the CCRT group. CONCLUSION: For patients with stage II and T3N0 NPC with adverse features treated using IMRT, no improvement in survival was gained by adding concurrent chemotherapy; however, the occurrence of acute toxicities increased significantly. For those combined with non-single adverse factors, the comprehensive treatment strategy needs further exploration.

Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial.

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .

Access to colorectal cancer screening in populations in China, 2020: A coverage-focused synthesis analysis.

In populations in China, colorectal cancer (CRC) screening can be mainly accessed through organized screening, opportunistic screening, and physical examination. This screening intervention is found to be effective but the exact coverage rate is difficult to measure. Based on data from published articles, official websites, and available program reports, the screening coverage rate and related indicators were quantified. A rapid review was then conducted to estimate the overall and the breakdown coverage rates of the sub-type screening services, by leveraging the numbers of articles and the by-type median sample sizes. Up to 2020, two central government-funded and four provincial/municipal-level organized CRC screening programs have been initiated and included in this analysis. For populations aged 40-74, the estimated coverage rate of organized programs in China was 2.7% in 2020, and the 2-year cumulative coverage rate in 2019-2020 was 5.3% and the 3-year cumulative coverage rate in 2018-2020 was 7.7%. The corresponding coverage rates of 50-74-year-olds were estimated to be 3.4%, 7.1%, and 10.3%, respectively. Based on the rapid review approach, the overall screening coverage rate for 40-74 years, considering organized screening programs, opportunistic screening, and physical examinations, was then estimated to be 3.0% in China in 2020. However, comparing the findings of this study with the number of health check-ups reported in the local national health statistics yearbooks suggests that the number of CRC physical examinations may be underestimated in this study. The findings suggest that further efforts are needed to improve population access to CRC screening in China. Furthermore, evidence for access to opportunistic CRC screening and physical examination is limited, and more quantitative investigation is needed.

Reduced-Volume Irradiation of Uninvolved Neck in Patients With Nasopharyngeal Cancer: Updated Results From an Open-Label, Noninferiority, Multicenter, Randomized Phase III Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported comparable 3-year regional relapse-free survival (RRFS) using elective upper-neck irradiation (UNI) in N0-1 nasopharyngeal carcinoma (NPC) compared with standard whole-neck irradiation (WNI). Here, we present the prespecified 5-year overall survival (OS), RRFS, late toxicity, and additional analyses. In this randomized trial, patients received UNI (n = 224) or WNI (n = 222) for an uninvolved neck. After a median follow-up of 74 months, the UNI and WNI groups had similar 5-year OS (95.9% v 93.1%, hazard ratio [HR], 0.63 [95% CI, 0.30 to 1.35]; P = .24) and RRFS (95.0% v 94.9%, HR, 0.96 [95% CI, 0.43 to 2.13]; P = .91) rates. The 5-year disease-free survivors in the UNI group had a lower frequency of hypothyroidism (34% v 48%; P = .004), neck tissue damage (29% v 46%; P < .001), dysphagia (14% v 27%; P = .002), and lower-neck common carotid artery stenosis (15% v 26%; P = .043). The UNI group had higher postradiotherapy circulating lymphocyte counts than the WNI group (median: 400 cells/µL v 335 cells/µL, P = .007). In conclusion, these updated data confirmed that UNI of the uninvolved neck is a standard of care in N0-1 NPC, providing outstanding efficacy and reduced long-term toxicity, and might retain more immune function.

Temperature-phased anaerobic sludge digestion effectively removes antibiotic resistance genes in a full-scale wastewater treatment plant.

