Serum Cytokines Correlate with Pretreatment Body Mass Index-Adjusted Body Weight Loss Grading and Cancer Progression in Patients with Stage III Esophageal Squamous Cell Carcinoma Undergoing ...Neoadjuvant Chemoradiotherapy Followed by Surgery. Circulating cytokines have been linked to the development of esophageal squamous cell carcinoma (ESCC) and its associated malnutrition process. Nonetheless, given the varied disease stages and treatment modalities in previous studies, the clinical relevance of their findings is limited. We retrospectively studied 52 patients with stage III ESCC who underwent neoadjuvant chemoradiotherapy and curative-intent surgery. We investigated the association of clinicopathological features, pretreatment laboratory data, and pretreatment inflammatory status, as indicated by the levels of albumin, C-reactive protein, and 10 circulating cytokines, namely tumor necrosis factor-alpha (TNF-α), interferon-gamma, interleukin-1-beta (IL-1β), IL-4, IL-6, IL-8, IL-12, IL-13, IL-17A, and IL-23, with malnutrition, as shown by body mass index-adjusted body weight loss (BMI-BWL) grading, cancer progression. Half the patients showed severe malnutrition and high BMI-BWL grades (3 and 4). Multivariate analysis revealed an independent association between the levels of three cytokines (TNF-α, ≤ 5.8 pg/ml; IL-1β, > 0.4 pg/ml; IL-6, ≤ 12.4 pg/ml) and high BMI-BWL grades and between IL-4 levels > 22.5 pg/ml and cancer progression. All 10 cytokines were closely correlated with each other. In conclusion, TNF-α, IL-1β, and IL-6 were independent markers of malnutrition status and IL-4 was a prognostic factor for cancer progression in this patient population.
Few prospective cohort trials have investigted the effect of pretreatment nutritional and inflammatory status on the clinical outcome of patients with cancer and optimal performance status and ...assessed the interplay between nutrition, inflammation, body composition, and circulating metabolites before treatment. Here, 50 patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 were prospectively recruited along with 43 healthy participants. Before concurrent chemoradiotherapy, compared with healthy controls, the cancer group showed lower levels of histidine, leucine, and phenylalanine and had low values in anthropometric and body composition measurements; however, the group displayed higher ornithine levels, more malnutrition, and severe inflammation. Pretreatment advanced Glasgow prognostic score (1 and 2) status was the sole prognostic factor for 3-year mortality rate and was associated with age and serum histidine levels in patients with cancer. Thus, even at the same tumor stage and ECOG PS, patients with LAHNSCC, poor nutrition, and high inflammation severity at baseline may have inferior survival outcomes than those with adequate nutrition and low inflammation severity. Assessment of pretreatment nutritional and inflammatory status should be included in the enrollment criteria in future studies.
Limited studies have assessed the associations of pretreatment serum glutamine level with clinicopathological characteristics and prognosis of colorectal cancer (CRC) patients. This study focuses on ...clarifying the clinical significance of baseline serum glutamine level in CRC patients. We retrospectively examine 123 patients with newly diagnosed CRC between 2009 and 2011. The associations of pretreatment serum glutamine level with clinicopathological characteristics, proinflammatory cytokines, overall survival (OS), and progression-free survival (PFS) were analyzed. We executed univariate and multivariate analyses to assess the associations between serum glutamine level and clinicopathological variables able to predict survival. Low glutamine levels were associated with older age, advanced stage, decreased albumin levels, elevated carcinoembryonic antigen levels, higher C-reactive protein levels, higher modified Glasgow prognostic scores, and higher proinflammatory cytokine levels. Furthermore, patients with low glutamine levels had poorer OS and PFS than those with high glutamine levels (
< 0.001 for both). In multivariate analysis, pretreatment glutamine level independently predicted OS (
= 0.016) and PFS (
= 0.037) in CRC patients. Pretreatment serum glutamine level constitutes an independent prognostic marker to predict survival and progression in CRC patients.
Few prospective cohort trials have evaluated the difference in treatment-interval total body composition (TBC) changes assessed by dual-energy X-ray absorptiometry (DXA) between two patient subgroups ...with locally advanced head and neck squamous cell carcinoma (LAHNSCC) receiving concurrent chemoradiotherapy (CCRT): oral cavity cancer with adjuvant CCRT (OCC) and non-oral cavity with primary CCRT (NOCC). This study prospectively recruited patients with LAHNSCC. Clinicopathological variables, blood nutritional/inflammatory markers, CCRT-related factors, and TBC data assessed by DXA before and after treatment were collected. Multivariate linear regression analysis identified the factors associated with treatment-interval changes in body composition parameters, including lean body mass (LBM), total fat mass (TFM), and bone mineral content (BMC). A total of 127 patients (OCC (n = 69) and NOCC (n = 58)) were eligible. Body composition parameters were progressively lost during CCRT in both subgroups. Extremities lost more muscle mass than the trunk for LBM, whereas the trunk lost more fat mass than the extremities for TFM. BMC loss preferentially occurred in the trunk region. Different factors were independently correlated with the interval changes of each body composition parameter for both OCC and NOCC subgroups, particularly mean daily calorie intake for LBM and TFM loss, and total lymphocyte count for BMC loss. In conclusion, treatment-interval TBC changes and related contributing factors differ between the OCC and NOCC subgroups.
