Histone acetyltransferase hMOF promotes S phase entry and tumorigenesis in lung cancer

hMOF is the major acetyltransferase of histone H4 lysine 16 (H4K16) in humans, but its biological function is not well understood. In this study, hMOF was found to be more frequently highly expressed in non-small cell lung cancer (NSCLC) than corresponding normal tissues (P < 0.001). In addition, up-regulation of H4K16 acetylation was also more frequent in NSCLC than normal tissues (P = 0.002). Furthermore, hMOF promotes the cell proliferation, migration and adhesion of NSCLC cell lines. Microarray analysis and chromatin immunoprecipitation (ChIP) assays suggest that hMOF modulates proliferation and metastasis by regulating histone H4K16 acetylation at the promoter regions of downstream target genes. Moreover, hMOF promotes S phase entry via Skp2. These findings suggest that hMOF contributes to NSCLC tumorigenesis.     

Valeur pronostique de la TEP/TDM dans le bilan initial du cancer du col utérin : SUVmax de la tumeur primitive et stadification ganglionnaire

PurposeWe investigated the prognostic significance of F-18 fluorodeoxyglucose (FDG) uptake measured as maximum Standardized Uptake Value (SUV_max) in primary tumor by positron emission tomography/computed tomography (PET/CT) in cervical cancer. The secondary objective was to determine the accuracy of the PET/CT for detecting pelvic lymph node (PLN) and para-aortic lymph node (PALN) metastases.MethodsThis retrospective study included 49 consecutive patients with stage IB1 to IVB cervical cancer. Univariate analysis was performed to determine the relationships between SUV_max value and pathological prognostics factors. Survival was estimated by Kaplan-Meier method. The gold standard of LN metastases was histologic.ResultsA significant difference in SUV_max was observed between stage I and stage II, stage I and stage IV and tumor size ≤ 4 cm and > 4 cm (P = 0.0001). There was a significant correlation between the SUV_max and tumor maximal size (r = 0.597) (P < 0.0001). PLN metastasis was found to be predictive of progression-free survival (P = 0.0007). The negative predictive value (NPV) of the PET/CT for PALN was 100% for locally advanced cervical carcinoma in 24 patients. The specificity and NPV of the PET/CT for PLN in eight early-stage cervical cancer were 100% and 87.5% (7/8) respectively. The PET/CT false-negative PLN measured less than 2 mm.ConclusionOur results demonstrate a correlation between SUV_max and tumor maximal size, which represents an indicator of tumor aggressiveness. PET/CT is effective to predict the absence of PALN in locally advanced cervical carcinoma. PET/CT is not sufficient to predict PLN in early-stage cancer without lymphadenectomy.     

Rôle de la TEP au 18F-FDG dans l’évaluation des volumes cibles chez des patients atteints de CBNPC traités par radiochimiothérapie

Currently ¹⁸F-FDG-PET is the gold standard to evaluate tumor response after chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC). PET can also determine the volumes to be treated by radiotherapy, in inoperable patients. The aim of our mixed (prospective and retrospective) study concerned 28 patients with NSCLC, was to quantify the variation of the metabolic activity of lesions and their volumes after chemotherapy. We also studied the impact of change of these volumes on the definition of radiotherapy target volumes. Patients with stage II–IV and inoperable NSCLC were included. Two PET scans were performed: before treatment (PET1), then after two to six courses of chemotherapy (PET2). Of the 28 patients included, we observed complete metabolic response in six patients (21%), partial metabolic response in 13 patients (46%), stable disease in seven patients (25%), and progressive metabolic disease in two patients (7%), according to the PERCIST criteria. We observed significant variation (P < 0.001) of metabolic activity (estimated by SULpeak or SUVmax) for primary tumor as well as for overall lesions between the two PET scans. Thus, the target volumes of radiotherapy decreased significantly (P < 0.01) in PET2. Our results confirm that ¹⁸F-FDG-PET is not only a powerful technique for treatment evaluation but also a useful tool for radiotherapy planning after chemotherapy, in the context of personalized treatments.     

