Optimization of collimator angle combined island blocking with parked gap achieves superior normal tissue sparing in SBRT planning of multiple liver lesions.

PURPOSE: To propose an efficient collimator angle optimization method by combining island blocking (IB) and parked gap (PG) problem to reduce the radiotherapy dose for normal tissue. The reduction will be done with single-isocenter multi-lesion volumetric modulated arc therapy (VMAT) for the stereotactic body radiation therapy (SBRT) of liver cancer. METHODS: A novel collimator angle optimization algorithm was developed based on the two-dimensional projection of targets on a beam's eye view (BEV) plane as a function of gantry and collimator angle. This optimization algorithm minimized the sum of the combined IB and PG (IB & PG) areas from all gantry angles for each arc. For comparison, two SBRT plans were respectively generated for each of the 20 retrospective liver cancer cases with multiple lesions. One plan was optimized using the IB & PG algorithm, and the other plan was optimized with a previously reported optimization algorithm that only considered the IB area. Plans were then evaluated and compared using typical dosimetric metrics. RESULTS: With the comparable target coverage, IB & PG plans had significantly lower D500cc , D700cc , mean dose (Dmean ), and V15 of normal liver tissues when compared to IB plans. The median percent reductions were 3.32% to 5.36%. The D1cc , D5cc , and Dmean for duodenum and small intestine in IB & PG plans were significantly reduced in a range from 7.60% up to 16.03%. Similarly, the median integral dose was reduced by 3.73%. Furthermore, the percentage of normal liver Dmean sparing when IB & PG plans compared to IB plans, was found to be positively correlated (ρ = 0.669, P = 0.001) with the inter-target distance. CONCLUSION: The proposed IB & PG algorithm has been demonstrated to outperform the IB algorithm in almost all normal tissue sparing, and the magnitude of liver sparing was positively correlated with inter-target distance.

Network pharmacology, molecular docking and experimental study of CEP in nasopharyngeal carcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: The Stephania cephalantha Hayata is an important traditional medicinal plant widely used in traditional medicine to treat cancer. Cepharanthine (CEP) was extracted from the roots of Stephania cephalantha Hayata. It has been found to exhibit anticancer activity in different types of cancer cells. Nevertheless, the activity of CEP against nasopharyngeal carcinoma (NPC) and its underlying mechanism warrant further investigation. AIMS OF THE STUDY: NPC is an invasive and highly metastatic malignancy that affects the head and neck region. This research aimed to investigate the pharmacological properties and underlying mechanism of CEP against NPC, aiming to offer novel perspectives on treating NPC using CEP. MATERIALS AND METHODS: In vitro, the pharmacological activity of CEP against NPC was evaluated using the CCK-8 assay. To predict and elucidate the anticancer mechanism of CEP against NPC, we employed network pharmacology, conducted molecular docking analysis, and performed Western blot experiments. In vivo validation was performed through a nude mice xenograft model of human NPC, Western blot and immunohistochemical (IHC) assays to confirm pharmacological activity and the mechanism. RESULTS: In a dose-dependent manner, the proliferation and clonogenic capacity of NPC cells were significantly inhibited by CEP. Additionally, NPC cell migration was suppressed by CEP. The results obtained from network pharmacology experiments revealed that anti-NPC effect of CEP was associated with 8 core targets, including EGFR, AKT1, PIK3CA, and mTOR. By performing molecular docking, the binding capacity of CEP to the candidate core proteins (EGFR, AKT1, PIK3CA, and mTOR) was predicted, resulting in docking energies of -10.0 kcal/mol for EGFR, -12.4 kcal/mol for PIK3CA, -10.8 kcal/mol for AKT1, and -8.6 kcal/mol for mTOR. The Western blot analysis showed that CEP effectively suppressed the expression of EGFR and the phosphorylation levels of downstream signaling proteins, including PI3K, AKT, mTOR, and ERK. After CEP intervention, a noteworthy decrease in tumor size, without inducing any toxicity, was observed in NPC xenograft nude mice undergoing in vivo treatment. Additionally, IHC analysis demonstrated a significant reduction in the expression levels of EGFR and Ki-67 following CEP treatment. CONCLUSION: CEP exhibits significant pharmacological effects on NPC, and its mechanistic action involves restraining the activation of the EGFR/PI3K/AKT pathway. CEP represents a promising pharmaceutical agent for addressing and mitigating NPC.

