N‐glycan based models improve diagnostic efficacies in hepatitis B virus‐related hepatocellular carcinoma

The early diagnosis of hepatocellular carcinoma (HCC) is of great clinical desirable due to lack of specific and sensitive markers. Alterations in the sugar chains of glycoprotein synthesized by the liver contribute to the molecular basis of abnormalities in carcinogenesis. This study aims to construct and assess the diagnostic value of N‐glycan based diagnostic model in HCC identification and follow‐up. A total of 393 subjects including HBV‐related HCC, liver fibrosis and healthy controls were recruited. Follow‐up was carried out before and after surgical treatment in HCC. N‐glycome of serum glycoprotein was profiled by DNA sequencer‐assisted fluorophore‐assisted carbohydrate electrophoresis (DSA‐FACE). Multiparameters diagnostic models were constructed based on N‐glycan markers. The result found that 2 N‐glycan structure abundances (NG1A2F, Peak 4; NA3Fb, Peak 9) were useful as N‐glycan markers. The diagnostic efficacy of the log ratio [log(p9/4)] was similar to that of AFP in differentiating HCC from fibrosis. The accuracy and sensitivity of the diagnostic model combining AFP and N‐glycan markers (Cscore B) were increased 7–10% compared with that of AFP. Log(p9/4) was more efficient in monitoring the progression of HCC with regarding to vascular invasion at improved specificity (16%) and accuracy (8%) compared with that of AFP. The N‐glycan markers were found to be changed significantly after surgical resection in HCC follow‐up. We conclude that the branching α (1,3)‐fucosylated triantennary glycan and a biantennary glycan are promising as N‐glycan markers. The diagnostic models based on the N‐glycan markers and AFP improve the efficacy in HCC diagnosis and progression monitoring.     

RUNX1 amplification in AML with myelodysplasia‐related changes and ring 21 chromosomes

Ring 21 is an unstable structural abnormality of chromosome 21 that can lead to RUNX1 gene amplification. We present a unique case with a carrier patient of a constitutional ring chromosome 21 (partial monosomy and trisomy 21) with dysmorphic features and congenital malformations phenotype, who developed acute myeloid leukaemia with myelodysplasia‐related changes and two ring 21 chromosomes with RUNX1 amplification. The patient's constitutional ring 21 chromosome showed alterations in tumour suppressor genes, and oncogenes, but not in RUNX1. RUNX1 gene expression at acute myeloid leukaemia diagnosis, showed no upregulation, so other genes may also be the genetic amplification targets in this patient. Copyright © 2016 John Wiley & Sons, Ltd.     

Health‐related quality of life in long‐term breast cancer survivors

BACKGROUND:

The Survivor's Health and Reaction (SHARE) study examined health‐related quality of life (HRQL) in breast cancer patients who had participated in Cancer and Leukemia Group B Trial 8541 from 1985 to 1991.

METHODS:

In total, 245 survivors (78% of eligible patients) who were 9.4 to 16.5 years postdiagnosis (mean, 12.5 years postdiagnosis) completed HRQL surveys relating to 5 domains. Analyses examined HRQL domains according to 3 different chemotherapy dose levels that were administered in the original treatment trial: low‐dose cyclophosphamide, doxorubicin, and fluorouracil (CAF) at 300 mg/m², 30 mg/m², and 300×2 mg/m², respectively, over 4 cycles; standard‐dose CAF at 400 mg/m², 40 mg/m², and 400×2 mg/m², respectively, over 6 cycles; and high‐dose CAF at 600 mg/m², 60 mg/m² and 600×2 mg/m², respectively, over 4 cycles.

RESULTS:

In univariate analyses, a statistically significant difference was observed on the Medical Outcomes Study 36‐item short form Physical Role Functioning subscale by treatment group, with lower mean scores in the standard treatment arm (mean, 65.05) compared with mean scores in the low‐dose arm (mean, 74.66) and the high‐dose arm (mean, 84.94; P.0001). However, multivariate analysis revealed that treatment arm no longer was statistically significant, whereas the following factors were associated with decreased physical role functioning: age ≥60 years (odds ratio [OR], 3.55; P = .006), increased comorbidity interference total score (OR, 1.64; P = .005), lower vitality (OR, 1.05; P = .0002), and increased menopausal symptoms (OR, 1.04 P = .02).

