Efficacy and safety of anlotinib combined with the STUPP regimen in patients with newly diagnosed glioblastoma: a multicenter, single-arm, phase II trial.

OBJECTIVE: Glioblastomas are highly vascularized malignant tumors. We determined the efficacy and safety of the anti-angiogenic multi-kinase inhibitor, anlotinib, for a newly diagnosed glioblastoma. METHODS: This multicenter, single-arm trial (NCT04119674) enrolled 33 treatment-naïve patients with histologically proven glioblastomas between March 2019 and November 2020. Patients underwent treatment with the standard STUPP regimen [fractionated focal irradiation in daily fractions of 1.8-2 Gy given 5 d/w × 6 w (total = 54-60 Gy)] or radiotherapy plus continuous daily temozolomide (TMZ) (75 mg/m2 of body surface area/d, 7 d/w from the first to the last day of radiotherapy), followed by 6 cycles of adjuvant TMZ (150-200 mg/m2 × 5 d during each 28-d cycle) plus anlotinib (8 mg/d on d 1-14 of each 3-w cycle for 2 cycles during concomitant chemoradiotherapy, 8 maximal cycles as adjuvant therapy, followed by maintenance at 8 mg/d. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AEs). RESULTS: Thirty-three patients received the planned treatment. The median PFS was 10.9 months (95% CI, 9.9-18.7 months) and the 12-month PFS rate was 48.5%. The median OS was 17.4 months (95% CI, 14.5-21.1 months) and the 12-month OS rate was 81.8%. The most common AEs included hypertriglyceridemia [58% (n = 19)], hypoalbuminemia [46% (n = 15)], and hypercholesterolemia [46% (n = 15)] during concurrent chemoradiotherapy and leukopenia [73% (n = 24)], hypertriglyceridemia [67% (n = 22)], and neutropenia [52% (n = 17)] during adjuvant therapy. Five patients discontinued treatment due to AEs. HEG1 (HR, 5.6; 95% CI, 1.3-23.7; P = 0.021) and RP1L1 alterations (HR, 11.1; 95% CI, 2.2-57.2; P = 0.004) were associated with a significantly shorter PFS. CONCLUSIONS: Anlotinib plus the STUPP regimen has promising anti-tumor activity against glioblastoma and manageable toxicity. HEG1 and RP1L1 alterations might be novel predictive biomarkers of the response to anlotinib.

The map of bone metastasis in nasopharyngeal carcinoma: A real-world study.

OBJECTIVES: The aim of this study was to compare the metastatic patterns of synchronous bone metastasis (SBM) and metachronous bone metastasis (MBM) in nasopharyngeal carcinoma (NPC). METHODS: This study included bone metastases in NPC patients from 2005 to 2016 in a Chinese hospital. Cohort 1 was collected from 2005 to 2010 for discovery, and Cohort 2 from 2011 to 2016 for validation. The chi-squared test, Wilcoxon rank sum test, and Kaplan-Meier technique were used to compare site, time, and survival between cohorts 1 and 2. Prognostic factors were analyzed using univariate or multivariate Cox regression. RESULTS: Cohort 1 had 112 individuals with SBM and 394 with MBM, and cohort 2 had 328 with SBM and 307 with MBM. The thoracic vertebra was the most frequently affected site of metastasis. Patients with SBM more often had metastasis to the cervical vertebrae compared with patients with MBM (34.5% vs. 22.3%, p < 0.05). Patients with SBM had better overall survival (42.2 months, 95% CI: 33.9-50.7) than patients with MBM (24.9 months, 95% CI: 22.2-28.7). Age at bone metastasis detection, metastasis to other organs, and more bone metastasis locations were associated with worse prognosis. The majority of MBMs occurred at 7 to 18 months after NPC diagnosis. CONCLUSION: Radiotherapy does not modify the metastatic patterns of NPC bone metastases. Patients with SBM tend to have metastasis to the cervical vertebra, which is close to the nasopharynx. Paying more attention to bone metastases during follow-up in the first 2 years after an NPC diagnosis.

Metabolic engineering of Halomonas campaniensis strain XH26 to remove competing pathways to enhance ectoine production.