Long-term outcomes of metastasis-directed stereotactic body radiation therapy in metastatic nasopharyngeal carcinoma.

BACKGROUND: The study aims to evaluate the outcomes of metastasis-directed stereotactic body radiation therapy (SBRT) in metastatic nasopharyngeal carcinoma (mNPC). METHODS: We reviewed all SBRT conducted in patients with mNPC in our institution between 2013 and 2022. Systemic therapy was performed with chemotherapy with or without anti-programmed death-1 (PD-1) therapy. Local treatment delivered with ablative purpose in stereotactic setting with dose/fraction ≥5 Gy was evaluated. Kaplan-Meier analyses were used to determine the rates of local control (LC), progression-free survival (PFS), and overall survival (OS). Univariate and multivariate analyses were performed by Cox regression. RESULTS: A total of 54 patients with 76 metastatic sites receiving SBRT were analyzed. Median follow-up was 49 months. The 3-year LC, PFS, and OS rates were 89.1%, 29.4%, and 57.9%, respectively. Adding a PD-1 inhibitor to SBRT tended to prolong median OS (50.1 vs. 32.2 months, p = 0.068). Patients receiving a biological effective dose (BED, α/ß = 10) ≥ 80 Gy had a significantly longer median OS compared to those who received a lower dose (not reached vs. 29.5 months, p = 0.004). Patients with oligometastases (1-5 metastases) had a better median OS (not reached vs. 29.5 months, p < 0.001) and PFS (34.3 vs. 4.6 months, p < 0.001). Pretreatment EBV-DNA and maintenance therapy were also significant predictors for OS. CONCLUSIONS: Metastatic NPC patients could benefit from metastases-directed SBRT in combination with systemic therapy.

Dosimetric comparison in sparing normal tissue dosage by using auto-SBRT planning in oligo liver tumors.

Purpose: The study aimed to compare the dosimetric distribution of VMAT plans by increasing the number of half arcs in liver SBRT and investigate the effect by using automatic plan software in plan optimization. Method: Thirty-one patients with oligo liver tumors were randomly selected. VMAT treatment plans with different numbers of coplanar half arcs were generated. Result: Adding arcs significantly increased the PTV, D2%, D50%, and CI, but sacrificed the plan homogeneity. It also decreased the maximum dose of normal tissues such as the stomach, duodenum, and spinal cord and reduced Dmean, D500cc, and D700cc for the liver. Nevertheless, the diminishing effect gradually decayed into three arcs. Meanwhile, the addition of arcs substantially extended the beam-on time. Conclusion: In the context of SBRT for oligo liver tumors, increasing the number of coplanar half arcs will improve PTV conformity and offer better protection for OARs, albeit at the expense of increased treatment duration. Considering the trade-off between plan quality and treatment efficiency, a three-arc plan may be more suitable for clinical implementation.

Advancements of radiotherapy for recurrent head and neck cancer in modern era.

Head and neck cancer is a kind of cancer which can be eradicated from radical radiation therapy. However, with best efforts, nearly 40% patients will experience locoregional recurrence. Locoregional recurrence is the main cause of cancer-related death in head and neck cancers, so local treatments play a key role in improving progression free survival. In the last decades, radiation techniques have been tremendously developed, highly conformal radiation techniques such as intensity-modulated radiotherapy, stereotactic body radiation therapy, brachytherapy and proton or heavy ion radiation therapy have their unique radiobiological advances. Although reirradiation is widely used in clinical practice, but little is known when comparing the different techniques. In this review, we will provide a comprehensive overview of the role of reirradiation in recurrent head and neck cancers including radiation techniques, patient selection, overall clinical benefits, and toxicities.

Chimeric antigen receptor engineered natural killer cells for cancer therapy.

