16 research outputs found
New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients
<p>Abstract</p> <p>Background</p> <p>Current practice is to perform a completion axillary lymph node dissection (ALND) for breast cancer patients with tumor-involved sentinel lymph nodes (SLNs), although fewer than half will have non-sentinel node (NSLN) metastasis. Our goal was to develop new models to quantify the risk of NSLN metastasis in SLN-positive patients and to compare predictive capabilities to another widely used model.</p> <p>Methods</p> <p>We constructed three models to predict NSLN status: recursive partitioning with receiver operating characteristic curves (RP-ROC), boosted Classification and Regression Trees (CART), and multivariate logistic regression (MLR) informed by CART. Data were compiled from a multicenter Northern California and Oregon database of 784 patients who prospectively underwent SLN biopsy and completion ALND. We compared the predictive abilities of our best model and the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram) in our dataset and an independent dataset from Northwestern University.</p> <p>Results</p> <p>285 patients had positive SLNs, of which 213 had known angiolymphatic invasion status and 171 had complete pathologic data including hormone receptor status. 264 (93%) patients had limited SLN disease (micrometastasis, 70%, or isolated tumor cells, 23%). 101 (35%) of all SLN-positive patients had tumor-involved NSLNs. Three variables (tumor size, angiolymphatic invasion, and SLN metastasis size) predicted risk in all our models. RP-ROC and boosted CART stratified patients into four risk levels. MLR informed by CART was most accurate. Using two composite predictors calculated from three variables, MLR informed by CART was more accurate than the Nomogram computed using eight predictors. In our dataset, area under ROC curve (AUC) was 0.83/0.85 for MLR (n = 213/n = 171) and 0.77 for Nomogram (n = 171). When applied to an independent dataset (n = 77), AUC was 0.74 for our model and 0.62 for Nomogram. The composite predictors in our model were the product of angiolymphatic invasion and size of SLN metastasis, and the product of tumor size and square of SLN metastasis size.</p> <p>Conclusion</p> <p>We present a new model developed from a community-based SLN database that uses only three rather than eight variables to achieve higher accuracy than the Nomogram for predicting NSLN status in two different datasets. </p
fused pyrazole synthesis by n-n bond formation: The pyrazolo [5,1-b] benzothiazole system
Treatment of (benzothiazol-2-yl)acetone oxime 1 with excess trifluoroacetic anhydride (TFAA) at room temperature produces 2-methyl-3-trifluoroacetylpyrazoIo[5, l-Z\u3e ]benzothiazole 11 in 71-92 % yield depending on the purity of the oxime. Compound 11 is reduced by NaBHi to the corresponding alcohol 12 and hydrolyzed to the corresponding carboxylic acid 13 under alkaline conditions. Other reagents commonly used to promote Beckmann rearrangement of oximes cause only decomposition of 1 to intractable materials. Š 2011 by Walter de Gruyter GmbH & Co. All rights reserved
Enantioselective Single and Dual a-CâH Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer
Cyclic amines are ubiquitous structural motifs found in pharmaceuticals and biologically active natural products, making methods for their elaboration via direct CâH functionalization of considerable synthetic value. Herein, we report the development of an iron-based biocatalytic strategy for enantioselective a-CâH functionalization of pyrrolidines via a carbene transfer reaction with diazoacetone. Currently unreported for organometallic catalysts, this transformation can be accomplished in high yields, high catalytic activity and high stereoselectivity (up to 99:1 e.r. and 20,350 TON) using engineered variants of cytochrome P450 CYP119 from Sulfolobus solfataricus. This methodology was further extended to enable enantioselective a-CâH functionalization in the presence of ethyl diazoacetate as carbene donor (up to 89:11 e.r. and 8,920 TON), and the two strategies were combined to achieve a one-pot as well as a tandem dual CâH functionalization of the cyclic amine substrate with enzyme-controlled diastereo- and enantiodivergent selectivity. This biocatalytic approach is amenable to gram-scale synthesis and can be applied to drug scaffolds for late-stage CâH functionalization. This work provides an efficient and tunable method for direct asymmetric a-CâH functionalization of saturated N-heterocycles which should offer new opportunities for the synthesis, discovery, and optimization of bioactive molecules
Synthesis of Spiropiperidine Lactam Acetyl-CoA Carboxylase Inhibitors
The synthesis of 4â˛,6â˛-dihydrospiroÂ[piperidine-4,5â˛-pyrazoloÂ[3,4-<i>c</i>]Âpyridin]-7â˛(2â˛<i>H</i>)-one-based
acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown
N-2 <i>tert</i>-butyl pyrazolospirolactam core was synthesized
from ethyl 3-amino-1<i>H</i>-pyrazole-4-carboxylate in a
streamlined 10-step synthesis requiring only one chromatography procedure.
The described synthetic strategy provides pyrazolo-fused spirolactams
from halogenated benzylic arenes and cyclic carboxylates. Key steps
include a regioselective pyrazole alkylation providing the N-2 <i>tert</i>-butyl pyrazole and a Curtius rearrangement under both
conventional and flow conditions to install the hindered amine via
a stable and isolable isocyanate. Finally, a Parham-type cyclization
was used to furnish the desired spirolactam. An analogous route provided
efficient access to the related N-1 isopropyl lactam series. Elaboration
of the lactam cores via amidation enabled synthesis of novel ACC inhibitors
and the identification of potent analogues