Factor In Squamous Cell Carcinoma Research Articles

Risk of oesophageal cancer among patients previously hospitalised with eating disorder

BackgroundIt has been suggested that the risk of oesophageal adenocarcinoma might be increased in patients with a history of eating disorders due to acidic damage to oesophageal mucosa caused by self-induced vomiting practiced as a method of weight control. Eating disorders have also been associated with risk factors for squamous cell carcinoma of the oesophagus, including alcohol use disorders, as well as smoking and nutritional deficiencies, which have been associated with both main sub-types of oesophageal cancer. There have been several case reports of oesophageal cancer (both main sub-types) arising in patients with a history of eating disorders. MethodsWe used linked records of hospitalisation, cancer registration and mortality in Scotland spanning 1981–2012 to investigate the risk of oesophageal cancer among patients with a prior history of hospitalisation with eating disorder. The cohort was restricted to patients aged ≥10 years and <60 years at the date of first admission with eating disorder. Disregarding the first year of follow-up, we calculated indirectly standardised incidence ratios using the general population as the reference group to generate expected numbers of cases (based on age-, sex-, socio-economic deprivation category-, and calendar period-specific rates of disease). ResultsAfter exclusions, the cohort consisted of 3617 individuals contributing 52,455 person-years at risk. The median duration of follow-up was 13.9 years. Seven oesophageal cancers were identified, as compared with 1.14 expected, yielding a standardised incidence ratio of 6.1 (95% confidence interval: 2.5–12.6). All were squamous cell carcinomas arising in females with a prior history of anorexia nervosa. ConclusionsPatients hospitalised previously with eating disorders are at increased risk of developing oesophageal cancer. Confounding by established risk factors (alcohol, smoking, and nutritional deficiency) seems a more likely explanation than acidic damage through self-induced vomiting because none of the incident cases of oesophageal cancer were adenocarcinomas, and because the study cohort had higher than background rates of hospitalisation with alcohol-related conditions and chronic obstructive pulmonary disease.

Metadherin regulation of vascular endothelial growth factor expression is dependent upon the PI3K/Akt pathway in squamous cell carcinoma of the head and neck.

Our previous study indicated overexpression of metadherin (MTDH) is an adverse prognostic factor in squamous cell carcinoma of the head and neck (SCCHN) and promotes SCCHN cell proliferation and invasion. However, its mechanism remains unclear. Recent studies have indicated that MTDH is a cancer-metastasis-associated molecule that participates in the process of angiogenesis. Therefore, the study is aimed to investigate that whether vascular endothelial growth factor (VEGF), as one of the most potent proangiogenic cytokines, is regulated by MTDH and the role of the phosphatidylinositide 3-kinases/Protein Kinase B (PI3K/Akt) pathway in this process of regulation and the clinical significance of both MTDH and VEGF in SCCHN.Immunohistochemistry was used to assay the expression of MTDH and VEGF in a cohort of 189 SCCHN patients with intact follow-up information. The expression of MTDH was then upregulated or inhibited by lentivirus-mediated MTDH Complementary deoxyribonucleic acid or MTDH short hairpin ribonucleic acid (shRNA) to observe the resulting alterations in VEGF expression and the PI3K/Akt signaling pathway in SCCHN cell lines. In addition, the PI3K/Akt pathway was modulated to observe the resulting changes in the MTDH-mediated expression of VEGF.The immunohistochemistry data showed that MTDH expression is positively correlated with VEGF expression in SCCHN tissues. Moreover, the overexpression of MTDH in SCCHN Tu686 and 5-8F cells led to increases in the expression of VEGF, and this effect was accompanied by activation of the PI3K/Akt pathway. Conversely, shRNA-mediated knockdown of MTDH led to decreased VEGF expression. In addition, inhibition of the Akt signaling pathway reversed the upregulation of VEGF resulting from MTDH overexpression. Moreover, the survival analysis revealed that VEGF is an independent prognostic factor, and a combined survival analysis based on both MTDH and VEGF showed synergistic effects in the prognosis evaluation of SCCHN patients.The findings of the present study demonstrate that MTDH regulates the expression of VEGF via the PI3K/Akt signaling pathway, indicating the potential role of the MTDH-mediated activation of VEGF signaling pathway in SCCHN angiogenesis and metastasis.