Ectoine has gained considerable attention as a high-value chemical with significant application potential and market demand. This study aimed to increase ectoine yields by blocking the metabolic shunt pathway of L-aspartate-4-semialdehyde, the precursor substrate in ectoine synthesis. The homoserine dehydrogenase encoded by hom in H. campaniensis strain XH26 is responsible for the metabolic shunt of L-aspartate-4-semialdehyde to glycine. CRISPR/Cas9 technology was used to seamlessly knockout hom, blocking the metabolic shunt pathway to increase ectoine yields. The ectoine yield of XH26/Δhom was 351.13 mg (g CDW)-1 after 48 h of incubation in 500 mL shake flasks using optimal medium with 1.5 mol L-1 NaCl, which was significantly higher than the 239.18 mg (g CDW)-1 of the wild-type strain. Additionally, the absence of the ectoine metabolic shunt pathway affects betaine synthesis, and thus the betaine yields of XH26/Δhom was 19.98 mg (g CDW)-1, considerably lower than the 69.58 mg (g CDW)-1 of the wild-type strain. Batch fermentation parameters were optimized, and the wild-type strain and XH26/Δhom were fermented in 3 L fermenters, resulting in a high ectoine yield of 587.09 mg (g CDW)-1 for the defective strain, which was significantly greater than the ectoine yield of 385.03 mg (g CDW)-1 of the wild-type strain. This study showed that blocking the metabolic shunt of synthetic substrates effectively increases ectoine production, and a reduction in the competitively compatible solute betaine appears to promote increased ectoine synthesis.

Comparative genomic analysis of Halomonas campaniensis wild-type and ultraviolet radiation-mutated strains reveal genomic differences associated with increased ectoine production.

Ectoine is a natural amino acid derivative and one of the most widely used compatible solutes produced by Halomonas species that affects both cellular growth and osmotic equilibrium. The positive effects of UV mutagenesis on both biomass and ectoine content production in ectoine-producing strains have yet to be reported. In this study, the wild-type H. campaniensis strain XH26 (CCTCCM2019776) was subjected to UV mutagenesis to increase ectoine production. Eight rounds of mutagenesis were used to generate mutated XH26 strains with different UV-irradiation exposure times. Ectoine extract concentrations were then evaluated among all strains using high-performance liquid chromatography analysis, alongside whole genome sequencing with the PacBio RS II platform and comparison of the wild-type strain XH26 and the mutant strain G8-52 genomes. The mutant strain G8-52 (CCTCCM2019777) exhibited the highest cell growth rate and ectoine yields among mutated strains in comparison with strain XH26. Further, ectoine levels in the aforementioned strain significantly increased to 1.51 ± 0.01 g L-1 (0.65 g g-1 of cell dry weight), representing a twofold increase compared to wild-type cells (0.51 ± 0.01 g L-1) when grown in culture medium for ectoine accumulation. Concomitantly, electron microscopy revealed that mutated strain G8-52 cells were obviously shorter than wild-type strain XH26 cells. Moreover, strain G8-52 produced a relatively stable ectoine yield (1.50 g L-1) after 40 days of continuous subculture. Comparative genomics analysis suggested that strain XH26 harbored 24 mutations, including 10 nucleotide insertions, 10 nucleotide deletions, and unique single nucleotide polymorphisms. Notably, the genes orf00723 and orf02403 (lipA) of the wild-type strain mutated to davT and gabD in strain G8-52 that encoded for 4-aminobutyrate-2-oxoglutarate transaminase and NAD-dependent succinate-semialdehyde dehydrogenase, respectively. Consequently, these genes may be involved in increased ectoine yields. These results suggest that continuous multiple rounds of UV mutation represent a successful strategy for increasing ectoine production, and that the mutant strain G8-52 is suitable for large-scale fermentation applications.

Characteristics and trends of globally registered glioma clinical trials in the past 16 years.

