Analysis of MUC6 polymorphisms on the clinicopathologic characteristics of Asian patients with oral squamous cell carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) are generally associated with tobacco consumption, alcohol abuse or both. Mucins (MUCs) are high-molecular-weight glycoproteins produced by many epithelial tissues. Many studies have indicated that MUCs play an important role in cancer metastasis. MUC6 expression has been observed in gastric and oncocytic phenotypes and plays an important role during cancer progression. We found that levels of MUC6 are lower in Asian HNCC patients and affect the disease-free survival of HNCC patients. Next, we investigated the combined effect of MUC6 polymorphisms and exposure to environmental carcinogens on the susceptibility to and clinicopathological characteristics of HNCC. Three single-nucleotide polymorphisms (SNPs) of MUC6 (rs7481521, rs6597947 and rs61869016) were analysed using real-time PCR. After adjusting for other co-variants, we found that carrying a CC genotype at MUC6 rs6597947 led to a lower risk of developing oral squamous cell carcinoma (OSCC) than wild-type carriers among non-betel-quid chewers. Moreover, male oral cancer patients who carried the AA + CC genotype at MUC6 rs6597947 had a lower risk of lymph node metastasis than other genotypes, suggesting a significant functional compromise and decompensated disease. Therefore, our findings suggest that genetic variations in MUC6 may correlate to OSCC and indicate the progression in OSCC patients.

TRIM21 Polymorphisms are associated with Susceptibility and Clinical Status of Oral Squamous Cell Carcinoma patients.

Squamous cell cancer of head and neck (HNSCC) is the sixth most common malignancy worldwide. One of the most common HNSCC types is oral squamous cell carcinoma (OSCC), which is the fifth leading cause of cancer death in Taiwan. Tripartite motif 21 (TRIM21) has been reported to play an important role in different cancer types. We found a correlation between TRIM21 and survival of HNSCC patients, but little information exists about how altered TRIM21 expression contributes to tumorigenesis. Thus, we investigated the combined effect of TRIM21 polymorphisms and exposure to environmental carcinogens on the susceptibility and clinicopathological characteristics of OSCC. Two single-nucleotide polymorphisms (SNPs) of TRIM21 (rs4144331, rs915956) from 1194 healthy controls and 1192 OSCC patients were analyzed by real-time PCR. Among 1632 smokers, TRIM21 polymorphism carriers with the betel-nut chewing habit had a ~4.8-fold greater risk of OSCC than TRIM21 wild-type carriers without the betel-nut chewing habit. After adjusting for other covariants, OSCC patients with G/T at TRIM21 rs4144331 had a high risk for distant metastasis compared with G/G homozygotes. This study is the first to examine the risk factors associated with TRIM21 SNPs in OSCC progression and development. Thus, our findings suggest that this study is the first to examine the risk factors associated with TRIM21 SNPs in OSCC progression and development and suggest that interactions between mutant genes may alter the susceptibility to OSCC.

A rare case of synchronous multiple primary lung cancer with different responses to gefitinib.

Differentiating multiple primary lung cancer (MPLC) from lung metastasis is important, and the pathology and gene mutations may be different between the tumors. A lung biopsy to differentiate lesions should be considered, especially when the response of different tumors to treatment is distinct.

Focal conformal fractionated radiotherapy vs. radiosurgery for lung cancer patients with limited brain metastases.