Downregulation of MTSS1 expression is an independent prognosticator in squamous cell carcinoma of the lung.

Background:The metastasis suppressor 1 (MTSS1) is a newly discovered protein putatively involved in tumour progression and metastasis.Material and Methods:Immunohistochemical expression of MTSS1 was analysed in 264 non-small-cell lung carcinomas (NSCLCs).Results:The metastasis suppressor 1 was significantly overexpressed in NSCLC compared with normal lung (P=0.01). Within NSCLC, MTSS1 expression was inversely correlated with pT-stage (P=0.019) and histological grading (P<0.001). NSCLC with MTSS1 downregulation (<20%) showed a significantly worse outcome (P=0.007). This proved to be an independent prognostic factor in squamous cell carcinomas (SCCs; P=0.041), especially in early cancer stages (P=0.006).Conclusion:The metastasis suppressor 1 downregulation could thus serve as a stratifying marker for adjuvant therapy in early-stage SCC of the lung.

Correlation between squamous cell carcinoma of the lung and human papillomavirus infection and the relationship to expression of p53 and p16.

The number of non-small-cell lung cancer (NSCLC) patients reported as infected with human papillomavirus (HPV) varies among countries and by race and geographical location. Furthermore, the relationship between HPV and the expressions of p53 and p16 remains unclear. A large cohort of NSCLC patients from Shanghai was studied. Paraffin sections from 128 cases of lung adenocarcinoma (ADC) and 134 cases of squamous cell carcinoma (SQC) were collected from the Shanghai Chest Hospital. Samples were analyzed by polymerase chain reaction (PCR) and reverse dot blot for detection of HPV DNA and by immunohistochemistry for detection of p53 and p16 expressions. The rate of HPV infection in SQC cases was significantly higher than in ADC cases (12.69 versus 3.91%). Females with SQC had a significantly higher rate of HPV infection compared to males with SQC (18.75 versus 7.14%, p = 0.044). HPV infection was correlated with gender and age in SQC but not with the degree of tumor differentiation, TNM stage, or smoking. Koilocytosis was significantly correlated to the tumor differentiation grade, regardless of age and TNM stage. The expressions of p53 and p16 were correlated with HPV infection and the tumor histological type but not with the degree of tumor differentiation, TNM stage, smoking, gender, or age. p53-positive expression was significantly higher in HPV-infected SQC cases than in those not infected with HPV. There was no statistically significant difference in the expression of p16 between the two groups. Data showed that HPV infection may be an important virulence factor in SQC, particularly in female patients. HPV infection appears to be involved in cancer progression in SQC by promoting the expression of p53; however, p16 cannot be used as a surrogate marker for HPV infection in SQC.

Role of fibroblast growth factor in squamous cell carcinoma of the bladder: Prognostic biomarker and potential therapeutic target

BackgroundWe evaluated the association of fibroblast growth factor (FGF2) expression with pathologic features and clinical outcomes of squamous cell carcinoma (SCC) of the urinary bladder. MethodsImmunohistochemistry of FGF2 was performed on radical cystectomy specimens with pure SCC from 1997 to 2003. The relationship between FGF2 and pathologic parameters and oncological outcome was assessed. ResultsThe study included 151 patients with SCC (98 men) with a median age of 52 years (range: 36–74y). Schistosomal infection was found in 81% of patients. Pathologic category was T2 and T3 in 88% of patients and the grade was low in>50%. Lymph node invasion and lymphovascular invasion were found in 30.5% and 16%. Altered FGF2 was associated with tumor grade (P = 0.014), lymph node invasion, and lymphovascular invasion (P = 0.042). Altered FGF2 was associated with both disease recurrence and cancer-specific mortality (P≤0.001) in Kaplan-Meier analyses and was an independent predictor of cancer recurrence (hazard ratio = 2.561, P = 0. 009) and cancer-specific mortality (hazard ratio = 2.679, P = 0. 033) in multivariate Cox regression analyses. Adding FGF2 to a model including standard clinicopathologic prognostics (pathologic T category, lymph node status, and grade) showed a significant improvement (6%) in accuracy of prediction poor oncological outcome. ConclusionsFGF2 overexpression is associated with aggressive pathologic features and worse outcomes after radical cystectomy for SCC, suggesting a good prognostic and possible therapeutic role.