Background: Advancement in the treatment of glioma has been vacant since temozolomide has proved its therapeutic value in glioblastoma in 2005. Aim: To help investigators understand the landscape of glioma clinical research, we analyzed the characteristics and trends of globally registered glioma trials in the past decades. Methods: This is a cross-sectional analysis of glioma trials registered on ClinicalTrials.gov between January 2006 and December 2021. Characteristics regarding phase, enrollment number, study design and type, funding source, tumor site, pathology, patient status, age of population, trial purpose, and participating country were abstracted, and chronological shifts were analyzed. Results: There were 1531 registered glioma trials involved 58 participating countries. The trial purpose concerning surgery, radiotherapy, chemotherapy, targeted therapy, tumor-treating fields, immunotherapy, other antiglioma therapy and non-antiglioma research trial accounts for 3.5%, 6.5%, 9.5%, 28.9%, 2.0%, 16.4%, 12.5%, and 20.6%, respectively. In the past 16 years, the numbers of chemotherapy and targeted therapy trials declined; tumor-treating fields and immune checkpoint inhibitor application trials sprang at the latter half period; Immunotherapy, other antiglioma therapy and non-antiglioma research trials escalated (all above p trend < 0.005). The trend also showed the phased trials registered diminishingly and that the trials which focused on glioblastoma registered incrementally (those two p trend < 0.05). Among 784 drug therapy trials, it was included 45 cytotoxic drugs, 186 targeted drugs, 19 immune checkpoint inhibitors, 78 other drugs, and five immunomodulatory drugs. Two trials belonged to Bayesian adaptive randomized design. By the end of December 2021, 309 trials had publications. Only everolimus and tumor-treating fields exhibited meaningful survival benefit in specific glioma patients in phase 3 trials. Conclusion: Meaningful effective treatments regarding drugs or methods for glioma were difficult to be found. Bayesian adaptive platform trials may accelerate clinical research in glioma. Development of novel treatment modalities for glioma is still challenged.

Integrative Genomic and Transcriptomic Analysis of Primary Malignant Gliomas Revealed Different Patterns Between Grades and Somatic Mutations Related to Glioblastoma Prognosis.

Background: As reflected in the WHO classification of glioma since 2020, genomic information has been an important criterion in addition to histology for glioma classification. There is a significant intergrade difference as well as intragrade difference of survival probability among glioma patients. Except the molecular criteria used in the WHO classification, few studies have explored other genomic factors that may be underlying these survival differences, especially in Chinese populations. Here, we used integrative genomic approaches to characterize a Chinese glioma cohort to search for potential prognostic biomarkers. Methods: We recruited 46 Chinese patients with primary malignant glioma. All the patients were analyzed with whole-exome sequencing (WES) and 27 of them were analyzed with RNA-seq. We compared the molecular features between patients in different WHO grades. We classified the glioblastoma (GBM) patients into two groups (good vs poor survival) using six-month progression-free survival (PFS6) status and compared the genomic profiles between the two groups. Results: We found grade II and grade III patients cluster together (LGG) and they are different from GBM in unsupervised clustering analysis with RNA-seq data. Gene set enrichment analysis (GSEA) comparing GBM and the LGG group suggested that GBM had upregulation of multiple pathways related to genome integrity and immune cell infiltration. Further comparison of somatic mutations between the two groups revealed TOPAZ1 as a novel mutation associated with GBM and prevalence of CNV in multiple genes in GBM. Comparison between PFS6 good and poor GBM patients revealed six genes (TRIML2, ROCK1, PKD1, OBSCN, HECTD4, and ADCY7) were significantly mutated and two genes (NTRK1 and B2M) had more CNV alterations in the poor prognosis group. Conclusion: Taken together, our molecular data revealed that GBM patient showed distinct characteristics related to individual gene, chromosome integrity, and infiltrating immune cells compared to LGG (grade II/III) patients. We also identified few novel genes with SNV or CNV, which might be the potential markers for clinical outcome of GBM.

Rosai-Dorfman disease in the central nervous system with two isolated lesions originated from a single clone: a case report.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare, benign, idiopathic non-Langerhans cell histiocytosis. Cases of RDD in the CNS are extremely rare but lethal. RDD is thought to represent a reactive process. Recent studies proposed a subset of RDD cases that had a clonal nature. However, its clone origin is poorly understood. CASE PRESENTATION: We present a rare case of RDD in the CNS with two isolated lesions. These two lesions were removed successively after two operations. No seizure nor recurrence appears to date (2 years follow-up). Morphological and immunohistochemical profiles of these two lesions support the diagnosis of RDD. Based on the whole-exome sequencing (WES) data, we found the larger lesion has a higher tumor mutational burden (TMB) and more driver gene mutations than the smaller lesion. We also found seven common truncal mutations in these two lesions, raising the possibility that they might stem from the same ancestor clone. CONCLUSIONS: Overall, this is the first report about clonal evolution of RDD in the CNS with two isolated lesions. Our findings contribute to the pathology of RDD, and support the notion that a subset of cases with RDD is a clonal histiocytic disorder driven by genetic alterations.