Clinical significance of serum transforming growth factor-β1 in lung cancer

Background: Transforming growth factor-β1 (TGF-β1) plays a critical role in human cancer development. Present study aimed to explore the clinical significance of serum TGF-β1 levels in patients with lung cancer and analyze the relationship between TGF-β1 and existing tumor markers for lung cancer. Methods: Serum was collected from 118 patients with lung cancer and 40 healthy volunteers. Serum TGF-β1 levels were measured by enzyme-linked immunosorbent assay (ELISA), and the association with various clinical characteristics was analyzed. The diagnostic value of TGF-β1 was assessed alone and in combination with existing tumor markers for lung cancer. Results: Serum TGF-β1 levels were significantly higher in patients with lung cancer compared to healthy volunteers [0.6 × 10⁵ (0.4 × 10⁵, 0.9 × 10⁵) pg/ml vs 0.5 × 10⁵ (0.3 × 10⁵, 0.7 × 10⁵) pg/ml, P = 0.040]. Although there was a positive correlation between serum TGF-β1 levels and advanced stages, the significant difference was not found between early stages and advanced stages (P = 0.116). The ability of serum TGF-β1 to discriminate lung cancer at a cutoff value of 79,168 pg/ml exhibited sensitivity of 30.6% and specificity of 97.5%. Serum TGF-β1 levels were correlated to cytokeratin fragment 21-1 (CYFRA21-1; R = 0.308, P = 0.020) and neuron-specific enolase (NSE; R = 0.558, P = 0.003). The diagnostic accuracy rates for the existing lung-tumor markers, as SCC, CYFRA21-1, and NSE, were increased from 20.0%, 34.6%, and 45.9% to 48.9%, 51.7%, and 54.5%, respectively by the inclusion of serum TGF-β1 levels. Conclusion: Quantification of serum TGF-β1 levels by ELISA may provide a novel complementary tool for the clinical diagnosis of lung cancer.     

Analyse texturale en TEP au FDG des cancers pulmonaires non à petites cellules de stade localement avancé : valeur pronostique de l’entropie

IntroductionIn the current context of personalized medicine, textural analysis promises to be an accurate approach of cancer prognosis. The lack of standardization and the multitude of textural indices limited radiomics studies reproducibility as an obstacle of introduction of textual analysis into clinical practice. Our study assessed the prognostic value of entropy in 18F-FDG PET/CT in locally advanced non-small cell lung cancer (NSCLC).MethodPatients who performed 18F-FDG PET/CT for lung cancer staging between September 2015 and April 2017 in 2 hospitals were included for conventional and textural PET parameters extraction. A retrospective analysis of patient was performed over 24 months to determine the progression-free survival and overall survival.ResultsForty-two patients were included. Progression-free survival was significantly correlated with entropy on multivariate regression (cut-off at 8.4) with a hazard ratio of 3.04 (95 % CI 1.13–8.16) (P = 0.03), as MTV (P < 0.001). Neither conventional PET parameters nor entropy was a significant association with overall survival.ConclusionThese results confirmed the external validity and robustness of FDG PET entropy as an independent prognostic factor of progression-free survival in patients with locally advanced NSCLC, in addition to Conventional PET.     

Tolerability and toxicity of prophylactic cranial irradiation in patients with non-small cell lung cancer – Results of a phase II study (with estimation of hematological toxicity,pituitary function and magnetic resonance spectra changes)

AimTo evaluate the tolerability and toxicity of PCI in patients with NSCLC.BackgroundProphylactic cranial irradiation (PCI) is a standard treatment for patients with small cell lung cancer. There are data showing a decreasing ratio of brain metastases after PCI for non-small cell lung cancer (NSCLC-non small cell lung cancer) patients but, so far, there is no evidence for increasing overall survival. The main concern in this setting is the tolerance and toxicity of the treatment.Materials and methodsFrom 1999 to 2007, 50 patients with NSCLC treated with radical intent underwent PCI (30 Gy in 15 fractions). Mean follow-up was 2.8 years. The tolerability and hematological toxicity were evaluated in all patients, a part of participants had done neuropsychological tests, magnetic resonance imaging with ¹H nuclear magnetic resonance spectra, and estimation of pituitary function.ResultsDuring follow-up, 20 patients developed distant metastases, 4-brain metastases. Fourteen (30%) patients had acute side effects: (headache, nausea, erythema of the skin). The symptoms did not require treatment breaks. Six patients complained of late side effects (vertigo, nausea, anxiety, lower extremity weakness, deterioration of hearing and olfactory hyperesthesia). Hematological complications were not observed. Testosterone levels tended to decrease (p = 0.062). Visual-motor function deteriorated after treatment (p < 0.059). Performance IQ decreased (p < 0.025) and the difference between performance IQ and verbal IQ increased (p < 0.011). Degenerative periventricular vascular changes were observed in two patients. Analysis of the spectroscopic data showed metabolic but reversible alterations after PCI.ConclusionPCI in the current series was well tolerated and associated with a relatively low toxicity.     

