Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

YTHDC1-dependent m6A modification modulated FOXM1 promotes glycolysis and tumor progression through CENPA in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) exhibits heightened aggressiveness compared with other breast cancer (BC) subtypes, with earlier relapse, a higher risk of distant metastasis, and a worse prognosis. Transcription factors play a pivotal role in various cancers. Here, we found that factor forkhead box M1 (FOXM1) expression was significantly higher in TNBC than in other BC subtypes and normal tissues. Combining the findings of Gene Ontology (GO) enrichment analysis and a series of experiments, we found that knockdown of the FOXM1 gene attenuated the ability of TNBC cells to proliferate and metastasize both in vivo and in vitro. In addition, Spearman's test showed that FOXM1 significantly correlated with glycolysis-related genes, especially centromere protein A (CENPA) in datasets (GSE76250, GSE76124, GSE206912, and GSE103091). The effect of silencing FOXM1 on the inhibition of CENPA expression, TNBC proliferation, migration, and glycolysis could be recovered by overexpression of CENPA. According to MeRIP, the level of m6A modification on FOMX1 decreased in cells treated with cycloleucine (a m6A inhibitor) compared with that in the control group. The increase in FOXM1 expression caused by YTHDC1 overexpression could be reversed by the m6A inhibitor, which indicated that YTHDC1 enhanced FOXM1 expression depending on m6A modification. Therefore, we concluded that the YTHDC1-m6A modification/FOXM1/CENPA axis plays an important role in TNBC progression and glycolysis.

Distinct functions of CAR-T cells possessing a dectin-1 intracellular signaling domain.

Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacies in treating hematopoietic malignancies, but not in the solid tumors. Incorporating costimulatory signaling domains, such as ICOS or 4-1BB, can positively influence CAR-T cell functions and then the immune responses. These CAR-engineered T cells have showed their enhanced persistence and effector functions with improved antitumor activities, and provided a new approach for the treatment of solid tumors. Here, we designed novel 2nd generation CARs with a costimulatory signaling molecule, dectin-1. The impacts of dectin-1 signaling domain on CAR-T cells were evaluated in vitro and in vivo. Our data show that in vitro cytokine secretions by HER2 or CD19 specific CAR-T cells increase significantly via incorporating this dectin-1 signaling domain. Additional properties of these novel CAR-T cells are affected by this costimulatory domain. Compared with a popular reference (i.e., anti-HER2 CAR-T cells with 4-1BB), in vitro T cell functions and in vivo antitumor activity of the dectin-1 engineered CAR-T cells are similar to the 4-1BB based, and both are discrete to the mock T cells. Furthermore, we found that the CAR-T cells with dectin-1 show distinct phenotype and exhaustion marker expression. These collective results suggest that the incorporation of this new signaling domain, dectin-1, into the CARs may provide the clinical potential of the CAR-T cells through this signaling domain in treating solid tumors.

The Hippo Effector Transcriptional Coactivator with PDZ-Binding Motif Cooperates with Oncogenic ß-Catenin to Induce Hepatoblastoma Development in Mice and Humans.

Hepatoblastoma (HB) is the most common pediatric liver tumor. Though Wnt/ß-catenin and Hippo cascades are implicated in HB development, studies on crosstalk between ß-catenin and Hippo downstream effector transcriptional coactivator with PDZ-binding motif (TAZ) in HB are lacking. Expression levels of TAZ and ß-catenin in human HB specimens were assessed by immunohistochemistry. Functional interplay between TAZ and ß-catenin was determined by overexpression of an activated form of TAZ (TAZS89A), either alone or combined with an oncogenic form of ß-catenin (ΔN90-ß-catenin), in mouse liver via hydrodynamic transfection. Activation of TAZ often co-occurred with that of ß-catenin in clinical specimens. Although the overexpression of TAZS89A alone did not induce hepatocarcinogenesis, concomitant overexpression of TAZS89A and ΔN90-ß-catenin triggered the development of HB lesions exhibiting both epithelial and mesenchymal features. Mechanistically, TAZ/ß-catenin-driven HB development required TAZ interaction with transcriptional enhanced associate domain factors. Blockade of the Notch cascade did not inhibit TAZ/ß-catenin-dependent HB formation in mice but suppressed the mesenchymal phenotype. Neither Yes-associated protein nor heat shock factor 1 depletion affected HB development in TAZ/ß-catenin mice. In human HB cell lines, silencing of TAZ resulted in decreased cell growth, which was further reduced when TAZ knockdown was associated with suppression of either ß-catenin or Yes-associated protein. Overall, our study identified TAZ as a crucial oncogene in HB development and progression.