BACKGROUND: For lung cancer (LC) patients with limited brain metastases (LBM), radiosurgery (RS) was the current preferred strategy. We aimed to report our experience regarding an alternative strategy (focal conformal fractionated radiotherapy, FCFRT) for these patients in this cohort study. METHODS: We identified LC patients with LBM treated with either FCFRT or RS within 2016-2019 without prior brain local treatment via in-house databases. The characteristics of patients, disease, treatment, and outcome were retrospectively obtained via chart review and peer review. The 1st day of FCFRT or RS was the index date. Overall survival (OS) was calculated from the index date to the last date of contact or death via the Kaplan-Meier method. Log-rank test was used in univariate analyses (UVA) whereas Cox regression method was used in the multivariate analyses (MVA). The incidence of local progression (LP) or distal brain metastases (DBM) was estimated by the competing risk approach with death as the competing risk. RESULTS: We identified 23 eligible patients. The median dose/fractionation for FCFRT was 36 Gy/10 fractions. The median dose for RS was 20 Gy. The Lung-molGPA prognostic groups' distribution for these two groups was not statistically different. After a median follow-up of 8 months (range, 1-38 months), the OS was not statistically different in UVA [P value 0.9]. The adjusted hazard ratio of death was 0.96 when FCFRT was compared to RS in MVA (95% CI, 0.21-5.22). There was also no statistical significant difference in LP (P value 0.79) or DBM (P value 0.88). CONCLUSIONS: For LC patients with LBM, the OS was not statistically different for definitive FCFRT or RS. There was also no statistical difference in LP or DBM. Further studies should be considered to clarify the indication of FCFRT.

Prognostic Significance of Oligometastatic Disease Classification by the ESTRO/EORTC of Cancer for Patients With Lung Cancer Treated With Definitive Radical Radiotherapy.

BACKGROUND: Randomized controlled trials had demonstrated local therapy, such as radiotherapy, can improve outcomes of patients with lung cancer with oligometastatic disease (OMD). However, the definition of OMD is not uniform and the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) proposed a new classification in 2020 comprising nine subtypes. Therefore, we aimed to investigate the prognostic significance of this European classification for patients with lung OMD treated with definitive radical radiotherapy. PATIENTS AND METHODS: We identified eligible patients via an in-house database. Patient, disease, and treatment characteristics, as well as outcomes, were obtained via chart review plus peer review. Overall and progression-free survival were estimated via the Kaplan-Meier method. Log-rank test was used in univariate analysis and Cox regression in multivariable analyses to investigate the prognostic significance of the subtypes of OMD. RESULTS: We identified 35 eligible patients with six different OMD subtypes treated from 2011 to 2019. After a median follow-up of 23 (range=2-88) months, the median progression-free and overall survival were 11 and 38 months, respectively. The prognosis for patients with the subtype 'induced oligoprogression' was statistically worse than for those without in both univariate (p=0.02) and multivariate (adjusted hazard ratio for death=4.8, 95% confidence interval=1.4-16.2, p=0.01) analyses. CONCLUSION: We found the subtype with induced oligoprogression in the European classification to be associated with worse survival. Further studies are needed to confirm our finding.

A population-based study of primary chemoradiotherapy in clinical stage III non-small cell lung cancer: intensity-modulated radiotherapy versus 3D conformal radiotherapy.

AIM: To compare the effectiveness of intensity-modulated radiotherapy (IMRT) vs. 3D conformal radiotherapy (3DCRT) for clinical stage III non-small cell lung cancer (NSCLC) treated with primary chemoradiotherapy via a population-based retrospective cohort analysis. PATIENTS AND METHODS: Using the Collaboration Center of Health Information Application (CCHIA) database, we identified 99 patients with stage III NSCLC treated with primary chemoradiotherapy from 2007 to 2009, with complete data available for analysis. We compared the risk of death within two years of diagnosis and the hazard ratio for death between those treated with IMRT and those with 3DCRT. Univariate and multivariate analyses were conducted to determine the efficacy of IMRT and 3DCRT. Sensitivity analyses were also conducted to assess relationships in the various subgroups. RESULTS: The risk of death within two years of diagnosis was similar for IMRT and 3DCRT (36% vs. 37%, p=0.97). For the entire follow-up period, the probability of death was not statistically different when IMRT was compared to 3DCRT (p=0.8). On multivariate analysis, the adjusted hazard ratio of death was statistically insignificantly higher for IMRT vs. 3DCRT (hazard ratio of death=1.54, 95% confidence interval=0.82-2.91, p=0.18). The results remained similar in the sensitivity analyses. CONCLUSION: Our population-based analysis from CCHIA suggests that for patients with clinical stage III NSCLC treated with primary chemoradiotherapy, the survival outcome of those treated with IMRT was not superior to those treated with 3DCRT. Further prospective studies and cost-effectiveness analyses are warranted.

