DNA methylation profiles of cancer-related fatigue associated with markers of inflammation and immunometabolism.

Cancer patients are commonly affected by fatigue. Herein, we sought to examine epigenetic modifications (i.e., DNA methylation) related to fatigue in peripheral blood among patients during and after treatment for head and neck cancer (HNC). Further, we determined whether these modifications were associated with gene expression and inflammatory protein markers, which we have previously linked to fatigue in HNC. This prospective, longitudinal study enrolled eligible patients with data collected at pre-radiotherapy, end of radiotherapy, and six months and one-year post-radiotherapy. Fatigue data were reported by patients using the Multidimensional Fatigue Inventory (MFI)-20. DNA methylation (Illumina MethylationEPIC) and gene expression (Applied Biosystems Clariom S) arrays and assays for seven inflammatory markers (R&D Systems multiplex) were performed. Mixed models and enrichment analyses were applied to establish the associations. A total of 386 methylation loci were associated with fatigue among 145 patients (False Discovery Rate [FDR] < 0.05). Enrichment analyses showed the involvement of genes related to immune and inflammatory responses, insulin and lipid metabolism, neuropsychological disorders, and tumors. We further identified 16 methylation-gene expression pairs (FDR < 0.05), which were linked to immune and inflammatory responses and lipid metabolism. Ninety-one percent (351) of the 386 methylation loci were also significantly associated with inflammatory markers (e.g., interleukin 6, c-reactive protein; FDR < 0.05), which further mediated the association between methylation and fatigue (FDR < 0.05). These data suggest that epigenetic modifications associated with inflammation and immunometabolism, in conjunction with relevant gene expression and protein markers, are potential targets for treating fatigue in HNC patients. The findings also merit future prospective studies in other cancer populations as well as interventional investigations.

Chemoprevention of head and neck cancer: a review of current approaches and future perspectives.

Head and neck squamous cell carcinoma (HNSCC) is a spectrum of heterogeneous malignancies. A variety of genetic, environmental, and lifestyle factors contribute to the development of HNSCC. Carcinogenesis is a multistep process in which cell proliferation-associated oncogenes and cell cycle regulation-associated tumor suppressor genes are dysregulated resulting in premalignant lesions. Immune evasion is a critical step in the progression of benign lesions to advanced cancer. This review discusses the advances that have been made in chemoprevention strategies for HNSCC. The rationale for the use of chemopreventive agents to inhibit head and neck cancer development is highlighted by the positive outcomes of several clinical trials. We discuss the potential of some of the commonly studied agents including vitamin A analogues, EGFR inhibitors, COX-2 inhibitors, metabolic modulators, and natural compounds such as green tea, immunotherapy and photodynamic therapy to prevent HNSCC. Our review provides insight into the potential benefits of these agents and the gaps that remain to be addressed. The published results reaffirm the promise of chemoprevention in head and neck cancer and suggest that continued exploration is needed to overcome the limitations. Since the current focus on chemopreventive agents is limited, major efforts in precision oncology approaches and substantial increase in funding will promote research into chemoprevention which will eventually decrease the incidence of HNSCC.

[Association between heavy metal mixed exposure and neonatal birth weight in pregnancy].

The impact of prenatal exposure to a mixture of heavy metals on birth weight in newborns has been a topic of ongoing interest. In this study, 258 mothers and infants from the New Hampshire Birth Cohort Study (NHBCS) were selected as the study subjects, and the concentrations of seven heavy metals in the placenta, including Aluminum (Al), Cobalt (Co), Chromium (Cr), Nickel (Ni), Plumbum (Pb), Selenium (Se) and Arsenic (As) were collected. And the birth weight of newborns, the relevant covariates of mothers and newborns were collected. Three analytical methods, Weighted Quantile Sum (WQS) regression, Quantile g-computation (QGC) and Bayesian kernel machine regression (BKMR) were employed. After adjusting for maternal gestational age, pre-pregnancy BMI, smoking status, education level, parity, gestational age and newborn gender, the combined three methods showed that the total effect of mixed exposure of seven heavy metals on birth weight was negative. Specifically, the WQS analysis revealed that Se had the greatest impact on birth weight, followed by Al. The QGC results showed that the heavy metal associated with the reduction of birth weight was mainly Se and Al in female and male infants, respectively. The BKMR analysis demonstrated a negative combined effect of the seven heavy metals on birth weight in both male and female infants, with Se having the highest posterior inclusion probabilities (PIPs) for female infants (0.45), and Al having the highest PIPs for male infants (0.64) after stratification by gender. In summary, mixed exposure to heavy metals during pregnancy was associated with a decrease in newborn birth weight. Furthermore, there are gender effects with Se and Al associated with decreased birth weight in female and male infants, respectively. These findings provide a theoretical basis for the development of public health policies aimed at preventing adverse pregnancy outcomes and improving the health of newborns.

