Association between organophosphate flame retardant exposure and lipid metabolism: data from the 2013-2014 National Health and Nutrition Examination Survey.

Organophosphate flame retardants (OPFRs) are emerging environmental pollutants that can be detected in water, dust, and biological organisms. Certain OPFRs can disrupt lipid metabolism in animal models and cell lines. However, the effects of OPFRs on human lipid metabolism remain unclear. We included 1,580 participants (≥20 years) from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to explore the relationship between OPFR exposure and lipid metabolism biomarkers. After adjusting for confounding factors, results showed that one-unit increases in the log levels of diphenyl phosphate (DPhP) (regression coefficient = -5.755; S.E. = 2.289; p = 0.023) and log bis-(1-chloro-2-propyl) phosphate (BCPP) (regression coefficient = -4.637; S.E. = 2.019; p = 0.036) were negatively associated with the levels of total cholesterol (TC) in all participants. One-unit increases in the levels of DPhP (regression coefficient = -2.292; S.E. = 0.802; p = 0.012), log bis (1,3-dichloro-2-propyl) phosphate (BDCPP) (regression coefficient = -2.046; S.E. = 0.825; p = 0.026), and log bis-2-chloroethyl phosphate (BCEP) (regression coefficient = -2.604; S.E. = 0.704; p = 0.002) were negatively associated with the levels of high-density lipoprotein cholesterol (HDL-C). With increasing quartiles of urine BDCPP levels, the mean TC levels significantly decreased in all participants (p value for trend = 0.028), and quartile increases in the levels of DPhP (p value for trend = 0.01), BDCPP (p value for trend = 0.001), and BCEP (p value for trend<0.001) were negatively corelated with HDL-C, with approximately 5.9, 9.9, and 12.5% differences between the upper and lower quartiles. In conclusion, DPhP, BDCPP, and BCEP were negatively related to HDL-C concentration, whereas DPhP and BCPP levels were negatively associated with TC level. Thus, exposure to OPFRs may interfere with lipid metabolism.

Similar survival after endoscopic submucosal dissection and esophagectomy in early esophageal cancer and synchronous or metachronous head and neck cancer.

BACKGROUND: Early-stage esophageal cancer is treated using endoscopic submucosal dissection and esophagectomy. Field cancerization in patients with early-stage esophageal cancer affects treatment outcomes and causes synchronous or metachronous head and neck cancers. We hypothesized that esophagectomy could provide better overall and relapse-free survivals in patients with esophageal cancer and synchronous or metachronous head and neck cancer. METHODS: We retrospectively identified patients with early esophageal squamous cell carcinoma and synchronous or metachronous head and neck cancers. We separated the patients into endoscopic submucosal dissection and esophagectomy groups to compare overall and relapse-free survivals. RESULTS: The study included 106 patients, 25 of whom underwent endoscopic submucosal dissection and 81 underwent esophagectomy. Overall and relapse-free survivals did not show significant differences between the two groups for both synchronous and metachronous head and neck cancers. CONCLUSIONS: Endoscopic submucosal dissection could provide similar overall and relapse-free survivals in patients with esophageal cancer and synchronous or metachronous head and neck cancer.

FDG PET/CT and Endoscopic Ultrasound for Preoperative T-Staging of Esophageal Squamous Cell Carcinoma.

This study aimed to compare the diagnostic performances of endoscopic ultrasound (EUS) and FDG PET/CT in the preoperative T-staging of esophageal squamous cell carcinoma (ESCC) and determine whether their innovative coordination achieves better prediction. In total, 100 patients diagnosed with ESCC, 57 without (CRT[-]sub) and 43 with (CRT[+]sub) neoadjuvant chemoradiotherapy, undergoing EUS and FDG PET/CT, followed by surgical resection of the tumor, were included in this analysis. EUS classified T-stages based on the depth of primary tumor invasion, and FDG PET/CT used thresholded maximal standardized uptake value (SUVmax) classifications. By employing pathology results as the reference standard, we assessed the accuracy of EUS and FDG PET/CT, evaluated their concordance using the κ statistic, and conducted a comparative analysis between the two modalities through McNemar's chi-square test. FDG PET/CT had higher overall accuracy than EUS (for CRT[-]sub: 71.9%, κ = 0.56 vs. 56.1%, κ = 0.31, p = 0.06; for CRT[+]sub: 65.1%, κ = 0.50 vs. 18.6%, κ = 0.05, p < 0.01) in predicting pT- and ypT-stage. Our proposed method of incorporating both FDG PET/CT and EUS information could achieve higher accuracies in differentiating between early and locally advanced disease in the CRT[-]sub group (82.5%) and determining residual viable tumor in the CRT[+]sub group (83.7%) than FDG PET/CT or EUS alone. FDG PET/CT had a better diagnostic ability than EUS to predict the (y)pT-stage of ESCC. Our complementary method, which combines the advantages of both imaging modalities, can deliver higher accuracy for clinical applications of ESCC.