Immunohistochemical expression of apoptosis regulators in squamous cell carcinoma of the cervix and their association with human papillomavirus 16/18 subtypes.

Human papillomavirus (HPV) infection is an important aetiological factor in squamous cell carcinoma (SCC) of the cervix. Limited studies have been focused on the differences between carcinogenesis of SCCs with and without HPV infection. The main goal of this study is to determine the expression of some of the apoptotic pathway regulators, including P53, Bax and Bcl2 in SCCs with and without high risk HPV 16/18 infection. Cross sectional study. A total of 42 paraffin-embedded blocks with the histopathological diagnosis of invasive SCC with determined HPV 16/18 status were selected; half of them were HPV positive and the rest were negative. Afterwards, immunohistochemistry stained slides for p53, Bcl2 and Bax were evaluated with H-score, multiplicative and Additive Quick score by two pathologists; in cases of controversy about the results, the mean results were recorded. Mean results and percentage of expression of our three markers were significantly higher in the HPV 16/18 infected group than in uninfected individuals: Respectively, the mean score for Bcl2, Bax and p53 staining according to H-scoring method was 68.5, 234, 106.4 in the HPV 16/18 infected group and 4.5, 218.8, 5.07 in the uninfected group; and the Multiplicative Quick score was 4, 14.6, 8.2 in the HPV 16/18 infected group and 3, 12.3, 3.5 in the uninfected group. High risk HPVs possibly act in favour of apoptotic pathway inactivation. The significant difference in apoptotic pathway between SCCs with and without high risk HPVs suggests a different early carcinogenesis pathway.

IMP3 expression is associated with poor survival in cervical squamous cell carcinoma.

Insulin-like growth factor II messenger RNA (mRNA)-binding protein 3 (IMP3) is an oncofetal protein that promotes tumor progression and metastasis in a number of malignancies. However, the clinical significance of IMP3 expression in squamous cell carcinoma (SCC) of the uterine cervix is unclear. In this study, the correlation between IMP3 expression and cervical cancer progression and prognosis was assessed by immunohistochemistry. IMP3 expression was observed in a large number of tissue specimens from patients with normal cervical tissues, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III, and SCC. IMP3 protein and mRNA expression was also determined in the SiHa and HeLa human cervical cancer cell lines. IMP3 expression was observed in 0 (0%) of 62 CIN I, 0 (0%) of 38 CIN II, and 9 (8.7%) of 104 CIN III specimens. Of the 96 SCC cases, IMP3 expression was detected in 54 cases (56.3%). Significant difference in IMP3 expression existed between all of the groups tested (P < .001). IMP3 protein and mRNA expressions in SiHa and HeLa cell lines were dramatically increased, as compared with normal tissue (P < .001). IMP3 expression was significantly related to age (P < .001), International Federation of Gynecology and Obstetrics stage (P < .001), and lymph node metastasis (P = .001). IMP3 expression was also shown to be an independent prognostic factor in SCC. In conclusion, these findings suggest that IMP3 expression may be a prognostic indicator of SCC.