Inhibitory effect of dihydroaustrasulfone alcohol on the migration of human non-small cell lung carcinoma A549 cells and the antitumor effect on a Lewis lung carcinoma-bearing tumor model in C57BL/6J mice.

There are many major causes of cancer death, including metastasis of cancer. Dihydroaustrasulfone alcohol, which is isolated from marine coral, has shown antioxidant activity, but has not been reported to have an anti-cancer effect. We first discovered that dihydroaustrasulfone alcohol provided a concentration-dependent inhibitory effect on the migration and motility of human non-small cell lung carcinoma (NSCLC) A549 cells by trans-well and wound healing assays. The results of a zymography assay and Western blot showed that dihydroaustrasulfone alcohol suppressed the activities and protein expression of matrix metalloproteinase (MMP)-2 and MMP-9. Further investigation revealed that dihydroaustrasulfone alcohol suppressed the phosphorylation of ERK1/2, p38, and JNK1/2. Dihydroaustrasulfone alcohol also suppressed the expression of PI3K and the phosphorylation of Akt. Furthermore, dihydroaustrasulfone alcohol markedly inhibited tumor growth in Lewis lung cancer (LLC)-bearing mice. We concluded that dihydroaustrasulfone alcohol is a new pure compound with anti-migration and anti-tumor growth activity in lung cancer and might be applied to clinical treatment in the future.

Economic Burden of Diabetes Mellitus on Patients with Respiratory Failure Requiring Mechanical Ventilation during Hospitalizations.

OBJECTIVES: To examine the economic burden of diabetes mellitus (DM) on medical expenditure among patients with respiratory failure (RF) requiring mechanical ventilation during hospitalization. METHODS: We extracted the data from Taiwan National Health Research Insurance Database for those adult patients on their first hospitalization for RF requiring mechanical ventilation between 2004 and 2010. We examined associations between medical expenditure and the presence of comorbid DM. We performed independent t tests, chi-square tests, and multivariate linear regression analysis to identify factors associated with excess medical expenditure. RESULTS: Of 347,961 patients hospitalized with first occurrence of RF requiring mechanical ventilation, 123,023 (35.36%) patients were documented to have a previous diagnosis of DM. Patients with RF and DM were sicker and consumed more health care resources than did patients with RF without DM. After adjusting for the specified covariates, mechanically ventilated patients with RF and DM consumed at least US $618 more of total inpatient medical expenditure than did patients with RF without DM. There were statistically significant interactions between age and DM on their total inpatient medical expenditure regardless of discharge status. CONCLUSIONS: DM was associated with more severe disease status and higher consumption of medical expenditure during hospitalizations among mechanically ventilated patients due to first occurrence of RF in Taiwan. These findings provide scientific evidence to facilitate appropriate resource allocation and formulate programs for higher quality of care in the future in Taiwan and other countries.

Pleura detection in chest computed tomography with application for nodule detection.

This paper proposes an efficient algorithm for detecting pleural objects that come in contact with a nodule. To reduce complexity, the algorithm recursively performed a curve-fitting method on each slice of the volume of interest to locate the object between the parietal and visceral pleurae surfaces and measured the quality of the fitting curve. When a nodule contacted the surfaces of the chest wall or diaphragm, they were automatically separated using the fitting curve. The algorithm was performed on 864 slices of 40 nodules. The segmentation results were visually inspected by a consensus of attending physicians to search for any segmentation errors. The consensus accepted 93.6% of the segmentation results.