Levels of organophosphate flame retardants and their metabolites among 391 volunteers in Taiwan: difference between adults and children.

Background: Organophosphate flame retardants (OPFRs) are ubiquitous in the environment. The compositions and concentrations of different OPFRs metabolites vary in different environments depending on different human activities. The objective of the present study was to evaluate the exposure of different age groups to OPFRs in Taiwan. Methods: Volunteers provided urine samples and responded to questionnaires including demographic factors, underlying disease, lifestyle information, and occupation from October 2021 to January 2022. OPFR measurements were performed using a Waters Acquity Ultra-Performance Liquid Chromatography system coupled with a Waters Xevo TQ-XS mass spectrometer. Results: A total of 391 volunteers (74 children and 317 adults) were enrolled in this study. The concentrations (presented as µg/g creatinine) of bis(1,3-dichloro-2-propyl) phosphate (BDCPP, p = 0.029) and tri-n-butyl phosphate (TNBP, p = 0.008) were higher in the adult group, while the concentrations of bis-2-chloroethyl phosphate (BCEP, p = 0.024), diphenyl phosphate (DPHP, p < 0.001), tris(1,3-dichloro-2-propyl) phosphate (TDCPP, p = 0.009), and Tris(2-butoxyethyl) phosphate (TBEP, p = 0.007) were higher in the child group. Compared with school age children (>6 years), the concentration of di(2-n-butoxyethyl) phthalate (DBEP, 1.14 vs. 0.20 µg/g creatinine, p = 0.001), DPHP (1.23 vs. 0.54 µg/g creatinine, p = 0.036), TBEP (1.63 vs. 0.29 µg/g creatinine, p < 0.001), and the sum of OPFR metabolites (ΣOPFRs, 6.58 vs. 2.04 µg/g creatinine, p < 0.001) were statistically higher in preschool-aged children. After adjusting for confounding factors, pre-school age [odds ratio (OR): 4.579, 95% confidence interval (CI): 1.389-13.115] and current smoker (OR: 5.328, 95%CI: 1.858-14.955) were independently associated with the risk of ΣOPFRs higher than 90 percentile. Conclusion: This study revealed the distribution of different OPFRs metabolites in children and adults. DBEP, DPHP, TBEP, and ΣOPFR were higher in preschool-aged children. Pre-school age and current smoking status were independent risk factors for ΣOPFRs higher than 90 percentile.

Evaluation of Sinonasal Outcome Test (SNOT-22) Domains in the Assessment of the Quality of Life in Patients with Nasopharyngeal Carcinoma.

Background: Few instruments are available for assessing the otorhinologic-related quality of life (QOL) in nasopharyngeal carcinoma (NPC) patients. Therefore, we evaluated whether the 22-item Sinonasal Outcome Test (SNOT-22) could be applied to these patients. Methods: Patients diagnosed with NPC, who had been treated with standard protocol and followed up in our institute between 2019 and 2022, were invited to join the cross-sectional study during their clinic visits. All participants completed the SNOT-22 and Eustachian Tube Dysfunction Questionnaire-7 once they were recruited. Confirmatory factor analysis (CFA) was performed to decide the most suitable model for the underlying SNOT-22 subdomains, along with various validity and reliability tests. Results: We identified a total of 275 patients, with 84 (30.5%) women and 191 (69.5%) men. The mean age was 54.1 years (standard deviation: 11.2). Among these patients, 171 (62.1%) were in late stages, and 260 (94.5%) received chemoradiotherapy as treatment. The median interval between primary RT treatment and questionnaire completion was 50 months (interquartile range: 29-93). CFA supported a five-factor model for the SNOT-22 for NPC patients, including nasal, ear/facial, sleep, function, and emotion domains. The internal consistency and test-retest reliability of the SNOT-22 domain score were good. In addition, known-group validity was good for the SNOT-22 total score and domain scores according to the disease recurrence status. Conclusion: Psychometric analyses supported the reliability and validity of a five-domain SNOT-22 for assessing otorhinologic-related QOL in NPC patients.