Glycosylated Alpha-1-acid glycoprotein 1 as a potential lung cancer serum biomarker

Presently existing screening approaches for lung cancer are not being proving sufficient and sensitive, so a study was conducted to identify disease related biomarker proteins for diagnostic applications. A total of 100 lung cancer patients (88 non-small cell lung cancer and 12 small cell lung cancer) and 50 healthy controls were included in this study. Serum samples of patients and healthy controls were subjected to a series of proteomic approaches and as a result of two dimensional gel electrophoresis, a ∼43 kDa protein was found to be differentially expressed compared to healthy controls. Quantitative profiling of two dimensional gels by Dymension software analysis displayed 3.58 fold increased expression of ∼43 kDa protein in squamous cell carcinoma and 2.92 fold in case of adenocarcinoma. Mass spectrometric analysis resulted in identification of 8 differentially expressed proteins, out of which human Alpha-1-acid glycoprotein 1 was targeted for further validations. This candidate protein exhibited N-linked glycosylation at five amino acid residues; 33, 56, 72, 93, and 103 with significant score of 0.66, 0.78, 0.78, 0.53 and 0.66, respectively. Sandwich ELISA quantified high serum levels of Alpha-1-acid glycoprotein 1 in squamous cell carcinoma (2.93 g/l ± 1.22) and adenocarcinoma (2.39 g/l ± 1.13) when compared with healthy controls (0.83 g/l ± 0.21). One-way ANOVA analysis predicted highly significant variation of Alpha-1-acid glycoprotein 1, among all the study types (F-value 65.37, p-value 0.000). This study may prove as a non-invasive, cost effective and sensitive scheme for diagnosis of lung cancer, by passing the expensive and painful screening procedures.     

Importance of IL-10 and IL-6 during chronic hepatitis c genotype-1 treatment and their relation with IL28B

This paper investigates serum levels of interleukin 10 (IL-10) and interleukin 6 (IL-6) in patients with chronic hepatitis C genotype 1 (CHC-GT1), the relation of each with clinical and virological characteristics, how they affect the response to combined therapy and their relation with the IL28B polymorphisms rs12979860. Serum level expression and the polymorphism of IL-10, IL-6 and IL28B were determined in 138 CHC-GT1 patients, treated with pegylated interferon/ribavirin (pegIFN-α/RBV) for 48 weeks, in the following samples: baseline, week-12 (during treatment) and week-72 (post-treatment). 77 patients (56%) presented Sustained Virological Response (SVR) and 61 (44%) were non-SVR. Multivariate logistic regression showed that age ? 40 years (aOR = 3.7, 95%CI = 1.5–8.9, P = 0.004), low activity of gamma glutamyl transferase (GGT) (aOR = 0.9, 95%CI = 0.98–0.99, P = 0.028), CC genotype of IL28B polymorphim (aOR = 2.7, 95%CI = 1.0–7.2, P = 0.044) and low IL-6 (aOR = 0.5, 95%CI = 0.3–1.0, P = 0.038) were predictor factors of virological response. In all patients, following treatment, IL-6 decreased at week-12 (P = 0.004) from baseline and had returned to basal values at week-72. Serum IL-10 concentration was significantly decreased at week-72 only in SVR patients (P ? 0.001). When patients were stratified by IL28B polymorphisms rs12979860 CC vs non-CC patients, a statistically significant decrease in IL-10 at week-72 in both groups was observed (P = 0.003 and P ? 0.001, respectively). None of the polymorphisms of IL-10 or IL-6 studied were associated with SVR.ConclusionsCC genotype of IL28B and low IL-6 serum concentration are factors associated independently with SVR. Moreover, decreased IL-10 at week-72 is associated with SVR in both CC and non-CC patients, and both factors are important to determine the effectiveness of treatment.     