Concurrent chemoradiotherapy with/without induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: Long-term results of phase 3 randomized controlled trial.

To report long-term results of a randomized controlled trial that compared cisplatin/fluorouracil/docetaxel (TPF) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC). Patients with stage III-IVB (except T3-4 N0) NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239). IC included three cycles of docetaxel (60 mg/m2 d1), cisplatin (60 mg/m2 d1), and fluorouracil (600 mg/m2 /d civ d1-5) every 3 weeks. Patients from both groups received intensity-modulated radiotherapy concurrently with three cycles of 100 mg/m2 cisplatin every 3 weeks. After a median follow-up of 71.5 months, the IC plus CCRT group showed significantly better 5-year failure-free survival (FFS, 77.4% vs. 66.4%, p = 0.019), overall survival (OS, 85.6% vs. 77.7%, p = 0.042), distant failure-free survival (88% vs. 79.8%, p = 0.030), and locoregional failure-free survival (90.7% vs. 83.8%, p = 0.044) compared to the CCRT alone group. Post hoc subgroup analyses revealed that beneficial effects on FFS were primarily observed in patients with N1, stage IVA, pretreatment lactate dehydrogenase ≥170 U/l, or pretreatment plasma Epstein-Barr virus DNA ≥6000 copies/mL. Two nomograms were further developed to predict the potential FFS and OS benefit of TPF IC. The incidence of grade 3 or 4 late toxicities was 8.8% (21/239) in the IC plus CCRT group and 9.2% (22/238) in the CCRT alone group. Long-term follow-up confirmed that TPF IC plus CCRT significantly improved survival in locoregionally advanced NPC with no marked increase in late toxicities and could be an option of treatment for these patients.

Post-radiotherapy PET/CT for predicting treatment outcomes in head and neck cancer after postoperative radiotherapy.

PURPOSE: The purpose of this study was to retrospectively review the role of post-treatment (post-tx) FDG-PET/CT scans in patients receiving postoperative intensity-modulated radiotherapy (IMRT) for head and neck squamous cell carcinomas (HNSCC). MATERIALS AND METHODS: Eighty-two patients with HNSCC treated with surgery and postoperative IMRT with or without chemotherapy from October 15, 2008 to December 31, 2014 that had post-tx PET/CT within 6 months of completing IMRT were included. PET/CT was considered positive based on multi-disciplinary review integrating clinical information. Survival analysis was performed using the Kaplan-Meier method. Categorical and continuous predictors of positive post-tx PET/CT were evaluated using Fisher's exact test and logistic regression, respectively. Predictors for survival outcomes were evaluated with log-rank testing. A p ≤ 0.05 was considered statistically significant. RESULTS: Median follow-up was 3.88 years. For all patients, 3-year overall survival (OS) and recurrence-free survival (RFS) were 71.8% and 61.3%, respectively. Patients with positive post-tx PET/CT had worse OS compared to those with negative post-tx PET/CT (log rank p < 0.001). For patients with positive post-tx PET/CT, 3-year OS was 11.2% compared to 89.9% for patients with negative post-tx PET/CT. The positive predictive value (PPV) of PET/CT was 100% for local recurrence (LR), regional recurrence (RR) and distant metastasis (DM). The negative predictive values (NPV) for LR, RR and DM were 89.0%, 89.2%, and 85.9%, respectively. Perineural invasion (p = 0.009), p16 status (p = 0.009), non-oropharyngeal primary site (p = 0.002), and the use of chemotherapy (p = 0.01) were independent predictors of positive PET/CT. CONCLUSIONS: Post-tx PET/CT after postoperative radiation is prognostic for survival outcomes. The PPV of post-tx PET for recurrence was excellent, allowing for early detection of recurrent disease. Post-tx PET/CT should be considered after postoperative radiation.