Sludge is a major by-product and the final reservoir of antibiotic resistance genes (ARGs) in wastewater treatment plants (WWTPs). Temperature-phased anaerobic digestion (TPAD), consisting of thermophilic anaerobic digestion (AD) (55 °C) and mesophilic AD processes (37 °C), has been implemented in WWTPs for sludge reduction while improving the biomethane production. However, the impact of TPAD on the ARGs' fate is still undiscovered in lab-scale experiments and full-scale WWTPs. This study, for the first time, investigated the fate of ARGs during the TPAD process across three seasons in a full-size WWTP. Ten typical ARGs and one integrase gene of class 1 integron (intI1) involving ARGs horizontal gene transfer were examined in sludge before and after each step of the TPAD process. TPAD reduced aac(6')-Ib-cr, blaTEM, drfA1, sul1, sul2, ermb, mefA, tetA, tetB and tetX by 87.3-100.0 %. TPAD reduced the overall average absolute abundance of targeted ARGs and intI1 by 92.39 % and 92.50 %, respectively. The abundance of targeted ARGs in sludge was higher in winter than in summer and autumn before and after TPAD. During the TPAD processes, thermophilic AD played a major role in the removal of ARGs, contributing to >60 % removal of ARGs, while the subsequent mesophilic AD contributed to a further 31 % removal of ARGs. The microbial community analysis revealed that thermophilic AD reduced the absolute abundance of ARGs hosts, antibiotic resistant bacteria. In addition, thermophilic AD reduced the abundance of the intI1, while the intI1 did not reproduce during the mesophilic AD, also contributing to a decline in the absolute abundance of ARGs in TPAD. This study demonstrates that TPAD can effectively reduce the abundance of ARGs in sludge, which will suppress the transmission of ARGs from sludge into the natural environment and deliver environmental and health benefits to our society.

Communication in Social Networking Sites on Offline and Online Social Support and Life Satisfaction Among University Students: Tie Strength Matters.

PURPOSE: Use of social networking sites (SNS) is highly prevalent among college and university students. Conflicting findings were found on the effects of SNS use on well-being, and very few studies examined the effects of social interaction with strong ties and weak ties on SNS on online and offline social support. The present study examined the association between social interaction with weak ties and strong ties on SNS and life satisfaction among Chinese college and university students. The mediating role of online social support and offline social support was also examined. METHODS: A cross-sectional survey was conducted among 26,547 students from 30 colleges/universities in Shanxi province, China. RESULTS: Social interaction with strong ties on SNS was associated with increased offline social support but had no significant association with online support. Social interaction with weak ties on SNS was associated with higher level of online support, but lower level of offline social support. Both offline and online social support were associated with life satisfaction. The direct effects of social interaction with strong ties and weak ties on life satisfaction were not significant. Mediation analyses supported the full mediating effect of offline social support in the relationship between social interaction with strong ties and life satisfaction, while online and offline support mediated the relationship between social interaction with weak ties and life satisfaction. DISCUSSION: Social interaction with strong ties and weak ties on the SNS was associated with life satisfaction through different pathways. Interventions to maximize the benefits of SNS use are warranted.

Distinct clinical characteristics in stage III rectal cancer among different age groups and treatment outcomes after neoadjuvant chemoradiotherapy.

Background: There is a rapidly increasing incidence of early-onset colorectal cancer (EO-CRC) which threatens the survival of young people, while aging also represents a challenging clinical problem. Objectives: We aimed to investigate the differences in the clinical characteristics and prognosis in stage III rectal cancer (RC), to help optimize treatment strategies. Design and methods: This study included 757 patients with stage III RC, all of whom received neoadjuvant chemoradiotherapy and total mesorectal excision. The whole cohort was categorized as very early onset (VEO, ⩽30 years old), early onset (EO, >30 years old, ⩽50 years old), intermediate onset (IO, >50 years, ⩽70 years), or late onset (LO, >70 years old). Results: There were more female VEO patients than males, more mucinous adenocarcinoma, signet-ring cell carcinoma, pre-treatment cT4 stage, and higher pre-treatment serum carbohydrate antigen 19-9 compared with the other three groups. VEO patients had the worst survival with the highest RC-related mortality (34.5%), recurrence (13.8%), and metastasis (51.7%). LO patients had the highest non-RC-related mortality rate (16.6%). The Cox regression model showed VEO was a negative independent prognostic factor for disease-free survival [DFS, hazard ratio (HR): 2.830, 95% confidence interval (CI): 1.633-4.904, p < 0.001], distant metastasis-free survival (DMFS, HR: 2.969, 95% CI: 1.720-5.127, p < 0.001), overall survival (OS, HR: 2.164, 95% CI: 1.102-4.249, p = 0.025), and cancer-specific survival (CSS, HR: 2.321, 95% CI: 1.145-4.705, p = 0.020). LO was a negative independent factor on DFS (HR: 1.800, 95% CI: 1.113-2.911, p = 0.017), DMFS (HR: 1.903, 95% CI: 1.150-3.149, p = 0.012), OS (HR: 2.856, 95% CI: 1.745-4.583, p < 0.001), and CSS (HR: 2.248, 95% CI: 1.282-3.942, p = 0.005). VEO patients had better survival in the total neoadjuvant therapy-like (TNT-like) pattern on DFS (p = 0.039). IO patients receiving TNT-like patterns had better survival on DFS, OS, and CSS (p = 0.006, p = 0.018, p = 0.006, respectively). Conclusion: In stage III RC, VEO patients exhibited unique clinicopathological characteristics, with VEO a negative independent prognostic factor for DFS, DMFS, OS, and CSS. VEO and IO patients may benefit from a TNT-like treatment pattern.