EPID-based in vivo dosimetry for stereotactic body radiotherapy of non-small cell lung tumors: Initial clinical experience

PurposeEPID-based in vivo dosimetry (IVD) has been implemented for stereotactic body radiotherapy treatments of non-small cell lung cancer to check both isocenter dose and the treatment reproducibility comparing EPID portal images.Methods15 patients with lung tumors of small dimensions and treated with volumetric modulated arc therapy were enrolled for this initial experience. IVD tests supplied ratios R between in vivo reconstructed and planned isocenter doses. Moreover a γ-like analysis between daily EPID portal images and a reference one, in terms of percentage of points with γ-value smaller than 1, P_γ<1, and mean γ-values, γ_mean, using a local 3%–3 mm criteria, was adopted to check the treatment reproducibility. Tolerance levels of 5% for R ratio, P_γ<1 higher than 90% and γ_mean lower than 0.67 were adopted.ResultsA total of 160 EPID images, two images for each therapy session, were acquired during the treatment of the 15 patients. The overall mean of the R ratios was equal to 1.005 ± 0.014 (1 SD), with 96.9% of tests within ± 5%. The 2 D image γ-like analysis showed an overall γ_mean of 0.39 ± 0.12 with 96.1% of tests within the tolerance level, and an average P_γ<1 value equal to 96.4 ± 3.6% with 95.4% of tests with P_γ<1 > 90%. Paradigmatic discrepancies were observed in three patients: a set-up error and a patient morphological change were identified thanks to CBCT image analysis whereas the third discrepancy was not fully justified.ConclusionsThis procedure can provide improved patient safety as well as a first step to integrate IVD and CBCT dose recalculation.     

5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones as potential anticancer agents with anti-inflammatory properties

A series of novel 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones (3a–z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI₅₀ = 850 nM), against leukemia SR cancer cells (GI₅₀ = 1.45 μM), and OVCAR-3 (GI₅₀ = 1.26 μM) ovarian cancer cell lines. The structurally related compound 3s had a GI₅₀ value of 1.77 μM against MDA-MB-435 cells. The N-naphthoyl analogue 3t had GI₅₀ values of 1.30 and 1.91 μM against HOP-92 non-small cell lung cancer and MDA-MB-435 melanoma cell lines, respectively. The related analogue 3w had GI₅₀ values of 1.09 μM against HOP-92 non-small cell lung cancer cell lines. Interestingly, docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands with strong hydrophobic and hydrogen bonding interactions. Thus, compounds 3k, 3t, 3s, and 3w constitute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer therapy.     

HapMap-based study identifies risk sub-region on chromosome 19q13.3 in relation to lung cancer among Chinese

Background: Chromosome 19q13.3 has been identified as one of the regions that associate with cancer risk in previous studies. Methods: We systematically examined the 70.772 kb region comprising four genes on chromosome 19q13.3 among Chinese using the haplotype-tagging SNP (htSNP) approach and the HapMap platform. The study involved 339 lung cancer cases and 358 non-cancer controls. Two htSNPs (rs1046282 and rs735482) captured most of the common haplotypes of CD3EA and the combined effects of sixteen htSNPs provided high coverage of common haplotypes of ERCC2, PPP1R13L, CD3EAP and ERCC1. Results: Both carriers of variant CC genotype [adjusted OR (95% CI) = 1.28 (1.02–1.60), P = 0.04] and variant C-allele among >20 years’ smokers [OR (95% CI) = 2.13 (1.24–3.67), P = 0.006] for CD3EAP rs735482 were at increased risk of lung cancer. Four haplotype blocks of strong linkage disequilibrium were identified. The haplotype ERCC2 rs3916874^G and rs238415^C [OR (95% CI) = 1.26 (1.02–1.57), P = 0.03] in block 1 and the haplotype PPP1R13L rs4803817^A, CD3EAP rs1046282^T, rs735482^C, ERCC1 rs3212980^A, rs3212964^G [OR (95% CI) = 3.56 (1.55–8.18), P = 0.005] in block 3 were associated with lung cancer risk. MDR (multifactor dimensionality reduction) analysis demonstrated the best significant model of two-attributes containing smoking duration and rs2298881 in ERCC1 (P = 0.004–0.005) and suggested that the effects of high-order interactions among smoking duration and ERCC2, PPP1R13, ERCC1 htSNPs could modulate lung cancer risk. Conclusions: HapMap-based study of 19q13.3 identified that genetic variation of CD3EAP and two loci were associated with lung cancer risk and interaction of smoking duration and genetic variants was the strongest predictor of lung cancer risk in a Chinese population.     