Circulating tumor cells with karyotyping as a novel biomarker for diagnosis and treatment of nasopharyngeal carcinoma.

BACKGROUND: Circulating tumor cells (CTCs) have been considered great clinical significance in various cancers. However, it remains unknown that how is the role of CTCs in patients with nasopharyngeal carcinoma (NPC). We investigated the value of CTCs enumeration and karyotyping in NPC. METHODS: In the present study, we applied integrated subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) automatic testing system to detect and characterize CTCs of NPC patients. Enumeration and aneuploidy of chromosome 8 in CTCs were examined in various stages of patients with NPC. The changes of CTCs number and karyotyping post to chemotherapy were investigated in NPC. RESULTS: CTCs were detected by SE-iFISH in 46 out of 50 pre-treatment NPC patients, and performed a positive rate of 92.0%. No significant association was found between disease staging and CTCs detection rate. CTCs number constantly increased with TNM stage rising (from stage II to stage IV) no matter in newly diagnosed patients without distant metastasis (M0) and relapsed or distant metastatic patients. The number of CTCs decreased after treatment in patients with partial response (PR), while increased in patients with progressive disease or stable disease (PD/SD). More interestingly, CTCs karyotyping indicated that aneuploidy of chromosome 8 in CTCs was dramatically related to chemotherapeutic efficacy in NPC. Positive correlation was found between CTCs count and plasma EBV DNA level of NPC patients. CONCLUSIONS: CTCs could be detected in various stages of NPC patients using SE-iFISH. CTCs number could indicate the severity degree of disease in NPC. Dynamically monitoring the variations in CTCs number may predict chemotherapy efficacy during treatment. CTCs karyotyping is related to the sensibility of chemotherapy and drug resistance, and karyotyping of CTCs might predict therapeutic efficacy and evaluate chemo-resistance in NPC. CTCs could be used as a monitoring indicator in the fields of treatment, diagnosis and follow-up of NPC.

Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial.

BACKGROUND: The value of adding cisplatin, fluorouracil, and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to compare TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in a suitably powered trial. METHODS: We did an open-label, phase 3, multicentre, randomised controlled trial at ten institutions in China. Patients with previously untreated, stage III-IVB (except T3-4N0) nasopharyngeal carcinoma, aged 18-59 years without severe comorbidities were enrolled. Eligible patients were randomly assigned (1:1) to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone (three cycles of 100 mg/m2 cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy). Induction chemotherapy was three cycles of intravenous docetaxel (60 mg/m2 on day 1), intravenous cisplatin (60 mg/m2 on day 1), and continuous intravenous fluorouracil (600 mg/m2 per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy. Randomisation was by a computer-generated random number code with a block size of four, stratified by treatment centre and disease stage (III or IV). Treatment allocation was not masked. The primary endpoint was failure-free survival calculated from randomisation to locoregional failure, distant failure, or death from any cause; required sample size was 476 patients (238 per group). We did efficacy analyses in our intention-to-treat population. The follow-up is ongoing; in this report, we present the 3-year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov, number NCT01245959. FINDINGS: Between March 1, 2011, and Aug 22, 2013, 241 patients were assigned to induction chemotherapy plus concurrent chemoradiotherapy and 239 to concurrent chemoradiotherapy alone. After a median follow-up of 45 months (IQR 38-49), 3-year failure-free survival was 80% (95% CI 75-85) in the induction chemotherapy plus concurrent chemoradiotherapy group and 72% (66-78) in the concurrent chemoradiotherapy alone group (hazard ratio 0·68, 95% CI 0·48-0·97; p=0·034). The most common grade 3 or 4 adverse events during treatment in the 239 patients in the induction chemotherapy plus concurrent chemoradiotherapy group versus the 238 patients in concurrent chemoradiotherapy alone group were neutropenia (101 [42%] vs 17 [7%]), leucopenia (98 [41%] vs 41 [17%]), and stomatitis (98 [41%] vs 84 [35%]). INTERPRETATION: Addition of TPF induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival in locoregionally advanced nasopharyngeal carcinoma with acceptable toxicity. Long-term follow-up is required to determine long-term efficacy and toxicities. FUNDING: Shenzhen Main Luck Pharmaceuticals Inc, Sun Yat-sen University Clinical Research 5010 Program (2007037), National Science and Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10), Health & Medical Collaborative Innovation Project of Guangzhou City (201400000001), Planned Science and Technology Project of Guangdong Province (2013B020400004), and The National Key Research and Development Program of China (2016YFC0902000).