Natural killer (NK) cells, a unique component of the innate immune system, are inherent killers of stressed and transformed cells. Based on their potent capacity to kill cancer cells and good tolerance of healthy cells, NK cells have been successfully employed in adoptive cell therapy to treat cancer patients. In recent years, the clinical success of chimeric antigen receptor (CAR)-T cells has proven the vast potential of gene-manipulated immune cells as the main force to fight cancer. Following the lessons learned from mature gene-transfer technologies and advanced strategies in CAR-T therapy, NK cells have been rapidly explored as a promising candidate for CAR-based therapy. An exponentially growing number of studies have employed multiple sources of CAR-NK cells to target a wide range of cancer-related antigens, showing remarkable outcomes and encouraging safety profiles. Clinical trials of CAR-NK cells have also shown their impressive therapeutic efficacy in the treatment of hematological tumors, but CAR-NK cell therapy for solid tumors is still in the initial stages. In this review, we present the favorable profile of NK cells as a potential platform for CAR-based engineering and then summarize the outcomes and strategies of CAR-NK therapies in up-to-date preclinical and clinical investigations. Finally, we evaluate the challenges remaining in CAR-NK therapy and describe existing strategies that can assist us in devising future prospective solutions.

Cost-effectiveness of trastuzumab deruxtecan in previously treated human epidermal growth factor receptor 2-low metastatic breast cancer.

Background: Results from DESTINY-Breast04 trial revealed that trastuzumab deruxtecan (T-DXd) improved both progression-free survival and overall survival for patients with human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC). However, the economic impact of this practice remains unclear. The purpose of this study was to evaluate the cost-effectiveness of T-DXd on HER2-low mBC from the viewpoint of U.S. payers. Methods: Using the clinical data from the DESTINY-Breast04 trial, a three-state Markov model was created to assess the economic and health effects of T-DXd versus chemotherapy. The incremental cost-effectiveness ratio (ICER) and willingness-to-pay threshold were determined and compared. One-way and probabilistic sensitivity analysis were used to measure parameter uncertainty. Results: In the overall HER2-low population, T-DXd provided additional 0.47 quality-adjusted life-years (QALYs) at an increased cost of $149,222 compared with chemotherapy, yielding an ICER of $317,494/QALY. The ICER was $353,903/QALY in the hormone receptor (HR)-positive subgroup, which decreased to $259,825/QALY in the HR-negative subgroup. The sensitivity analysis found that T-DXd would not be cost-effective in the base-case. The expected cost of T-DXd will be less than $4,281/cycle ($11.33/mg) or $1,903/cycle ($5.03/mg) to achieve a 50 or 90% cost-benefit probability, respectively. Conclusions: T-DXd provides significant health benefit for patients with HER2-low mBC compared with chemotherapy but is unlikely to be cost-effective in the United States.

Melatonin attenuates acute and chronic itch in mice: the antioxidant and anti-inflammatory effects of melatonin receptors.

Background: Itch is a common symptom of skin diseases and significantly reduces patients' quality of life. Melatonin has anti-inflammatory and antioxidant effects. Our study examined the potential anti-itch effects of melatonin (N-acetyl-5-methoxytryptamine) in mice. Methods: We detected the effects of melatonin and its receptors on acute and chronic itch by conducting itching behavioral experiments in male C57 mice. Reactive oxygen species (ROS) levels and calcium ion (Ca2+) mobilization during acute itching production were explored using flow cytometry and calcium imaging techniques. Melatonin expression in the serum of the chronic itch model mice was determined by enzyme-linked immunoassays. Hematoxylin and eosin staining show the effects of melatonin on skin thickness in a chronic itch model. Cytokine and chemokine levels were determined by quantitative polymerase chain reaction. Results: We discovered that compound 48/80 (C48/80)- and chloroquine (CQ)-induced scratching were significantly decreased by intraperitoneal (i.p), intradermal, and intrathecal administration of melatonin in a dose-dependent manner in mice, and the co-administration of melatonin receptor antagonists abolished the anti-itch effects of i.d melatonin. The incubation of melatonin significantly decreased the intracellular ROS levels induced by C48/80 and CQ in cultured ND7/23 cells from a mouse x rat hybridoma nerve as neuron. Melatonin inhibited intracellular Ca2+ increases induced by CQ (but not C48/80) in cultured dorsal root ganglia (DRG) neurons. Melatonin (50 mg/kg i.p) attenuated imiquimod (IMQ)- or acetone and diethyl ether followed by acetone-ether-water (AEW)-induced chronic itch and epidermal hyperplasia in mice. Finally, melatonin treatment reduced the IMQ-induced expression of ST2 and interleukin-33 (IL-33) or the AEW-induced expression of interleukin 31 (IL-31) and interleukin 31 receptor A (IL-31 RA) in the mice. Conclusions: Collectively, our results indicate that melatonin attenuates acute and chronic itch, possibly via melatonin receptors, and its antioxidant, and anti-inflammatory effects in mice.

