Addition of nimotuzumab to concurrent chemoradiotherapy after induction chemotherapy improves outcomes of patients with locally advanced nasopharyngeal carcinoma.

Purpose: To investigate the survival outcomes and toxicities associated with the addition of nimotuzumab to concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal carcinoma (LANPC) patients who received induction chemotherapy (IC). Methods: Patients with stage III-IVA nasopharyngeal carcinoma who received IC and CCRT between January 2017 and October 2021 were retrospectively included. We aimed to compare the locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) between patients treated with CCRT+nimotuzumab and CCRT alone. Results: We included 411 patients in the analysis. Of these patients, 267 (65.0%) and 144 (35.0%) had CCRT+nimotuzumab and CCRT alone, respectively. Similar LRFS was found between those with and without nimotuzumab (92.9% vs. 92.6%, p = 0.855). The 3-year DMFS was 88.2% and 76.2% in those with and without nimotuzumab (p = 0.002). The 3-year DFS was 83.4% and 70.6% in those with and without nimotuzumab treatment (p = 0.003). The 3-year OS was 92.1% and 81.1% in those with and without nimotuzumab (p = 0.003). The multivariate Cox regression analysis indicated that the addition of nimotuzumab was independently associated with better DMFS (hazard ratio [HR] 0.606, p = 0.049), DFS (HR 0.613, p = 0.028), and OS (HR 0.497, p = 0.019). No significant differences in major toxicities were found between the two treatment arms, including hematologic toxicities, hepatoxicity, nephrotoxicity, gastrointestinal reactions, and mucositis (all p > 0.05). Conclusion: The addition of nimotuzumab to CCRT after IC in LANPC has shown promising results in improving treatment outcomes and acceptable toxicities.

Metronomic S1 Adjuvant Chemotherapy Improves Survival in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma.

Purpose: To investigate the efficacy and safety of using metronomic S1 adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma (LANPC). Materials and Methods: We retrospectively collected data on patients diagnosed with LANPC between January 2016 and December 2021. All patients were treated with induction chemotherapy and concurrent chemoradiotherapy with or without metronomic chemotherapy (MC). Toxicities during MC were recorded. The chi-square test, Kaplan-Meier methods, propensity score matching (PSM), and Cox proportional hazards model were used for statistical analyses. Results: A total of 474 patients were identified, including 64 (13.5%) and 410 (83.5%) patients with or without receiving MC, respectively. Patients who received metronomic S1 had significantly better 3-year locoregional recurrence-free survival (LRFS) (100% vs. 90.9%, p=0.038), distant metastasis-free survival (DMFS) (98.5% vs. 84.1%, p=0.002), disease-free survival (DFS) (98.4% vs. 77.5%, p<0.001), and overall survival (OS) (98.0% vs. 87.7%, p=0.008) compared to those without metronomic S1. The multivariate prognostic analysis revealed that metronomic S1 was identified as an independent prognostic factor associated with better DMFS (hazard ratio [HR] 0.074, p=0.010), DFS (HR 0.103, p=0.002) and OS (HR 0.127, P=0.042), but not in LRFS (p=0.071). Similar results were found using PSM. Common adverse events observed in the metronomic S1 group included leukopenia, neutropenia, increased total bilirubin, anorexia, rash/desquamation, and hyperpigmentation. All patients with adverse events were grade 1-2. Conclusion: It is worth conducting a randomized controlled trial to assess the effect of metronomic S1 on survival outcomes and toxicities of LANPC.

A Pilot Study of Anlotinib as a Combination Treatment in Advanced Nasopharyngeal Carcinoma.