Urinary levels of organophosphate flame retardants metabolites in a young population from Southern Taiwan and potential health effects.

Background: Organophosphate flame retardants (OPFRs) are widely distributed in the environment and their metabolites are observed in urine, but little is known regarding OPFRs in a broad-spectrum young population from newborns to those aged 18 years. Objectives: Investigate urinary levels of OPFRs and OPFR metabolites in Taiwanese infants, young children, schoolchildren, and adolescents within the general population. Methods: Different age groups of subjects (n=136) were recruited from southern Taiwan to detect 10 OPFR metabolites in urine samples. Associations between urinary OPFRs and their corresponding metabolites and potential health status were also examined. Results: The mean level of urinary Σ10 OPFR in this broad-spectrum young population is 2.25 µg/L (standard deviation (SD) of 1.91 µg/L). Σ10 OPFR metabolites in urine are 3.25 ± 2.84, 3.06 ± 2.21, 1.75 ± 1.10, and 2.32 ± 2.29 µg/L in the age groups comprising of newborns, 1-5 year-olds, 6-10 year-olds, and 11-18 year-olds, respectively, and borderline significant differences were found in the different age groups (p=0.125). The OPFR metabolites of TCEP, BCEP, DPHP, TBEP, DBEP, and BDCPP predominate in urine and comprise more than 90% of the total. TBEP was highly correlated with DBEP in this population (r=0.845, p<0.001). The estimated daily intake (EDI) of Σ5OPFRs (TDCPP, TCEP, TBEP, TNBP, and TPHP) was 2,230, 461, 130, and 184 ng/kg bw/day for newborns, 1-5 yr children, 6-10 yr children, and 11-17 yr adolescents, respectively. The EDI of Σ5OPFRs for newborns was 4.83-17.2 times higher than the other age groups. Urinary OPFR metabolites are significantly correlated with birth length and chest circumference in newborns. Conclusion: To our knowledge, this is the first investigation of urinary OPFR metabolite levels in a broad-spectrum young population. There tended to be higher exposure rates in both newborns and pre-schoolers, though little is known about their exposure levels or factors leading to exposure in the young population. Further studies should clarify the exposure levels and factor relationships.

Low p16 Cytoplasmic Staining Predicts Poor Treatment Outcome in Patients with p16-Negative Locally Advanced Head and Neck Squamous Cell Carcinoma Receiving TPF Induction Chemotherapy.

Human papillomavirus (HPV) has been proven to be associated with head and neck squamous cell carcinoma (HNSCC), and diffuse p16 unclear staining is usually considered as HPV-positive. The aim of the current study was to investigate the role of p16 cytoplasmic staining in HNSCC prognosis. A total of 195 HNSCC patients who received docetaxel, cisplatin, and 5-fluouracil (TPF) induction chemotherapy followed by chemoradiotherapy were enrolled. The status of p16 cytoplasmic staining was determined using immunohistochemistry. The median follow-up was 26.0 months for the whole study population and 90.3 months for 51 living survivors. p16 cytoplasmic staining was low in 108 patients and high in 87 patients. Low expression of p16 cytoplasmic staining and primary tumor location in the oral cavity were both independent factors indicating a worse response rate to TPF induction chemotherapy in the univariate and multivariate analyses. The logistic regression model also showed that low expression of p16 cytoplasmic staining and clinical N2-3 status were independent prognostic factors for worse progression-free survival and overall survival. Our study showed that p16 cytoplasmic staining could predict the treatment response to TPF induction chemotherapy and is an independent prognostic factor of survival in HNSCC.

The associations between renal disease severity and exposure to organophosphate flame retardants in patients with chronic kidney disease.

