Citations

Abstract Innovations and Challenges in Renal Cancer, chaired by Michael B. Atkins, was held April 28 to 29, 2006 in Cambridge, Massachusetts. The conference brought together leading experts in the fields of cancer research, medical oncology, urology, immunology, radiology, and immunotherapy, with the goal of advancing the field of renal cancer treatment by critiquing new data from ongoing clinical trials and stimulating communication among those involved in basic and clinical research. The conference proceedings published in this educational supplement to Clinical Cancer Research are intended to provide timely information and recommendations on important aspects of renal cancer genetics and biology and advances in prognostic classification and treatment.

Abstract Mammographic breast density is a strong risk factor for breast cancer but whether breast density is a general marker of susceptibility or is specific to the location of the eventual cancer is unknown. A study of 372 incident breast cancer cases and 713 matched controls was conducted within the Mayo Clinic mammography screening practice. Mammograms on average 7 years before breast cancer were digitized, and quantitative measures of percentage density and dense area from each side and view were estimated. A regional density estimate accounting for overall percentage density was calculated from both mammogram views. Location of breast cancer and potential confounders were abstracted from medical records. Conditional logistic regression was used to estimate associations, and C-statistics were used to evaluate the strength of risk prediction. There were increasing trends in breast cancer risk with increasing quartiles of percentage density and dense area, irrespective of the side of the breast with cancer (Ptrends < 0.001). Percentage density from the ipsilateral side [craniocaudal (CC): odds ratios (ORs), 1.0 (ref), 1.7, 3.1, and 3.1; mediolateral oblique (MLO): ORs, 1.0 (ref), 1.5, 2.2, and 2.8] and the contralateral side [CC: ORs, 1.0 (ref), 1.8, 2.2, and 3.7; MLO: ORs, 1.0 (ref), 1.6, 1.9, and 2.5] similarly predicted case-control status (C-statistics, 0.64-65). Accounting for overall percentage density, density in the region where the cancer subsequently developed was not a significant risk factor [CC: 1.0 (ref), 1.3, 1.0, and 1.2; MLO: 1.0 (ref), 1.1, 1.0, and 1.1 for increasing quartiles]. Results did not change when examining mammograms 3 years on average before the cancer. Overall mammographic density seems to represent a general marker of breast cancer risk that is not specific to breast side or location of the eventual cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(1):43–9)

Abstract In this study, we observed loss of heterozygosity (LOH) in human chromosomal fragment 6q25.1 in sporadic lung cancer patients. LOH was observed in 65% of the 26 lung tumors examined and was narrowed down to a 2.2-Mb region. Single-nucleotide polymorphism (SNP) analysis of genes located within this region identified a candidate gene, termed p34. This gene, also designated as ZC3H12D, C6orf95, FLJ46041, or dJ281H8.1, carries an A/G nonsynonymous SNP at codon 106, which alters the amino acid from lysine to arginine. Nearly 73% of heterozygous lung cancer tissues with LOH and the A/G SNP also exhibited loss of the A allele. In vitro clonogenic and in vivo nude mouse studies showed that overexpression of the A allele exerts tumor suppressor function compared with the G allele. p34 is located within a recently mapped human lung cancer susceptibility locus, and association of the p34 A/G SNP was tested among these families. No significant association between the less frequent G allele and lung cancer susceptibility was found. Our results suggest that p34 may be a novel tumor suppressor gene involved in sporadic lung cancer but it seems not to be the candidate familial lung cancer susceptibility gene linked to chromosomal region 6q23-25. [Cancer Res 2007;67(1):93–9]

Background— Aortic valve calcification (AVC) is considered degenerative. Recent data suggested links to atherosclerosis or coronary disease (CAD). Methods and Results— AVC and coronary artery calcifications (CAC) were prospectively assessed by Electron-Beam-Computed-Tomography in 262 population-based research participants ≥60 years. AVC was frequent (27%) with aging ( P <0.01) and in men ( P <0.05). AVC was associated with diabetes, hypertension, higher body-mass-index, and serum glucose (all P <0.05). AVC was a marker of higher prevalence ( P <0.01) and severity of CAD (CAC score: 441±802 versus 265±566, P <0.05) independently of age. After follow-up of 3.8±0.9 years, AVC score increased (94±271 versus 54±173, P <0.01, +11±32 U/year), faster with higher baseline AVC score ( P <0.01). Compared with participants remaining free of AVC, de novo acquisition of AVC was associated with higher LDL-cholesterol (141±31 versus 121±27 mg/dL, P <0.05) and faster CAC progression (+78±87 versus +28±47 U/year, P <0.05). In multivariate analysis, LDL-cholesterol independently determined AVC acquisition while higher baseline AVC scores determined faster progression of existing AVC. Conclusion— In the population, AVC is frequent with aging and atherosclerotic risk factors. AVC is a marker of subclinical CAD. AVC is progressive, appearing de novo with progressive atherosclerosis whereas established AVC progresses independently of atherosclerotic risk factors and faster with increasing initial AVC loads.