AIMS: To investigate the short-term objective response and treatment toxicity of anlotinib as a combination treatment in patients with Recurrent or Metastatic Nasopharyngeal Carcinoma (RM-NPC). METHODS: Patients with RM-NPC who received anlotinib as a combination treatment between March 2021 and July 2022 were retrospectively analyzed.The efficacy and safety of anlotinib as a combination treatment were analyzed. RESULTS: A total of 17 patients with RM-NPC were included in this study. Of these patients, 2 (11.8%) had local recurrence, 4 (23.5%) had cervical lymph node recurrence, and 11 (64.9%) had distant failure. The most common metastatic site was the liver (47.1%), followed by the lung (23.5%) and bone (23.5%). Anlotinib was given as first-line treatment in 3 patients (17.6%), second lines treatment in 7 patients (41.2%), and third to six-lines treatment in 7 patients (41.2%). All patients received anlotinib combined with chemotherapy and/or immunotherapy. One patient achieved a complete response (5.9%), 7 patients had a partial response (41.2%), 5 patients had stable disease (29.4%), and 4 patients had progressive disease (23.5%). The overall disease control rate and the overall response rate were 76.5% and 47.1%, respectively. The median progression-free survival was 8.1 months, and the median overall survival was not reached. The incidence of grade 3 adverse events was 30%. No unexpected side effects or treatment-related death were observed. CONCLUSION: Anlotinib, as a combination treatment, has a promising antitumor activity and a manageable safety profile in patients with RM-NPC. Our results add to the growing evidence that supports the benefits of combining antiangiogenic drugs in RM-NPC. Randomized controlled clinical trials investigating the evaluation of anlotinib are warranted.

Residual plasma Epstein-Barr virus DNA after intensity-modulated radiation therapy is associated with poor outcomes in nasopharyngeal carcinoma.

Aim: To investigate the effects of residual plasma Epstein-Barr virus (EBV) DNA levels after 3 months of intensity-modulated radiation therapy (IMRT) (postIMRT-EBV DNA) on prognosis in patients with nasopharyngeal carcinoma. Methods: Data from 300 patients were retrospectively collected for analysis. Results: Of these patients, 25 (8.3%) and 275 (91.7%) had positive and negative postIMRT-EBV DNA, respectively. Multivariate survival analysis showed that EBV DNA >688 IU/ml was independently associated with inferior distant metastasis-free survival (p = 0.003) and progression-free survival (p = 0.002). Moreover, postIMRT-EBV DNA was independently associated with inferior locoregional recurrence-free survival (hazard ratio: 4.325; p = 0.018), distant metastasis-free survival (hazard ratio: 10.226; p < 0.001) and progression-free survival (hazard ratio: 10.520; p < 0.001). Conclusion: Positive postIMRT-EBV DNA is a prognostic biomarker for nasopharyngeal carcinoma.

Xerostomia: An easily ignored symptom induced by induction chemotherapy in patients with nasopharyngeal carcinoma.

BACKGROUND: To investigate the prevalence and predictive factors of xerostomia during induction chemotherapy (IC) in patients with nasopharyngeal carcinoma (NPC). METHODS: We prospectively enrolled NPC patients who received IC between October 2020 and October 2021. The Visual Analogue Scale (VAS) and Xerostomia Inventory (XI) were used to evaluate the condition of xerostomia. The volume of the submandibular gland (SMG) was also calculated before and after IC. RESULTS: Fifty-two patients were enrolled in this study. Of these patients, 32.7% (n = 17) experienced xerostomia before IC. There were 32 (61.5%) patients suffered from xerostomia after IC, including 21 (40.4%) patients with newly diagnosed xerostomia after IC and 11 (21.1%) patients complained their xerostomia aggravated in those with xerostomia before IC. The median XI scores increased from 11 (standard deviation [SD], 2.930) to 18 (SD 3.995), 16 (SD 3.605), and 17 (SD 4.331) after the first, second, and third cycles of IC, respectively. The median score of VAS also increased from 0 to 4 during the following three cycles of IC. In those with IC-related xerostomia, the SMG volume after IC was significantly decreased compared with those without IC-related xerostomia (P = 0.001). The reduction of the SMG volume after IC was the independent risk factor for xerostomia (P = 0.002). CONCLUSION: Approximately two-thirds of NPC patients suffered from IC-related xerostomia and patients with a reduction of SMG volume after IC had a higher risk of xerostomia.

Risk factors of early thyroid dysfunction after definitive radiotherapy in nasopharyngeal carcinoma patients.