Organophosphate flame retardants (OPFRs) are emerging and widespread environmental pollutants with potential health hazards, including nephrotoxicity. However, the exposure patterns and nephrotoxic potential of OPFRs are yet to be investigated in patients with chronic kidney disease (CKD). We conducted a cross-sectional study involving 166 patients with CKD stratified by estimated glomerular filtration rate (eGFR) and severity of proteinuria. The urinary concentrations of 10 OPFR compounds were measured to evaluate the exposure patterns. Clinical and urinary OPFR profiles were compared among subgroups to identify whether the OPFR compounds were independently correlated with eGFR and proteinuria. Additionally, lifestyle factors were compared among subgroups stratified by median concentrations of urinary OPFR compounds associated with renal disease severity. This study revealed universal exposure to OPFRs in the CKD population, with an overall urinary detection rate of 98.80 %. Furthermore, after adjusting for covariates, the urinary concentration of bis(2-chloroethyl) phosphate (BCEP) was identified as an independent predictor of lower eGFR (low vs high eGFR, odds ratio (OR) (95 % confidence interval (CI)), 1.761 (1.032-3.005) per log µg/g creatinine, p = 0.038), and the urinary concentration of bis(2-butoxyethyl) phosphate (BBOEP) was independently correlated with overt proteinuria in CKD patients (with vs without overt proteinuria, OR (95 % CI), 1.813 (1.065-3.086) per log µg/g creatinine, p = 0.028). Moreover, frequent seafood consumption was negatively correlated with urinary BCEP concentration (high vs low BCEP, OR (95 % CI), 0.455 (0.228-0.908), p = 0.025), and age was inversely associated with urinary BBOEP concentration (high vs low BBOEP, OR (95 % CI), 0.968 (0.937-0.999) per year, p = 0.048). In conclusion, our investigation highlights the extensive exposure to OPFRs and the independent association between renal disease severity and urinary BCEP/BBOEP concentrations in the CKD population, indicating the nephrotoxic potential of these pollutants.

Long-term survival after pulmonary metastasectomy in patients with esophageal squamous cell carcinoma with lung metastasis.

OBJECTIVES: Esophageal squamous cell carcinoma with pulmonary metastasis has a poor prognosis, and the only treatment modality is systemic therapy such as chemotherapy. Previous studies showed that pulmonary metastasectomy may provide benefits and has been suggested in selected patients with colorectal cancer, renal cancer, and sarcoma. However, there were few literatures evaluating the impact and treatment outcome of pulmonary metastasectomy in esophageal squamous cell carcinoma patients with isolated lung metastases. Therefore, we conducted this study. METHODS: We retrospectively reviewed our patients with esophageal squamous cell carcinoma with pulmonary metastasis. Patients with extrapulmonary metastasis were excluded. We categorized them into two groups - the pulmonary resection group and the systemic treatment only group. We compared the overall survival and progression-free survival between groups, and also analyzed the surgical modality, which includes single or multiple port surgery. RESULTS: The analysis included 44 esophageal squamous cell carcinoma patients with lung metastasis. Among these 44 patients, 14 patients have received pulmonary metastasectomy, and 30 patients received systemic treatment only. Patients who received pulmonary metastasectomy had significantly better overall survival (p < 0.0001) and progression-free survival (p = 0.038) than those who received only systemic treatment. The one-year overall survival and progression-free survival were 100% and 48% in patients receiving pulmonary metastatectomy, and 49% and 33% in patients receiving only systemic treatment. Among 14 patients receiving pulmonary metastatectomy, 10 patients underwent single port surgery. There were no postoperative complications in these 14 patients. CONCLUSION: Esophageal squamous cell carcinoma patients with lung metastasis who can receive pulmonary metastasectomy have better prognosis, and some patients can achieve long-term survival. Our findings suggest that aggressive pulmonary metastasectomy is suggested in esophageal squamous cell carcinoma patients with if no contraindication. Key question: How about the role of pulmonary metastasectomy in esophageal squamous cell carcinoma patients with isolated lung metastasis? KEY FINDINGS: Patients who received pulmonary metastasectomy had better overall survival and progression-free survival than those who received only systemic treatment. TAKE HOME MESSAGE: Esophageal cancer with isolated pulmonary metastasis can be treated aggressively with pulmonary metastasectomy if no contraindication.

Effect of glycated hemoglobin A1c on the survival of patients with oral squamous cell carcinoma: A multi-institutional database cohort study.