Study on the impact of pretreatment malnutrition on treatment outcomes in locally advanced head and neck cancer (LAHNC) patients is still lacking. We prospectively collected various malnutrition ...assessment methods including nutrition indexes, inflammatory biomarkers, and lean body mass index (LBMI) data before treatments. The one year mortality rate was assessed, and the factors associated with this outcome were investigated. Furthermore, the association between malnutrition assessment methods was examined. A total of 113 patients were enrolled. By prognostic stratification based on the prognostic nutritional index (PNI) and platelet-to-lymphocyte ratio (PLR) combination, the low PNI/high PLR group had highest and the high PNI/low PLR group had the lowest mortality rate. Furthermore, the PNI was positively correlated with the LBMI, and the PLR was inversely correlated with the LBMI. PNI and PLR were found to be independent prognostic factors of one year mortality and also associated with the loss of muscle.
We investigated risk factors for treatment interruption (TI) in patients with locally advanced head and neck squamous-cell carcinoma (LAHNSCC) following concurrent chemoradiotherapy (CCRT), under the ...provision of recommended calorie and protein intake; we also evaluated the associations between clinicopathological variables, calorie and protein supply, nutrition–inflammation biomarkers (NIBs), total body composition change (TBC), and a four-serum-amino-acid metabolite panel (histidine, leucine, ornithine, and phenylalanine) among these patients. Patients with LAHNSCC who completed the entire planned CCRT course and received at least 25 kcal/kg/day and 1 g of protein/kg/day during CCRT were prospectively recruited. Clinicopathological variables, anthropometric data, blood NIBs, CCRT-related factors, TBC data, and metabolite panels before and after treatment were collected; 44 patients with LAHNSCC were enrolled. Nine patients (20.4%) experienced TIs. Patients with TIs experienced greater reductions in hemoglobin, serum levels of albumin, uric acid, histidine, and appendicular skeletal mass, and suffered from more grade 3/4 toxicities than those with no TI. Neither increased daily calorie supply (≥30 kcal/kg/day) nor feeding tube placement was correlated with TI. Multivariate analysis showed that treatment-interval changes in serum albumin and histidine levels, but not treatment toxicity, were independently associated with TI. Thus, changes in serum levels of albumin and histidine over the treatment course could cause TI in patients with LAHNSCC following CCRT.
This study investigates whether the appendicular skeletal muscle index (ASMI) was an independent prognostic predictor for patients with locally advanced head and neck cancer (LAHNC) receiving ...concurrent chemoradiotherapy (CCRT) and whether there were any differences in lean mass loss in different body regions during CCRT.
In this prospective study, we analyzed the clinicopathological variables and the total body composition data before and after treatment. The factors associated with the 2-year recurrence-free survival rate (RFSR) were analyzed via logistic regression analysis.
A total of 98 patients were eligible for analysis. The body weight, body mass index, and all parameters of body composition significantly decreased after CCRT. The pretreatment ASMI was the only independent prognostic factor for predicting the 2-year RFSR (hazard ratio, 0.235; 95% confidence interval, 0.062-0.885;
= 0.030). There was at least 5% reduction in total lean and fat mass (
< 0.001); however, the highest lean mass loss was observed in the arms (9.5%), followed by the legs (7.2%), hips (7.1%), waist (4.7%), and trunk (3.6%).
The pretreatment ASMI was the only independent prognostic predictor for the 2-year RFSR of LAHNC patients undergoing CCRT. Asynchronous loss of lean mass may be observed in different body parts after CCRT.