Increase in IkappaB kinase alpha expression suppresses the tumor progression and improves the prognosis for nasopharyngeal carcinoma.

Recent studies have suggested that the action of IkappaB kinase alpha (IKKα) as a tumor suppressor is crucial in the development of skin carcinoma, but its role in nasopharyngeal carcinoma (NPC) remains unknown. We examined the IKKα expression in specimens from 157 NPC patients by immunohistochemistry and analyzed the effect of IKKα on prognosis. The functional significance of IKKα expression in NPC cell lines was investigated by IKKα overexpression or downregulation in in vitro studies. The in vitro assays revealed that the IKKα expression was negatively correlated with the invasiveness, migration, and angiogenesis of NPC cells. Overexpression or downregulation of IKKα could significantly repress or enhance the above characteristics, respectively, and these effects were independent of IKKα kinase or EBNA1. In 157 NPC cases, IKKα was differentially expressed in NPC tissues. High expression of IKKα was associated significantly with a high disease-free survival (DFS; P = 0.002) or overall survival (OS; P = 0.014). Multivariate analyses showed that the IKKα expression was an independent risk factor for DFS (HR, 2.302; P = 0.011) and OS (HR, 3.578; P = 0.006). Our findings indicated that IKKα plays a crucial role as a tumor suppressor that suppresses the invasion, metastasis, and angiogenesis of NPC cells in vitro and correlates with the survival in NPC patients. Therefore, IKKα is not only a novel independent prognostic indicator in NPC, but also targeting IKKα expression may provide a potential therapeutic strategy for NPC.

Chemokine CXCL16 expression suppresses migration and invasiveness and induces apoptosis in breast cancer cells.

BACKGROUND: Increasing evidence argues that soluble CXCL16 promotes proliferation, migration, and invasion of cancer cells in vitro. However, the role of transmembrane or cellular CXCL16 in cancer remains relatively unknown. In this study, we determine the function of cellular CXCL16 as tumor suppressor in breast cancer cells. METHODS: Expression of cellular CXCL16 in breast cancer cell lines was determined at both RNA and protein levels. In vitro and in vivo studies that overexpressed or downregulated CXCL16 were conducted in breast cancer cells. RESULTS: We report differential expression of cellular CXCL16 in breast cancer cell lines that was negatively correlated with cell invasiveness and migration. Overexpression of CXCL16 in MDA-MB-231 cells led to a decrease in cell invasion and migration and induced apoptosis of the cells; downregulation of CXCL16 in MCF-7 cells increased cell migration and invasiveness. Consistent with the in vitro data, CXCL16 overexpression inhibited tumorigenesis in vivo. CONCLUSIONS: Cellular CXCL16 suppresses invasion and metastasis of breast cancer cells in vitro and inhibits tumorigenesis in vivo. Targeting of cellular CXCL16 expression is a potential therapeutic strategy for breast cancer.

[Expression of Chemokine receptor CXCR6 and its significance in breast cancer cell lines].