Objectives: Few studies have evaluated the impact of blood glucose levels on cancer prognosis. We investigated the association between hemoglobin A1c (HbA1c) and survival in oral squamous cell carcinoma (OSCC) patients. Materials and Methods: A 19-year retrospective cohort study of OSCC patients was performed using the Chang Gung Research Database to identify and enroll 7279 patients diagnosed with OSCC between January 2001 and June 2020. A total of 3600 patients were recruited after performing 1:2 frequency-matching between patients with DM and non-DM. A Cox's regression model was used to evaluate the relative hazards of all-cause mortality (ACM) and disease-specific mortality (DSM) in relation to HbA1c. Results: An unadjusted Cox's regression model indicated that DM, in addition to high levels of HbA1c, were statistically prognostic of poor survival. An adjusted hazard ratio (aHR) of HbA1c ≥ 8% interval at the initial diagnosis of OSCC was statistically higher for DSM (1.25 to 2.24) compared to the non-DM group in different regression models. Considering the effect of sustained HbA1c control in 699 patients, the aHR of mean HbA1c ≥ 9% interval was statistically higher for ACM (1.78 to 2.13) compared to the reference group (7% ≤ HbA1c< 8%). In addition, increased hazards of ACM (2.09 to 2.18) and DSM (2.20 to 2.41) were consistently observed in the highest quartiles of average real variability of HbA1c. Conclusion: Poor and unstable control of HbA1c could strongly predict the risks of mortality in OSCC patients with DM.

Aberrant miR-874-3p/leptin/EGFR/c-Myc signaling contributes to nasopharyngeal carcinoma pathogenesis.

BACKGROUND: Leptin is important in physiological and pathological functions in various cancers, however, the significance and mechanisms of leptin in nasopharyngeal carcinoma remain ambiguous. METHODS: Leptin expression was analyzed by QPCR, immunohistochemistry, Western blotting, and TCGA database. The impact of gain- or loss-of-function of leptin were determined by MTT, colony formation, wound healing, and Transwell assays in NPC cells, and by a xenograft tumor model. Leptin-modulated glucose consumption and lactate production were assessed by ELISA. Furthermore, leptin-regulated signaling pathways were examined by QPCR and Western blotting assays. The immunoprecipitation assay was conducted to determine interaction between leptin and EGFR. In addition, miR-874-3p-regulated leptin expression was evaluated using bioinformatics, QPCR, luciferase assay, AGO2-RIP assay, and Western blotting. RESULTS: In this study, we found that leptin was highly expressed in the sera and tumor tissues of patients with NPC, and elevated leptin expression was associated with advanced clinical features and poor prognosis. Functional assays demonstrated that leptin remarkably promoted NPC cell growth, motility, and glycolysis in vitro and in vivo. Mechanistically, leptin associated with EGFR, resulting in enhanced cell growth through the regulation of cell-cycle related markers, glycolysis-related genes, and EGFR/AKT/c-Myc signaling. Moreover, leptin potentiated the invasive capacity of NPC cells by promoting EMT. We further explored that miR-874-3p influenced leptin-mediated NPC progression. Overexpression of miR-874-3p prevented cell growth, motility, glucose consumption, and lactate production in NPC cells, whereas miR-874-3p inhibition had the opposite effects. AGO-RIP assays confirmed that Argonaute 2 (AGO2), a protein associated with miR-874-3p, regulated leptin expression in NPC cells. The rescue assays indicated that inhibition of leptin suppressed the effects of miR-874-3p inhibitor. In clinical specimens, miR-874-3p was negatively correlated with leptin. CONCLUSIONS: Leptin may serve as a novel prognostic factor and potential therapeutic target for patients with NPC. In addition, a newly discovered regulatory axis of leptin/EGFR/AKT/c-Myc can provide a novel therapeutic strategy for NPC.

SDF-1α predicts poor prognosis in patients with locally advanced esophageal squamous cell carcinoma receiving definitive concurrent chemoradiotherapy.

BACKGROUND: Stromal cell-derived factor-1α (SDF-1α) is a chemokine associated with tumor progression in various types of cancers. The current study aimed to evaluate whether pre-treatment or kinetics of SDF-1α can predict the prognosis in patients with esophageal squamous cell carcinoma (ESCC) receiving definitive concurrent chemoradiotherapy (CCRT). METHODS: A total of 97 patients with ESCC were identified at Kaohsiung Chang Gung Memorial Hospital between January 2010 and December 2015. Serum concentration of SDF-1α was measured at day 0 (pre-treatment) and chemotherapy day 28 to determine its kinetics and the cut-off level of pre-chemotherapy SDF-1α was 1.5 ng/mL. Two ESCC cell lines, TE1 and KYSE30, were selected to evaluate the function of SDF-1α. RESULTS: Univariate and multivariate analyses showed that pre-treatment SDF-1α ≥ 1.5 ng/mL and an increased SDF-1α level after treatment were significantly associated with worse progression-free survival (p = 0.021 and p = 0.008, respectively) and overall survival (p = 0.005 and p < 0.001, respectively). In addition, patients with pre-treatment SDF-1α ≥ 1.5 ng/mL and increased SDF-1α levels after treatment were found to have poor response to CCRT. Moreover, these cell lines were treated with chemotherapeutic agents (cisplatin or 5-FU) and SDF-1α, alone or in combination. Our in vitro study results showed SDF-1α promoted the proliferation of tumor cells and overcame the cytotoxic effect of chemotherapy (p < 0.001). CONCLUSION: Our study suggested that SDF-1α plays an important role in ESCC disease progression and that pre-treatment SDF-1α level and kinetics of SDF-1α are the independent prognostic factors for ESCC patients receiving definitive CCRT. Periodic determinations of serum SDF-1α level may be valuable to predict prognosis of ESCC in clinical practice.