Clinical and prognostic analysis of second primary squamous cell carcinoma of the tongue after radiotherapy for nasopharyngeal carcinoma

We have investigated the clinical characteristics and prognostic factors of squamous cell carcinoma (SCC) of the tongue after definitive radiotherapy for nasopharyngeal carcinoma, and evaluated the effect of common therapeutic regimens for these patients. We retrospectively reviewed follow-up data for patients whose nasopharyngeal carcinoma had been treated by radiotherapy, and selected the 68 who had then developed SCC of the tongue, in the border of the tongue in half, and in the dorsum in 25 (37%). Eight of the 68 patients had clinical lymph node metastasis (12%), and 45 presented with stage I-II disease at the time of the diagnosis of the SCC (66%). Resection or radiotherapy alone was an effective treatment for patients with stage I-II SCC of the tongue, but patients with stage III-IV disease had a poor prognosis, despite being given multidisciplinary treatment. Multivariate analysis showed that the risk factors that independently influenced the survival of these patients were use of alcohol, recurrence of their nasopharyngeal carcinoma, the latency period, and the clinical TNM stage. Tongue SCC after radiotherapy was generally at an early stage and commonly occurred on the border or the dorsum of the tongue, with few lymph node metastases. Resection or radiotherapy is an effective treatment, and the risk factors that independently influenced the survival of patients indicate that improving the technique of radiotherapy and close follow-up after nasopharyngeal cancer are vitally important.

Prognostic Factors of Squamous Cell Carcinoma of the Buccal Mucosa: A Retrospective Study of 168 Cases in North China

Buccal mucosa squamous cell carcinoma (BSCC) is considered a rare and aggressive malignancy that has a high rate of locoregional recurrence. The aim of this study was to analyze the outcome of surgical therapy as a treatment for BSCC in a North Chinese population over a period of 14 years. A retrospective study was performed by reviewing the records and pathologies of 168 patients with BSCC who were treated at the Department of Oral and Maxillofacial Surgery, Stomatological Hospital, Peking University, from June 1999 to September 2013. The rates of local, regional, and locoregional recurrence were 47.3%, 13.5%, and 6.8%, respectively. The neck metastasis rate in patients classified as having cN0 was 28.4%, and the occult metastasis rate in patients with BSCC stages T2 to T4 was higher than 15%. Neck metastases were most common at levels I and II. The 3-year disease-free survival, overall survival, and disease-specific survival rates were 60.6%, 74.6%, and 78.0%, respectively. Gender, T stage, pathologic node status, and pathologic grade were significant factors in determining disease-specific survival. However, only pathologic node status (P = .002) was an independent predictive factor of 3-year disease-specific survival. Buccal carcinoma is an aggressive disease with high rates of local and regional recurrence. In seeking to offer better prognoses and quality of life, extensive resection of the primary tumor, supraomohyoid neck dissection, and preferred free flap reconstruction are the therapies that have been recommended and used in the authors' hospital during the past 10 years.

SLC23A2-05 (rs4987219) and KRAS-LCS6 (rs61764370) polymorphisms in patients with squamous cell carcinoma of the head and neck.

Cancer is a genetic disease that is highly influenced by environmental factors. To determine the risk factors of squamous cell carcinoma of the head and neck, two polymorphisms, solute carrier family 23 member 2 (SLC23A2-05 [rs4987219]) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-LCS6 (rs61764370), and environmental factors, including smoking and alcohol consumption, were studied in a population. The present study included 165 males diagnosed with squamous cell carcinoma of the head and neck. The control group consisted of 230 healthy male subjects without cancer or a family history of cancer. The SLC23A2-05 and KRAS-LCS6 polymorphisms were analyzed by polymerase chain reaction followed by enzymatic digestion. All patients and healthy subjects were assessed with regard to their smoking habit and alcohol consumption as these are considered to be risk factors for cancer. The statistical analysis was performed using logistic regression, Fisher’s exact and χ2 tests. Additional analyses were performed using the programs, multi-factor dimensionality reduction (MDR; version 2.0) and MDR permutation test (version 0.4.7), which consider all variables as risk factors simultaneously. The results of the present study demonstrate that the SLC23A2-05 and KRAS-LCS6 polymorphisms are not a risk factor for squamous cell carcinoma of the head and neck. In the same samples, the association of alcohol consumption (P<0.001) and smoking habit (P<0.001) with cancer presence was positive when each variable was considered individually. Concerning the environmental factors, a positive association of smoking habit and alcohol consumption with cancer, although not with ethnicity (ratio, 1.0244; testing balance accuracy, 0.8733; P<0.001) was identified using the MDR tool, which analyzed the variables and polymorphism genotypes simultaneously. In conclusion, in the present study, squamous cell carcinoma of the head and neck was highly affected by environmental factors when compared with the affect of SLC23A2-05 and KRAS-LCS6 polymorphisms.