BACKGROUND: To explore the patterns and risk factors of early thyroid dysfunction in nasopharyngeal carcinoma (NPC) patients within 1 year after intensity-modulated radiation therapy (IMRT). METHODS: Patients with NPC who received definitive IMRT between April 2016 and April 2020 were included. All patients had normal thyroid function before definitive IMRT. The chi-square test, Student's T-test, Mann-Whitney U test, Kaplan-Meier method, receiver operating characteristics curve, and Cox proportional hazard analysis were used for statistical analysis. RESULTS: A total of 132 NPC patients were identified. Of these patients, 56 (42.4%) had hypothyroidism and 17 (12.9%) had hyperthyroidism. The median time to hypothyroidism and hyperthyroidism was 9 months (range, 1-12 months) and 1 month (range, 1-6 months) after definitive IMRT, respectively. In patients with hypothyroidism, 41 (73.2%) had subclinical hypothyroidism and 15 (26.8%) had clinical hypothyroidism. In those with hyperthyroidism, 12 patients (70.6%) had subclinical hyperthyroidism, and five patients (29.4%) had clinical hyperthyroidism. Age, clinical stage, thyroid volume, and V45 were independent risk factors for early radiation-induced hypothyroidism within 1 year after IMRT. Patients aged <47 years, stage III/IV disease, or pre-irradiation thyroid volume < 14 cm3 had higher risks of developing hypothyroidism. CONCLUSION: Primary subclinical hypothyroidism was the most common subtype of early thyroid dysfunction in NPC patients within 1 year after IMRT. Age, clinical stage, thyroid volume, and V45 were independent risk factors for early radiation-induced hypothyroidism in NPC patients.

Deep-penetration functionalized cuttlefish ink nanoparticles for combating wound infections with synergetic photothermal-immunologic therapy.

The challenge of wound infections post-surgery and open trauma caused by multidrug-resistant bacteria poses a constant threat to clinical treatment. As a promising antimicrobial treatment, photothermal therapy can effectively resolve the problem of drug resistance in conventional antibiotic antimicrobial therapy. Here, we report a deep-penetration functionalized cuttlefish ink nanoparticle (CINP) for photothermal and immunological therapy of wound infections. CINP is decorated with zwitterionic polymer (ZP, namely sulfobetaine methacrylate-methacrylate copolymer) to form CINP@ZP nanoparticles. Natural CINP is found to not only exhibit photothermal destruction of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli), but also trigger macrophages-related innate immunity and enhance their antibacterial functions. The ZP coating on the surface of CINP enables nanoparticles to penetrate into deeply infected wound environment. In addition, CINP@ZP is further integrated into the thermosensitive Pluronic F127 gel (CINP@ZP-F127). After in situ spraying gel, CINP@ZP-F127 is also documented notable antibacterial effects in mice wound models infected with MRSA and E. coli. Collectively, this approach combining of photothermal therapy with immunotherapy can promote delivery efficiency of nanoparticles to the deep foci of infective wounds, and effectively eliminate wound infections.

Prognostic effect of residual plasma Epstein-Barr viral DNA after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: To assess the prognostic effect of plasma Epstein-Barr virus (EBV) DNA load after induction chemotherapy (postIC -EBV DNA) on survival outcomes in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: Patients who were diagnosed with LA-NPC between August 2017 and October 2021 were included. The chi-squared test, receiver operating characteristic, Kaplan-Meier survival analysis, and Cox proportional hazard model were used for statistical analysis. RESULTS: We included 172 patients with EBV DNA-positive LA-NPC in this study. There were 35.5% (n = 61) of patients had plasma residual EBV DNA after induction chemotherapy (IC). Patients with higher EBV DNA before IC (p < 0.001) and advanced nodal stage (p = 0.031) were significantly related to a higher rate of residual postIC -EBV DNA. Patients with detectable postIC -EBV DNA had inferior 3-year locoregional relapse-free survival (LRFS) (86.7% vs. 96.9%, p = 0.020), distant metastasis-free survival (DMFS) (76.8% vs. 94.2%, p < 0.001), disease-free survival (DFS) (68.2% vs. 91.1%, p < 0.001), and overall survival (OS) (87.8% vs. 97.9%, p = 0.044) compared to those with undetectable postIC -EBV DNA. The multivariate prognostic analyses showed that detectable postIC -EBV DNA was the independent prognostic factor related to LRFS (p = 0.032), DMFS (p = 0.010), and DFS (p = 0.004) than those with undetectable postIC -EBV DNA. Pretreatment EBV DNA load had no prognostic effect in the multivariate analyses. CONCLUSIONS: The monitoring of plasma postIC -EBV DNA has improved prognostication in LA-NPC. Our findings suggest that postIC -EBV DNA may be a robust indicator to identify the optimal candidate for intensive treatment.

