Thyroid cancer incidence has been rising in the United States, and this trend has often been attributed to heightened medical surveillance and the use of improved diagnostics. Thyroid cancer ...incidence varies by sex and race/ethnicity, and these factors also influence access to and utilization of healthcare. We therefore examined thyroid cancer incidence rates by demographic and tumor characteristics based on 48,403 thyroid cancer patients diagnosed during 1980-2005 from the Surveillance, Epidemiology and End Results program of the National Cancer Institute. The rates varied by histologic type, sex, and race/ethnicity. Papillary carcinoma was the only histologic type for which incidence rates increased consistently among all racial/ethnic groups. Subsequent analyses focused on the 39,706 papillary thyroid cancers diagnosed during this period. Papillary carcinoma rates increased most rapidly among females. Between 1992-1995 and 2003-2005, they increased nearly 100% among White non-Hispanics and Black females but only 20% to 50% among White Hispanics, Asian/Pacific Islanders, and Black males. The increases were most rapid for localized stage and small tumors; however, rates also increased for large tumors and tumors of regional and distant stage. Since 1992-1995, half the overall increase in papillary carcinoma rates was due to increasing rates of very small (<or=1.0 cm) cancers, 30% to cancers 1.1 to 2 cm, and 20% to cancers>2 cm. Among White females, the rate of increase for cancers>5 cm almost equaled that for the smallest cancers. Medical surveillance and more sensitive diagnostic procedures cannot completely explain the observed increases in papillary thyroid cancer rates. Thus, other possible explanations should be explored.
To examine the contribution of B-cell activation molecules to B-cell follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), a prospective study was conducted using pre-diagnosis serial ...serum samples from the US Department of Defense Serum Repository.
Each case (n = 142 FL, n = 211 DLBCL) was matched to two controls on age, gender, race, military branch, and blood collection dates. Immune activation molecules (IL1β, IL2, IL4, IL5, IL6, IL10, IL12, CXCL13, IL8, TNFα, IFNγ, GM-CSF, VEGF, sCD30, IgE) were quantified using ELISA or multiplex immunometric (Luminex) assay. Longitudinal data were analyzed using linear mixed modeling. As serial specimens were collected over several years before diagnosis, we evaluated the temporal dynamics of these markers.
Increased serum levels of sCD30, CXCL13, and to a lesser extent IL10, were associated with both FL and DLBCL in cases compared with controls, with a median follow-up of 5.5 years from the earliest specimen collection to diagnosis date. Significant increasing sCD30 and CXCL13 trajectories for FL and DLBCL subtypes were noted starting at the earliest time points and with IL10 levels increasing significantly at time points closer to diagnosis.
These results suggest that sCD30, CXCL13, and IL10 may contribute to the etiology of FL and DLBCL and are potential biomarkers for these non-Hodgkin lymphoma subtypes.
The increasing trajectories of the B-cell activation molecules, sCD30, CXCL13, and to a lesser extent IL10, may indicate early disease-induced effects or reflect the chronic stimulation of B-cells that promotes the development of FL and DLBCL subtypes.
Human acellular dermal matrices have gained increasing use in immediate expander-based breast reconstruction. However, some studies suggest that these grafts may be associated with a higher incidence ...of infection and seroma. To evaluate complication rates after matrix-based breast reconstruction, the authors conducted a prospective, multicenter, cohort study to evaluate a sterile human acellular dermal matrix in immediate expander-based breast reconstruction, specifically, to determine whether it offered a more favorable risk profile with respect to infection and seroma. A secondary purpose was to determine whether the sterilization process affects graft incorporation.
The authors performed 65 consecutive tissue expander-based breast reconstructions in a cohort of patients over a 1-year period using a single protocol. Sterile human matrix was used in all cases. The patients were evaluated for early complications (infection, seroma) and graft incorporation at the time of exchange or definitive reconstruction. Biopsies were performed in the first 20 reconstructions to provide histologic correlation of graft incorporation.
Complications occurred in three breasts (4.6 percent), including one case of cellulitis (1.5 percent) and two cases of partial mastectomy flap necrosis (3.0 percent) that required débridement. There were no seromas or explantations. The grafts were incorporated in all cases and verified histologically in the first 20 biopsies.
Sterile human acellular dermal matrix can offer reliable matrix incorporation and a low complication rate. Sterilization does not negatively impact incorporation of the graft. The infection and seroma rates in this prospective study compare favorably to those in previous studies with nonsterilized (aseptic) acellular dermal matrix.
Evaluate the prognostic factors influencing lung cancer survival under a universal health care system and determine if access to care eliminates clinical outcome disparity.
Retrospective case series ...review.