Only few prospective cohort trials have evaluated the risk factors for the 2-year mortality rate between two patient subgroups with locally advanced head and neck squamous cell carcinoma (LAHNSCC): ...oral cavity cancer with adjuvant concurrent chemoradiotherapy (CCRT) (OCC) and non-oral cavity cancer with primary CCRT (NOCC), under the recommended calorie intake and investigated the interplay among calorie supply, nutrition-inflammation biomarkers (NIBs), and total body composition change (TBC), as assessed using dual-energy X-ray absorptiometry (DXA). Patients with LAHNSCC who consumed at least 25 kcal/kg/day during CCRT were prospectively recruited. Clinicopathological variables, blood NIBs, CCRT-related factors, and TBC data before and after treatment were collected. Factor analysis was performed to reduce the number of anthropometric and DXA-derived measurements. Cox proportional hazards models were used for analysis. We enrolled 123 patients with LAHNSCC (69 with OCC and 54 with NOCC). The mean daily calorie intake correlated with the treatment interval changes in total body muscle and fat. Patients consuming ≥30 kcal/kg/day had lower pretreatment levels but exhibited fewer treatment interval changes in anthropometric and DXA measurements than patients consuming <30 kcal/kg/day. In the multivariate analysis of the 2-year mortality rate, the prognostic influence of the recommended calorie intake could not be confirmed, but different risk factors (performance status, pretreatment platelet-to-lymphocyte ratio, and treatment interval body muscle changes in patients with OCC; age, pretreatment neutrophil-to-lymphocyte ratio, and body fat storage in patients with NOCC) showed independent effects. Therefore, the inflammation status and body composition, but not the recommended calorie supply, contribute to the 2-year mortality rate for patients with LAHNSCC receiving CCRT.
Few prospective cohort trials have evaluated the potential risk factors of early treatment failure of locally advanced oral cavity squamous cell carcinoma (LAOCSCC) patients following the completion ...of postoperative adjuvant concurrent chemoradiotherapy (CCRT). We collected clinicopathological variables, nutrition-inflammatory markers and total body composition data assessed by dual-energy X-ray absorptiometry (DXA) before and after CCRT. A factor analysis was used to reduce the number of DXA-derived parameters. Cox proportional hazard models were applied to determine the risk factors associated with early treatment failure defined as tumor progression or death within 180 days of CCRT completion. A total of 69 patients were eligible for analysis. After CCRT, the body weight, body mass index, nutritional markers, and muscle mass decreased, whereas C-reactive protein level increased. Five factors reflecting different body composition statuses were identified. A total of 21 patients (30.4%) developed early treatment failure. Comorbidities (hazard ratio ((HR)), 2.699; 95% confidence interval ((CI)), 1.005–7.913; p = 0.044), radiation duration (HR, 1.092; 95% CI, 1.015–1.174; p = 0.018) and the pretreatment body muscle mass (HR, 0.578; 95% CI, 0.345–0.957; p = 0.037) independently contributed to early treatment failure. Comorbidities, longer radiation duration, and lower pretreatment body muscle mass are predictive factors for early treatment failure in LAOCSCC patients following postoperative adjuvant CCRT completion.
Head and neck squamous cell carcinoma (HNSCC) faces low response rates to anti-PD-1 immunotherapies, highlighting the need for enhanced treatment strategies. Auranofin, which inhibits thioredoxin ...reductase (TrxR) through its gold-based composition, has shown potential in cancer treatment. It targets the TrxR system, essential for safeguarding cells from oxidative stress. The overproduction of TrxR in cancerous cells supports their proliferation. However, auranofin's interference with this system can upset the cellular redox equilibrium, boost levels of reactive oxygen species, and trigger the death of cancer cells. This study is the first to highlight TXNRD1 as a crucial factor contributing to resistance to anti-PD-1 treatment in HNSCC. In this study, we identified targetable regulators of resistance to immunotherapy-induced ferroptosis in HNSCC. We observed a link of thioredoxin reductase 1 (TXNRD1) with tumoral PD-L1 expression and ferroptosis suppression in HNSCC. Moreover, HNSCC tumors with aberrant TXNRD1 expression exhibited a lack of PD-1 response, NRF2 overexpression, and PD-L1 upregulation. TXNRD1 inhibition promoted ferroptosis in HNSCC cells with NRF2 activation and in organoid tumors derived from patients lacking a PD-1 response. Mechanistically, TXNRD1 regulated PD-L1 transcription and maintained the redox balance by binding to ribonucleotide reductase regulatory subunit M2 (RRM2). TXNRD1 expression disruption sensitized HNSCC cells to anti-PD-1–mediated Jurkat T-cell activation, promoting tumor killing through ferroptosis. Moreover, TXNRD1 inhibition through auranofin cotreatment synergized with anti-PD-1 therapy to potentiate immunotherapy-mediated ferroptosis by mediating CD8+ T-cell infiltration and downregulating PD-L1 expression. Our findings indicate that targeting TXNRD1 is a promising therapeutic strategy for improving immunotherapy outcomes in patients with HNSCC.
•TXNRD1 and PD-L1 expression effectively predict non-responsiveness to anti-PD-1 therapy in HNSCC.•TXNRD1 overexpression indicates NRF2 hyperactivation in HNSCC, marking a subtype with aggression, chemoresistance, metastasis, and poor outcomes.•Auranofin-induced NRF2 upregulation inhibited TXNRD1 and suppressed HMOX1 expression, triggering ferroptosis in HNSCC.
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