Expression pattern of m6A regulators is significantly correlated with malignancy and antitumor immune response of breast cancer.

More than 24 regulators have been revealed to dynamically participant in N6-methyladenosine (m6A) RNA methylation, and play critical roles in tumorigenesis and development of cancers. However, their functional roles have not been comprehensively clarified in breast cancer. Here we systematically analyzed the RNA sequencing data of 24 main m6A RNA methylation regulators in 775 breast cancer patients from The Cancer Genome Atlas dataset. Consensus clustering of the 24 m6A regulators was carried out and identified two patient subgroups, RNA methylation 1/2 (RM1/2). RM1 demonstrated generally lower RNA methylation modification than that of RM2, and had significantly shorter overall survival. The hallmarks of PI3K/AKT signaling in cancer, KRAS signaling and angiogenesis were significantly enriched in RM1. Moreover, the association between m6A regulators and antitumor immune response was also investigated in this study and revealed that RM2 was associated with significantly higher expressions of HLA-A, higher numbers of tumor-infiltrating CD8+ T cells, helper T cells and activated NK cells, but lower expressions of PD-L1, PD-L2, TIM3, and CCR4 than RM1. In conclusion, the expression pattern of m6A regulators was significantly correlated with the malignancy, prognosis and antitumor immune response in breast cancer, which might serve as potential targets and biomarkers for immunotherapy.

Identification of a 15-pseudogene based prognostic signature for predicting survival and antitumor immune response in breast cancer.

Pseudogenes are noncoding RNAs that have been revealed to play critical roles in oncogenesis and tumor progression. However, their functional roles have not been comprehensively clarified in breast cancer. Here, we systematically analyzed the RNA sequencing data of 13931 pseudogenes in 775 breast cancer patients from The Cancer Genome Atlas dataset, and ultimately identified 15 prognostic pseudogenes by univariate Cox proportional hazard regression. A risk score model was constructed based on the prognostic pseudogenes via LASSO analysis and dichotomized patients into low- and high-risk subgroups. Patients in the high-risk group had a significantly shorter overall survival than those in the low-risk group. The prognostic value of these 15 pseudogenes and the risk score model were further validated in the European Genome-Phenome Archive dataset. Furthermore, we performed consensus clustering of the 15 prognostic pseudogenes and found that their expression pattern was significantly associated with tumor malignancy and host antitumor immune response, in terms of infiltrating immune cell compositions, antigen presenting genes expression, cytolytic activity and T-cell exhausted markers. This study indicated that these 15 prognostic pseudogenes were significantly correlated with tumor malignancy and host antitumor immune response in breast cancer, and might serve as potential targets for immunotherapy.

Genetic variants in GHR and PLCE1 genes are associated with susceptibility to esophageal cancer.

BACKGROUND: Esophageal cancer (EC) is the leading cause of cancer-related mortality worldwide. The underlying genetic risk factors remain unclear. The association between gene growth hormone receptor (GHR) and phospholipase C epsilon 1 (PLCE1) polymorphisms and the EC risk were identified in this study. METHODS: A total of 506 EC cases and 507 controls were included in this research. Two SNPs (rs6898743 of GHR and rs2274223 of PLCE1) were selected and genotyped. The associations between gene polymorphisms and the EC risk were assessed by logistic regression analysis. The databases RegulomeDB, GTEx, and UALCAN were used for functional annotations. RESULTS: In the allelic frequencies analysis, the rs6898743 of GHR was associated with decreased susceptibility of EC (OR = 0.83, 95% CI: 0.70-1.00, p = 0.049), while rs2274223 of PLCE1 was associated with increased 0.25-fold EC risk (OR = 1.25, 95% CI: 1.02-1.53, p = 0.037). The "GC" genotype of rs6898743 was associated with a 0.24-fold decreased risk of EC under co-dominant model (OR = 0.76, 95% CI: 0.58-0.99, p = 0.046), and the "GA" genotype of rs2274223 was associated with increased EC risk under co-dominant model (OR = 1.36, 95% CI: 1.04-1.77, p = 0.023). Using GTEx database, rs2274223 was found to be significant associated with increased PLCE1 expression (p = 4.1 × 10-7 ) in esophagus muscularis. The UALCAN database demonstrated that the GHR gene was under-expressed in esophageal cancer tissues (p = 0.017). CONCLUSION: The gene GHR and PLCE1 polymorphisms are associated with EC in the general population and the results need to be verified in future.