OBJECTIVE: To detect the expression of Chemokine receptor CXCR6 in invasive breast cancer cell lines and normal mammary epithelial cell line, and assess the relationship between CXCR6 expression and malignant behavior of breast cancer cells. METHODS: Expression level of CXCR6 in different invasive breast cancer cell lines (SK-BR-3, MCF-7, MDA-MB-231) and normal mammary epithelial cell line (MCF-10A)was detected by real time reverse transcription-polymerase chain reaction (real time-PCR) and Western blot. Lentivirus was employed to interfere CXCR6 expression in MDA-MB-231. MTT assay and transwell chamber were used to study proliferative and invasive ability of those cells respectively. Vascular enothelial growth factor (VEGF) expression was detected to study the role of CXCR6 in angiogenesis. RESULTS: At both mRNA level and protein level, normal mammary epithelial cell line MCF-10A showed the weakest CXCR6 expression. The breast cancer cell lines expressed CXCR6 in different levels, the expression level of CXCR6 in highly invasive cell line MDA-MB-231 was significantly higher than that in two low-invasive cell lines SK-BR-3 and MCF-7 (P < 0.05). Silencing CXCR6 gene by Lentivirus-mediated RNA interference in MDA-MB-231 inhibited its proliferation ability, invasion ability and angiogenesis ability in vitro (P < 0.05). CONCLUSION: Different invasive breast cancer cell lines express CXCR6 at different levels, positively correlated with its invasive ability.

Effects of tislelizumab on health-related quality of life in patients with recurrent or metastatic nasopharyngeal cancer.

BACKGROUND: This study evaluated health-related quality of life (HRQoL) in the RATIONALE-309 (NCT03924986) intent-to-treat (ITT) population and in a subgroup of patients with liver metastases. METHODS: Patients were randomized 1:1 to tislelizumab + chemotherapy or placebo + chemotherapy. As the secondary endpoint, HRQoL was evaluated using seven selected scores from the EORTC QLQ-C30 and QLQ Head and Neck Cancer module (QLQ-H&N35). RESULTS: Of 263 randomized patients in the ITT population (tislelizumab + chemotherapy n = 131, placebo + chemotherapy n = 132), 43% had liver metastases (tislelizumab + chemotherapy n = 56; placebo + chemotherapy n = 57). No differences in change in selected scores on the QLQ-C30 from baseline to cycle 4 or cycle 8 were observed for the ITT or liver metastases subgroup. No differences in selected QLQ-H&N35 scores were observed between the arms from baseline to cycle 4. In the ITT population and the liver metastases subgroup, a greater reduction from baseline to cycle 8 was observed in the tislelizumab + chemotherapy arm than the placebo + chemotherapy arm in QLQ-H&N35 pain score. At cycle 8 in the liver metastases subgroup, the tislelizumab + chemotherapy arm experienced greater improvement in the QLQ-H&N35 senses problems score than the placebo + chemotherapy arm. Differences in time to deterioration between arms were not observed. CONCLUSIONS: The current findings, along with improved survival and favorable safety, suggests that tislelizumab + chemotherapy represents a potential first-line treatment for recurrent or metastatic nasopharyngeal cancer.

Evaluation of the sensitivity of two 3D diode array dosimetry systems to setup error for quality assurance (QA) of volumetric-modulated arc therapy (VMAT).