Cost-effectiveness analysis of trastuzumab deruxtecan versus trastuzumab emtansine for HER2-positive breast cancer.

Background: The DESTINY-Breast03 clinical trial demonstrated that trastuzumab deruxtecan (T-DXd) outperformed trastuzumab emtansine (T-DM1) in progression-free survival (PFS) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC). Considering the excessive cost of antibody-drug conjugates, the clinical value of T-DXd must be assessed by both its efficacy and cost. We compared the cost-effectiveness of T-DXd and T-DM1 for patients with HER2-positive mBC pretreated with anti-HER2 antibodies and a taxane from the perspectives of the United States (US) and China. Methods: A comprehensive Markov model based on the DESTINY-Breast03 phase III randomized clinical trial was used to compared the cost and effectiveness of T-DXd and T-DM1 for HER2-positive mBC. Data on direct medical cost and utilities were collected from published literatures. The recorded data included the costs, quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER) and incremental net-health benefit (INHB). Sensitivity analysis was conducted to measure the potential uncertainty due to parameter variability. Additional subgroup cost-effectiveness analysis was performed. Results: Treatment of HER2-positive mBC with T-DXd gained 0.73 QALYs compared with T-DM1 strategy. The incremental cost was $59,942 in the US, with an ICER of $ 82,112/QALY and an INHB of 0.33 QALYs, respectively. In China, the incremental cost of T-DXd versus T-DM1 was $222,680, with an ICER of $305,041/QALY and a negative INHB of -5.18 QALYs. At willingness-to-pay (WTP) threshold of $150,000/QALY in the US and $37,653/QALY in China, the probability of T-DXd as the dominant option was 77.5 and 0.1%, respectively. The unit price of T-DXd greatly influenced the results according to one-way sensitivity analysis. To meet the 50% or 90% chance of being cost-effective, the estimated cost of T-DXd would need to be less than $17.24/mg and $12.06/mg in China, respectively. Conclusion: T-DXd is more cost-effective than T-DM1 for patients with HER2-positive mBC in the US, but not in China at current drug prices.

A novel dosimetric metrics-based risk model to predict local recurrence in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy.

BACKGROUND: To develop a risk model based on dosimetric metrics to predict local recurrence in nasopharyngeal carcinoma (NPC) patients treated with intensive modulated radiation therapy (IMRT). METHODS: 493 consecutive patients were included, among whom 44 were with local recurrence. One-to-two propensity score matching (PSM) was used to balance variables between recurrent and non-recurrent groups. Dosimetric metrics were extracted, and critical dosimetric predictors of local recurrence were identified by Cox regression model. Moreover, recurrent sites and patterns were examined by transferring the recurrent tumor to the pretreatment planning computed tomography. RESULTS: After PSM, 44 recurrent and 88 non-recurrent patients were used for dosimetric analysis. The univariate analysis showed that eight dosimetric metrics and homogeneity index were significantly associated with local recurrence. The risk model integrating D5 and D95 achieved a C-index of 0.706 for predicting 3-year local recurrence free survival (LRFS). By grouping patients using median value of risk score, patients with risk score ˃ 0.885 had significantly lower 3-year LRFS (66.2% vs. 86.4%, p = 0.023). As for recurrent features, the proportion of relapse in nasopharynx cavity, clivus, and pterygopalatine fossa was 61.4%, 52.3%, and 40.9%, respectively; and in field, marginal, and outside field recurrence constituted 68.2%, 20.5% and 11.3% of total recurrence, respectively. CONCLUSIONS: The current study developed a novel risk model that could effectively predict the LRFS in NPC patients. Additionally, nasopharynx cavity, clivus, and pterygopalatine fossa were common recurrent sites and in field recurrence remained the major failure pattern of NPC in the IMRT era.

A nomogram for predicting late radiation-induced xerostomia among locoregionally advanced nasopharyngeal carcinoma in intensity modulated radiation therapy era.

