Effect of hydroxyurea on immature reticulocyte fraction in sickle cell anemia.

Immature reticulocyte fraction (IRF) is a good indicator of bone marrow erythropoiesis in response to hemolysis or tissue hypoxia and is markedly increased in sickle cell disease (SS). We compared IRF changes in SS patients with those who were treated with hydroxyurea (SS-HU), and those who had concurrent alpha globin gene deletion (SS-(- deletion). Forty-two patients including 16 SS, 16 SS-HU, and 10 SS-alpha-deletion patients were studied. Significant decreases (P <.01) in reticulocyte indices including IRF, the reticulocyte percentage, and absolute reticulocyte count (ARC) were observed in SS-alpha-deletion compared to SS patients. On the other hand, although the reticulocyte percentage (P <.01) and ARC (P <.01) were significantly decreased in SS-HU compared with SS patients, the IRF was persistently elevated in both groups (P = .4), suggesting continuous bone marrow stimulation in SS-HU patients in response to tissue hypoxia. The possible underlying physiological mechanisms are discussed.

Neutrophil VCS parameters are superior indicators for acute infection.

A reliable and cost-effective laboratory method for diagnosing early bacterial infection is needed. The purpose of this study is to compare the sensitivity and specificity of the mean neutrophil volume (MNV) and neutrophil volume distribution width (NDW) parameters with manual band counts, as well as absolute neutrophil count (ANC) and Creactive protein (CRP). We analyzed the clinical history and laboratory data from 242 adult patients with subsequent randomization into 3 groups: patients with no apparent clinical evidence of infection (group 1), localized infection (group 2), and severe infection (group 3). Total white blood cell counts, percentage of neutrophils, ANC, band counts, MNV, and NDW were progressively elevated from group 1 to group 3. There were good correlations between MNV and ANC (P < .05) or band counts (P < .001). Similarly, the NDW correlated well with ANC (P < .001) and band counts (P < .05). Statistical analyses further confirmed that the MNV and NDW were better parameters, with larger areas under the curve than those of CRP, band count, and ANC. The neutrophil VCS parameters, MNV and NDW, have superior sensitivity and specificity compared to manual band count, ANC, and CRP. MNV and NDW are useful indicators in diagnosing acute infectious processes.

p66 Shc and tyrosine-phosphorylated Shc in primary breast tumors identify patients likely to relapse despite tamoxifen therapy.

INTRODUCTION: Shc adapter proteins are secondary messenger proteins involved in various cellular pathways, including those mediating receptor tyrosine kinase signaling and apoptosis in response to stress. We have previously reported that high levels of tyrosine-phosphorylated Shc (PY-Shc) and low levels of its inhibitory p66 Shc isoform are strongly prognostic for identifying both early node-negative and more advanced, node-positive, primary breast cancers with high risk for recurrence. Because aberrant activation of tyrosine kinases upstream of Shc signaling proteins has been implicated in resistance to tamoxifen--the most widely prescribed drug for treatment of estrogen receptor-positive breast cancer--we hypothesized that Shc isoforms may identify patients at increased risk of relapsing despite tamoxifen treatment. METHODS: Immunohistochemical analyses of PY-Shc and p66 Shc were performed on archival primary breast cancer tumors from a population-based cohort (60 patients, 9 relapses) and, for validation, an independent external cohort (31 patients, 13 relapses) in which all patients received tamoxifen as a sole systemic adjuvant prior to relapse. RESULTS: By univariate and multivariate analyses, the Shc proteins were very strong and independent predictors of treatment failure in both the population-based cohort (interquartile hazard ratio = 8.3, 95% confidence interval [CI] 1.8 to 38, P = 0.007) and the validating cohort (interquartile relative risk = 12.1, 95% CI 1.7 to 86, P = 0.013). CONCLUSION: These results suggest that the levels of PY-Shc and p66 Shc proteins in primary tumors identify patients at high risk for relapsing despite treatment with tamoxifen and therefore with further validation may be useful in guiding clinicians to select alternative adjuvant treatment strategies.

Shc proteins are strong, independent prognostic markers for both node-negative and node-positive primary breast cancer.

Activated Shc signaling proteins are implicated in many pathways associated with aggressive disease, and many breast cancer cell lines derived from highly aggressive tumors contain high levels of activated, tyrosine phosphorylated (PY)-Shc (the M(r) 46000 and M(r) 52000 isoforms) relative to levels of an inhibitory M(r) 66000 Shc isoform. It was, therefore, hypothesized that high amounts of PY-Shc relative to the M(r) 66000 Shc isoform would serve as a marker for aggressive neoplasms. Semiquantitative immunohistochemical analyses of PY-Shc and p66 Shc were performed on archival primary breast tumor specimens from 116 women, 17 of whom experienced relapse (6.1 years median follow-up of nonrelapsed patients). Consistent with our hypothesis, staining intensities demonstrated that increased amounts of PY-Shc (P = 0.01) and decreased expression of p66-Shc protein (P = 0.028) correlated with disease recurrence. Modeled as the ratio of PY-Shc to p66 Shc, the Shc ratio correlated strongly with nodal status (P = 0.003), tumor stage (P = 0.0025), and disease stage (P = 0.002) and was 2-fold higher in primary tumors of patients who subsequently relapsed (P < 0.001). Univariate Cox proportional hazards analysis of relapse-free survival demonstrated the prognostic value of PY-Shc (P = 0.01), p66 Shc (P = 0.04), and the Shc ratio (P = 0.004) as continuous variables, with a hazard ratio (HR) of 10 (P = 0.007) for the Shc ratio. Shc ratio cut points of <0.35 and >0.65 were identified and independently validated to maximize negative predictive value and positive predictive value. Patients with low Shc ratios (n = 36) had a 0.08 HR of relapse (P = 0.007) compared with patients with high Shc ratios, experiencing an 8-year cumulative 2.9% and 55% relapse hazard, respectively, compared with a 22% relapse hazard in the total cohort. The Shc ratio had similar prognostic value for disease-specific survival. In multivariate models, the Shc ratio, both as a continuous variable and as a cut point-categorized variable, was independent of all measured covariates (including nodal status, tumor stage, disease stage, grade, estrogen receptor status, and adjuvant therapy) and was a stronger prognostic marker than all but nodal status. All relapsed node-positive patients had very high Shc ratios (>0.80; P = 0.006) in their primary tumors. Furthermore, the Shc ratio was a strong, independent prognostic indicator in node-negative patients (79 patients, 10 recurrences), with a HR of 0.086 (P = 0.02) that was independent of clinical markers and adjuvant therapy. Patients with low and high Shc ratios experienced a 3.6% and 64% relapse hazard, respectively, compared with 20% in the total node-negative cohort.