The purpose of this study is to evaluate the sensitivities of 3D diode arrays to setup error for patient-specific quality assurance (QA) of volumetric-modulated arc therapy (VMAT). Translational setup errors of ± 1, ± 2, and ± 3 mm in the RL, SI, and AP directions and rotational setup errors of ± 1° and ± 2° in the pitch, roll, and yaw directions were set up in two phantom systems, ArcCHECK and Delta4, with VMAT plans for 11 patients. Cone-beam computed tomography (CBCT) followed by automatic correction using a HexaPOD 6D treatment couch ensured the position accuracy. Dose distributions of the two phantoms were compared in order to evaluate the agreement between calculated and measured values by using γ analysis with 3%/3 mm, 3%/2 mm, and 2%/2 mm criteria. To determine the impact on setup error for VMAT QA, we evaluated the sensitivity of results acquired by both 3D diode array systems to setup errors in translation and rotation. For the VMAT QA of all patients, the pass rate with the 3%/3 mm criteria exceeded 95% using either phantom. For setup errors of 3 mm and 2°, respectively, the pass rates with the 3%/3mm criteria decreased by a maximum of 14.0% and 23.5% using ArcCHECK, and 14.4% and 5.0% using Delta4. Both systems are sensitive to setup error, and do not have mechanisms to account for setup errors in the software. The sensitivity of both VMAT QA systems was strongly dependent on the patient-specific plan. The sensitivity of ArcCHECK to the rotational error was higher than that of Delta4. In order to achieve less than 3% mean pass rate reduction of VMAT plan QA with the 3%/3 mm criteria, a setup accuracy of 2 mm/1° and 2 mm/2° is required for ArcCheck and Delta4 devices, respectively. The cumulative effect of the combined 2 mm translational and 1° rotational errors caused 3.8% and 2.4% mean pass rates reduction with 3%/3 mm criteria, respectively, for ArcCHECK and Delta4 systems. For QA of VMAT plans for nasopharyngeal cancer (NPC) using the ArcCHECK system, the setup should be more accurate.

[Expression of non-secretory CXCL16 and its impact on biological characteristics in breast cancer cell lines].

OBJECTIVE: To detect the expression of non-secretory CXCL16 and its impact on malignant biological behaviors in breast cancer cell lines. METHODS: RT-PCR was carried out to examine the expression of CXCL16 mRNA in breast cancer cell lines with different aggressiveness SK-BR-3, MCF-7, MDA-MB-231, MDA-MB-435S and human mammary normal epithelial cell; MCF-10A. The eukaryotic expression plasmid of CXCL16 was transfected into MDA-MB-231 cells and overexpression of CXCL16 was confirmed by Real time PCR and Western blot. Boyden Chamber assay was used to determine cell migration and invasion, while MTT assay was performed to determine cell proliferation. RESULTS: Among four breast cancer cell lines, CXCL16 mRNA was highly expressed in MCF-7, lowly expressed in MDA-MB-231, while MCF-10A faintly expressed CXCL16. Overexpression of CXCL16 led to a decrease in cell migration, invasion but not proliferation in MDA-MB-231 cells. CONCLUSION: Expression of non-secretory CXCL16 is associated with aggressiveness of breast cancer cell lines, and CXCL16 expression inhibits cell migration and invasion in vitro.

Prognostic value of a microRNA signature in nasopharyngeal carcinoma: a microRNA expression analysis.