Association of hypoxia inducible factor-1α polymorphisms with susceptibility to non-small-cell lung cancer.

Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of cellular response to hypoxia and has been suggested to play an important role in tumorigenesis and metastasis. The aim of this study was to investigate the role of HIF-1α-1772 C/T (P582S) and -1790 G/A (A588T) polymorphisms in the susceptibility to and severity of non-small-cell lung cancer (NSCLC). Using a case-control study design and polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) analysis, the allele frequencies and genotype distributions of each single nucleotide polymorphism in 285 NSCLC cases and 300 gender-matched controls were compared. The distribution of the genotype frequencies of HIF-1α-1772 C/T and -1790 G/A were significantly different between the NSCLC and the controls. Logistic regression analysis revealed that higher odds ratios (ORs) for lung cancer were observed for individuals with HIF-1α-1772 T/T genotype against CC/CT genotypes (an OR of 4.04, 95% confidence interval [CI] = 2.02-8.08, P = 0.0001), and HIF-1α-1790 A/A genotype against GG/GA genotypes (an OR of 4.42, 95% CI 2.22-8.78, P < 0.0001). There were no relationship between HIF-1α-1772 C/T or -1790 G/A allele distribution and disease severity of NSCLC (P > 0.05). However, those patients carrying a HIF-1α-1772 T/T genotype or a HIF-1α-1790 A/A had a tendency toward inferior prognosis compared with other patients.

Vascular endothelial growth factor C as a predictor of early recurrence and poor prognosis of resected stage I non-small cell lung cancer.

INTRODUCTION: Stage I non-small cell lung cancer (NSCLC) is potentially curable after completely resection, but early recurrence may infl uence prognosis. This study hypothesises that vascular endothelial growth factor C (VEGF-C) plays a key role in predicting early recurrence and poor survival of patients with stage I NSCLC. MATERIALS AND METHODS: The expression of VEGF-C was immuno-histochemically (IHC) analysed in tumour samples of primary stage I NSCLC and correlated to early recurrence (< 36 months), disease-free survival, and overall survival in all 49 patients. RESULTS: Early recurrence was identifi ed in 16 patients (33%), and the early recurrence rate in strong and weak VEGF-C activity was significantly different (P = 0.016). VEGF-C was also an independent risk factor in predicting early recurrence (HR = 3.98, P = 0.02). Patients with strong VEGF-C staining also had poor 3-year disease-free survival (P = 0.008) and overall survival (P = 0.007). CONCLUSION: Strong VEGF-C IHC staining could be a biomarker for predicting early recurrence and poor prognosis of resected stage I NSCLC, if the results of the present study are confirmed in a larger study. A more aggressive adjuvant therapy should be used in this group of patients.

Association of genetic polymorphisms of CXCL12/SDF1 gene and its receptor, CXCR4, to the susceptibility and prognosis of non-small cell lung cancer.

BACKGROUND: The aim of this study was to evaluate the relations of chemokine CXCL12, previously known as stromal cell-derived factor-1 (SDF1), and its receptor, CXCR4, gene variants on non-small cell lung cancer (NSCLC) risk and disease severity. METHODS: Through a case-control study design, genomic DNA samples of 247 NSCLC patients and 328 age and sex-matched controls were subjected to polymerase chain reaction-restriction fragment length polymorphism analysis. The validity of this technique was proven by direct sequencing of amplified products. Statistical analyses were conducted to explore the contribution of polymorphism of the CXCL12/SDF1 gene and CXCR4, in the susceptibility to and prognosis of NSCLC. RESULTS: Overall, the genotype frequencies of CXCL12/SDF1 gene and CXCR4, were significantly different between lung cancer patients and controls (p<0.0001), and also different between patients with lung cancers of various stages (p<0.0001). Logistic regression analysis revealed that higher odds ratios (ORs) for lung cancer were seen for individuals with CXCL12/SDF1 AA (an OR of 1.95, 95% CI 1.08-3.50, p=0.018), or CXCR4 TT (an OR of 4.71, 95% CI 1.99-11.2, p<0.0001), and for individuals with both CXCL12/SDF1 AA and CXCR4 TT genotypes (an OR of 12.4, 95% CI 1.56-98.3, p=0.002). The patients carrying a homologous AA genotype at CXCL12/SDF1, or a homologous TT genotype at CXCR4, had a tendency to advanced disease and toward poorer prognoses compared with other patients. CONCLUSION: A significant association between the polymorphisms of CXCL12/SDF1 and CXCR4, and the susceptibility to and prognosis of NSCLC was demonstrated.