Chitinase 3 like 1 is associated with tumor angiogenesis in cervical cancer

Elevated serum levels of a secreted glycoprotein chitinase 3 like 1 (CHI3L1) are associated with poor prognosis and short survival time of patients with cervical cancer (CxCa). Our previous microarray data showed the increased expression of CHI3L1 in invasive CxCa compared to normal tissue, implicating a potential role of CHI3L1 in CxCa. To establish the pathological role of CHI3L1 in the development of CxCa, this study focused on its expression in CxCa and angiogenic impacts in tumor vessel formation. CHI3L1 activated angiogenesis by promoting endothelial cell migration and tube formation in vitro but failed to protect CxCa cell lines, CaSki and HeLa against apoptosis induced by γ-irradiation. In addition, the capability of CHI3L1 to induce proliferation and migration of CaSki and HeLa cells was cell type specific. In an analysis of 103 specimens from CxCa patients, increased expression levels of CHI3L1 mRNA and protein in invasive CxCa were 4-fold (P < 0.05) and 2-fold (P < 0.01), respectively, stronger than those in normal subjects. The immunostaining of CHI3L1 was positively correlated with VEGF expression (P = 0.0019) and microvessel density (P = 0.0110). Moreover, CHI3L1 expression was also positively associated with cancer metastasis (P = 0.011). The data suggest the crucial role of CHI3L1 by promoting angiogenesis, which may contribute to the development and progression of CxCa. The findings help establish CHI3L1 as a prognostic biomarker and therapeutic target for CxCa patients.     

New antiproliferative 7-(4-(N-substituted carbamoylmethyl)piperazin-1-yl) derivatives of ciprofloxacin induce cell cycle arrest at G2/M phase

New N-4-piperazinyl derivatives of ciprofloxacin 2a–g were prepared and tested for their cytotoxic activity. The primary in vitro one dose anticancer assay experienced promising cytotoxic activity against different cancer cell lines especially non-small cell lung cancer. Independently, compounds 2b, 2d, 2f and 2g showed anticancer activity against human non-small cell lung cancer A549 cells (IC₅₀ = 14.8, 24.8, 23.6 and 20.7 μM, respectively) compared to the parent ciprofloxacin (IC₅₀ >100 μM) and doxorubicin as a positive control (IC₅₀ = 1 μM). The flow cytometric analysis for 2b showed dose dependent G₂/M arrest in A549 cells. Also, 2b increased the expression of p53 and p21 and decreased the expression of cyclin B1 and Cdc2 proteins in A549 cells without any effect on the same proteins expression in WI-38 cells. Specific inhibition of p53 by pifithrin-α reversed the G₂/M phase arrest induced by the 2b compound, suggesting contribution of p53 to increase. Taken together, 2b induced G₂/M phase arrest via p53/p21 dependent pathway. The results indicate that 2b can be used as a lead compound for further development of new derivatives against non-small cell lung cancer.     

Telomere length and risk of melanoma,squamous cell carcinoma,and basal cell carcinoma

