GLUT 1 receptor expression and circulating levels of fasting glucose in high grade serous ovarian cancer.

In recent years, the poorly remarkable goals achieved in terms of patients' important outcomes for ovarian cancer have fueled our interest toward the study of its metabolic roots. Within this research pipeline, we assessed the association between the expression of the glucose transporter GLUT1, as expressed at the tumor tissue level, and circulating pre-surgical levels of fasting glucose in a case series including data from 40 patients with high FIGO stage serous ovarian cancer. Patients who provided data to the current analysis were randomly selected from a larger cohort. To our purposes, the procedures related to serum and tissue collection, storage and biomarker assessment were highly standardized and centralized at the institutional laboratories. The GLUT1 antibody SPM498 SPRING (REF. E13810) was used at a 1:500 dilution in 2 µm slides. Staining for GLUT1 was observed at the cell membrane level in all the cases assessed, but strong staining was described in 29 (72.5%) of them. The agreement between the two independent reviewers was 100%. Strong GLUT1 staining was inversely associated with circulating levels of fasting glucose, with a particularly striking difference for patients in the lowest fasting glucose tertile (p = 0.044). These results support the biological plausibility of the association of interest. If confirmed in larger studies, our findings may help clarify the potentials of biomarkers related to energy metabolism in terms of prognosis definition, treatment assignment, and outcome interpretation for patients with high FIGO stage serous ovarian cancer.

Baff serum level predicts time to first treatment in early chronic lymphocytic leukemia.

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia (CLL) [i.e. mutational status of the immunoglobulin heavy chain variable region (IgVH), ZAP-70 and CD38 expression] and serum levels of B cell-activating factor (BAFF of the TNF family) by evaluating the impact of these variables on the time to first treatment (TFT) in a series of 169 previously untreated CLL patients in Binet stage A. Higher levels of BAFF were more frequently associated with female gender (P=0.02), younger age (P=0.01), Rai stage 0 (P=0.002), higher platelet count (P=0.005), mutated IgVH disease (P=0.002), higher occurrence of normal cytogenetic profile or presence of 13q deletion (P=0.02), low ZAP-70- (P=0.003), and CD38-expression (P=0.02). Maximally selected log-rank statistic plot identified a serum BAFF concentration of 0.313 ng/mL as the best cut-off (P<0.0001). This threshold recognized two subsets of patients with different TFT (P<0.0001). Because in multivariate analysis soluble BAFF [Hazard ratio (HR), 8.23; confidence Interval (CI) 95%,3.0-22.6, P<0.0001] and mutational status of IgVH (HR=2.60; CI 95% 1.10-6.14, P=0.03) maintained the discriminating power their combined effect on clinical outcome was assessed. When three groups were considered: (1) low-risk (n=93), patients with concordant IgVH(mut) and higher soluble BAFF; (2) intermediate-risk (n=50), patients with IgVH(mut) and low BAFF levels or IgVH(unmut) and soluble higher BAFF;(3) high-risk (n=26), patients with concordant IgVH (unmut) and low soluble BAFF, the 2-yr TFTs were, respectively, 95%, 85%, and 41% (P<0.0001). In conclusion, our results indicate that in early B-cell CLL, the biological profile including among other parameters soluble BAFF may provide a useful insight into the complex interrelationship of prognostic variables.

Increased serum BAFF (B-cell activating factor of the TNF family) level is a peculiar feature associated with familial chronic lymphocytic leukemia.

In a series of 84 chronic lymphocytic leukemia (CLL) patients we sought to establish whether BAFF (B-cell activating factor of the TNF family) circulating levels correlated with clinical characteristics of disease. BAFF serum levels were significantly higher in 20 healthy controls (i.e., median 695 ng/mL, range 389-1040) in comparison to the whole population of CLL patients (median 376, range 93-8914; P<0.0001). After setting a cut-off at the median value observed in healthy controls (i.e., 695 ng/mL) we found that 6 out of 15 (40%) patients with familial CLL had increased BAFF levels while the same occurred only in 5 out of 64 (7.2%) patients with sporadic CLL (P=0.0007). No significant difference in age (P=0.82), sex (P=0.97), Binet clinical stage (P=0.20), incidence of autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia (ITP) (P=0.47), mutational status of IgVH (P=1.00), CD38 (P=0.34) and ZAP-70 expression (P=0.16) could be detected between patients with sporadic and familial CLL, respectively. The only feature characterizing familial CLL patients was a higher serum BAFF level (sporadic CLL 336 ng/mL, range 93-925; familial CLL 601 ng/mL, range 138-8914; P=0.002). Our data suggest that BAFF levels are elevated in patients with familial CLL. The small cohort of patients used implies that a larger study is needed to reinforce the observation.

Serum level of CD26 predicts time to first treatment in early B-chronic lymphocytic leukemia.