BACKGROUND: Dry mouth sensation cannot be improved completely even though parotids are spared correctly. Our purpose is to develop a nomogram to predict the moderate-to-severe late radiation xerostomia for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) in intensity modulated radiation therapy (IMRT) / volumetric modulated arc radiotherapy (VMAT) era. METHODS: A dataset of 311 patients was retrospectively collected between January 2010 and February 2013. The binary logistic regression was to estimate each factor's prognostic value for development of moderate-to-severe patient-reported xerostomia at least 2 years (Xer2y) after completion of radiotherapy. Therefore, we can develop a nomogram according to binary logistic regression coefficients. This novel model was validated by bootstrapping analyses. RESULTS: Contralateral Parotid mean dose (coMD<24.4Gy), VMAT (yes), and platinum-based concurrent chemoradiotherapy (no) were significantly related to patient-reported xerostomia at least 2 years (Xer2y) (all p < 0.001), and were included in the nomogram. Receiver operating characteristic (ROC) analysis revealed AUC (area under the ROC curve) with the value of 0.811 (0.710-0.912) of the nomogram, which was significantly higher than coMD 0.698 (0.560-0.840) from QUANTEC2010 (p<0.001). Calibration plots illustrated that the predicted Xer2y was close to the actual observation, and decision curve analyses (DCA) indicated valid positive net benefits. CONCLUSION: We developed a feasible nomogram to predict patient-rated Xer2y based on comprehensive individual data in patients with LA-NPC in the real world. The proposed model is able to facilitate the development of treatment plan and quality of life improvement.

Case Report: High-Level MET Amplification as a Resistance Mechanism of ROS1-Tyrosine Kinase Inhibitors in ROS1-Rearranged Non-Small Cell Lung Cancer.

BACKGROUND: Although C-ros oncogene 1 (ROS1) targeted therapies have demonstrated remarkable efficacy in ROS1-rearranged non-small cell lung cancer (NSCLC), patients inevitably develop resistance to ROS1-tyrosine kinase inhibitors (TKIs). Commonly acquired resistance mechanisms include a second mutation of the ROS1 kinase domain and activation of bypass signaling pathways. However, MMNG HOS Transforming gene (MET) amplification has not been reported as a novel mechanism of ROS1-TKIs resistance. CASE PRESENTATION: We report a case of a 62-year-old man diagnosed with ROS1-rearranged metastatic lung adenocarcinoma, who received first-line treatment with crizotinib for 19 months. During the course of disease, the primary lung tumor was under control while the brain metastasis progressed despite the treatment with lorlatinib. The biopsy and genetic tests of the metastatic brain tumor showed a high level of MET amplification (32 copies). However, fluorescence in situ hybridization of the primary cancer showed no MET amplification, suggesting that MET amplification may be associated with an acquired resistance to ROS1-TKIs. SUMMARY: This case suggested that MET amplification could be explored as a potential mechanism for developing ROS1-TKIs resistance. Combination treatment with highly potent and selective MET-TKIs warrants further investigations.

m6A Regulators Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization In Nasopharyngeal Carcinoma.

Background: The role of RNA N6-methyladenosine (m6A) modification in tumor progression and metastasis has been demonstrated. Nonetheless, potential biological function of m6A modification patterns in nasopharyngeal carcinoma (NPC) remains unknown. Methods: The m6A modification patterns were comprehensively evaluated based on 26 m6A regulators in NPC, and m6A subtype and also m6A score were identified and systematically correlated with representative tumor characteristics. Results: Two distinct m6A subtypes were determined and were highly consistent with immune activated and immune suppressed phenotypes, respectively. More representative m6A scores of individual tumors could predict tumor microenvironment (TME) infiltration, mRNA based stemness index (mRNAsi), EBV gene expression, genetic variation, and prognosis of NPC patients. Low m6A score, characterized by activation of immunity and suppression of mRNAsi and EBV gene, indicated an activated TME phenotype and better PFS and also lower risk of recurrence and metastasis. High m6A score, characterized by activation of Wnt and NF-κB signaling pathway and lack of effective immune infiltration, indicated an immune suppressed TME phenotype and poorer survival. Low m6A score was also correlated with increased tumor mutation burden (TMB) and better response to immunotherapy, and vice versa. A significant therapeutic advantage in patients with low m6A score was confirmed with an anti-PDL1 immunotherapy cohort. Conclusions: m6A patterns played an important role in the diversity and complexity of TME. m6A score could be used to evaluate the m6A pattern of individual tumor to enhance our understanding of TME infiltration and guide more effective immunotherapy strategies.