Background: Telomeres help maintain chromosomal structure and may influence tumorigenesis. We examined the association between telomere length and skin cancer in a clinic-based case-control study of 198 melanoma cases, 136 squamous cell carcinoma (SCC) cases, 185 basal cell carcinoma (BCC) cases, and 372 healthy controls. Methods: Cases were histologically confirmed patients treated at the Moffitt Cancer Center and University of South Florida Dermatology Clinic in Tampa, FL. Controls self-reported no history of cancer and underwent a skin cancer screening exam at study enrollment to rule out the presence of skin cancer. Quantitative real time PCR was used to measure telomere length in peripheral blood samples. Results: Melanoma patients had longer telomeres than controls (odds ratio (OR) = 3.75; 95% confidence interval (CI): 2.02–6.94 for highest versus lowest tertile) (P for trend = <0.0001). In contrast, longer telomere length was significantly inversely associated with SCC (OR = 0.01; 95% CI: 0.00–0.05 for highest versus lowest tertile) (P for trend = <0.0001) and BCC (OR = 0.10; 95% CI: 0.06–0.19 for highest versus lowest tertile) (P for trend = <0.0001). Conclusion: Telomere length may be involved in the development of skin cancer, although the effect on cancer risk differs for melanoma and non-melanoma carcinomas. Our findings suggest that long telomere length is positively associated with melanoma while inversely associated with SCC and BCC.     

Genetic polymorphisms involved in the inflammatory response and lung cancer risk: A case-control study in Japan

Evidence is accumulating that chronic inflammation may have an important mechanism for the development and progression of lung cancer. Therefore, genetic polymorphisms in genes that involved in the inflammatory response may be associated with lung cancer risk. We evaluated the role of tumor necrosis factor α (TNFA) rs1799724, interleukin 1β (IL1B) rs16944, IL6 rs1800796, myeloperoxidase (MPO) rs2333227 and C-reactive protein (CRP) rs2794520 in a case-control study comprised of 462 lung cancer cases and 379 controls in a Japanese population. Unconditional logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% CI). CRP rs2794520 (OR = 1.64, 95% CI = 1.19–2.26) and IL6 rs1800796 (OR = 1.41, 95% CI = 1.02–1.96) were associated with lung cancer risk. In addition, we assessed interactions between the polymorphisms and smoking. The polymorphisms did not significantly modify the association between smoking and lung cancer. As TNFA triggers a cytokine cascade, the modifying effect of the TNFA rs1799724 genotypes on the association of any of the remaining polymorphisms with lung cancer risk was also examined. There was a significant interaction between TNFA rs1799724 and MPO rs2333227 (P_interaction = 0.058). Future studies involving larger control and case populations will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the inflammation pathway in lung cancer.     

Genetic variation in a miR-335 binding site in BIRC5 alters susceptibility to lung cancer in Chinese Han populations

Polymorphisms in 3′ untranslated region (UTR) of cancer-related genes might affect their regulation by microRNAs (miRNAs) and thereby contribute to carcinogenesis. In this study, we screened single nucleotide polymorphisms (SNPs) in 3′ UTR of cancer-related genes and investigated their effects on risk of lung cancer. First, we genotyped seven SNPs in a Chinese Han population with 600 lung cancer patients and 600 matched healthy controls and found that compared with the TT genotype of rs2239680 in 3′ UTR of baculoviral IAP repeat containing 5 (BIRC5), C allele was associated with a significantly increased risk of lung cancer and advanced pathologic stage, with the odds ratio for participants carrying the CT or CC genotype being 1.50 [95% confidence interval (CI) 1.20–1.89, P < 0.01] and 2.29 (95% CI 1.64–3.18, P < 0.01), respectively. These results were further replicated and confirmed in another independent population with 1000 lung cancer cases and 1000 matched healthy controls. In support of the postulation that the 3′ UTR SNP may directly affect miRNA-binding site, reporter gene assays indicated BIRC5 was a direct target of miR-335, and the rs2239680 T > C change resulted in altered regulation of BIRC5 expression. Moreover, BIRC5 was over expressed in lung cancer tissues compared with the normal lung tissues, and the protein levels of BIRC5 correlated with SNP genotypes in normal lung tissues. Our findings defined a 3′ UTR SNP in human BIRC5 oncogene that may increase individual susceptibility to lung cancer probably by attenuating the interaction between miR-335 and BIRC5.     