Analysis of retinal microvasculature features in amblyopic eyes: A meta-analysis.

PURPOSE: This meta-analysis aimed to evaluate retinal vessel density (VD) in amblyopic patients using optical coherence tomography angiography (OCTA). METHODS: PubMed, Web of Science, Embase, and Cochrane Library databases were systematically searched for published articles comparing retinal microvasculature characteristics in patients with amblyopia and controls. Continuous variable outcomes were assessed using the mean difference (MD) with a 95% confidence interval. Review Manager Version 5.30 was used for the analysis. RESULTS: Thirteen qualified articles were pooled in this meta-analysis. Compared with controls, the foveal whole enface VD of superficial (SCP) and deep capillary plexus (DCP) of patients as measured by 3×3-mm scans were significantly lower in amblyopia eyes (MD: -1.37, P = 0.0003; MD: 1.70, P < 0.00001, respectively). Similarly, in the 6×6-mm scans, foveal whole enface VD of the SCP and DCP were remarkably lower in amblyopia eyes than in controls (MD: -2.24, P = 0.03; MD: -5.08, P = 0.04, respectively). The parafoveal VD of SCP in 3×3-mm scans (MD: -1.96, P < 0.00001) was also lower in amblyopic patients than in controls. Similarly, in 6×6-mm scans, amblyopia eyes showed a significant decrease, and a trending decrease in the parafoveal VD of the SCP (MD: -3.85, P = 0.007) and DCP (MD: -3.03, P = 0.10), respectively. For whole radial peripapillary capillary (RPC), VD was significantly reduced in amblyopic patients compared to controls (MD = -0.83, P < 0.00001). In addition, the deep foveal avascular zone (FAZ) was larger in amblyopic eyes than in the controls (MD = 0.55, P= 0.007). CONCLUSIONS: Our data suggest that whole foveal and parafoveal VD and RPC whole VD were reduced in patients with amblyopia. Moreover, our results reveal that the FAZ is larger in amblyopic patients. Consequently, OCTA may have the potential for diagnosing and monitoring patients with amblyopia.

Stemness Subtypes and Scoring System Predict Prognosis and Efficacy of Immunotherapy in Soft Tissue Sarcoma.

Tumor stemness has been reported to play important roles in cancers. However, a comprehensive analysis of tumor stemness remains to be performed to investigate the specific mechanisms and practical values of stemness in soft tissue sarcomas (STS). Here, we applied machine learning to muti-omic data of patients from TCGA-SARC and GSE21050 cohorts to reveal important roles of stemness in STS. We demonstrated limited roles of existing mRNAsi in clinical application. Therefore, based on stemness-related signatures (SRSs), we identified three stemness subtypes with distinct stemness, immune, and metabolic characteristics using consensus clustering. The low-stemness subtype had better prognosis, activated innate and adaptive immunity (e.g., infiltrating B, DC, Th1, CD8+ T, activated NK, gamma delta T cells, and M1 macrophages), more enrichment of metabolic pathways, more sites with higher methylation level, higher gene mutations, CNA burdens, and immunogenicity indicators. Furthermore, the 16 SRS-based stemness prognostic index (SPi) was developed, and we found that low-SPi patients with low stemness had better prognosis and other characteristics similar to those in the low-stemness subtype. Besides, low-stemness subtype and low-SPi patients could benefit from immunotherapy. The predictive value of SPi in immunotherapy was more accurate after the addition of MSI into SPi. MSIlowSPilow patients might be more sensitive to immunotherapy. In conclusion, we highlighted mechanisms and practical values of the stemness in STS. We also recommended the combination of MSI and SPi which is a promising tool to predict prognosis and achieve precise treatments of immunotherapy in STS.