XPA gene rs1800975 single nucleotide polymorphism and lung cancer risk: a meta-analysis

No clear consensus has been reached on the XPA gene rs1800975 polymorphism and lung cancer risk. We performed a meta-analysis in an effort to systematically explore the possible association. We conducted a computer retrieval of PubMed, Embase, Wanfang, China National Knowledge Infrastructure Platform, and VIP databases prior to November 2013. References of retrieved articles were also screened. The fixed- and the random-effects model were applied for dichotomous outcomes to combine the results of the individual studies. According to the inclusion criteria, 10 articles (11 studies) were finally included. In overall, statistical association could be found between rs1800975 polymorphism and lung cancer in recessive genetic model [AA vs. (AG + GG): P = 0.02, OR = 1.16, 95% CI 1.02-1.31, P heterogeneity = 0.14, fixed-effects model]. In the East Asians, significant association was found in allele comparison model (A vs. G: P = 0.03, OR = 1.13, 95% CI 1.01-1.26, P heterogeneity = 0.39, fixed-effects model), in recessive genetic model [AA vs. (AG + GG): P = 0.005, OR = 1.30, 95% CI 1.08-1.56, P heterogeneity = 0.58, fixed-effects model] and in the homozygote comparison (AA vs. GG: P = 0.02, OR = 1.30, 95% CI 1.04-1.63, P heterogeneity = 0.39, fixed-effects model). No evidence suggested that rs1800975 polymorphism might associate with lung cancer in other ethnicities. Stratification analysis performed by histologic types indicated that AA genotype might represent a risk factor for squamous cell carcinoma [AA vs. (AG + GG): P = 0.01, OR = 1.42, 95% CI 1.08-1.86, P heterogeneity = 0.27, fixed-effects model; AA vs. GG: P = 0.03, OR = 1.43, 95% CI 1.04-1.96, P heterogeneity = 0.21, fixed-effects model]. No association was observed in adenocarcinoma subgroup. Our study suggested that XPA rs1800975 polymorphism might associate with lung cancer risk in overall and in East Asians. This polymorphism might also associate with squamous cell carcinoma.

Evaluation of Nerves in Mohs Micrographic Surgery: Histologic Mimickers of Perineural Invasion and Nervous Tissue on Frozen Section

Perineural invasion (PNI) is an important histologic finding and may be a negative prognostic factor for squamous cell carcinoma (SCC). It may be associated with more-aggressive tumor behavior. Mohs surgeons encounter microscopic PNI regularly and must be able to diagnose it accurately to guide care decisions. To describe benign histologic mimickers of PNI and neural structures in SCC commonly encountered on frozen, hematoxylin and eosin-stained sections and to review how to differentiate them from PNI. Review of the literature regarding histologic mimickers of PNI and additional contributions to frozen section PNI and nerve tissue mimickers. We describe benign findings, including arrector pili muscles, eccrine muscles, vessels, granulomatous inflammation, and eddies of SCC, that may each be mistaken for nerves or PNI. We discuss the ways in which they may be distinguished on frozen sections and review other commonly encountered entities that resemble PNI. Perineural inflammation and peritumoral fibrosis are common mimickers of PNI on frozen section, although other mimickers exist on permanent sections. Normal structures may appear "neural" by way of frozen tissue orientation, processing, or inflammation and thus must be differentiated from nerve tissue and PNI during Mohs surgery.