Efficacy and Safety of Locoregional Radiotherapy With Chemotherapy vs Chemotherapy Alone in De Novo Metastatic Nasopharyngeal Carcinoma: A Multicenter Phase 3 Randomized Clinical Trial.

Importance: The role of locoregional radiotherapy in patients with de novo metastatic nasopharyngeal carcinoma (mNPC) is unclear. Objective: To investigate the efficacy and safety of locoregional radiotherapy in de novo mNPC. Design, Setting, and Participants: Patients with biopsy-proven mNPC, who demonstrated complete or partial response (RECIST v1.1) following 3 cycles of cisplatin and fluorouracil chemotherapy, were enrolled. Eligible patients were randomly assigned (1:1) to receive either chemotherapy plus radiotherapy or chemotherapy alone. Overall, 126 of 173 patients screened were eligible to the study, and randomized to chemotherapy plus radiotherapy (n = 63) or chemotherapy alone (n = 63). Median (IQR) follow-up duration was 26.7 (17.2-33.5) months. Interventions: The chemotherapy regimens were fluorouracil continuous intravenous infusion at 5 g/m2 over 120 hours and 100 mg/m2 intravenous cisplatin on day 1, administered every 3 weeks for 6 cycles. Patients assigned to the chemotherapy plus radiotherapy group received intensity-modulated radiotherapy (IMRT) after chemotherapy. Main Outcomes and Measures: The primary end point of the study was overall survival (OS). The secondary end point was progression-free survival (PFS) and safety. Results: Overall, 126 patients were enrolled (105 men [83.3%] and 21 women [16.7%]; median [IQR] age, 46 [39-52] years). The 24-month OS was 76.4% (95% CI, 64.4%-88.4%) in the chemotherapy plus radiotherapy group, compared with 54.5% (95% CI, 41.0%-68.0%) in the chemotherapy-alone group. The study met its primary end point of improved OS (stratified hazard ratio [HR], 0.42; 95% CI, 0.23-0.77; P = .004) in favor of chemotherapy plus radiotherapy. Progression-free survival was also improved in the chemotherapy plus radiotherapy group compared with the chemotherapy-alone group (stratified HR, 0.36; 95% CI, 0.23-0.57). No significant differences in acute hematological or gastrointestinal toxic effects were observed between the treatment arms. The frequency of acute grade 3 or higher dermatitis, mucositis, and xerostomia was 8.1%, 33.9%, and 6.5%, respectively, in the chemotherapy plus radiotherapy group. The frequency of late severe grade 3 or higher hearing loss and trismus was 5.2% and 3.4%, respectively, in the chemotherapy plus radiotherapy group. Conclusions and Relevance: In this randomized clinical trial, radiotherapy added to chemotherapy significantly improved OS in chemotherapy-sensitive patients with mNPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02111460.

Genome-wide association study identifies genetic susceptibility loci and pathways of radiation-induced acute oral mucositis.