Purpose High-grade gliomas (HGGs; WHO grades 3-4) are highly diverse, with survival times ranging from months to years. WHO 2000 grading criteria for high-grade oligodendroglial neoplasms [anaplastic oligoastrocytoma (AOA) and anaplastic oligodendroglioma (AO)] remain subjective, and the existence of grade 4 variants is controversial. Patients and Methods Overall survival (OS) of 1,093 adult patients with a cerebral HGG newly diagnosed between 1990 and 2005 was analyzed by univariate and multivariate models for significance of the following factors: patient age, surgery type, year of diagnosis, endothelial proliferation, necrosis, oligodendroglial histology, treatment center, and chromosome 1p, 19q, 7p (EGFR), and 10q (PTEN) abnormalities by fluorescence in situ hybridization (FISH). Results Necrosis was a statistically significant predictor of poor OS on univariate and multivariate analyses in AOA but not in AO. Median OS for patients with necrotic AOA (22.8 months) was significantly worse than for patients with non-necrotic AOA (86.9 months; P < .0001) but was better than conventional glioblastomas (9.8 months; P < .0001). In addition to patient age, the following were significant independent prognostic factors (P ≤ .001): grade and surgery type for the entire HGG cohort; modified grade for AOA (3 v 4); and modified grade, 1p/19q codeletion status, and oligodendroglial histology for the 586 HGGs analyzed by FISH. Conclusion Stratification of AOA, but not of pure AO, into grades 3 and 4 on the basis of necrosis is prognostically justified and is more powerful than the current approach. Both routine histology and genetic testing provide independent, prognostically useful information.

Purpose The purpose of this study was to analyze prognostic factors for patients with newly diagnosed primary CNS lymphoma (PCNSL) in order to establish a predictive model that could be applied to the care of patients and the design of prospective clinical trials. Patients and Methods Three hundred thirty-eight consecutive patients with newly diagnosed PCNSL seen at Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) between 1983 and 2003 were analyzed. Standard univariate and multivariate analyses were performed. In addition, a formal cut point analysis was used to determine the most statistically significant cut point for age. Recursive partitioning analysis (RPA) was used to create independent prognostic classes. An external validation set obtained from three prospective Radiation Therapy Oncology Group (RTOG) PCNSL clinical trials was used to test the RPA classification. Results Age and performance status were the only variables identified on standard multivariate analysis. Cut point analysis of age determined that patients age ≤ 50 years had significantly improved outcome compared with older patients. RPA of 282 patients identified three distinct prognostic classes: class 1 (patients < 50 years), class 2 (patients ≥50; Karnofsky performance score [KPS] ≥ 70) and class 3 (patients ≥ 50; KPS < 70). These three classes significantly distinguished outcome with regard to both overall and failure-free survival. Analysis of the RTOG data set confirmed the validity of this classification. Conclusion The MSKCC prognostic score is a simple, statistically powerful model with universal applicability to patients with newly diagnosed PCNSL. We recommend that it be adopted for the management of newly diagnosed patients and incorporated into the design of prospective clinical trials.

ABSTRACT Recombinant human adenovirus is a useful gene delivery vector for clinical gene therapy. Minor capsid protein IX of adenovirus has been of recent interest since multiple studies have shown that modifications can be made to its C terminus to alter viral tropism or add molecular tags and/or reporter proteins. We examined the structure of an engineered adenovirus displaying the enhanced green fluorescent protein (EGFP) fused to the C terminus of protein IX. Cryoelectron microscopy and reconstruction localized the C-terminal EGFP fusion between the H2 hexon and the H4 hexon, positioned between adjacent facets, directly above the density previously assigned as protein IIIa. The original assignment of IIIa was based largely on indirect evidence, and the data presented herein support the reassignment of the IIIa density as protein IX.