Targeting MYO1B impairs tumorigenesis via inhibiting the SNAI2/cyclin D1 signaling in esophageal squamous cell carcinoma.

Myosin-related proteins play an important role in cancer progression. However, the clinical significance, biological functions, and mechanisms of myosin 1B (MYO1B), in esophageal squamous cell carcinoma (ESCC) remain unclear. The clinical relevance of MYO1B, SNAI2, and cyclin D1 in ESCC was determined by immunohistochemistry, Oncomine, and GEPIA databases. The oncogenic roles of MYO1B were determined by CCK8, colony formation assays, wound healing, and Transwell assay. MYO1B, SNAI2, and cyclin D1 at mRNA and protein levels in ESCC cells were detected by qPCR and Western blot analysis. In our study, we found that MYO1B expression was increased in ESCC tissue samples and correlated with tumor stage, TNM stage, and poor outcomes. Functional assays indicated that depletion of MYO1B impaired oncogenesis, and enhanced chemosensitivity in ESCC. Bioinformatic analysis and mechanistic studies illustrated that SNAI2 was a key downstream effector of MYO1B. Suppression of MYO1B downregulated expression of SNAI2, thereby inhibiting the SNAI2/cyclin D1 pathway. Furthermore, a selective inhibitor of cyclin D1 activation reversed siMYO1B cells overexpressing SNAI2-elicited aggressive phenotypes of ESCC cells. MYO1B positively correlated with SNAI2 and cyclin D1 in ESCC samples, and higher SNAI2 expression was also associated with poor prognosis in ESCC patients. Our finding demonstrated that MYO1B activates the SNAI2/cyclin D1 pathway to drive tumorigenesis and cisplatin cytotoxicity in ESCC, indicating that MYO1B is a potential therapeutic target for patients with ESCC.

JMJD3 suppresses tumor progression in oral tongue squamous cell carcinoma patients receiving surgical resection.

Background: Jumonji domain-containing-3 (JMJD3) is reported to be a histone H3 lysine 27 (H3K27) demethylase and a tumor suppressor gene. The present study designed to investigate the crucial role of JMJD3 in oral tongue squamous cell carcinoma (OTSCC) patients who received surgical resection. Methods: We enrolled a total of 156 OTSCC patients receiving surgical resection, including 73 patients (47%) with high expression of JMJD3 and 83 patients (53%) harboring low expression of JMJD3. Two OTSCC cell lines, SAS and Cal 27, were used to explore the modulation of cancer. GSK-J4, a potent inhibitor of JMJD3, was used to treat the two OTSCC cell lines. The Chi-square test was performed to examine between-group differences in categorical variables; the Kaplan-Meier method was used to investigate survival outcome in univariate analysis, and the Cox regression model was used for multivariate analysis. Results: The median follow-up period was 59.2 months and he five-year disease-free survival (DFS) and overall survival (OS) rates were 46.2% and 50.0%, respectively. Better five-year DFS (59% versus 35%) and five-year OS (63% versus 39%) were mentioned in patients with high expression of JMJD3 compared to those with low expression of JMJD3. High expression of JMJD3 was significantly associated with superior DFS and OS in the univariate and multivariate analyses. Following successful inhibition of JMJD3 by GSK-J4, western blotting analysis showed the decreased expression of Rb and p21. Conclusion: Our study showed that high expression of JMJD3 is a good prognostic factor in OTSCC patients who underwent surgical resection.

Neoadjuvant Carboplatin/Paclitaxel versus 5-Fluorouracil/Cisplatin in Combination with Radiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: A Multicenter Comparative Study.

