Prognostic impact of residual disease in simultaneous additional excision specimens after one-step breast conserving therapy with negative final margin status in primary breast cancer

Purpose

The purpose of this study was the evaluation of risk factors for local recurrence after breast conserving surgery (BCS) with special focus on the impact of residual disease in specimens of simultaneous additional excisions (AE) from the tumor cavity on patients' outcome in patients with negative final margin status after one-step BCS.

Influence of substrate structure on substrate binding to the renal organic cation/H+ exchanger

 The carrier-mediated exchange of H⁺ for organic cations (”OC/H⁺ exchange”) is the active step in OC secretion in renal proximal tubules. Although hydrophobicity is known to be an important criterion for binding of substrates to this transporter, the degree to which steric parameters of substrate structure influence binding to the exchanger is unclear. We examined this issue by measuring the inhibition of OC/H⁺ exchange produced by a group of quaternary ammonium compounds which share a common structural motif: an N ¹-pyridinium residue. Activity of the OC/H⁺ exchanger was determined by measuring transport of [¹⁴C]tetraethylammonium (TEA) in brush-border membrane vesicles (BBMV) from rabbit renal cortex. Transport was measured in the presence of a pH gradient (pH_in 6.0; pH_out 7.5) to maximize TEA/H⁺ exchange. Apparent inhibitory constants (K _i values) for each test agent were measured. The test agents included 4-phenylpyridiniums and 3-phenylpyridiniums, quinoliniums and acridiniums. The planar structure of these compounds permits a direct test of whether the presence of planar hydrophobic mass in different orientations relative to the pyridinium motif exerts a systematic effect on substrate binding to the OC/H⁺ exchanger. The hydrophobicity of each group of compounds was systematically varied by addition of different substituents at the quaternary nitrogen. Whereas decreases in K _i proved to be proportional to hydrophobicity, the position of the phenyl-ring substituent(s) had no effect on substrate interaction with the exchanger. The results led to the development of a preliminary quantitative structure–activity relationship (QSAR) correlating substrate hydrophobicity and substrate binding to the OC/H⁺ exchanger. This QSAR was used to predict the binding of 1-methyl-4-phenylpyridinium (MPP⁺), (+) and (–)nicotine, (+) and (–)ephedrine, quinine and quinidine to the OC/H⁺ exchanger. Molecular graphics representation of the 3D structures of the test agents was used to develop a working model of a hydrophobic, planar receptor surface on the OC/H⁺ exchanger against which substrates are suggested to interact during binding. Development of the QSAR and receptor surface model open the way to quantitative tests of the specific physical and structural determinants of substrate selectivity by the renal OC/H⁺ exchanger. Received: 20 July 1998 / Received after revision and accepted: 19 October 1998     

The Economics of Health Care for Elderly Blacks

Inflation and spiraling medical costs are adversely affecting the income and health status of elderly Americans. Monies spent for technological advances in medicine resulting in the introduction of more sophisticated instruments and medications have resulted in higher costs for health care. Over the past decade, medical care prices have increased at a rate faster than the cost of living. The percent of the Gross National Product spent for health care has steadily increased. This paper examines the costs involved with health care delivery to the elderly black population, trends in hospitalization and individualized care, and the quality of health care given to elderly black individuals in comparison with that received by the general population.     

Vaccination reshapes the virus-specific T cell repertoire in unexposed adults

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The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review.

Evidence supporting the role of hematopoietic stem cell transplantation (SCT) in the therapy of acute lymphoblastic leukemia (ALL) in children is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations based on the evidence are presented in a table in this review (Summary of Treatment Recommendations Made by the Expert Panel for Pediatric Acute Lymphoblastic Leukemia) and were reached unanimously by a panel of ALL experts. The priority areas of needed future research in pediatric ALL are unrelated marrow or blood donor versus unrelated cord blood donor allogeneic SCT; alternative, nonfamily allogeneic donor versus autologous SCT; better methods for identifying high-relapse-risk patients; assessments of the effect of current chemotherapy regimens on early relapse; and use of pre-SCT detection of minimal residual disease to predict post-SCT outcomes.     

SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model

The aim of the study was to investigate inhibitory effects of the receptor tyrosine kinase (RTK) inhibitor SU11248 against CSF-1R and osteoclast (OC) formation. We developed an in vivo model of breast cancer metastasis to evaluate efficacy of SU11248 against tumor growth and tumor-induced osteolysis in bone. The in vitro effects of SU11248 on CSF-1R phosphorylation, OC formation and function were evaluated. Effects on 435/HAL-Luc tumor growth in bone were monitored by in vivo bioluminescence imaging (BLI), and inhibition of osteolysis was evaluated by measurement of serum pyridinoline (PYD) concentration and histology. Phosphorylation of the receptor for M-CSF (CSF-1R) expressed by NIH3T3 cells was inhibited by SU11248 with an IC50 of 50-100 nM, consistent with CSF-1R belonging to the class III split kinase domain RTK family. The early M-CSF-dependent phase of in vitro murine OC development and function were inhibited by SU11248 at 10-100 nM. In vivo inhibition of osteolysis was confirmed by significant lowering of serum PYD levels following SU11248 treatment of tumor-bearing mice (P = 0.047). Using BLI, SU11248 treatment at 40 mg/kg/day for 21 days showed 64% inhibition of tumor growth in bone (P = 0.006), and at 80 mg/kg/day showed 89% inhibition (P = 0.001). Collectively, these data suggest that SU11248 may be an effective and tolerated therapy to inhibit growth of breast cancer bone metastases, with the additional advantage of inhibiting tumor-associated osteolysis.