BACKGROUND: MicroRNAs (miRNAs) can be used as prognostic biomarkers in many types of cancer. We aimed to identify miRNAs that were prognostic in patients with nasopharyngeal carcinoma. METHODS: We retrospectively analysed miRNA expression profiles in 312 paraffin-embedded specimens of nasopharyngeal carcinoma from Sun Yat-sen University Cancer Center (Guangzhou, China) and 18 specimens of non-cancer nasopharyngitis. Using an 873 probe microarray, we assessed associations between miRNA signatures and clinical outcome in a randomly selected 156 samples (training set) and validated findings in the remaining 156 samples (internal validation set). We confirmed the miRNAs signature using quantitative RT-PCR analysis in 156 samples from a second randomisation of the 312 samples, and validated the miRNA signature in 153 samples from the West China Hospital of Sichuan University in Chengdu, China (independent set). We used the Kaplan-Meier method and log-rank tests to estimate correlations of the miRNA signature with disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival. FINDINGS: 41 miRNAs were differentially expressed between nasopharyngeal carcinoma and non-cancer nasopharyngitis tissues. A signature of five miRNAs, each significantly associated with DFS, was identified in the training set. We calculated a risk score from the signature and classified patients as high risk or low risk. Compared with patients with low-risk scores, patients with high risk scores in the training set had shorter DFS (hazard ratio [HR] 2·73, 95% CI 1·46-5·11; p=0·0019), DMFS (3·48, 1·57-7·75; p=0·0020), and overall survival (2·48, 1·24-4·96; p=0·010). We noted equivalent findings in the internal validation set for DFS (2·47, 1·32-4·61; p=0·0052), DMFS (2·28, 1·09-4·80; p=0·030), and overall survival (2·87, 1·38-5·96; p=0·0051) and in the independent set for DFS (3·16, 1·65-6·04; p=0·0011), DMFS (2·39, 1·05-5·42; p=0·037), and overall survival (3·07, 1·34-7·01; p=0·0082). The five-miRNA signature was an independent prognostic factor. A combination of this signature and TNM stage had better prognostic value than did TNM stage alone in the training set (area under receiver operating characteristics 0·68 [95% CI 0·60-0·76] vs 0·60 [0·52-0·67]; p=0·013), the internal validation set (0·70 [0·61-0·78] vs 0·61 [0·54-0·68]; p=0·012), and the independent set (0·70 [0·62-0·78] vs 0·63 [0·56-0·69]; p=0·032). INTERPRETATION: Identification of patients with the five-miRNA signature might add prognostic value to the TNM staging system and inform treatment decisions for patients at high risk of progression. FUNDING: Science Foundation of Chinese Ministry of Health, National Natural Science Foundation of China, Pearl River Scholar Funded Scheme, Guangdong Key Scientific and Technological Innovation Program, Guangdong Natural Science Foundation, Fundamental Research Funds for the Central Universities.

CDK4/6 Inhibitors in the First-Line Treatment of Postmenopausal Women with HR+/HER2- Advanced or Metastatic Breast Cancer: An Updated Network Meta-Analysis and Cost-Effectiveness Analysis.

(1) Background: This study aimed to conduct a NMA and CEA combined study to compare the effectiveness and cost-effectiveness of different CDK4/6 inhibitors (Abem, Palbo, and Ribo) plus NSAI with placebo plus NSAI in the first-line treatment of postmenopausal women with HR+/HER2- ABC from the perspective of payers in China. (2) Methods: Studies which evaluated CDK4/6 inhibitors plus NSAI for HR+/HER2- ABC were searched. A Bayesian NMA was carried out and the main outcomes were the hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS). The costs and efficacy of first-line therapies for HR+/HER2- ABC were evaluated using the Markov model. The main outcomes in the CEA were incremental cost-utility ratios (ICURs), incremental monetary benefit (INMB), and incremental net-health benefit (INHB). The robustness of the model was assessed by one-way, three-way, and probabilistic sensitivity analyses. Then, we further simulated the impact of different prices of CDK4/6 inhibitors on the results. (3) Results: Seven studies involving 5347 patients were included in the NMA. The three first-line CDK4/6 inhibitors plus NSAI groups provided significant PFS and OS superiority to NSAI alone. Abem + NSAI represented a significant statistical advantage onPFS (HR 0.74, 95% CI 0.61-0.90, p = 0.009) and indicated a trend of being the best OS benefit compared to the placebo + NSAI group (HR 0.89, 95% CI 0.72-1.08). The Abem + NSAI, Palbo + NSAI, and Ribo + NSAI groups resulted in additional costs of $12,602, $20,391, and $81,258, with additional effects of 0.38, 0.31, and 0.30 QALYs, respectively, leading to an ICUR of $33,163/QALY, $65,777/QALY, and $270,860/QALY. Additional pairwise comparisons showed that Abem + NSAI was the only cost-effective option in three CDK4/6 inhibitors plus NSAI groups at a willingness-to-pay (WTP) of $38,029/QALY. The sensitivity analyses showed that the proportion of receiving subsequent CDK4/6 inhibitors and the cost of Abem significantly influenced the results of Abem + NSAI compared with placebo + NSAI. (4) Conclusion: From the perspective of Chinese payers, Abem + NSAI was a cost-effective treatment option compared with placebo + NSAI at the WTP of $38,029/QALY, since only the ICUR of $33,163/QALY of Abem + NSAI was lower than the WTP of $38,029/QALY in China (2022). The Palbo + NSAI and Ribo + NSAI groups were not cost-effective unless drug prices were adjusted to 50% or 10% of current prices ($320.67 per cycle or $264.60 per cycle). (5) Others: We have prospectively registered the study with the PROSPERO, and the PROSPERO registration number is CRD42023399342.