CONCLUSIONS:

At 9.4‐16.5 years after their original diagnosis, differences in physical role functioning among breast cancer survivors who had received 3 different dose levels of chemotherapy were explained by clinical and demographic variables, such as age, fatigue, menopausal symptoms, and comorbidities. Prospective studies are needed to further assess the role of these factors in explaining HRQL and physical role functioning among long‐term survivors. Cancer 2009. © 2009 American Cancer Society.     

Integrating expression‐related SNPs into genome‐wide gene‐ and pathway‐based analyses identified novel lung cancer susceptibility genes

Traditional pathway analysis map single nucleotide polymorphisms (SNPs) to genes according to physical position, which lacks sufficient biological bases. Here, we incorporated genetics of gene expression into gene‐ and pathway‐based analysis to identify genes and pathways associated with lung cancer risk. We identified expression‐related SNPs (eSNPs) in lung tissues and integrated these eSNPs into three lung cancer genome‐wide association studies (GWASs), including 12,843 lung cancer cases and 12,639 controls. We used SKAT‐C for gene‐based analysis, and conditional analysis to identify independent eSNPs of each gene. ARTP algorithm was used for pathway analysis. A total of 374,382 eSNPs in the GWAS datasets survived quality control, which were mapped to 5,084 genes and 2,752 pathways. In the gene‐based analysis, nine genes showed significant associations with lung cancer risk. Among them, TP63 (3q28), RP11‐650L12.2 (15q25.1) and CHRNA5 (15q25.1) were located in known lung cancer susceptibility loci. We also validated two newly identified susceptibility loci (RNASET2 and AL133458.1 in 6q27, and MPZL3 in 11q23.3). Besides, DVL3 (3q27.1), RP11‐522I20.3 (9q21.32) and CCDC116 (22q11.21) were identified as novel lung cancer susceptibility genes. Pathway analysis showed that pathways involved in protein structure, the Notch signaling pathway and the nicotinic acetylcholine receptor‐related pathways were associated with lung cancer risk. Combing eSNPs, gene‐ and pathway‐based analysis identifies novel lung cancer susceptibility genes, which serves as a powerful approach to decipher biological mechanisms underlying GWAS findings.     

Health‐related quality of life among survivors of aggressive non‐Hodgkin lymphoma

BACKGROUND:

Non‐Hodgkin lymphoma (NHL) is the fifth most common cancer among men and women. Patients with aggressive NHL receive intense medical treatments that can significantly compromise health‐related quality of life (HRQOL). However, knowledge of HRQOL and its correlates among survivors of aggressive NHL is limited.

METHODS:

Self‐reported data on HRQOL (physical and mental function, anxiety, depression, and fatigue) were analyzed for 319 survivors of aggressive NHL. Survivors 2 to 5 years postdiagnosis were selected from the Los Angeles County Cancer Registry. Bivariate and multivariable methods were used to assess the influence of sociodemographic, clinical, and cognitive health‐appraisal factors on survivors' HRQOL.

RESULTS:

After accounting for other covariates, marital status was associated with all HRQOL outcomes (P < .05). Younger survivors reported worse mental function and higher levels of depression, anxiety, and fatigue (P < .01). Survivors who had more comorbid conditions or lacked private health insurance reported worse physical and mental function and higher levels of depression and fatigue (P < .05). Survivors who experienced a recurrence reported worse physical function and higher levels of depression and fatigue (P < .05). With the exception of a nonsignificant association between perceived control and physical function, greater perceptions of personal control and health competence were associated significantly with more positive HRQOL outcomes (P < .01).

CONCLUSIONS:

The current results indicated that survivors of aggressive NHL who are younger, are unmarried, lack private insurance, or experience greater illness burden may be at risk for poorer HRQOL. Cognitive health‐appraisal factors were strongly related to HRQOL, suggesting potential benefits of interventions focused on these mutable factors for this population. Cancer 2013. © 2012 American Cancer Society.     