Assessing survival outcomes of patients with oral tongue squamous cell carcinoma: Focus on age, sex, and stage.

BACKGROUND: The purpose of this study was to provide further insights into whether age and/or sex are associated with prognosis in oral tongue squamous cell carcinoma. METHODS: This was a retrospective cohort study utilizing hospital registry data from 2006 to 2016 obtained from the National Cancer Database. Identified patients were divided into various cohorts based on age, sex, and staging. A descriptive analysis was performed using chi-square tests and overall survival rates were estimated using Kaplan-Meier method. RESULTS: A total of 17 642 patients were included in the study. The 5-year overall survival rates were 82.0% (95% CI: 79.8%-84.0%) in younger patients versus 67.5% (95% CI: 66.7%-68.3%, p-value <0.0001) older patients. The median overall survival for females was 143.4 months (95% CI: 133.2-NA) versus 129.8 (95% CI: 125.4-138.7, p-value <0.0001) in males. CONCLUSIONS: Our analysis suggests that younger age and female sex are both predictors of improved survival in oral tongue squamous cell carcinoma.

Intensity-Modulated Reirradiation Therapy With Nivolumab in Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma: A Nonrandomized Controlled Trial.

Importance: Intensity-modulated radiation therapy (IMRT) reirradiation of nonmetastatic recurrent or second primary head and neck squamous cell carcinoma (HNSCC) results in poor progression-free survival (PFS) and overall survival (OS). Objective: To investigate the tolerability, PFS, OS, and patient-reported outcomes with nivolumab (approved standard of care for patients with HNSCC) during and after IMRT reirradiation. Design, Setting, and Participants: In this multicenter nonrandomized phase 2 single-arm trial, the treatment outcomes of patients with recurrent or second primary HNSCC who satisfied recursive partitioning analysis class 1 and 2 definitions were evaluated. Between July 11, 2018, and August 12, 2021, 62 patients were consented and screened. Data were evaluated between June and December 2023. Intervention: Sixty- to 66-Gy IMRT in 30 to 33 daily fractions over 6 to 6.5 weeks with nivolumab, 240 mg, intravenously 2 weeks prior and every 2 weeks for 5 cycles during IMRT, then nivolumab, 480 mg, intravenously every 4 weeks for a total nivolumab duration of 52 weeks. Main Outcomes and Measures: The primary end point was PFS. Secondary end points included OS, incidence, and types of toxic effects, including long-term treatment-related toxic effects, patient-reported outcomes, and correlatives of tissue and blood biomarkers. Results: A total of 62 patients were screened, and 51 were evaluable (median [range] age was 62 [56-67] years; 42 [82%] were male; 6 [12%] had p16+ disease; 38 [75%] had salvage surgery; and 36 [71%.] had neck dissection). With a median follow-up of 24.5 months (95% CI, 19.0-25.0), the estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P = .002 within a 1-year timeframe. The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis. Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck Questionnaire quality of life scores remained stable and consistent across all time points. A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed. Conclusions and Relevance: This multicenter nonrandomized phase 2 trial of IMRT reirradiation therapy and nivolumab suggested a promising improvement in PFS over historical controls. The treatment was well tolerated and deserves further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT03521570.

China Alzheimer's Disease and Neurodegenerative Disorder Research (CANDOR) -A Prospective Cohort Study for Alzheimer's Disease and Vascular Cognitive Impairment.