Association of polymorphisms in the genes of the urokinase plasminogen activation system with susceptibility to and severity of non-small cell lung cancer.

BACKGROUND: Urokinase plasminogen activating (uPA) system is implicated in neoplastic progression. High tissue levels of uPA system components correlate with a poor prognosis in lung cancer. The present study examined the single nucleotide polymorphisms (SNPs) of uPA and the corresponding receptor, uPAR, for exploring their roles in non-small cell lung cancer (NSCLC). METHODS: The allele frequencies and genotype distributions of uPA rs4065 C/T and uPAR rs344781 (-516 T/C) among 375 NSCLC cases and 380 healthy controls were examined using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) analysis. Putative association between the above SNPs and clinicopathological characteristics of NSCLC were also analyzed. RESULTS: The genotype frequencies of the variant homozygotes of uPA and uPAR were significantly different between NSCLC and control subjects. Significant association was also observed between the examined genotypes and disease stage of NSCLC. Logistic regression analysis revealed that individuals with uPA rs4065 TT genotype have higher odds ratios (ORs) for lung cancer. Whereas, subjects with uPAR-344781 CC genotype have lower ORs for lung cancer. The patients carrying a homozygous TT genotype at uPA rs4065, or at least a T allele at uPAR-344781 (-516), had a tendency to develop advanced disease. CONCLUSIONS: Our results revealed that genetic polymorphisms of the uPA rs4065 C/T and uPAR rs344781 (-516 T/C) were associated with the susceptibility and severity of NSCLC.

Association of EcoRI polymorphism of the metastasis-suppressor gene NME1 with susceptibility to and severity of non-small cell lung cancer.

BACKGROUND: Human lung cancer cells with high metastatic potential show reduced expression of the metastasis-suppressor gene NME1. However, the biallelic EcoRI polymorphism of this gene has not been studied in lung cancer. With this allelic association study, we aimed to investigate the impact of polymorphisms of the NME1 gene on the susceptibility to and severity of non-small cell lung cancer (NSCLC). METHODS: Through a case-control study design, genomic DNA samples of 255 NSCLC patients and 303 controls, who were age and sex-matched and recruited from the health check-up unit, were subjected to polymorphism analysis with polymerase chain reaction-restriction fragment length polymorphism technique. The validity of this technique was proven by direct sequencing of polymerase chain reaction products. Statistical analyses were conducted to explore the contribution of polymorphism of the metastasis-suppressor gene NME1 in the susceptibility to and severity of NSCLC. RESULTS: Overall, the genotype frequencies of NME1 gene were significantly different between lung cancer patients and controls (p < 0.0001), and also different between patients with lung cancers of various stages (p < 0.0001). Logistic regression analysis revealed that higher odds ratios (ORs) for lung cancer were seen in patients homozygous (+/+) for variant allele (an OR of 4.02, 95% CI 2.39-6.76; p < 0.0001). Patients carrying a variant polymorphic homozygote (+/+) also had a tendency to advanced disease (p = 0.001). CONCLUSION: A significant association between the polymorphisms of NME1 gene and the susceptibility to and severity of lung cancer was demonstrated.