Survival Outcomes and Treatment Decision by Human Papillomavirus Status Among Patients With Stage IVC Head and Neck Squamous Cell Carcinoma.

PURPOSE: To investigate the influence of human papillomavirus (HPV) status on survival outcomes and treatment decisions for patients with de novo stage IV head and neck squamous cell cancers (HNSCC). METHODS: Patients initially diagnosed with de novo stage IVC HNSCC between 2010 and 2015 were identified from the Surveillance, Epidemiology, and End Results database. Cox multivariable analyses were performed to determine prognostic factors associated with head and neck cancers specific survival (HNCSS) and overall survival (OS). RESULTS: We identified 303 patients who received chemotherapy in this study, including 52.5% of them had HPV-positive disease. HPV-positive HNSCC had better HNCSS (P < 0.001) and OS (P < 0.001) compared to those with HPV-negative disease. The results of Cox multivariable analyses showed that HPV-negative status (P = 0.007), N3 stage (P = 0.004), bone metastases (P < 0.001), and lung metastases (P = 0.003) were associated with worse HNCSS. Similar results were found regarding the OS. The sensitivity analyses indicated that HPV-positive HNSCC patients who were treated with radiotherapy had better survival outcomes. However, no survival benefits were found in those with HPV-positive disease receiving surgery. For HPV-negative patients, no survival benefit was observed among those treated with radiotherapy or surgery. CONCLUSIONS: Approximately half of the stage IVC HNSCC patients are HPV-related. The presence of HPV infection appears to be strongly associated with the survival outcome in patients with de novo stage IV HNSCC. Determination of HPV status may help guide clinicians in prognostic assessment and treatment decision-making in this population.

Cognitive dysfunction in patients with nasopharyngeal carcinoma after induction chemotherapy.

OBJECTIVE: This prospective study aimed to assess the incidence, details of the change of cognitive dysfunction, and predictive factors of cognitive function impairment associated with induction chemotherapy (IC) in nasopharyngeal carcinoma (NPC) patients. METHOD: We prospectively included NPC patients who treated with IC from December 2018 to January 2020. Montreal cognitive assessment (MoCA) was used to measure cognitive function, and score less than 26 was defined as cognitive dysfunction. Multivariate logistic regression analysis was applied to assess the independent predictors associated with cognitive function impairment. RESULTS: A total of 76 patients were recruited, 10 patients were excluded due to refusal or unable to finish the questionnaire, and 66 patients were analyzed in this study. The median age of the patients was 48.5 years (range, 24-69 years). There was 89.4% of patients received ≥3 circles of IC. For the entire group, 27.3% had cognitive dysfunction, of which attention, language, short-term memory, and orientation showed significant downward trends, while visuospatial/executive function, naming, and abstraction demonstrated no prominent decrease. In patients having cognitive function impairment, 77.8% of them occurred after the first circle of IC. Gender (P = 0.039) and education (P = 0.03) were significant predictors for cognitive dysfunction. Female patients (female vs. male: 50% vs. 20%) and patients with lower educational levels (lower vs. higher: 37.8% vs. 11.8%) were more likely to suffer cognitive dysfunction. In addition, age (P = 0.572) and chemotherapy circles (P = 0.68) had no association with cognitive dysfunction. CONCLUSION: Approximately 25% of NPC patients suffered cognitive dysfunction after IC, especially in female patients and patients with lower educational levels.

A study of dry eye after cataract surgery in MGD patients.

OBJECTIVE: To investigate the dry eye symptoms after cataract surgery in MGD patients and their relationships METHODS: The study included 115 patients (115 eyes) with age-related cataract that underwent uncomplicated cataract surgery, and the patients were divided into two groups according to the MGD diagnostic criteria: group A (MGD group) and group B (control group). Schirmer I test (ST-I), tear breakup time (TBUT), and corneal fluorescein staining (CFS) were performed preoperatively and at 3 days, 7 days, 14 days, and 30 days postoperatively. We also measured eyelid meibomian gland morphology, meibomian gland expression, and meibum character scores before and after the cataract surgery. RESULTS: Postoperatively, in group A, TBUT decreased and CFS scores increased significantly. ST-I increased in the early postoperative course but decreased later. The eyelid margin morphology scores and meibomian gland expression scores of group A significantly increased after the cataract operation. Thus, patients with MGD may have a greater chance of developing the dry eye disease after cataract surgery. Cataract surgery may aggravate the signs of MGD, and the severity of MGD may positively correlate with TBUT, CFS, and corneal lesions after surgery. CONCLUSIONS: The characteristics of dry eye after cataract surgery in patients with MGD are different from common cataract patients, changes in the early postoperative phase to the ocular surface were caused by surgical factors, and the damages to epithelial function in the later postoperative phase were mainly associated with the inflammation of the meibomian gland and eyelid.

