Citations

Abstract Purpose: Release of inhibitory coregulatory proteins into the circulation may represent one mechanism by which tumors thwart immune responses. Our objective was to determine whether soluble B7-H1 (sB7-H1) levels in patients with clear cell renal cell carcinoma (ccRCC) are associated with pathologic features and patient outcome. Experimental Design: We developed an ELISA for quantification of sB7-H1 in biological fluids. Biochemical confirmation of the measured analyte as sB7-H1 was done by protein microsequencing using supernates from tumor cell lines. Biological activity of sB7-H1 was assessed in vitro utilizing T-cell apoptosis assays. We tested sB7-H1 levels in the sera from 172 ccRCC patients and correlated sB7-H1 levels with pathologic features and patient outcome. Results: sB7-H1 was detected in the cell supernatants of some B7-H1–positive tumor cell lines. Protein sequencing established that the measured sB7-H1 retained its receptor-binding domain and could deliver proapoptotic signals to T cells. Higher preoperative sB7-H1 levels were associated with larger tumors (P < 0.001), tumors of advanced stage (P = 0.017) and grade (P = 0.044), and tumors with necrosis (P = 0.003). A doubling of sB7-H1 levels was associated with a 41% increased risk of death (P = 0.010). Conclusion: Our observations suggest that sB7-H1 may be detected in the sera of ccRCC patients and that sB7-H1 may systemically impair host immunity, thereby fostering cancer progression and subsequent poor clinical outcome. Clin Cancer Res; 17(7); 1915–23. ©2011 AACR.

Abstract Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-186.

Abstract The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels was investigated in relation to mammary tumorigenesis. 10-wks old MMTV-TGF-α female mice were assigned to ad libitum fed (AL; AIN-93M diet), ICR (3-week 50% caloric restriction, AIN-93M-mod diet, 2× protein, fat, vitamins, and minerals followed by 3-wks 100% AL consumption of AIN-93M), and CCR (calorie and nutrient intake matched for each 6-wks ICR cycle, ∼75% of AL) groups. Mice were sacrificed at 79 (end of restriction) or 82 (end of refeeding) wks of age. Serum was obtained in cycles 1, 3, 5, 8, 11, and terminal. Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad. Although we did not show an association of either adiponectin or leptin with individual mice in relation to mammary tumorigenesis, we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction. Cancer Prev Res; 4(4); 568–81. ©2011 AACR.

ABSTRACTBackground:The relations between hepatic steatosis and histological features of hepatocyte injury in children with nonalcoholic fatty liver disease have yet to be examined. The aims of the present study were to establish associations between steatosis amount, type, and distribution in a well‐characterized group of children with biopsy‐proven nonalcoholic fatty liver disease (NAFLD).Patients and Methods:One hundred eight children with NAFLD seen in 5 centers were studied. Clinical and laboratory data were collected. Hematoxylin‐eosin and Masson trichrome stains were evaluated by 2 expert liver pathologists. Steatosis grade (0–3), type (macrovesicular, microvesicular, or mixed), and zone (1, 3, azonal, or panacinar) were determined. The NAFLD activity score and fibrosis stage were determined.Results:Median patient age was 12 years and median body mass index was 31 kg/m2. Fibrosis was present in 87%. The median NAFLD activity score was 4. Mild, moderate, and severe steatosis were present in 42%, 34%, and 24% of biopsies, respectively. Macrovesicular steatosis was present in 81% and mixed steatosis was present in 19%. Panacinar distribution of steatosis was most frequent (40%), followed by azonal (27%). Steatosis grade positively correlated with portal inflammation (P = 0.018). Azonal distribution positively correlated with presence of hepatocyte ballooning (P = 0.03). Biopsies with mixed steatosis were approximately 20 times more likely to have megamitochondria than those with macrovesicular steatosis alone (95% confidence interval 2.3–204.9). There was no relation between steatosis amount, type, or distribution to fibrosis stage.Conclusions:Specific histological patterns of steatosis in children are associated with histological markers of steatohepatitis. Ballooning and portal inflammation correlated well with features of steatosis.