BACKGROUND: Radiation-induced oral mucositis (OM) is one of the most common acute complications for head and neck cancer. Severe OM is associated with radiation treatment breaks, which harms successful tumor management. Radiogenomics studies have indicated that genetic variants are associated with adverse effects of radiotherapy. METHODS: A large-scale genome-wide scan was performed in 1467 nasopharyngeal carcinoma patients, including 753 treated with 2D-CRT from Genetic Architecture of the Radiotherapy Toxicity and Prognosis (GARTP) cohort and 714 treated with IMRT (192 from the GARTP and 522 newly recruited). Subgroup analysis by radiotherapy technique was further performed in the top associations. We also performed physical and regulatory mapping of the risk loci and gene set enrichment analysis of the candidate target genes. RESULTS: We identified 50 associated genomic loci and 64 genes via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping and gene-based analysis, and 36 of these loci were replicated in subgroup analysis. Interestingly, one of the top loci located in TNKS, a gene relevant to radiation toxicity, was associated with increased OM risk with OR = 3.72 of the lead SNP rs117157809 (95% CI 2.10-6.57; P = 6.33 × 10-6). Gene set analyses showed that the 64 candidate target genes were enriched in the biological processes of regulating telomere capping and maintenance and telomerase activity (Top P = 7.73 × 10-7). CONCLUSIONS: These results enhance the biological understanding of radiotherapy toxicity. The association signals enriched in telomere function regulation implicate the potential underlying mechanism and warrant further functional investigation and potential individual radiotherapy applications.

Long-Term Survival and Prognostic Factors in Locoregionally Advanced Nasopharyngeal Carcinoma Patients Treated with TPF Induction Chemotherapy followed by Cisplatin-Combined Concurrent Chemoradiotherapy.

Purpose: The objective of this study was to report long-term results of docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and identify prognostic factors for this group of patients. Materials and Methods: From December 2010 to January 2015, 109 patients with locoregionally advanced (III-IVB) NPC were included. Patients were scheduled to complete TPF induction chemotherapy followed by cisplatin based CCRT. Failure-free survival (FFS), overall survival (OS), locoregional failure-free survival (LRFFS) and distant failure-free survival (DFFS) served as clinical outcomes. Kaplan-Meier method, Cox proportional hazards model and receiver operating characteristic (ROC) curves were used for analyzing. Results: With a median follow-up of 60.2 months (range, 7.9-91.6 months), 3-year FFS, OS, LRFFS, and DFFS were 76.8%, 85.1%, 88.3%, and 84.1%, respectively. The highest incidence rate of recurrence and metastasis were in the first year after treatment. Multivariate analyses showed that age, total time of radiation therapy (RTT), and total time of therapy (TTT) were independent prognostic factors for FFS and OS. Body mass index (BMI), RTT and TTT were significant variables predicting DFFS. TTT was the only independent prognostic factor for LRFFS. Conclusion: This study indicated that TPF regimen produced encouraging results in Asian patients with locoregionally advanced nasopharyngeal carcinoma. Toxicity was tolerable and reversible. However, overall treatment time is an important factor that we should take into consideration when make plans of induction chemotherapy related treatment.

ZWINT is the next potential target for lung cancer therapy.

PURPOSE: We aimed to analyze the expression of ZWINT, NUSAP1, DLGAP5, and PRC1 in tumor tissues and adjacent tissues with public data. METHODS: The expression patterns of four genes were detected in cancer tissues and adjacent tissues by qRT-PCR. The overall survival analysis was used to explore these genes in lung adenocarcinoma and squamous cell carcinoma patients. Knockdown assays were used to select the most suitable gene among these four genes. Cell function assays with the knockdown gene were conducted in A549 and NCL H226 cells. The role of the knockdown gene in lung cancer was dissected in a mice tumor model. Transcriptome sequencing analyses with the knockdown gene were analyzed. RESULTS: Overexpression of these genes was significantly detected in cancer tissues (P < 0.01). Overall survival revealed that high expression of these genes is closely related with poor prognosis of lung adenocarcinoma patients (P < 0.05). Knockdown of ZWINT reduced proliferation in NCI H226 and A549 cells (P < 0.05). Knockdown also inhibited cell migration, invasion, apoptosis, and colony formation (P < 0.05). ZWINT knockdown reduced tumor volume (P < 0.05). Transcriptome sequencing of ZWINT knockdown-treated A549 and NCI H226 cells indicated that 100 and 426 differentially expressed genes were obtained, respectively. Gene ontology analysis suggested that binding, biological regulation, and multicellular organismal processes were the most enriched. KEGG analysis revealed that TNF, P53, and PI3K signal networks would be the most potential ZWINT-related pathways and were identified by Western blot analysis. CONCLUSIONS: ZWINT may be a novel target for lung cancer therapy.