BACKGROUND: Alzheimer's disease (AD) and vascular cognitive impairment (VCI) are the two main causes of dementia. AD and VCI share similar symptoms of cognitive decline and may be attributable to similar risk factors. Establishing a prospective cohort to compare VCI and AD would help to understand vascular risk factors related to dementia. OBJECTIVES: China Alzheimer's disease and Neurodegenerative Disorder Research (CANDOR) study is a prospective multicenter cohort study. It aims to study the similarities and differences between AD and post stroke cognitive impairment (PSCI) in neuroimaging changes, disease progression, and multiple omics studies. DESIGN: This is an ongoing study. From July 31, 2019, to August 1, 2022, we recruited 1449 participants with ages between 40 and 100 years. The cohort included three groups: AD group, PSCI group, and normal cognitive (NC) group. Data were collected in face-to-face interviews at baseline, and will be followed up every year for 4 years. The PSCI group had additional follow-ups at 3-month and 6-month after enrollment. Brain Magnetic Resonance Imaging (MRI) included high-resolution sequences for intracranial arteries. Cognitive assessments and follow-up information will be prospectively collected. Biological specimens including blood and urine at baseline were collected and tested. PARTICIPANTS: The targeted sample size of PSCI group was 500, AD group with 600 and NC group with 2000. There were 1449 participants enrolled. Include 508 participants were in NC group, 387 in AD group and 554 in PSCI group. MEASUREMENTS: Demographics, clinical parameters, and medical examinations were collected and performed. Cognitive assessment was performed to assess all cognitive domains including memory, language, executive function, and orientation function. CONCLUSIONS: The CANDOR study is a prospective cohort study. Data from this cohort provide us an opportunity to investigate the contribution of vascular factors to dementia pathogenesis.

Efficacy of Systemic Bevacizumab for Recurrent Respiratory Papillomatosis with Pulmonary Involvement.

OBJECTIVES: Pulmonary papillomatosis is a rare but severe manifestation of recurrent respiratory papillomatosis (RRP). Efficacy data of systemic bevacizumab for pulmonary RRP are limited. This study's objective was to characterize disease response of pulmonary RRP to systemic bevacizumab. METHODS: A retrospective review was performed to identify patients with pulmonary RRP seen at three medical institutions. Clinical symptoms, CT findings, and disease response were compared before and after initiation of systemic bevacizumab therapy. Disease response was categorized as complete response, partial response, stabilization, or progression for each subsite involved by papilloma. RESULTS: Of the 12 pulmonary RRP patients treated with systemic bevacizumab, 4 (33.3%) were male, and 11 (91.7%) were juvenile-onset RRP patients. All presented with laryngeal, tracheal, and pulmonary RRP. The median (range) age at first bevacizumab infusion was 48.1 (19.5-70.2) years. Progression to pulmonary malignancy was identified in 3 (25.0%) patients, 2 before initiation of and 1 after complete cessation of bevacizumab therapy. Clinical symptoms such as dyspnea (75.0% vs. 25.0%; p = 0.01) and dysphagia and/or odynophagia (33.3 vs. 0.0%; p = 0.03) were significantly decreased following bevacizumab therapy. Compared with pre-treatment baseline, 9 (75.0%) patients experienced a stable-to-partial response in the lungs to systemic bevacizumab, and 10 (83.3%) experienced partial-to-complete responses in the larynx and trachea. CONCLUSION: Systemic bevacizumab is effective in stabilizing progression in even the most severe cases of RRP, with both a dramatic reduction in laryngeal and tracheal disease as well as a stable-to-partial response of pulmonary involvement in a majority of patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:577-581, 2024.

Reentrance of interface superconductivity in a high-Tc cuprate heterostructure.

Increasing the carrier density in a Mott insulator by chemical doping gives rise to a generic superconducting dome in high temperature superconductors. An intriguing question is whether a second superconducting dome may exist at higher dopings. Here we heavily overdope La2-xSrxCuO4 (0.45 ≤ x ≤ 1.0) and discover an unprecedented reentrance of interface superconductivity in La2-xSrxCuO4 /La2CuO4 heterostructures. As x increases, the superconductivity is weakened and completely fades away at x = 0.8; but it revives at higher doping and fully recovers at x = 1.0. This is shown to be correlated with the suppression of the interfacial charge transfer around x = 0.8 and the weak-to-strong localization crossover in the La2-xSrxCuO4 layer. We further construct a theoretical model to account for the sophisticated relation between charge localization and interfacial charge transfer. Our work advances both the search for and control of new superconducting heterostructures.