BACKGROUND: The most beneficial neoadjuvant chemoradiotherapy (nCRT) combination for esophageal squamous cell carcinoma (ESCC) in Asia remains uncertain. Herein, we compared the neoadjuvant carboplatin/paclitaxel (CROSS) regimen versus the cisplatin/5-fluorouracil (PF) regimen in combination with 41.4-50.4 Gy of radiotherapy. METHODS: Patients were stratified according to their nCRT regimen: CROSS + 41.4-45.0 Gy (CROSS), PF + 45.0 Gy (PF4500) or PF + 50.4 Gy (PF5040). Propensity score matching by inverse probability of treatment weighting (IPTW) was used to balance the baseline variables. RESULTS: Before IPTW, a total of 334 patients were included. The lowest chemotherapy completion rate was observed in the PF5040 group (76.2% versus 89.4% and 92.0% in the remaining two groups, respectively). Compared with CROSS, both PF groups showed more severe weight loss during nCRT and a higher frequency of post-esophagectomy anastomotic leaks. The use of PF5040 was associated with the highest rate of pathological complete response (45.3%). While CROSS conferred a significant overall survival benefit over PF4500 (hazard ratio [HR] = 1.30, 95% CI = 1.05 to 1.62, p = 0.018), similar survival figures were observed when compared with PF5040 (HR = 1.17, 95% CI = 0.94 to 1.45, p = 0.166). CONCLUSIONS: The CROSS regimen conferred a significant survival benefit over PF4500, although the similar survival figures were similar to those observed with PF5040. Considering the lower incidences of severe weight loss and post-esophagectomy anastomotic leaks, CROSS represents a safe and effective neoadjuvant treatment for Taiwanese patients with ESCC.

Exposure to tris(2-butoxyethyl) phosphate induces abnormal sperm morphology and testicular histopathology in male rats.

Tris(2-butoxyethyl) phosphate (TBEP) is one of the most abundant organophosphate flame retardants in the environment. This study aimed to evaluate the effect of TBEP exposure during adolescence on male reproductive function in adult rats. Male Sprague-Dawley rats were treated with 20 and 200 mg/kg body weight of TBEP or corn oil from postnatal day (PND) 42 to PND 105. A significant increase in the proportion of sperm with abnormal morphology (flattened head and bent tail) and superoxide anion (O2-.) production in the sperm of the 200 mg/kg treated group was observed (p < 0.05). Excessive production of sperm hydrogen peroxide (H2O2) was found in both the 20 and 200 mg/kg treatment groups (p < 0.05). Disruption of testicular structure was observed in the 20 and 200 mg/kg treated groups and seminiferous tubule degeneration was observed in the 200 mg/kg treated group. Our study demonstrated the adverse effects of TBEP on male reproductive function in rats.

The Radiation Dose to the Left Supraclavicular Fossa is Critical for Anastomotic Leak Following Esophagectomy - A Dosimetric Outcome Analysis.

Purpose: For locally advanced esophageal cancer, definitive concurrent chemoradiotherapy (CCRT) with a radiation dose of 50-50.4 Gy/25-28 Fx is prescribed, followed by adjuvant esophagectomy for better local control or salvage treatment if locoregional recurrence occurs. However, radiation injury before surgery may delay wound healing. We performed cervical anastomosis directly inside the left supraclavicular fossa (SCF), the irradiation target for esophageal cancer. The significance of radiation injury in patients with cervical anastomotic leak (AL) remains unclear. Thus, we assessed the influence of radiation on cervical AL in patients undergoing preoperative CCRT followed by esophagectomy. Patients and Methods: We defined the SYC zone, a portion of the region overlapping the left SCF. The radiation dose to the SYC zone was analyzed and correlated with AL in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were administered preoperative CCRT (radiation dose with 50-50.4 Gy/25-28 Fx to the primary esophageal tumor) followed by esophagectomy between October 2009 and January 2018. Receiver operating characteristic curve analysis and logistic regression were used to identify the optimal radiation factor to predict AL and the cutoff value. Results: The optimal radiation factor to predict AL was the mean dose to the SYC zone (area under the curve (AUC)=0.642), and the cutoff point of the mean dose was 48.55 Gray (Gy). For a mean SYC zone dose ≥48.55 Gy, the AL risk was sevenfold greater than that for <48.55 Gy (OR = 7.805; 95% CI: 1.184 to 51.446; P value = 0.033). Conclusion: Recognizing the SYC zone as an organ at risk and performing radiation evaluation are meaningful. A reduced mean dose of the SYC zone below 48.55 Gy results in a lower cervical AL rate following esophagectomy.