Cost-Effectiveness of Ribociclib for Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer.

PURPOSE: Ribociclib has provided significant improvements in progression-free survival (PFS) and overall survival (OS) of postmenopausal patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). However, given the high cost of ribociclib, its value must be evaluated based on cost-effectiveness. Thus, we aimed to explore the cost-effectiveness of ribociclib for postmenopausal patients with HR-positive and HER2-negative ABC. METHODS: A comprehensive Markov model was developed to estimate the cost-effectiveness of ribociclib plus fulvestrant versus placebo plus fulvestrant as first-line treatment for HR-positive, HER2-negative ABC. Variables were estimated based on data from the randomized Phase III MONALEESA-3 trial. Ten-year values were estimated for quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Direct treatment costs were estimated from the perspective of a United States payer. One-way and probabilistic sensitivity analyses were conducted to confirm the model's robustness. RESULTS: Ribociclib plus fulvestrant increased the treatment cost by $382,172 and provided 0.47 QALYs, relative to fulvestrant alone, which corresponded to an ICER of $813,132 per QALY. Sensitivity analyses revealed that ribociclib was unlikely to be cost-effective even under the most favorable assumptions. When the cost of ribociclib was <$1,384, there was a >50% chance of cost-effectiveness at a willingness-to-pay threshold of $150,000/QALY. Subgroup analyses also confirmed that ribociclib was not cost-effective. CONCLUSION: At current drug prices in the United States, ribociclib is unlikely to be cost-effective for treating postmenopausal patients with HR-positive HER2-negative ABC. Despite the clinical benefits of ribociclib, its cost would need to decrease to provide more favorable economic outcomes.

A novel immune checkpoint-related seven-gene signature for predicting prognosis and immunotherapy response in melanoma.

BACKGROUND: New emergence of immunotherapy has significantly improved clinical outcome of melanoma patients with advanced and metastatic diseases. We aimed to develop a gene signature based on the expression of PD-1/PD-L1 signaling pathway genes to predict prognosis and immunotherapy response in melanoma patients. METHODS: Melanoma samples from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) were used as the training set and external validation sets respectively. Prognostic genes for overall survival (OS) were identified by univariate Cox regression analysis. Then a multi-gene risk signature was established with the Least Absolute Shrinkage and Selector Operation (LASSO) regression and multivariate Cox regression. The predictive and prognostic value of gene signature was evaluated by Kaplan Meier curve, Time-dependent receiver operating characteristic (ROC) curve, and area under curve (AUC). Gene set enrichment analysis (GSEA) was performed to investigate the discrepantly enriched biological processes between low-risk and high-risk group of melanoma patients. RESULTS: A seven-gene risk signature (BATF2, CTLA4, EGFR, HLA-DQB1, IKBKG, PIK3R2, PPP3CA) was constructed. The signature was an independent risk factor for OS (hazard ratio = 1.544, p < 0.001) and it could robustly predict OS in both training and validation sets. Besides, high risk scores indicated advanced clinical stage and no response to immunotherapy for melanoma patients. GSEA demonstrated that high risk score was intimately associated with immune response and immune regulation. In conclusion, the novel seven-gene signature could serve as a robust biomarker for prognosis and a potential indicator of immunotherapy response in melanoma.

Durvalumab vs placebo consolidation therapy after chemoradiotherapy in stage III non-small-cell lung cancer: An updated PACIFIC trial-based cost-effectiveness analysis.