Gelanxinning capsule improves coronary microvascular dysfunction by inhibiting inflammation and restoring endothelial function.

OBJECTIVE: Gelanxinning capsule (GXSC) is a Chinese medicine to cure coronary artery disease (CAD) and a compound of Pueraria lobata, hawthorn extract, and gypenosides. However, whether GXSC could improve coronary microvascular dysfunction (CMD) is unknown. We aimed to demonstrate the therapeutic effect of GXSC on CMD and its underlying mechanisms in CAD patients. PATIENTS AND METHODS: This was a single-center, randomized control trial. A total of 78 patients diagnosed by selective coronary angiography (CAG) participated in this study. Patients' demographics, medical history, medications, and results of laboratory testing were collected. The index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were obtained by CAG and single-photon emission computed tomography (SPECT) separately. Fasting blood samples were obtained on the morning following the admission day. Concentrations of several molecules of inflammation, endothelial function, and coronary microvascular function were measured by ELISA. Patients were followed-up two months after discharge and fasting blood samples were also acquired. RESULTS: All patients were randomly divided into 2 groups: GXSC, 38 (48.7%), and control, 40 (51.3%). The intergroup comparison revealed no significant differences with respect to all baseline variables. As for inflammation biomarkers, proinflammatory NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and interleukin (IL)-1 were significantly decreased in GXSC compared with the control group (0.71±0.08 vs. 1.04±0.07, p<0.01 and 7.16±0.59 vs. 10.93±1.04, p<0.01). Anti-inflammatory adropin was increased in the GXSC group (7.75±0.59 vs. 5.71±0.68, p=0.03). As for indexes of endothelial function, the concentrations of syndecan (SDC) 1, SDC4 and heparan sulphates (HS) were significantly downregulated in 2 months GXSC treatment (3.31±0.28 vs. 4.85±0.43, p<0.01, 3.79±0.56 vs. 5.69±0.68, p=0.03 and 21.31±2.79 vs. 35.18±4.11 p<0.01). In addition, the level of SIRTUIN 1 (SIRT1), which is a vascular protective protein, was upregulated in GXSC group (5.63±0.30 vs. 4.22±0.37, p<0.01). As for molecules of coronary microvascular function, endocan, soluble urokinase plasminogen activator receptor (suPAR), and growth differentiation factor (GDF)-15 were significantly decreased consistently in GXSC compared with the control group (0.09±0.01 vs. 0.19±0.03, p<0.01, 4.44±0.40 vs. 5.73±0.40, p=0.03 and 2.08±0.17 vs. 2.69±0.18, p=0.02). CONCLUSIONS: In conclusion, GXSC could improve CMD by inhibiting inflammation and restoring endothelial function. GXSC might be an effective drug in CAD patients without obstructive epicardial coronary arteries but suffering from angina.

Associations of differentially expressed genes with psychoneurological symptoms in patients with head and neck cancer: A longitudinal study.

OBJECTIVE: Patients with head and neck cancer (HNC) experience psychoneurological symptoms (PNS, i.e., depression, fatigue, sleep disturbance, pain, and cognitive dysfunction) during intensity-modulated radiotherapy (IMRT) that negatively impact their functional status, quality of life, and overall survival. The underlying mechanisms for PNS are still not fully understood. This study aimed to examine differentially expressed genes and pathways related to PNS for patients undergoing IMRT (i.e., before, end of, 6 months, and 12 months after IMRT). METHODS: Participants included 142 patients with HNC (mean age 58.9 ± 10.3 years, 72.5% male, 83.1% White). Total RNA extracted from blood leukocytes were used for genome-wide gene expression assays. Linear mixed effects model was used to examine the association between PNS and gene expression across time. Gene Ontology (GO) enrichment analysis was employed to identify pathways related to PNS. RESULTS: A total of 1352 genes (162 upregulated, 1190 downregulated) were significantly associated with PNS across time (false discovery rate (FDR) < 0.05). Among these genes, 112 GO terms were identified (FDR < 0.05). The top 20 GO terms among the significant upregulated genes were related to immune and inflammatory responses, while the top 20 GO terms among the significant downregulated genes were associated with telomere maintenance. CONCLUSION: This study is the first to identify genes and pathways linked to immune and inflammatory responses and telomere maintenance that are associated with PNS in patients with HNC receiving IMRT. Inflammation and aging markers may be candidate biomarkers for PNS. Understanding biological markers may produce targets for novel interventions.