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia (CLL) [i.e. mutational status of the immunoglobulin heavy chain variable region (IgV(H)), ZAP-70- and CD38-expression] and serum levels of CD26 (dipeptidyl peptidase IV, DPP IV) by evaluating the impact of these variables on the time to first treatment (TFT) in a series of 69 previously untreated Binet stage A B-cell CLL patients. By using a commercial ELISA we found that with exception of a borderline significance for ZAP-70 (P = 0.07) and CD38 (P = 0.08), circulating levels of CD26 did not correlate with either Rai substages (P = 0.520) or other biomarker [beta2-microglobulin (P = 0.933), LDH (P = 0.101), mutational status of IgV(H) (P = 0.320)]. Maximally selected log-rank statistic plots identified a CD26 serum concentration of 371 ng/mL as the best cut-off. This threshold allowed the identification of two subsets of patients with CD26 serum levels higher and lower that 371 ng/mL respectively, whose clinical outcome was different with respect to TFT (i.e. 46% and 71% at 5 yr respectively; P = 0.005). Along with higher serum levels of CD26, the univariate Cox proportional hazard model identified absence of mutation in IgV(H) (P < 0.0001) as predictor of shorter TFT. As in multivariate analysis all these parameters maintained their discriminating power (mutational status of IgV(H,)P < 0.0001; soluble CD26, P = 0.02) their combined effect on clinical outcome was assessed. When three groups were considered: (1) Low-risk group (n = 31), patients with concordant IgVH(mut) and low level of soluble CD26; (2) intermediate risk group (n = 26), patients with discordant pattern; (3) high-risk group (n = 12), patients with concordant IgVH(unmut) and high level of soluble CD26, differences in the TFT were statistically significant, with a TFT at 5 yr of respectively 88%, 51% and 43% (P < 0.0001). Our results indicate that in early B-cell CLL biological profile including among other parameters soluble CD26 may provide a useful insight into the complex interrelationship of prognostic variables. Furthermore, CD26 along with mutational status of IgV(H) can be adequately used to predict clinical behavior of patients with low risk disease.

Cost-effectiveness in transient hypocalcemia post-thyroidectomy.

BACKGROUND: Three different strategies to manage transient hypocalcemia after total thyroidectomy were compared to evaluate cost-effectiveness. The reliability of total serum calcium (TSCa), ionized calcium (ICa), and intact parathyroid hormone (iPTH) were investigated to achieve this goal. METHODS: A multicenter, prospective randomized study was carried out with 169 patients. The strategies were "preventive" (oral calcium + vitamin D supplementation), "reactive" (therapy in hypocalcemia), and "predictive" (therapy if iPTH <10 pg/mL). RESULTS: TSCa had higher accuracy in identifying patients who developed hypocalcemia-related symptoms than ICa (84.6% vs 50.0%). TSCa 24 h after surgery showed 24.8% of patients with hypocalcemia, whereas TSCa 48 h after surgery identified a further 10.6% with hypocalcemia (only in the "reactive" and "predictive" groups). iPTH showed low sensitivity as a predictor of hypocalcemia. Between the 3 groups, there was no significant difference in hospitalization time or number of symptomatic hypocalcemic patients. Interestingly, the cost-per-patient was significantly different among the groups. CONCLUSIONS: None of the discussed strategies allowed for early discharge of patients without any risk of transient hypocalcemia. The "preventive" strategy was the most cost-effective, despite overtreatment.

Markers of increased angiogenesis and their correlation with biological parameters identifying high-risk patients in early B-cell chronic lymphocytic leukemia.

We wondered whether there was any association between the extent of increased angiogenesis and IgV(H) gene mutational status, expression of CD38 and ZAP-70 in early B-cell chronic lymphocytic leukemia (CLL) patients. Circulating levels of vascular endothelial growth factor (VEGF) correlated positively with ZAP-70-expression (P=0.03), CD38- expression (P=0.03) and mutational status of IgV(H) (P=0.005). The same did not apply when correlations were sought with either bone marrow angiogenesis or serum levels of basic fibroblatic growth factor (FGF-2). Studies to determine how to integrate variables reflecting increased angiogenesis with other prognostic markers such as CD38, ZAP-70, IgV(H) status and cytogenetic abnormalities are needed to optimize risk stratification for individual patients.

Metabolic Determinants and Anthropometric Indicators Impact Clinical-pathological Features in Epithelial Ovarian Cancer Patients.