Genome-Wide Association Study of Susceptibility Loci for Radiation-Induced Brain Injury.

BACKGROUND: Radiation-induced brain injury is a nonnegligible issue in the management of cancer patients treated by partial or whole brain irradiation. In particular, temporal lobe injury (TLI), a deleterious late complication in nasopharyngeal carcinoma, greatly affects the long-term life quality of these patients. Although genome-wide association studies (GWASs) have successfully identified single nucleotide polymorphisms (SNPs) associated with radiation toxicity, genetic variants contributing to the radiation-induced brain injury have not yet been assessed. METHODS: We recruited and performed follow-up for a prospective observational cohort, Genetic Architecture of Radiotherapy Toxicity and Prognosis, using magnetic resonance imaging for TLI diagnosis. We conducted genome-wide association analysis in 1082 patients and validated the top associations in two independent cohorts of 1119 and 741 patients, respectively. All statistical tests were two-sided. RESULTS: We identified a promoter variant rs17111237 (A > G, minor allele frequency [MAF] = 0.14) in CEP128 associated with TLI risk (hazard ratio = 1.45, 95% confidence interval = 1.26 to 1.66, Pcombined=3.18 × 10-7) which is in moderate linkage disequilibrium (LD) with rs162171 (MAF = 0.18, R2 = 0.69), the top signal in CEP128 (hazard ratio = 1.46, 95% confidence interval = 1.29-1.66, Pcombined= 6.17 × 10-9). Combining the clinical variables with the top SNP, we divided the patients into different subgroups with varying risk with 5-year TLI-free rates ranging from 33.7% to 95.5%. CEP128, a key component of mother centriole, tightly interacts with multiple radiation-resistant genes and plays an important role in maintaining the functional cilia, which otherwise will lead to a malfunction of the neural network. We found that A > G alteration at rs17111237 impaired the promoter activity of CEP128 and knockdown of CEP128 decreased the clonogenic cell survival of U87 cells under radiation. Noteworthy, 12.7% (27/212) of the GWAS-based associated genes (P < .001) were enriched in the neurogenesis pathway. CONCLUSIONS: This three-stage study is the first GWAS of radiation-induced brain injury that implicates the genetic susceptibility gene CEP128 involved in TLI development and provides the novel insight into the underlying mechanisms of radiation-induced brain injury.

Association between genetic variants in the XPG gene and gastric cancer risk in a Southern Chinese population.

Xeroderma pigmentosum group G (XPG) recognizes and excises DNA damage on the 3' side during the DNA repair process. Previous studies indicated that XPG gene polymorphisms may associate with gastric cancer susceptibility, but results were inconsistent. We evaluated the association of five potentially functional XPG polymorphisms (rs2094258 C>T, rs751402 C>T, rs2296147 T>C, rs1047768 T>C, and rs873601 G>A) with gastric cancer susceptibility in 1142 gastric cancer cases and 1173 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression models. Overall, no significant association was detected between any of selected polymorphism and gastric cancer risk. However, we found that individuals carrying 3-4 risk genotypes were at significantly higher risk of gastric cancer than those with 0-2 risk genotypes (OR=1.32, 95% CI=1.04-1.68, P=0.021). The stratification analysis revealed that the cumulative effect of risk genotypes (3-4 vs. 0-2) on gastric cancer were more prominent among subgroups older than 58 years and men. In conclusion, our results indicated that none of the selected XPG polymorphism could significantly alter gastric cancer susceptibility alone. These polymorphisms might collectively confer increased gastric cancer susceptibility. These findings would be strengthened by larger prospective multicenter studies involving different ethnic populations.

Polymorphisms in the XPC gene and gastric cancer susceptibility in a Southern Chinese population.