[Effect and mechanism of 1, 25(OH)2D3 on myocardial inflammation induced by Coxsackie virus B3 in mice].

Objective: To explore the effect and mechanism of 1, 25(OH)2D3 on myocardial inflammation induced by Coxsackie virus B3 (CVB3) in mice. Methods: Wild type (WT) and 1α-hydroxylase knockout [1(OH)ase-/-] male mice were divided into four groups: WT group, WT+CVB3 group, 1(OH)ase-/-+CVB3 group and 1(OH)ase-/-+CVB3+VD3 group, with 8 mice in each group. The indicators for evaluating myocardial cell injury were examined by different methods. The mRNA levels of pro-inflammatory cytokines [interlenkin (IL)-1ß, IL-6, interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α)] were determined by quantitative real-time PCR. Hematoxylin-eosin (HE) staining was used to observe the myocardial histopathological changes. The apoptosis of myocardial cells was detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and flow cytometry. Fluo-4/AM fluorescence probe was used to detect intracellular calcium ion content. Meanwhile, the expression levels of Ca2+/Calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) protein as well as endoplasmic reticulum stress-related proteins like glucose-related protein 78 (GRP78) and C/EBP homologous protein (CHOP) in the myocardial tissues were detected by Western blot. Results: Compared with WT group, the mRNA levels of pro-inflammatory factors increased in the cardiomyocytes of mice in WT+CVB3 group, including IL-1ß (14.88±3.32 vs 1.03±0.02, P=0.009), IL-6 (7.00±1.09 vs 1.81±0.18, P=0.005), IFN-γ (4.70±1.11 vs 1.34±0.34, P=0.006) and TNF-α (17.20±3.22 vs 1.02±0.12, P<0.001). Similarly, the infiltration of inflammatory cells, and the apoptosis rate of cardiomyocytes elevated (16.66%±1.09% vs 7.85%±1.12%, P=0.012). The level of calcium ions in myocardial cytoplasm was significantly higher in WT+CVB3 group than that in the WT group (2.98±1.05 vs 0.96±0.10, P=0.006). Likewise, the expression levels of pCaMKⅡ(1.97±0.34 vs 1.00±0, P<0.001), GRP78 (1.78±0.19 vs 1.00±0, P=0.005) and CHOP (1.62±0.09 vs 1.00±0, P=0.002) in WT+CVB3 group up-regulated. The above myocardial cell injury markers were more significant in the 1(OH)ase-/-+CVB3 group. In the 1(OH)ase-/-+CVB3+VD3 group, 1, 25(OH)2D3 supplementation significantly improved myocardial cell injury indicators. Meanwhile, the specific inhibitors of CaMKⅡ can also reduce the myocardial injury and apoptosis rate of CVB3-infected mice. Conclusion: 1, 25(OH)2D3 deficiency can aggravate myocardial inflammation through over activation of CaMKⅡ.

Circulating short chain fatty acids and fatigue in patients with head and neck cancer: A longitudinal prospective study.

Fatigue among patients with head and neck cancer (HNC) has been associated with higher inflammation. Short-chain fatty acids (SCFAs) have been shown to have anti-inflammatory and immunoregulatory effects. Therefore, this study aimed to examine the association between SCFAs and fatigue among patients with HNC undergoing treatment with radiotherapy with or without concurrent chemotherapy. Plasma SCFAs and the Multidimensional Fatigue Inventory-20 were collected prior to and one month after the completion of treatment in 59 HNC patients. The genome-wide gene expression profile was obtained from blood leukocytes prior to treatment. Lower butyrate concentrations were significantly associated with higher fatigue (p = 0.013) independent of time of assessment, controlling for covariates. A similar relationship was observed for iso/valerate (p = 0.025). Comparison of gene expression in individuals with the top and bottom 33% of butyrate or iso/valerate concentrations prior to radiotherapy revealed 1,088 and 881 significantly differentially expressed genes, respectively (raw p < 0.05). The top 10 Gene Ontology terms from the enrichment analyses revealed the involvement of pathways related to cytokines and lipid and fatty acid biosynthesis. These findings suggest that SCFAs may regulate inflammatory and immunometabolic responses and, thereby, reduce inflammatory-related symptoms, such as fatigue.