Inflammation‐induced activation of the indoleamine 2,3‐dioxygenase pathway: Relevance to cancer‐related fatigue

Cancer‐related fatigue (CRF) is a common complication of cancer and its treatment that can significantly impair quality of life. Although the specific mechanisms remain poorly understood, inflammation is now considered to be a distinct component of CRF in addition to effects of depression, anxiety, insomnia, and other factors. One key biological pathway that may link inflammation and CRF is indoleamine 2,3‐dioxygenase (IDO). Induced by inflammatory stimuli, IDO catabolizes tryptophan to kynurenine (KYN), which is subsequently converted into neuroactive metabolites. Here we summarize current knowledge concerning the relevance of the IDO pathway to CRF, including activation of the IDO pathway in cancer patients and, as a consequence, accumulation of neurotoxic KYN metabolites and depletion of serotonin in the brain. Because IDO inhibitors are already being evaluated as therapeutic agents in cancer, the elucidation of the relationship between IDO activation and CRF in cancer patients may lead to novel diagnostic and clinical approaches to managing CRF and its debilitating consequences. Cancer 2015;121:2129–2136. © 2015 American Cancer Society.     

Fluconazole plus flucytosine is a good alternative therapy for non‐HIV and non‐transplant‐associated cryptococcal meningitis: A retrospective cohort study

Cryptococcal meningitis (CM) carries a high risk of mortality with increasing incidences in immune competent hosts. Current treatments are not well tolerated, and evaluation of other treatments is needed. Fluconazole and 5‐flucytosine in treating immune competent hosts have not been characterised. To evaluate the efficacy of fluconazole and 5‐flucytosine in treating non‐HIV‐ and non‐transplant‐associated CM. We performed a retrospective cohort study of the outcomes in immune competent patients with CM treated with fluconazole and 5‐flucytosine or deoxycholate‐amphotericin B and 5‐flucytosine. The primary outcome was treatment response evaluated at the 12th week after initiation of antifungal therapy. A total of 43 and 47 patients received amphotericin B deoxycholate and 5‐flucytosine or fluconazole and 5‐flucytosine, respectively. A total of 38 (88.4%) patients cannot tolerate recommended doses of amphotericin B deoxycholate and 5‐flucytosine (patients needed dose reduction during the treatment). Patients given fluconazole and 5‐flucytosine had higher baseline cryptococcal burdens (median 3632 versus 900 cryptococci/mL, P = 0.008). No significant differences were seen in cryptococcus clearance (74.4% vs 70.2%, P = 0.814), treatment time (39 days, 20‐69 days vs 21 days, 7‐63 days, P = 0.107) and successful response (including complete and partial responses) rates (69.7% vs 72.3%, P = 0.820). Fluconazole and 5‐flucytosine treatment had lower total adverse events (19.1% vs 90.7%, P < 0.001). Fluconazole and 5‐flucytosine had relatively high efficacy with few adverse events in treating CM. Fluconazole and 5‐flucytosine therapy is promising in patients that do not tolerate or are not suited for amphotericin B deoxycholate treatment.     

Tumor suppressor XIAP‐Associated factor 1 (XAF1) cooperates with tumor necrosis factor‐related apoptosis‐inducing ligand to suppress colon cancer growth and trigger tumor regression

BACKGROUND:

XIAP‐associated factor 1 (XAF1) antagonizes the anticaspase activity of XIAP (X‐linked inhibitor of apoptosis) and functions as a tumor suppressor in colon cancer. The tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is known as a potential anticancer agent. In this study, the synergistic effect of XAF1 and TRAIL on colon cancer growth was investigated.

METHODS:

Adeno‐XAF1 virus was generated and purified. Cell apoptosis was detected by flow‐cytometry and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling assay. Protein expression of the different genes was determined by Western blot analysis. Tumorigenesis and tumor growth were assessed in subcutaneous nude mouse xenograft experiments.

RESULTS:

Stable overexpression of XAF1‐sensitized colon cancer cells to TRAIL‐induced apoptosis significantly increased the activity of caspase 3, 7, 8, and 9; released cytochrome c; and down‐regulated XIAP, survivin, and c‐IAP‐2. The restoration of XAF1 expression mediated by adenovirus (adeno‐XAF1) directly induced apoptosis, and synergized TRAIL‐induced apoptosis in colon cancer cells. Ex vivo transduction of adeno‐XAF1 suppressed colon cancer formation in vivo. Furthermore, adeno‐XAF1 treatment of mice significantly inhibited tumor growth, strongly enhanced TRAIL‐induced apoptosis and antitumor activity in colon cancer xenograft models in vivo, and markedly prolonged the survival. Notably, the combined treatment with adeno‐XAF1 and TRAIL completely eradicated the established tumors without detectable toxicity in normal tissue.

CONCLUSIONS:

The combined restoration of XAF1 expression and TRAIL treatment may be a potent strategy for colon cancer therapy. Cancer 2010. © 2010 American Cancer Society.