MicroRNA-296 mediated corneal neovascularization in an animal model of corneal burns after alkali exposures.

Alkali burns of the cornea may lead to permanent visual impairment or complete blindness. In the current study, the role of microRNA 296 (miR-296) was explored in mouse corneal neovascularization induced by alkali burns. An alkali burn model in Balb/c mice was developed to study chemical corneal injuries. The expression of the miR-296 gene was measured by reverse-transcription-quantitative polymerase chain reaction. Fibroblast growth factor 23 (FGF23) protein expression was measured by western blot analysis. Possible impacted pathways were analyzed by Kyoto Encyclopedia of Genes and Genomes pathway analysis. miR-296 gene expression was examined following chemical corneal injury and it was demonstrated that different topical eye medications decreased miR-296 gene expression. miR-296 may participate in cytokine-cytokine receptor interaction pathways to influence corneal inflammatory responses. It was also revealed that FGF23 was expressed following chemical corneal injury and that different treatments with topical eye drops decreased its expression. miR-296 is a novel molecular modulator for alkali burns in the mouse cornea.

Paclitaxel induces autophagy in gastric cancer BGC823 cells.

This paper explores the connection between paclitaxel, a chemotherapeutic agent, and gastric cancer cells. In this experiment, it is demonstrated that paclitaxel triggers autophagy and inhibits proliferation of gastric cancer cells. An 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to detect cell viability and the IC50 of paclitaxel. Western blot was used to detect the expression levels of P62, and to measure the protein expression of autophagy. Immunofluorescence was used to reveal the appearance of punctate structures in the cytoplasm-this ultrastructure associated with autophagy was observed by microscopy. Electron microscopy revealed the formation of double-membrane autophagosomes, a typical structure of autophagy. In conclusion, our research indicates that paclitaxel may influence gastric cancer BGC823 cells by way of inducing autophagy.

Combination therapy with bioengineered miR-34a prodrug and doxorubicin synergistically suppresses osteosarcoma growth.

Osteosarcoma (OS) is the most common form of primary malignant bone tumor and prevalent among children and young adults. Recently we have established a novel approach to bioengineering large quantity of microRNA-34a (miR-34a) prodrug for miRNA replacement therapy. This study is to evaluate combination treatment with miR-34a prodrug and doxorubicin, which may synergistically suppress human OS cell growth via RNA interference and DNA intercalation. Synergistic effects were indeed obvious between miR-34a prodrug and doxorubicin for the suppression of OS cell proliferation, as defined by Chou-Talalay method. The strongest antiproliferative synergism was achieved when both agents were administered simultaneously to the cells at early stage, which was associated with much greater degrees of late apoptosis, necrosis, and G2 cell cycle arrest. Alteration of OS cellular processes and invasion capacity was linked to the reduction of protein levels of miR-34a targeted (proto-)oncogenes including SIRT1, c-MET, and CDK6. Moreover, orthotopic OS xenograft tumor growth was repressed to a significantly greater degree in mouse models when miR-34a prodrug and doxorubicin were co-administered intravenously. In addition, multiple doses of miR-34a prodrug and doxorubicin had no or minimal effects on mouse blood chemistry profiles. The results demonstrate that combination of doxorubicin chemotherapy and miR-34a replacement therapy produces synergistic antiproliferative effects and it is more effective than monotherapy in suppressing OS xenograft tumor growth. These findings support the development of mechanism-based combination therapy to combat OS and bioengineered miR-34a prodrug represents a new natural miRNA agent.