Associations of inflammation with neuropsychological symptom cluster in patients with Head and neck cancer: A longitudinal study.

Purpose: Head and neck cancer (HNC) patients may experience multiple co-occurring neuropsychological symptoms (NPS) cluster, including fatigue, depression, pain, sleep disturbance, and cognitive impairment. While inflammation has been attributed as a key mechanism for some of these symptoms, its association with the NPS as a cluster of symptoms is unknown. Thus, the aim of this study was to examine the association between peripheral inflammation and NPS cluster among HNC patients over cancer treatment (radiotherapy with or without chemotherapy). Methods: HNC patients were recruited and followed at pre-treatment, end of treatment, three months and one-year post-treatment. Plasma inflammatory markers, including C-reactive protein (CRP), tumor necrosis factor-alpha (TNFA), soluble tumor necrosis factor receptor-2 (sTNFR2), interleukin-1 beta (IL1-ß), interleukin-6 (IL-6), interleukin-10 (IL-10), monocyte chemotactic protein-1 (MCP-1), and interleukin-1 receptor antagonist (IL-1RA) and patient-reported NPS cluster were collected at the 4 time points. Associations between inflammatory markers and the NPS cluster were analyzed using linear mixed-effects models and generalized estimating equations (GEE) models controlling covariates. Results: 147 HNC patients were eligible for analysis. 56% of the patients received chemoradiotherapy as treatment. The highest NPS cluster score was reported at the end of treatment, which gradually decreased over time. An increase in inflammatory markers including CRP, sTNFR2, IL-6 and IL-1RA was associated with higher continuous NPS cluster scores (p<0.001, p = 0.003, p<0.001, p<0.001; respectively). GEE further confirmed that patients with at least two moderate symptoms had elevated sTNFR2, IL-6, and IL-1RA (p = 0.017, p = 0.038, p = 0.008; respectively). Notably, this positive association between NPS cluster and inflammatory markers was still significant at one-year post-treatment for CRP (p = 0.001), sTNFR2 (p = 0.006), and IL-1RA (p = 0.043). Conclusions: Most HNC patients experienced NPS clusters over time, especially immediately after the end of treatment. Elevated inflammation, as represented by inflammatory markers, was strongly associated with worse NPS cluster over time; this trend was also notable at one-year post-treatment. Our findings suggest that peripheral inflammation plays a pivotal role in the NPS cluster over cancer treatment, including long-term follow-ups. Interventions on reducing peripheral inflammation may contribute to alleviating the NPS cluster in cancer patients.

[Mediating effect of self-efficacy on self-management ability and self-management behavior in patients with type 2 diabetes mellitus].

OBJECTIVE: To investigate the mechanism of self-efficacy between self-management ability and self-management behavior and its differences among patients with different disease courses through mediation tests. METHODS: In the study, 489 patients with type 2 diabetes who attended the endocrinology departments of four hospitals in Shanxi Province and Inner Mongolia Autonomous Region from July to September 2022 were enrolled as the study population. They were investigated by General Information Questionnaire, Diabetes Self-Management Scale, Chinese version of Diabetes Empowerment Simplified Scale, and Diabetes Self-Efficacy Scale. Mediation analyses were performed using the linear regression model, Sobel test, and Bootstrap test in the software Stata version 15.0 and divided the patients into different disease course groups for subgroup analysis according to whether the disease course was > 5 years. RESULTS: In this study, the score of self-management behavior in the patients with type 2 diabetes was 6.16±1.41, the score of self-management ability was 3.99±0.74, and the score of self-efficacy was 7.05±1.90. The results of the study showed that self-efficacy was positively correlated with self-management ability (r=0.33) as well as self-management behavior (r=0.47) in the patients with type 2 diabetes (P < 0.01). The mediating effect of self-efficacy accounted for 38.28% of the total effect of self-management ability on self-management behaviors and was higher in the behaviors of blood glucose monitoring (43.45%) and diet control (52.63%). The mediating effect of self-efficacy accounted for approximately 40.99% of the total effect for the patients with disease course ≤ 5 years, while for the patients with disease course > 5 years, the mediating effect accounted for 39.20% of the total effect. CONCLUSION: Self-efficacy enhanced the effect of self-management ability on the behavior of the patients with type 2 diabetes, and this positive effect was more significant for the patients with shorter disease course. Targeted health education should be carried out to enhance patients' self-efficacy and self-management ability according to their disease characteristics, to stimulate their inner action, to promote the development of their self-management behaviors, and to form a more stable and long-term mechanism for disease management.