Occurrence, fate, and remediation for per-and polyfluoroalkyl substances (PFAS) in sewage sludge: A comprehensive review.

Addressing per-and polyfluoroalkyl substances (PFAS) contamination is an urgent environmental concern. While most research has focused on PFAS contamination in water matrices, comparatively little attention has been given to sludge, a significant by-product of wastewater treatment. This critical review presents the latest information on emission sources, global distribution, international regulations, analytical methods, and remediation technologies for PFAS in sludge and biosolids from wastewater treatment plants. PFAS concentrations in sludge matrices are typically in hundreds of ng/g dry weight (dw) in developed countries but are rarely reported in developing and least-developed countries due to the limited analytical capability. In comparison to water samples, efficient extraction and cleaning procedures are crucial for PFAS detection in sludge samples. While regulations on PFAS have mainly focused on soil due to biosolids reuse, only two countries have set limits on PFAS in sludge or biosolids with a maximum of 100 ng/g dw for major PFAS. Biological technologies using microbes and enzymes present in sludge are considered as having high potential for PFAS remediation, as they are eco-friendly, low-cost, and promising. By contrast, physical/chemical methods are either energy-intensive or linked to further challenges with PFAS contamination and disposal. The findings of this review deepen our comprehension of PFAS in sludge and have guided future research recommendations.

Ketogenic diet ameliorates high-fat diet-induced insulin resistance in mouse skeletal muscle by alleviating endoplasmic reticulum stress.

OBJECTIVE: Ketogenic diets (KD) have been shown to alleviate insulin resistance (IR) by exerting anti-lipogenic and insulin sensitizing effects in the liver through a variety of pathways. The present study sought to investigate whether a ketogenic diet also improves insulin sensitization in skeletal muscle cells through alleviating endoplasmic reticulum stress. METHODS: High-fat diet-induced IR mice were allowed to a 2-week ketogenic diet. Insulin resistance and glucose tolerance were evaluated through GTT, ITT, and HOMA-IR. The C2C12 myoblasts exposed to palmitic acid were used to evaluate the insulin sensitization effects of ß-hydroxybutyric acid (ß-OHB). Molecular mechanisms concerning ER stress signaling activation and glucose uptake were assessed. RESULTS: The AKT/GSK3ß pathway was inhibited, ER stress signaling associated with IRE1, PERK, and BIP was activated, and the number of Glut4 proteins translocated to membrane decreased in the muscle of HFD mice. However, all these changes were reversed after 2 weeks of feeding on a ketogenic diet. Consistently in C2C12 myoblasts, the AKT/GSK3ß pathway was inhibited by palmitic acid (PA) treatment. The endoplasmic reticulum stress-related proteins, IRE1, and BIP were increased, and the number of Glut4 proteins on the cell membrane decreased. However, ß-OHB treatment alleviated ER stress and improved the glucose uptake of C2C12 cells. CONCLUSION: Our data reveal that KD ameliorated HFD-induced insulin resistance in skeletal muscle, which was partially mediated by inhibiting endoplasmic reticulum stress. The insulin sensitization effect of ß-OHB is associated with up regulation of AKT/GSK3ß pathway and the increase in the number of Glut4 proteins on the cell membrane.