Importance of High Clinical Suspicion in Diagnosing a Marjolin's Ulcer with an Unusual Presentation

Importance of High Clinical Suspicion in Diagnosing a Marjolin's Ulcer with an Unusual Presentation

Overexpression of melanoma-associated antigen D4 as an independent prognostic factor in squamous cell carcinoma of the esophagus.

71 Background: To pursue an urgently needed treatment target for esophageal cancer (EC), we investigated the function of the recently discovered melanoma-associated antigen (MAGE)-D4 in squamous cell EC. Methods: MAGE-D4 mRNA expression was analyzed in nine EC cell lines using quantitative reverse transcription-polymerase chain reaction (RT-PCR). In 65 surgical specimens of squamous cell EC with no prior neoadjuvant therapy, MAGE-D4 mRNA expression in EC tissues and corresponding normal tissues was analyzed and compared, and evaluated in terms of clinicopathological factors. In representative cases, MAGE-D4 protein distribution was analyzed immunohistochemically. Results: The heterogeneity of MAGE-D4 mRNA expression was confirmed in EC cell lines by quantitative RT-PCR. In surgical specimens, MAGE-D4 mRNA expression was significantly higher in EC tissues than in corresponding normal tissues (P &lt; 0.001). Patients with the highest MAGE-D4 mRNA expression in EC tissues (top quartile, n=17) had significantly shorter overall survival than patients with low expression (2-year survival: 44% and 73%, respectively, P = 0.006). Univariate analysis identified age (≥ 65 years), lymphatic involvement and high MAGE-D4 mRNA expression as significant prognostic factors; high MAGE-D4 mRNA expression was also an independent prognostic factor in multivariable analysis (hazard ratio: 2.194; P = 0.039), and was significantly associated with Brinkman index (P = 0.008) and preoperative carcinoembryonic antigen level (P = 0.002). Immunohistochemical MAGE-D4b expression was consistent with MAGE-D4mRNA profiling. Conclusions: Our results suggest that MAGE-D4 overexpression influences tumor progression and MADE-D4 can be a prognostic marker and a potential molecular target in squamous cell EC.

Reduced expression of DENND2D through promoter hypermethylation as an adverse prognostic factor in squamous cell carcinoma of the esophagus.

58 Background: Esophageal cancer ranks sixth in cancer mortality worldwide and patients with ESCC have a poor prognosis with a 5-year survival rate of less than 10%. Elucidation of the mechanisms of carcinogenesis and tumor progression in esophageal cancer is urgently needed to develop targets for therapy and prognostic biomarkers. In the present study, the expression and regulatory mechanism of the Differentially Expressed in Normal and Neoplastic cells Domain containing 2D (DENND2D), which is a regulator of Rab GTPases, were investigated to explore its potential as a tumor suppressor gene for esophageal squamous cell carcinoma (ESCC). Methods: The level of DENND2D mRNA expression in ESCC cell lines and surgical specimens was determined using a quantitative real-time reverse transcription-polymerase chain reaction assay, and the relationship between the expression level of DENND2D mRNA and clinicopathological factors was evaluated. The expression and distribution of DENND2D were determined using immunohistochemistry. DNA methylation analysis was performed to determine the regulatory mechanism of DENND2D expression in ESCC. Results: The level of DENND2D mRNA expression was reduced in 8/9 ESCC cell lines and in 59/65 surgical specimens, and the mean expression level was significantly lower in cancerous tissues than in corresponding normal tissues (p&lt;0.001). The expression pattern of DENND2D protein and mRNA was consistent. Downregulation of DENND2D mRNA in ESCC tissues was identified as an independent prognostic factor in multivariate analysis (hazard ratio: 2.194; p=0.039). The DENND2D promoter was methylated in five out of nine ESCC cell lines, and DNA demethylation reactivated DENND2D mRNA expression. Hypermethylation of DENND2D was frequently detected in ESCC tissues (64.6%) and was significantly associated with downregulation of DENND2D mRNA expression (P = 0.008). Conclusions: Our data suggest that DENND2D is a candidate tumor suppressor gene that was inactivated by promoter hypermethylation in patients with ESCC and may serve as a novel biomarker of ESCC.