Pembrolizumab and cabozantinib in recurrent metastatic head and neck squamous cell carcinoma: a phase 2 trial.

Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors, have immunomodulatory properties and have offered promising results when combined with anti-PD-1 agents. We conducted a phase 2, multicenter, single-arm trial of pembrolizumab and cabozantinib in patients with RMHNSCC who had Response Evaluation Criteria in Solid Tumors v.1.1 measurable disease and no contraindications to either agent. We assessed the primary end points of tolerability and overall response rate to the combination with secondary end points of progression-free survival and overall survival and performed correlative studies with PDL-1 and combined positive score, CD8+ T cell infiltration and tumor mutational burden. A total of 50 patients were screened and 36 were enrolled with 33 evaluable for response. The primary end point was met, with 17 out of 33 patients having a partial response (52%) and 13 (39%) stable disease with an overall clinical benefit rate of 91%. Median and 1-year overall survival were 22.3 months (95% confidence interval (CI) = 11.7-32.9) and 68.4% (95% CI = 45.1%-83.5%), respectively. Median and 1-year progression-free survival were 14.6 months (95% CI = 8.2-19.6) and 54% (95% CI = 31.5%-72%), respectively. Grade 3 or higher treatment-related adverse events included increased aspartate aminotransferase (n = 2, 5.6%). In 16 patients (44.4%), the dose of cabozantinib was reduced to 20 mg daily. The overall response rate correlated positively with baseline CD8+ T cell infiltration. There was no observed correlation between tumor mutational burden and clinical outcome. Pembrolizumab and cabozantinib were well tolerated and showed promising clinical activity in patients with RMHNSCC. Further investigation of similar combinations are needed in RMHNSCC. The trial is registered at ClinicalTrials.gov under registration no. NCT03468218 .

[Clinical characteristics and prognosis of anaplastic thyroid carcinoma: a 20-year single-center retrospective study].

Objectives: To investigate the clinical characteristics and prognoses of patients with anaplastic thyroid carcinoma(ATC), and to explore the value of multi-modality treatment in improving overall survival(OS) of ATC patients. Methods: Medical records including clinicopathological data of patients diagnosed with ATC at Cancer Hospital, Chinese Academy of Medical Sciences between 2001 and 2020 were retrospectively analyzed. The cohort were divided into surgery-only and multi-modality subgroups, and the latter included patients treated with surgery plus radiotherapy and/or medical therapy(including chemotherapy, target therapy and immunotherapy). Univariate survival analysis was conducted through Kaplan-Meier method, and multivariate survival analysis was performed using Cox proportional hazard model. Results: A total of 47 patients were included in the study, including 24 males and 23 females, with a median age of 63 years. After a median follow-up duration of 3.37 months, 42 patients died due to tumor recurrence or progression. The median OS of the cohort was 4.33 months. Univariate survival analysis demonstrated that symptoms of recurrent laryngeal nerve(RLN) involvement, distant metastasis, leukocyte elevation, and treatment modality were significantly associated with OS (P values all<0.05). Multivariate analysis showed that symptoms of RLN involvement(HR=2.49, 95%CI: 1.16-5.32, P=0.019), distant metastasis(HR=2.33, 95%CI: 1.06-5.16, P=0.036), and leukocyte elevation(HR=2.50, 95%CI: 1.16-5.40, P=0.020) were all independent risk factors for OS, while multi-modality therapy significantly prolonged OS compared with surgery alone(HR=0.22, 95%CI: 0.10-0.47, P<0.001). Conclusions: Among ATC patients, absence of symptoms of RLN invasion, normal leukocyte level and absence of distant metastasis at initial diagnosis are all independent protective factors for OS and multi-modality treatment can help to improve the prognosis.