Lung cancer survival is worse in men and in African Americans, thought to be related to poor general health in men and limited access to heath care in African Americans. The Military Health Care System, with unlimited access to care, provides an excellent setting for evaluating gender and racial disparities in lung cancer survival.
Lung cancers diagnosed at Walter Reed Army Medical Center, from 1990 to 2000, were evaluated by chart review for age, gender, race, smoking history, cancer history, histology, stage, and completeness of resection.
Seven hundred thirteen Caucasians and 173 African Americans, 2:1 male predominance, had a 22% 5-year survival. Cox model analysis showed that male gender hazard ratio (HR, 1.31) 95% confidence interval (95% CI), 1.02-1.68, advanced-stage disease (stage III: HR, 2.58; 95% CI, 1.57-4.26/stage IV: HR, 4.20; 95% CI, 2.51-7.41), and incomplete resection (HR, 4.06; 95% CI, 2.75-5.99) were predictors of poor outcome; whereas bronchoalveolar carcinoma features (HR, 0.35; 95% CI, 0.23-0.52) and smoking cessation >7 years (HR, 0.70; 95% CI, 0.49-0.99) were predictors of favorable outcome. No ethnic differences in survival were observed.
No racial disparities in survival when access to medical care is universal. Male gender, incomplete resection, and advanced stage are significant predictors of poor outcome in lung cancer.
Ulcerative colitis (UC) is a chronic inflammatory disease that produces reactive oxygen and nitrogen species and increases the risk of colorectal cancer (CRC). The p53 tumor suppressor gene is ...frequently mutated in UC-associated dysplastic lesions and CRC. We are exploring the hypothesis that p53 mutations in the nontumorous colonic tissue in noncancerous UC cases indicate genetic damage from exposure to exogenous and endogenous carcinogens and may identify individuals at increased cancer risk. We are reporting, for the first time, the frequency of specific p53 mutated alleles in nontumorous colon tissue from donors either with or without UC by using a highly sensitive genotypic mutation assay. Higher p53 mutation frequencies of both G:C to A:T transitions at the CpG site of codon 248 and C:G to T:A transitions at codon 247 were observed in colon from UC cases when compared with normal adult controls (P = 0.001 and P = 0.001, respectively). In the UC cases, higher p53 codon 247 and 248 mutation frequencies were observed in the inflamed lesional regions when compared with the nonlesional regions of their colon (P < 0.001 and P = 0.001). The colonic nitric oxide synthase-2 activity was higher in UC cases than in non-UC adult controls (P = 0.02). Our data are consistent with the hypothesis that a higher frequency of p53 mutant cells can be generated under oxidative stress in people with UC. The increased frequency of specific p53 mutated alleles in noncancerous UC colon tissue may confer susceptibility to the development of CRC in an inflammatory microenvironment.
We have investigated the hypothesis that nitric oxide synthase (NOS2), cyclooxygenase-2 (COX2), and vascular endothelial growth factor (VEGF) protein levels individually demonstrate a direct ...correlation with microvessel density (MVD) and clinical outcome in human non-small cell lung cancer (NSCLC). Furthermore, we hypothesized that MVD may explain the propensity of certain histological lung cancer subtypes for early metastasis via a hematological route. Immunohistochemically, we studied the protein expression levels of NOS2, COX2, and VEGF and MVD by counting CD31-reactive blood vessels (BVs) in 106 surgically resected NSCLC specimens. NOS2, COX2, and VEGF immunoreactivity were observed in 48, 48, and 58%, respectively, of the study subjects, and their levels correlated with MVD at the tumor-stromal interphase (P < or = 0.001). More adenocarcindmas and large cell carcinomas displayed overexpression of NOS2 when compared with squamous cell carcinoma (SCC; r = 0.44; P < 0.001). NOS2 and COX2 levels were found to correlate positively with VEGF status (r = 0.44; P < 0.001, 0.01, and 0.03, respectively). These results attest to the significant interaction of these factors in the angiogenesis of NSCLC. Although neither angiogenic factors nor MVD correlated with patient survival, the latter correlated with tumor clinical stage in both squamous (SCC; 73 BVs/mm2) and non-SCC (78 BVs/mm2) tumors. These results indicate that angiogenesis is a complex process that involves multiple factors including NOS2, COX2, and VEGF. Furthermore, the role of angiogenesis in the biology of various histological lung cancer types may be different. The complexity of angiogenesis may explain the modest results observed in antiangiogenesis therapy that target a single protein.