First-line immunotherapy combinations for recurrent or metastatic nasopharyngeal carcinoma: An updated network meta-analysis and cost-effectiveness analysis.

OBJECTIVES: Recently updated results of randomized clinical trials (RCTs) have confirmed that toripalimab, camrelizumab, and tislelizumab plus chemotherapy (TOGP, CAGP, and TIGP) significantly prolonged survival compared to placebo plus chemotherapy (PLGP) in the first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). However, the high cost of immunotherapies imposes a huge financial burden on patients and health care systems. MATERIALS AND METHODS: RCTs estimating immunotherapies for R/M-NPC were searched. A Bayesian network meta-analysis (NMA) was carried out; the main outcomes were hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS). The cost and efficacy of four first-line therapies were evaluated using the Markov model. The main outcome in the cost-effectiveness analysis (CEA) was incremental cost-utility ratios (ICURs). The model robustness was assessed by one-way, three-way, and probabilistic sensitivity analyses. RESULTS: Three RCTs (JUPITER-02, CAPTAIN-1st, and RATIONALE-309) involving 815 patients were included in the NMA. Compared with PLGP, chemo-immunotherapies have significantly longer PFS and OS. Compared to the PLGP group, TOGP, CAGP, and TIGP groups resulted in additional costs of $48 339, $22 900, and $23 162, with additional 1.89, 0.73, and 0.960 QALYs, respectively, leading to the ICURs of $25 576/QALY, $31 370/QALY, and $31 729/QALY. Pairwise comparisons showed TOGP was the most cost-effective option among chemo-immunotherapy groups. CONCLUSION: From the Chinese payers' perspective, first-line immunotherapy combination therapies provided significant survival and cost-effectiveness superiority over chemotherapy alone for patients with R/M-NPC at the WTP of $38 029/QALY. Among the three chemo-immunotherapy groups, TOGP was the most cost-effective option.

Network and pathway-based analysis of genes associated with esophageal squamous cell carcinoma.

Background: Although diagnostic methods and treatments have improved over the last few years, the 5-year survival rate of esophageal squamous cell carcinoma (ESCC) patients remains generally poor. The development of high-throughput technology has facilitated great achievements in localization of ESCC-related genes. To take a further step toward a thorough understanding of ESCC at a molecular level, the potential pathogenesis of ESCC needs to be deciphered. Methods: The interaction of ESCC-related genes was explored by collecting genes associated with ESCC and then performing gene enrichment assays, pathway enrichment assays, pathway crosstalk analysis, and extraction of ESCC-specific subnetwork to describe the relevant biochemical processes. Results: Through Gene Ontology (GO) enrichment analysis, many molecular functions related to response to chemical, cellular response to stimulus, and cell proliferation were found to be significantly enriched in ESCC-related genes. The results of pathway and pathway crosstalk analysis showed that pathways associated with multiple malignant tumors, the immune system, and metabolic processes were significantly enriched in ESCC-related genes. Through the analysis of specific subnetworks, we obtained some novel ESCC-related potential genes, such as MUC13, GSTO1, FIN, GRB2, CDC25C, and others. Conclusions: The molecular mechanism of ESCC is extremely complex. Some inducing factors change the expression status of many genes. The abnormal expression of genes mediates the biological processes involved in immunity and metabolism, apoptosis, and cell proliferation, leading to the occurrence of tumors. The genes MUC13, RYK, and FIN may be potential prognostic indicators of ESCC; GRB2 and CDC25C may be potential targets of ESCC in proliferation. Our work may provide valuable information for further understanding the molecular mechanisms for the development of ESCC.

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.

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.