Leptin Silencing Attenuates Lipid Accumulation through Sterol Regulatory Element-Binding Protein 1 Inhibition in Nasopharyngeal Carcinoma.

Leptin is a crucial regulator of metabolism and energy homeostasis in mammals. Many studies have investigated the impacts of leptin on human cancers, such as proliferation and metastasis. However, the mechanisms underlying leptin-mediated regulation of lipid metabolism in nasopharyngeal carcinoma (NPC) remain incompletely understood. In the current study, leptin downregulation ameliorated lipid accumulation, triglyceride, and cholesterol levels. Mechanistically, diminished leptin by siRNA not only inhibited sterol regulatory element-binding protein 1 (SREBP1), a master regulator of lipid metabolism, at the mRNA and protein levels, but also reduced SREBP1 downstream target expressions, such as fatty acid synthase (FASN) and stearoyl-CoA desaturase-1 (SCD1), in NPC cells. In addition, leptin expression could modulate the promoter activity of SREBP1. We also found that pharmacological inhibition of poly-ADP ribose polymerase-γ (PPAR-γ) resulted in increased SREBP1 expression in leptin-depleted NPC cells. Functionally, SREBP1 overexpression overcame the effects of leptin-silencing attenuated triglyceride level, cholesterol level and cell survival in NPC cells. Taken together, our results demonstrate that leptin is an important regulator of lipid metabolism in NPC cells and might could be a potential therapeutic target for treatment of NPC patients.

The Impact of Weight Loss during Chemoradiotherapy for Unresectable Esophageal Cancer: Real-World Results.

Weight loss is a common phenomenon presented in unresectable esophageal cancer (EC) patients during their definitive chemoradiotherapy (dCRT) treatment course. This study explored the prognostic value of weight changes during dCRT in unresectable EC patients. From 2009 to 2017, 69 cT4b thoracic EC patients undergoing complete curative dCRT without baseline malnutrition were included. Clinical factors were analyzed via the Cox proportional hazards model and survival was analyzed by the Kaplan−Meier method. During dCRT, the median weight loss percentage was 5.51% (IQR = 2.77−8.85%), and the lowest body weight was reached at 35 days (IQR = 23−43 days). Median OS of these patients was 13.5 months. Both univariate and multivariate analysis demonstrated that weight loss ≤ 4% during dCRT was significantly associated with superior OS with a hazard ratio of 2.61 (95% CI: 1.40−4.85, p = 0.002). The median OS for patients with weight loss ≤ 4% and >4% during dCRT was 59.6 months and 9.7 months, respectively (p = 0.001). Our study demonstrated that weight loss ≤ 4% during dCRT course is a favorable prognostic factor for cT4b EC patients. This index could serve as a nutrition support reference for unresectable EC patients receiving dCRT in the future.

Serum Levels of Stromal Cell-Derived Factor-1α and Vascular Endothelial Growth Factor Predict Clinical Outcomes in Head and Neck Squamous Cell Carcinoma Patients Receiving TPF Induction Chemotherapy.

Chemokines, such as stromal cell-derived factor-1α (SDF-1α) and vascular endothelial growth factor (VEGF), are associated with clinical outcomes in several cancer types. This study aimed to investigate the role of SDF-1α and VEGF in the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) who underwent TPF induction chemotherapy (docetaxel, cisplatin, and 5-fluorouracil). A total of 77 HNSCC patients were enrolled and circulating SDF-1α and VEGF values were examined at two time points for each patient, including pre-TPF treatment (treatment-naïve) and post-TPF treatment but before chemoradiotherapy. The median progression-free survival (PFS) and overall survival (OS) were 18.1 and 32.9 months, respectively. Decreased SDF-1α and VEGF levels after TPF treatment, post-TPF SDF-1α < 1500 pg/mL and VEGF value < 150 pg/mL were independent prognostic factors for better PFS and OS in univariate and multivariate analyses. A combination of SDF-1α and VEGF values may predict clinical outcomes significantly. Our study confirmed the role of SDF-1α and VEGF in the disease progression of HNSCC, and that decreased SDF-1α and VEGF after TPF treatment and lower post-TPF SDF-1α and VEGF values were associated with better prognosis in HNSCC patients who received induction chemotherapy with TPF followed by chemoradiotherapy.