INTRODUCTION: Recently updated three-year survival data from the PACIFIC trial showed that durvalumab consolidation therapy improved OS rates versus placebo for patients with unresectable stage III non-small cell lung cancer (NSCLC) after chemoradiotherapy. Considering the impact of the high cost of durvalumab, its cost-effectiveness should be updated to see if its cost-effectiveness has changed from the US payers' perspective. METHODS: A comprehensive Markov model was used to evaluate mean lifetime costs and effectiveness of first-line durvalumab consolidation therapy versus placebo for patients with unresectable stage III NSCLC imputing updated survival and quality-of-life data from the PACIFIC trial. The main endpoints include total costs, life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way, two-way, and probabilistic sensitivity analyses were conducted to access the uncertainty in the variables. We also considered durvalumab cost-effectiveness in the subgroups. RESULTS: Durvalumab consolidation therapy resulted in additional 1.34 LYs and 1.01 QALYs, resulting in an ICER of $138,920 per QALY versus the placebo treatment. One-way sensitivity analysis revealed that the utility values of two treatments, body weight, and unit cost of durvalumab have the greatest influence on the result. Subgroup analyses demonstrated that durvalumab was more cost effective for patients with non-squamous-cell lung cancer, followed by 25% or greater PD-L1 expression. Probabilistic sensitivity analysis showed that the probability of durvalumab being cost-effective versus the placebo is 62.6% at a willingness-to-pay (WTP) of $150,000 per QALY CONCLUSION: Our analyses demonstrated that receiving durvalumab consolidation therapy was more cost-effective than placebo at a WTP threshold of $150,000. These results can be of use to US practitioners in the application of durvalumab and for durvalumab prescription and reimbursement policies.

Real-World Cost-Effectiveness Analysis of Gemcitabine and Cisplatin Compared to Docetaxel and Cisplatin Plus Fluorouracil Induction Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma.

BACKGROUND: Addition of gemcitabine and cisplatin (GP) or docetaxel and cisplatin plus fluorouracil (TPF) to concurrent chemoradiotherapy (CCRT) significantly improved survival in locoregionally advanced nasopharyngeal carcinoma (NPC). However, an economic evaluation of these regimens remains unknown. The purpose of this study is to compare the cost-effectiveness of GP versus TPF regimen in the treatment of locoregionally advanced NPC in China. MATERIALS AND METHODS: A comprehensive Markov model was developed to evaluate the health and economic outcomes of GP versus TPF regimen for patients with locoregionally advanced NPC. Baseline and clinical outcome were derived from 158 patients with newly diagnosed stage III-IVA NPC between 2010 and 2015. We evaluated the quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs) from the perspective of the Chinese healthcare system. One-way sensitive analysis explored the impact of uncertainty in key model parameters on results, and probabilistic uncertainty was assessed through a Monte Carlo probabilistic sensitivity analysis. RESULTS: GP regimen provided an additional 0.42 QALYs with incremental cost of $3,821.99, resulting in an ICER of $9,099.98 per QALY versus TPF regimen at the real-world setting. One-way sensitivity analysis found that the results were most sensitive to the cost and proportion of receiving subsequent treatment in two groups. The probability that GP regimen being cost-effective compared with TPF regimen was 86.9% at a willingness-to-pay (WTP) of $31,008.16 per QALY. CONCLUSION: Using real-world data, GP regimen was demonstrated a cost-effective alternative to TFP regimen for patients with locoregionally advanced NPC in China. It provides valuable evidence for clinicians when making treatment decisions to improve the cost-effectiveness of treatment.

RNA helicase A interacts with nuclear factor kappaB p65 and functions as a transcriptional coactivator.

RNA helicase A (RHA), a member of DNA and RNA helicase family containing ATPase activity, is involved in many steps of gene expression such as transcription and mRNA export. RHA has been reported to bind directly to the transcriptional coactivator, CREB-binding protein, and the tumor suppressor protein, BRCA1, and links them to RNA Polymerase II holoenzyme complex. Using yeast two-hybrid screening, we have identified RHA as an interacting molecule of the p65 subunit of nuclear factor kappaB (NF-kappaB). The interaction between p65 and RHA was confirmed by glutathione-S transferase pull-down assay in vitro, and by co-immunoprecipitation assay in vivo. In transient transfection assays, RHA enhanced NF-kappaB dependent reporter gene expression induced by p65, tumor necrosis factor-alpha, or NF-kappaB inducing kinase. The mutant form of RHA lacking ATP-binding activity inhibited NF-kappaB dependent reporter gene expression induced by these activators. Moreover, depletion of RHA using short interfering RNA reduced the NF-kappaB dependent transactivation. These data suggest that RHA is an essential component of the transactivation complex by mediating the transcriptional activity of NF-kappaB.