Previous studies have reported that XPC gene polymorphisms may modify the individual susceptibility to gastric cancer. In this case-control study with a total of 1,142 cases and 1,173 controls, four potentially functional polymorphisms were genotyped in the XPC gene (rs2228001 A>C, rs2228000 C>T, rs2607775 C>G, and rs1870134 G>C) by Taqman assays and their associations were analyzed with the risk of gastric cancer in a Southern Chinese population. No significant association between any of XPC polymorphisms and gastric cancer risk was detected except for a borderline association with the rs2228000 CT/TT genotype (crude odds ratio =0.86, 95% confidence interval =0.73-1.02, P=0.088) when compared to the rs2228000 CC genotype. Further stratified analysis revealed that the protective effect of rs2228000 CT/TT on the risk of gastric cancer was only significant among subjects older than 58 years. In summary, results indicated that genetic variations in XPC gene may play a weak effect on gastric cancer susceptibility in Southern Chinese population, which warrants further confirmation in larger prospective studies with different ethnic populations.

Erratum to: Low expression of ULK1 is associated with operable breast cancer progression and is an adverse prognostic marker of survival for patients.

Erratum to: Breast Cancer Res Treat (2012),134:549­560,DOI 10.1007/s10549-012-2080-y. In the original publication of the article, Fig. 5c was published incorrectly. The authors apologize for this error and the correct Fig. 5c is given below.

Household inhalants exposure and nasopharyngeal carcinoma risk: a large-scale case-control study in Guangdong, China.

BACKGROUND: Epidemiological studies show that cigarette smoking increase the risk of nasopharyngeal carcinoma (NPC), however, whether other common, potentially adverse household inhalants increase NPC risk remains uncertain. METHODS: We conducted a large case-control study to explore the effects of household inhalants, such as incense, mosquito coil, cooking fumes, and wood combustion, on NPC risk. We recruited 1,845 cases and 2,275 controls from Guangdong province, a high-risk area for NPC in China, to obtain the demographic data and relevant exposure information through face-to-face interviews. RESULTS: We found that incense burning was associated with NPC risk by comparing frequent incense use with never using incense [OR and 95% confidence interval (CI) = 1.73, (1.43, 2.09)]. Wood fuel use was also associated with NPC risk compared with non-wood fire use [OR and 95% CI = 1.95, (1.65, 2.31)]. More intriguingly, we observed a significant addictive interaction between frequent incense burning and heavy cigarette smoking on NPC risk [synergistic index (SI) = 1.67; 95% CI: 1.01, 2.76]. We also found a significant joint effect between wood fuel use and NPC family history for NPC risk (SI = 1.77; 95% CI: 1.06, 2.96). However, neither mosquito oil nor cooking fumes were associated with NPC risk. CONCLUSIONS: Our study shows that incense smoke is not only the potential independent risk factor but also co-contributes with cigarette smoking to NPC risk. Moreover, wood combustion is another potential environmental risk factor and exerts a joint effect with NPC family history on NPC.

Intensity-modulated radiotherapy prolongs the survival of patients with nasopharyngeal carcinoma compared with conventional two-dimensional radiotherapy: A 10-year experience with a large cohort and long follow-up.

BACKGROUND: To evaluate the survival benefit of intensity-modulated radiotherapy (IMRT) compared with conventional two-dimensional radiotherapy (2D-CRT) in nasopharyngeal carcinoma (NPC) using a large cohort with long follow-up. METHODS: We retrospectively analysed 7081 non-metastatic NPC patients who received curative IMRT or 2D-CRT from February 2002 to December 2011. RESULTS: Of the 7081 patients, 2245 (31.7%) were administered IMRT, while 4836 (68.3%) were administered 2D-CRT. At 5 years, the patients administered IMRT had significantly higher local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS), progression-free survival (PFS) and overall survival (OS) (95.6%, 92.5%, 82.1% and 87.4%, respectively) than those administered 2D-CRT (90.8%, 88.5%, 76.7% and 84.5%, respectively; p<0.001). The distant metastasis-free survival (DMFS) was higher for IMRT than 2D-CRT, with borderline significance (87.6% and 85.7%, respectively; p=0.056). However, no difference was observed between IMRT and 2D-CRT in nodal relapse-free survival (NRFS; 96.3% and 97.4%, respectively; p=0.217). Multivariate analyses showed that IMRT was an independent protective prognostic factor for LRFS, LRRFS and PFS, but not NRFS, DMFS or OS. CONCLUSIONS: IMRT provided an improved LRFS, LRRFS and PFS in both the early and advanced T classifications and overall stage for non-disseminated NPC compared with 2D-CRT. However, no significant advantage was observed in NRFS, DMFS or OS when IMRT was used.