Abstract Background: The decision to use adjuvant chemotherapy in patients with early stage breast cancer is based in part on the estimation of risk of tumor recurrence by physicians, which traditionally relies heavily on tumor size, nodal status and a set of biologic tumor characteristics such as hormone receptor and HER2 expression. The Oncotype DX® assay is a 21-gene expression profile aiming to improve risk stratification, recurrence prediction and optimize selection of patients for adjuvant chemotherapy.Methods: We selected 154 consecutive patients with early stage estrogen receptor (ER) positive breast cancer and available Oncotype Dx® recurrence score (RS) for the study. Clinicopathologic data, including patient age, menopausal status, tumor size, histologic type, grade, mitotic activity, presence of lymphatic invasion (LVI), nodal status, hormone receptor and HER2 status on all patients were provided to four surgical oncologists, four medical oncologists and three pathologists, specializing in breast cancer diagnosis and management. Participants were asked to estimate the risk of recurrence of tumors based on available clinicopathologic data and to provide the three most important tumor features their risk estimates were based on. Risk estimates of participants were compared with RS results.Results: Based on the Oncotype Dx® results, 95 (61.7%), 45 (29.2%) and 14 (9.1%) tumors were of low (RS <18), intermediate (RS 18-30) and high (RS ≥31) risk, respectively. RS values showed a highly significant correlation with tumor grade, mitotic activity, LVI, hormone receptor and HER2 status, while no correlation with patient age, menopausal status, tumor size and histologic type was found. Participants' risk estimates agreed with those of the Oncotype Dx® assay in 54.2 ± 2.3 % (mean ± SEM, range 41.6 - 63.0%) of cases, while the risk of recurrence was over- and underestimated compared to RS results in 31.8 ± 3.1% (16.2 - 43.5%) and 14.1 ± 1.4% (7.1 - 22.7%), respectively. The rates of overestimation were significantly higher than those of underestimation (p = 0.0003). Although medical oncologists tended to overestimate the risk more frequently (38.1 ± 2.0%) compared to surgeons (28.7 ± 5.9%) and pathologists (27.5 ± 7.8%), the difference did not reach statistical significance. Estimation of the agreement of participants' risk assessment with RS results showed a mean kappa value of 0.2955 (range 0.1506 - 0.4123). No statistically significant difference in overall concurrence with RS results was found between surgeons, medical oncologists and pathologists. Participants ranked tumor stage/nodal status, hormone receptor status and tumor size to be the most important features when estimating recurrence risk.Conclusions: Based on traditional clinicopathologic features alone, surgeons, medical oncologists and pathologists tend to overestimate the risk of tumor recurrence as compared to Oncotype Dx® assay results. The RS may provide additional information regarding the intrinsic biological features of ER positive breast cancers and help tailoring treatment recommendations. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4061.

Abstract Background: Current guidelines recommend administration of chemotherapy for patients with breast carcinomas >1 cm in size, with consideration for patient age, comorbidities and tumor grade. However, it is unknown which patients actually benefit from therapy and overtreatment of a significant proportion of patients is a major concern. We investigated the impact of the Oncotype Dx® Recurrence Score (RS) on chemotherapy recommendations in early stage estrogen receptor (ER) positive breast cancer patients.Methods: We selected 154 patients with early stage ER positive breast cancer and available RS for the study. Clinicopathologic data, including age, menopausal status, tumor size, type, grade, mitotic activity, presence of lymphatic invasion, nodal status, hormone receptor and HER2 status on all patients were provided to four surgical oncologists, four medical oncologists and three pathologists, specializing in breast cancer diagnosis and management. Assuming that all patients were in good general health and would receive endocrine therapy, participants were asked whether they would also advovate adjuvant chemotherapy based on clinicopathologic data with and without knowledge of the RS, and to provide the three salient clinicopathologic features on which their recommendations were based. Changes in recommendations of participants following inclusion of RS data were compared.Results: Based on RS results, 95 (61.7%), 45 (29.2%) and 14 (9.1%) tumors were of low (RS <18), intermediate (RS 18-30) and high (RS ≥31) risk, respectively. The results are summarized in Table 1. Assuming that the hypothesis previously put forward that patients with low to intermediate risk RS are not likely to benefit from chemotherapy, 82.3 ± 1.3% (75.5 - 89.0%) and 69.0 ± 6.9% (5.9 - 85.7%) of patients for whom chemotherapy was recommended by the participants would be "overtreated" without and with the use of RS results (p = 0.0322). No statistically significant difference was found among surgeons, medical oncologists and pathologists. Participants ranked patient age/menopausal status, hormone receptor status and tumor stage/nodal status to be the most important features when recommending chemotherapy.Conclusions: Although current recommendations for adjuvant chemotherapy for early stage ER positive breast cancer patients are largely in line with published guidelines, inclusion of RS alters recommendations in about 25% of cases. While medical oncologists recommended chemotherapy more frequently compared to surgeons and pathologists, they were more likely to change recommendations in light of RS results.Table 1. Summary of results SurgeonsMedical oncologistsPathologistsp* Mean ± SEMRangeMean ± SEMRangeMean ± SEMRange Chemo without RS (%)29.2 ± 1.824.0 - 31.859.0 ± 5.046.8 - 70.846.8 ± 3.741.6 - 53.90.0156Chemo with RS (%)27.0 ± 5.611.0 - 36.438.6 ± 9.517.5 - 63.644.4 ± 5.833.8 - 53.90.1794No change (%)75.3 ± 7.054.5 - 85.766.7 ± 6.851.3 - 83.885.9 ± 6.478.6 - 98.70.3682Add chemo (%)11.2 ± 4.13.2 - 22.76.5 ± 1.93.2 - 11.75.8 ± 3.20.6 - 11.70.6882Avoid chemo (%)13.5 ± 3.94.5 - 22.726.8 ± 7.94.5 - 41.68.2 ± 4.50.6 - 16.20.2186*Kruskal-Wallis test Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4058.