High TMPRSS4 expression is a predictor of poor prognosis in cervical squamous cell carcinoma

Objective The aim of this study was to clarify the clinical role of TMPRSS4 expression in cervical squamous cell carcinoma (CSCC) and to investigate the role of TMPRSS4 in predicting outcomes of patients with CSCC. Methods The retrospective study enrolled 87 patients diagnosed with CSCC between 2004 and 2006. TMPRSS4 expression in CSCC was assessed by immunohistochemistry, and data on clinical variables were collected by retrospective chart review. The impact of TMPRSS4 expression on 5-year disease-free survival (DFS) and 5-year overall survival (OS) was assessed by Kaplan–Meier analysis and Cox proportional hazards modeling. Results The high expression of TMPRSS4 was 63.2% in 87 patients with CSCC, and 17.5% in 40 patients with benign cervical disease (P < 0.001). High TMPRSS4 expression was significantly associated with tumor grade (P = 0.005), lymph node metastasis (P = 0.004), and deep cervical stromal invasion (P = 0.025). Patients with high expression of TMPRSS4 had shorter OS and DFS than those with low expression (P = 0.0205 and P = 0.0318, respectively). In multivariate Cox regression analysis, high expression of TMPRSS4 was a potential prognostic indicator for OS (P = 0.041) and DFS (P = 0.015). Conclusion Our findings suggest that TMPRSS4 might play an important role in the progression of CSCC. TMPRSS4 could be a potential prognostic marker of CSCC.     

Significant association between hypolipoproteinemia(a) and lifetime risk of cancer: An autopsy study from a community-based Geriatric Hospital

BackgroundOur recent study showed that a low lipoproteinemia(a) [Lp(a)] level was a risk factor for cancer and all-cause deaths. The purpose of this study was to verify the role of the Lp(a) level on cancer among consecutive autopsy cases.MethodsThe subjects consisted of 1354 cases (775 men and 579 women). The average age at death was 79.9 years. Hypolipoproteinemia(a) was defined as an Lp(a) level of below 80 mg/L. Overall, 62.3% of the subjects had suffered from at least one to a maximum of five malignancies throughout their lives. The most frequent type of malignancy was gastric cancer, followed by leukemia, lung cancer, and colon cancer.ResultsThe cancer-bearing status decreased linearly according to the Lp(a) level in both men and women (P = 0.01 and P < 0.001, respectively). The median Lp(a) level was significantly lower among the cases with hepato-biliary–pancreatic cancers or hematopoietic malignancy, but was higher among cases with lung cancer, especially lung adenocarcinoma. Hypolipoproteinemia(a) was a significant risk factor for any origins of cancer, with an odds ratio of 1.94 (95% CI, 1.45–2.60; P < 0.001). It was also a risk factor for hepato-biliary cancers and leukemia, but it was a protective factor for lung cancer.ConclusionsOur findings suggested hypolipoproteinemia(a) would be a significant risk factor for cancer except lung cancer. This study complements our previous study showing that hypolipoproteinemia(a) would increase the lifetime risk of cancer other than lung cancer.     

Pulmonary CYP2A13 levels are associated with early occurrence of lung cancer—Its implication in mutagenesis of non-small cell lung carcinoma

CYP2A13, a human pulmonary specific cytochrome P450 enzyme, plays an important role in susceptibility to tobacco-specific nitrosamines (TSNAs)-induced lung cancer in humans. The pattern of CYP2A13 distribution in respiratory tract affects the susceptibility of the lung to carcinogens. CYP2A13 is expressed in the epithelium of trachea and bronchi; however its pattern of expression in human lung cancer remains largely unknown. This study aimed to determine the CYP2A13 expression in specimens from human non-small cell lung carcinomas (NSCLCs), i.e., adenocarcinoma and squamous carcinoma, by immunohistochemical (IHC) analysis and to identify the potential linkage between tumor CYP2A13 levels and some clinicopathological characteristics of NSCLC patients in Taiwan. The tumor CYP2A13 IHC staining signal was strong in 76% of the 112 study subjects. Study subjects (especially non-smoking or lung adenocarcinoma patients) with higher tumor CYP2A13 levels were younger. Multiple logistic regression analysis revealed that in younger subjects (age ≤ 66) and heavy smokers (pack-years ≥ 40), the odds ratio (OR) for positive tumor CYP2A13 staining was significantly higher than that for negative tumor CYP2A13 staining. Moreover, the association of EGFR gene mutations and positive tumor CYP2A13 staining was also revealed. In conclusion, these findings suggest the potential involvement of pulmonary CYP2A13 in the early occurrence of NSCLC as well as in the development of EGFR gene mutations.