Trends in adherence to NCCN guidelines for breast conserving therapy in women with Stage I and II breast cancer: Analysis of the 1998-2008 National Cancer Data Base.

OBJECTIVE: To examine temporal trends in guideline adherence for breast cancer local therapy, by race/ethnicity, socioeconomic and insurance status. BACKGROUND: Treatment guidelines recommend breast conserving therapy (BCT) for women with small cancers, but have been unevenly applied. A better understanding of time-trends in guideline adherence may point to interventions for correction. METHODS: Patients with tumors ≤2 cm (n = 1,081,075) were identified from 1123 NCDB hospitals, dividing the interval 1998-2011 into 5 segments. Significant differences in rates of guideline adherence over time for race/ethnicity, quartiles of income, education, and insurance status were identified using Chi-square tests. Random effects logistic regression was used to compute odds ratios (OR) for the likelihood of guideline adherence controlling for sociodemographic and clinical characteristics, hospital type and region. RESULTS: Multivariate models revealed disparities in use of BCT for women ≤39 years (OR 0.49, 95% CI 0.48-0.50); for Asians (OR 0.67, 95% CI 0.65-0.69); for women in the lowest education quartile (OR 0.89, 95% CI 0.87-0.91); and for women in rural regions, (OR 0.79 95% CI 0.76-0.81). The largest radiotherapy disparity was for the oldest women (OR 0.37, 95%CI 0.37-0.38), and in rural regions OR 0.67, 95% CI 0.63-0.71. Over time, differences persisted in BCT use (for race, income, education, insurance type); and for endocrine therapy (by race and education). CONCLUSION: There was mixed progress in reducing disparities in guideline adherence. These results are conservative, since the most favorable tumor stages were analyzed in the NCDB, which reflects higher quality of care than non-participating hospitals.

Surgical management of de novo stage IV breast cancer.

Management of the intact primary tumor in women presenting with stage IV breast cancer has classically been determined by the presence or absence of symptoms. However, multiple retrospective reviews completed over the past decade suggest a survival advantage with resection of the intact, asymptomatic primary tumor in these women. These reviews are not without bias, and recently completed randomized trials do not support a significant survival benefit, although local control benefits may exist. Completion of ongoing trials is needed to reach a definitive conclusion regarding the merit of primary tumor resection for local control and survival. Until unbiased data are available, local therapy for the asymptomatic primary cannot be routinely recommended, but may be considered in selected individuals, with multidisciplinary input, when systemic disease is well controlled.

Urinary podocyte mRNA excretion in children with D+HUS: a potential marker of long-term outcome.

BACKGROUND: Diarrhea-associated hemolytic uremic syndrome (D+HUS) causes acute renal failure and may lead to podocyte loss. Objective. To determine if the urinary mRNA excretion of podocyte proteins is detectable in children with D+HUS and if it is a biomarker of a poor long-term outcome. METHODS: Patients were randomly selected from participants in the SYNSORB Pk trial. Urine samples were collected daily during the first week of hospitalization. Specimens were also obtained in healthy volunteers. Synaptopodin and nephrin mRNA levels were measured using real-time PCR. RESULTS: Fifteen children, aged 4.9+/-2.8 years, were studied. Patients were categorized based on urinary mRNA levels into normal (marker:GAPDHmean + SD) in controls. Twelve patients (80%) had increased urinary podocyte mRNA excretion; 11 (73%) had high synaptopodin and 5 (33%) had high nephrin mRNA levels. Follow-up data were available in 13/15 patients, all of whom had normal blood pressure, urinalysis, and serum creatinine concentration. CONCLUSION: The isolation of podocyte mRNA from routine urine samples is feasible in children with D+HUS. Most patients have podocyturia based on synaptopodin and nephrin mRNA excretion. Larger studies with extended follow-up are required to determine the relationship of these biomarkers to long-term renal prognosis in D+HUS.

Urinary neutrophil gelatinase-associated lipocalcin in D+HUS: a novel marker of renal injury.

BACKGROUND: Diarrhea-associated hemolytic uremic syndrome (D+HUS) causes acute renal failure. Neutrophil gelatinase-associated lipocalcin (NGAL) is an early indicator of kidney injury. OBJECTIVE: To determine if urinary NGAL excretion is a biomarker of severe renal injury and predicts the need for dialysis in D+HUS. METHODS: Patients were randomly selected from among participants in the SYNSORB Pk trial. Urine samples were collected daily if available during the first week of hospitalization. NGAL levels were determined by ELISA. RESULTS: 34 children, age 5.9+/-3.9 yr, were studied; ten (29%) required dialysis. Patients were categorized based on urinary NGAL concentration within five days of hospitalization - <200 ng/ml and >or=200 ng/ml. Twenty patients (58%) had increased urinary NGAL excretion. The severity of D+HUS at enrollment was similar in the two groups. However, children with increased urinary NGAL levels had higher peak BUN and creatinine concentrations (P<0.01) and required dialysis more often, 9/20 versus 1/14 (P=0.024) compared to children with normal excretion. CONCLUSION: The majority of patients with D+HUS have renal tubular epithelial injury, as evidenced by elevated urinary NGAL excretion. Urinary NGAL levels below 200 ng/ml within five days of hospitalization may be an adjunctive marker that defines less severe renal involvement.

Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway.

The metastasis-suppressive activity of Nm23-H1 was previously correlated with its in vitro histidine protein kinase activity, but physiological substrates have not been identified. We hypothesized that proteins that interact with histidine kinases throughout evolution may represent partners for Nm23-H1 and focused on the interaction of Arabidopsis "two-component" histidine kinase ERS with CTR1. A mammalian homolog of CTR1 was previously reported to be c-Raf; we now report that CTR1 also exhibits homology to the kinase suppressor of Ras (KSR), a scaffold protein for the mitogen-activated protein kinase (MAPK) cascade. Nm23-H1 co-immunoprecipitated KSR from lysates of transiently transfected 293T cells and at endogenous protein expression levels in MDA-MB-435 breast carcinoma cells. Autophosphorylated recombinant Nm23-H1 phosphorylated KSR in vitro. Phosphoamino acid analysis identified serine as the major target, and two peaks of Nm23-H1 phosphorylation were identified upon high performance liquid chromatography analysis of KSR tryptic peptides. Using site-directed mutagenesis, we found that Nm23-H1 phosphorylated KSR serine 392, a 14-3-3-binding site, as well as serine 434 when serine 392 was mutated. Phosphorylated MAPK but not total MAPK levels were reduced in an nm23-H1 transfectant of MDA-MB-435 cells. The data identify a complex in vitro histidine-to-serine protein kinase pathway, which may contribute to signal transduction and metastasis.