Longitudinal Changes in Immune Activation Serum Biomarkers Prior to Diagnosis and Risk of B-cell NHL Subtypes.

BACKGROUND: 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. METHODS: 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 (IL1ß, 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. RESULTS: 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. CONCLUSIONS: 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. IMPACT: 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.

Evaluating sterile human acellular dermal matrix in immediate expander-based breast reconstruction: a multicenter, prospective, cohort study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Rising thyroid cancer incidence in the United States by demographic and tumor characteristics, 1980-2005.

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 (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.

Lung cancer staging: a case for a new T definition.

BACKGROUND: The purpose of this study is to determine a more refined T definition for lung cancer staging on the basis of clinical outcomes. METHODS: The Walter Reed Army Medical Center Tumor Registry and the Thoracic Surgery Tumor Clinic files were queried for lung cancers diagnosed from 1990 to 2000. Cox regression analysis and Kaplan-Meier survival curves for tumor size were used to analyze the impact of size on survival and relative risk, and then used to redefine T. Using the new T definition, the cohort was restaged, and the two staging system survivals were compared using Cox regression analysis. RESULTS: Tumor size was documented in 439 males and 226 females. Forty-two tumors were 1.0 cm or less, 133 were between 1.01 and 2.0 cm, 133 were between 2.01 and 3.0 cm, 91 were between 3.01 and 4.0, 96 were between 4.01 and 5.0, and 166 were greater than 5.0 cm. A survival advantage was noted for smaller lesions, with 5-year survivals of 48.6%, 45.9%, 26.6%, 27.0%, 14.4%, and 11.6%, respectively. Cox regression analysis revealed increased risk at 2.0 cm (hazards ratio, 2.014; 95% confidence interval, 1.24 to 3.26), 4.0 cm (hazards ratio, 2.51; 95% confidence interval, 1.53 to 4.09), and 5.0 cm (hazards ratio, 3.14; 95% confidence interval, 1.96 to 5.02). After redefining T, the new staging system showed a better 5-year survival in each stage. CONCLUSIONS: Lung cancer tumor size criteria should be changed to include T1 tumors 2.0 cm and less; T2 tumors between 2.0 and 4.0 cm or pleural invasion of T1 tumor; T3 tumors greater than 4.0 cm or pleural invasion of T2 tumors.

Unlimited access to care: effect on racial disparity and prognostic factors in lung cancer.

STUDY OBJECTIVE: Evaluate the prognostic factors influencing lung cancer survival under a universal health care system and determine if access to care eliminates clinical outcome disparity. DESIGN: Retrospective case series review. BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

TP53 mutation spectrum in lung cancer is not different in women and men.

Whether women are more susceptible to lung cancer than men has been controversial. Several case-control studies suggested that women have greater risk of lung cancer compared with men at similar levels of cigarette smoking, whereas some large cohort studies failed to observe this association. Other studies indicated that lung cancer may have biological characteristics and mechanisms of carcinogenesis that are gender specific. Therefore, we hypothesized that women are more susceptible to the carcinogenic effects of tobacco smoke exposure, as evidenced by a higher frequency of G:C-to-T:A somatic mutations in tumors from women in comparison with men at similar levels of tobacco smoke exposure. To investigate our hypothesis, we examined the TP53 mutational spectrum in a case-only (102 women and 201 men) series study where complete smoking information was available. A similar frequency and type of somatic TP53 mutations were observed in women and men. In conclusion, our study indicates that the TP53 mutation spectrum is similar in women and men. Our results are consistent with a recent large cohort study and summary of previous cohort studies, suggesting that women likely have equivalent susceptibility to lung cancer as men.

Polymorphisms in XPD and TP53 and mutation in human lung cancer.

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 P(int) = 0.027, G:C-->T:A TP53 mutation P(int) = 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.