Hemochromatosis and Wilson disease (WD), characterized by the excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the ...frequency of p53 mutated alleles in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, we have determined the frequency of p53 mutated alleles in nontumorous liver tissue from WD and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249 (P < 0.001) and C:G to A:T transversions and C:G to T:A transitions at codon 250 (P < 0.001 and P < 0.005) were found in liver tissue from WD cases, and a higher frequency of G:C to T:A transversions at codon 249 (P < 0.05) also was found in liver tissue from hemochromatosis cases. Sixty percent of the WD and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggests nitric oxide as a source of increased oxidative stress. A high level of etheno-DNA adducts, formed from oxyradical-induced lipid peroxidation, in liver from WD and hemochromatosis patients has been reported previously. Therefore, we exposed a wild-type p53 TK-6 lymphoblastoid cell line to 4-hydroxynonenal, an unsaturated aldehyde involved in lipid peroxidation, and observed an increase in G to T transversions at p53 codon 249 (AGG to AGT). These results are consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WD causes mutations in the p53 tumor suppressor gene.
The pattern of somatic mutations in TP53 is distinct for particular cancers and carcinogenic exposures, providing clues to disease etiology, e.g. G:C→T:A mutations in TP53 are more frequently ...observed in smoking-associated lung cancers. In order to investigate possible causes and mechanisms of lung cancer susceptibility differences, the TP53 gene was sequenced in a case-only study of lung cancers (206 men and 103 women). Our primary hypothesis was that the TP53 mutation spectrum is influenced by polymorphisms in genes involved in DNA repair and apoptosis. We observed a TP53 mutation frequency in exons 5–8 of 25%. Functional polymorphisms in XPD (Asp312Asn, rs1799793 and Lys751Gln, rs1052559), a protein required for nucleotide excision repair and with roles in p53-mediated apoptosis, were modestly associated with G:C→T:A mutations in TP53 in lung tumors Asp/Asn312 + Asn/Asn312 and/or Lys/Gln751 + Gln/Gln751 versus Asp/Asp312 + Lys/Lys751; odds ratio (OR) 2.73, 95% confidence interval (CI) 0.98–7.61, consistent with the role of this protein in repair of bulky carcinogen–DNA adducts. In addition, a TP53 polymorphism (Arg72Pro, rs1042522) with a known role in the efficiency of apoptosis was also associated with the presence of a TP53 mutation (Pro/Arg72 or Pro/Pro72 versus Arg/Arg72; OR 2.25, 95% CI 1.21–4.17) or a G:C→T:A mutation in TP53 (Pro/Arg72 or Pro/Pro72 versus Arg/Arg72; OR 2.42, 95% CI 0.97–6.04). An interaction between the XPD variant alleles (Asn312 and Gln751) and the TP53 Pro72 allele was observed for TP53 mutations (any TP53 mutation Pint = 0.027, G:C→T:A TP53 mutation Pint = 0.041). The statistical interaction observed in our study is consistent with the observed biological interaction for XPD and p53 in nucleotide excision repair and apoptosis. In conclusion, differences in TP53 mutation spectra in lung tumors are associated with several genetic factors and may reflect differences in lung cancer susceptibility and carcinogenesis.
The leucine-rich nuclear export signal (NES) is used to shuttle large cellular proteins from the nucleus to the cytoplasm. The nuclear export receptor Crm1 is essential in this process by recognizing ...the NES motif. Here, we show that the oncogenic hepatitis B virus (HBV) X protein (HBx) contains a functional NES motif. We found that the predominant cytoplasmic localization of HBx is sensitive to the drug leptomycin B (LMB), which specifically inactivates Crm1. Mutations at the two conserved leucine residues to alanine at the NES motif (L98A,L100A) resulted in a nuclear redistribution of HBx. A recombinant HBx protein binds to Crm1 in vitro. In addition, ectopic expression of HBx sequesters Crm1 in the cytoplasm. Furthermore, HBx activates NFκB by inducing its nuclear translocation in a NES-dependent manner. Abnormal cytoplasmic sequestration of Crm1, accompanied by a nuclear localization of NFκB, was also observed in hepatocytes from HBV-positive liver samples with chronic active hepatitis. We suggest that Crm1 may play a role in HBx-mediated liver carcinogenesis.
To eliminate any false-positive results, confirmatory standard automated sequencing was performedon each mutation. Del H11505 deletion; Ins H11505 insertion.Journal of the National Cancer Institute, ...Vol. 93, No. 21, November 7, 2001 BRIEF COMMUNICATION 1653fusika MO, Oser SM, Harrington AM, et al.Relationship between p53 mutations and inducible nitric oxide synthase expression inhuman colorectal cancer. J Natl Cancer Inst1999;91:868.(20) Wilson KT, Fu S, Ramanujam KS, MeltzerSJ.
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