BACKGROUND: Over the last twenty years, the efforts of the scientific community devoted to the comprehension and treatment of ovarian cancer have remained poorly remunerative, with the case-fatality ratio of this disease remaining disappointedly high. Limited knowledge of the basic principles regulating ovarian carcinogenesis and factors impacting the course of disease may significantly impair our ability to intervene in early stages and lessen our expectations in terms of treatment outcomes. In the present study, we sought to assess whether metabolic factors and anthropometric indicators, i.e., pre-treatment fasting glucose and body mass index, are associated with renown cancer related prognostic factors such as tumour stage and grade at diagnosis. MATERIALS AND METHODS: Study participants were 147 women diagnosed with epithelial ovarian cancer and treated with platinum based regimens and/or surgery at the Regina Elena National Cancer Institute of Rome, Italy. Glucose levels were assessed at the institutional laboratories on venous blood collected in overnight fasting conditions and prior to any therapeutic procedure. Stage was coded according to the FIGO staging system based on the results of the diagnostic workup, while tumour grade was locally assessed by an expert pathologist. Participants' characteristics were descriptively analyzed for the overall study population and in a subgroup of 70 patients for whom data on body mass index (BMI) were available. FIGO stage and grade were compared by categories of pre-treatment fasting glucose defined upon the median value, i.e., 89 mg/dl. The association of interest was tested in regression models including BMI. RESULTS: For the overall study population, patients in the lowest category of fasting glucose were significantly more likely to exhibit a FIGO stage III-IV at diagnosis compared with their counterpart in the highest glucose category (81.3 vs 66.7%, p: 0.021). Subgroup analysis in 70 patients with BMI data confirmed this association (81.5 vs 55.8, p: 0.049), which remained significant when tested in regression models including BMI (OR: 0.28 95% CI 0.086-0.89, p: 0.031). No relevant evidence emerged when testing the association between fasting glucose and tumour grade. CONCLUSIONS: In patients diagnosed with epithelial ovarian cancer, pre-treatment glucose levels appear to be inversely associated with FIGO stage. Further studies are warranted to eventually confirm and correctly interpret the implications of this novel finding.

Vitamin D insufficiency predicts time to first treatment (TFT) in early chronic lymphocytic leukemia (CLL).

Although vitamin D insufficiency is related to inferior prognosis in some cancers, limited data exist in hematologic malignancies. We evaluated the relationship between 25(OH)D serum levels and time to first treatment (TFT), a disease-specific end point, in 130 previously untreated Binet stage A chronic lymphocytic leukemia (CLL) patients. Measurement of 25(OH)D was performed by means of a direct, competitive chemiluminescence immunoassay using the DiaSorin LIAISON 25(OH)D TOTAL assay (DiaSorin, Inc., Stillwater, Minnesota). Overall, 41 patients (31.5%) had severe vitamin D insufficiency (<10 ng/mL), 66 (50.7%) had mild to moderate insufficiency (10-24 ng/mL), and 23 (17.6%) had 25(OH)D levels within the optimal range (25-80 ng/mL), with no relationship with between the season of sample collection and 25(OH)D level (P=0.188). A patient stratification according to these 3 groups led to significant difference in terms of TFT, with vitamin D insufficient patients having the shortest TFT (P=0.02). With respect to continuous 25(OH)D levels and clinical outcome, TFT was shorter as 25(OH)D decreased until a value of 13.5 ng/mL at which point the association of 25(OH)D and TFT remained constant. As a matter of fact, the 25(OH)D value of 13.5 ng/mL identified two patients subsets with different TFT risk (HR=1.91; 95% CI=1.06-3.44; P=0.03). In multivariate analysis the variable entering the model at a significant level were mutational status of IgVH (P<0.0001), serum thymidine kinase (P=0.02) and absolute lymphocyte count (P=0.03). Thus confirming the Mayo clinic experience, our data provide further evidence that 25(OH)D levels may be an important host factor influencing TFT of Binet stage A patients. Whether normalizing vitamin D levels may delay disease-progression of patients with early disease will require testing in future trials.

Does adiponectin act as an antiangiogenic factor in B-cell chronic lymphocytic leukemia?

Angiogenesis is involved in the pathogenesis of B-cell chronic lymphocytic leukemia (CLL), and high microvascular density has been found in CLL to be associated with a poor prognosis. In this study, we assessed serum levels of adiponectin in 69 patients with Binet stage A B-CLL, and these values were retrospectively correlated with bone marrow (BM) microvessel area and serum levels of vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), angiogenin, PECAM-1 (CD31), matrix metalloproteinase-9 (MMP-9), interleukin-8 (IL-8), syndecan-1, and the percentage of CD38(+) or ZAP-70(+) CLL cells. The positive correlation between serum levels of adiponectin and VEGF (P = .03) does not translate into an increase of the extent of BM angiogenesis (P = .404), FGF-2 (P = .348), angiogenin (P = .402), and CD31 (P = .248) serum concentrations. Accordingly, IL-8 (P = .175), syndecan-1 (P = .06), and MMP-9 (P = .144) circulating levels were not likely to reflect adiponectin concentration. Furthermore, patients with higher levels of adiponectin had a more favorable biological profile as defined by a lower number of both CD38(-) (r = -0.294; P = .02) and ZAP-70(+) (r = -0.285; P = .04). Finally, we evaluated the presence of adiponectin in B-CLL cells at gene expression level. RMA intensity values for adiponectin gene transcript denote a homogeneous low expression in B-CLL cells, whereas VEGF transcript was highly expressed with a degree of interpatient variability. Overall, these data seem to indicate that adiponectin could be involved as an antiangiogenic factor in B-CLL.