Genetic association between p53 codon 72 polymorphism and risk of cutaneous squamous cell carcinoma

This study was designed to obtain a conclusive result about the relevance of p53 codon 72 polymorphism to the risk of cutaneous squamous cell carcinoma (SCC). We performed an updated meta-analysis of 3,792 subjects (1,349 cancer cases and 2,443 controls) to summarize the data available for p53 codon 72 polymorphism and SCC risk. The association was estimated by odds ratios (ORs) with 95% confidence intervals (CIs). The meta-analysis showed no statistical significance for SCC risk associated with any of the genetic models of p53 codon 72 polymorphism. The analyses by ethnic subgroup also failed to produce significant associations. This study suggests that p53 codon 72 polymorphism does not appear to represent a significant susceptibility factor for SCC in Caucasians.

Reduced expression of DENND2D through promoter hypermethylation is an adverse prognostic factor in squamous cell carcinoma of the esophagus

Esophageal cancer ranks sixth in cancer mortality worldwide and patients with esophageal squamous cell carcinoma (ESCC) have a poor prognosis with a 5-year survival rate of less than 10%. Elucidation of the mechanisms of carcinogenesis and tumor progression in esophageal cancer is urgently required to develop targets for therapy and prognostic biomarkers. In the present study, the expression and regulatory mechanism of the differentially expressed in normal and neoplastic cells domain containing 2D (DENND2D), which is a regulator of Rab GTPases, were investigated to explore its potential as a tumor suppressor gene for ESCC. The level of DENND2D mRNA expression in ESCC cell lines and surgical specimens was determined using a quantitative real-time reverse transcription-polymerase chain reaction assay, and the relationship between the expression levels of DENND2D mRNA and clinicopathological factors was evaluated. The expression and distribution of DENND2D were determined using immunohistochemistry. DNA methylation analysis was performed to determine the regulatory mechanism of DENND2D expression in ESCC. The level of DENND2D mRNA expression was reduced in 8/9 ESCC cell lines and in 59/65 surgical specimens, and the mean expression levels were significantly lower in cancerous tissues compared to corresponding normal tissues (p<0.001). The expression pattern of DENND2D protein and mRNA was consistent. Downregulation of DENND2D mRNA in ESCC tissues was identified as an independent prognostic factor in multivariate analysis (hazard ratio, 2.194; p=0.039). The DENND2D promoter was methylated in 5/9 ESCC cell lines, and DNA demethylation reactivated DENND2D mRNA expression. Hypermethylation of DENND2D was frequently detected in ESCC tissues (64.6%) and was significantly associated with downregulation of DENND2D mRNA expression (P=0.008). Taken together, our data suggest that DENND2D is a candidate tumor suppressor gene that was inactivated by promoter hypermethylation in patients with ESCC and may serve as a novel biomarker of ESCC.

Human papillomaviruses in intraepithelial neoplasia and squamous cell carcinoma of the conjunctiva