Long-Term Follow-up of Parenteral Bevacizumab In Patients with Recurrent Respiratory Papillomatosis.

OBJECTIVE: The clinical course of recurrent respiratory papillomatosis (RRP) varies from spontaneous remission to severe airway obstruction with wide variability in recurrence. Standard treatment involves debulking to improve voice and/or breathing. Non-surgical therapies are emerging in hopes of non-operative disease control. This retrospective review analyzes long-term safety, efficacy, and durability of clinical control in the largest reported series of parenteral bevacizumab in adults with RRP. METHODS: Twenty-three patients with known RRP who have been receiving off-label systemic bevacizumab were included. Dosage, infusion interval, number of cycles, debulking requirements, subjective outcomes, adverse events, and reasons for treatment termination were investigated. RESULTS: Patients have been followed for an average of 791.43 (21-1468) days. The most common starting dosing regimen was 15 mg/kg at 3 weeks in 11 followed by 10 mg/kg at 6 weeks intervals in 6 individuals. Long-term maintenance dosage varied with the least intensive regimen being 10 mg/kg at 14-week intervals. Subjective improvement of voice and/or breathing was reported in 18/23 subjects. The median time for patients that needed a procedure after treatment was 634 days. Procedures after infusions decreased from 3.08 ± 2.48 procedures in the year prior to 0.52 ± 1.12 during systemic Bevacizumab, and to 0.86 ± 2.05 after stopping bevacizumab. Therapy termination occurred in 8 subjects where only 3 were due to adverse events. CONCLUSION: Parenteral bevacizumab remains a well-tolerated treatment for patients with recalcitrant RRP. There appears to be a durable reduction in the frequency of debulking surgery requirements although on a maintenance regimen. Laryngoscope, 133:2725-2733, 2023.

Outcomes Stratification of Head and Neck Cancer Using Pre- and Post-treatment DNA Methylation From Peripheral Blood.

PURPOSE: Established prognostic factors for head and neck squamous cell carcinoma (HNSCC) mostly consist of clinical and tumor features assessed before treatment. We report a novel application of DNA methylation in peripheral blood before and after radiation therapy to further improve outcomes stratification. METHODS AND MATERIALS: Peripheral blood samples from patients with nonmetastatic HNSCC were obtained for methylation analysis 1 week before and 1 month after radiation therapy. Patients were randomized 1:1 to a Discovery Cohort or a Validation Cohort. In the Discovery Cohort, associations between genome-wide methylation change (posttreatment minus pretreatment) and recurrence-free survival (RFS) as well as overall survival (OS) were evaluated using Cox regression. A methylation risk score (MRS) was then constructed from methylation levels at the top associated sites, filtered for residing within the regulatory regions of genes expressed in cells of hematopoietic lineage. The prognostic value of MRS was separately assessed in the Discovery and Validation Cohorts. RESULTS: Between December 2013 and September 2018, 115 patients participated in this study. Human papilloma virus negative status, oral cavity cancer, gastrostomy tube insertion, and higher neutrophil count before radiation therapy were associated with shorter RFS and OS (P < .05). Genes downstream of the methylation sites comprising MRS are HIF1A, SF1, LGALS9, and FUT5, involved in hypoxia response, blood cell maturation, and immune modulation. High MRS (in the top third) was significantly associated with worse RFS (hazard ratio [HR], 7.1; 95% confidence interval [CI], 1.4-35.5; P = .016) and OS (HR, 15.9; 95% CI, 1.6-153.6; P = .017) in the Discovery Cohort, independent of the aforementioned risk factors. These findings were replicated in the Validation Cohort, for which high MRS also independently predicted worse RFS (HR, 10.2; 95%, CI 2.4-43.4; P = .002) and OS (HR, 3.7; 95% CI, 1.3-10.4; P = .015). CONCLUSIONS: We successfully trained and validated a signature of DNA methylation in peripheral blood before and after radiation therapy that stratified outcomes among patients with HNSCC, implicating the potential for genomics-tailored surveillance and consolidation treatment.