The infection with human papillomavirus (HPV) has been described as a risk factor for squamous cell carcinoma of the conjunctiva (SCCC), although the evidence is conflicting. To assess the relation between HPV infection and intraepithelial neoplasia or SCCC, we evaluated archived material from biopsies of the conjunctiva performed at the Maputo Central Hospital (Mozambique) in patients with suspected eye cancer. The quality of DNA was assessed by PCR using β-globin-specific primers. A total of 22 consecutive biopsies (intraepithelial neoplasia, SCCC, and benign conditions) positive for β-globin were further tested for HPV infection by PCR using the general primers GP5+/GP6+ and CPI/CPII. In addition, PCR with type-specific primers HPV 16 and HPV 18 was performed. Nineteen biopsies corresponded to intraepithelial neoplasia (two low-grade and nine high-grade) or SCCC (n=8), from which 11 (57.9%) tested positive for HPV infection; nine were positive for CPI/CPII, including one case also positive for GP5+/GP6+ and HPV 18, and the remaining two tested positive only for HPV 16. HPV DNA was not detected in any of the three biopsies of benign conditions. These results suggest a stronger association between infection with cutaneous HPV and SCCC than for mucosal HPV. However, further research is required to clarify the relation between HPV and SCCC as well as to understand the potential of the HPV vaccine currently available for cervical cancer to prevent SCCC.

Overexpression of melanoma-associated antigen D4 is an independent prognostic factor in squamous cell carcinoma of the esophagus

To pursue an urgently needed treatment target for esophageal cancer (EC), we investigated the function of the recently discovered melanoma-associated antigen (MAGE)-D4 in squamous cell EC. MAGE-D4 messenger RNA (mRNA) expression was analyzed in nine EC cell lines using quantitative reverse transcription polymerase chain reaction. In 65 surgical specimens of squamous cell EC with no prior neoadjuvant therapy, MAGE-D4 mRNA expression in EC tissues and corresponding normal tissues was analyzed and compared, and evaluated in terms of clinicopathological factors. In representative cases, MAGE-D4 protein distribution was analyzed immunohistochemically. The heterogeneity of MAGE-D4 mRNA expression was confirmed in EC cell lines by quantitative reverse transcription polymerase chain reaction. In surgical specimens, MAGE-D4 mRNA expression was significantly higher in EC tissues than in corresponding normal tissues (P < 0.001). Patients with the highest MAGE-D4 mRNA expression in EC tissues (top quartile, n = 17) had significantly shorter overall survival than patients with low expression (2-year survival: 44% and 73%, respectively, P = 0.006). Univariate analysis identified age (≥65 years), lymphatic involvement, and high MAGE-D4 mRNA expression as significant prognostic factors; high MAGE-D4 mRNA expression was also an independent prognostic factor in multivariable analysis (hazard ratio: 2.194; P = 0.039) and was significantly associated with Brinkman index (P = 0.008) and preoperative carcinoembryonic antigen level (P = 0.002). Immunohistochemical MAGE-D4b expression was consistent with MAGE-D4 mRNA profiling. Our results suggest that MAGE-D4 overexpression influences tumor progression, and MADE-D4 can be a prognostic marker and a potential molecular target in squamous cell EC.

Diet and lifestyle factors and risk of subtypes of esophageal and gastric cancers: classification tree analysis

PurposeAlthough risk factors for squamous cell carcinoma of the esophagus and adenocarcinomas of the esophagus (EA), gastric cardia (GC), and other (noncardia) gastric (OG) sites have been identified, little is known about interactions among risk factors. We sought to examine interactions of diet, other lifestyle, and medical factors with risks of subtypes of esophageal and gastric cancers. MethodsWe used classification tree analysis to analyze data from a population-based case-control study (1095 cases, 687 controls) conducted in Connecticut, New Jersey, and western Washington State. ResultsFrequency of reported gastroesophageal reflux disease symptoms was the most important risk stratification factor for EA, GC, and OG, with dietary factors (EA, OG), smoking (EA, GC), wine intake (GC, OG), age (OG), and income (OG) appearing to modify the risk of these cancer sites. For esophageal squamous cell carcinoma, smoking was the most important risk stratification factor, with gastroesophageal reflux disease, income, race, noncitrus fruit, and energy intakes further modifying risk. ConclusionVarious combinations of risk factors appear to interact to affect risk of each cancer subtype. Replication of these data mining analyses are required before suggesting causal pathways; however, the classification tree results are useful in partitioning risk and mapping multilevel interactions among risk variables.