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The aim of the study is to assess patient outcomes, complications, impact on rehospitalizations, and healthcare costs in patients with malignant ascites treated with tunneled catheters. A total of 84 patients with malignant ascites (mean age, 60 years) were treated with tunneled catheters. Patients with peritoneal carcinomatosis and malignant ascites treated with tunneled drain catheter placement over a 3-year period were studied. Overall survival from the time of ascites and catheter placement were stratified by primary cancer and analyzed using the Kaplan–Meier method. Complications were graded by the Common Terminology Criteria for Adverse Events v3.0 (CTCAE). The differences between pre- and post-catheter admissions, hospitalizations, and Emergency Department (ED) visits, as well as related inpatient expenses were compared using paired t tests. There were no significant differences in gender, age, or race between different primary cancer subgroups. One patient (1 %) developed bleeding (CTCAE-2). Four patients (5 %) developed local cellulitis (CTCAE-2). Three patients (4 %) had prolonged hospital stay (between 7 and 10 days) to manage ascites-related complications such as abdominal distention, discomfort, or pain. Comparison between pre- and post-catheter hospitalizations showed significantly lower admissions (−1.4/month, p

Novel second-generation taxoids with systematic modifications at the C2, C10, and C3'N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third-generation taxoids". 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in beta-tubulin as well, wherein the drug resistance is mediated by the beta-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.

To investigate the intra- and inter-observer agreement and correlation between CT and MR measurements of skeletal muscle area (SMA) in the abdomen.CT and MR images from twelve patients were analyzed by two blinded observers using segmentation software (MITK-3M3, Mint Medical and Slice-O-Matic, Tomovision) to quantify SMA. MR images included T1w "in-phase", T1w "out-of-phase", and T2w sequences. Inter- and intra-observer agreement was assessed using the intraclass correlation coefficient (ICC). Pearson correlation coefficient (r) was used to correlate measurements obtained on MR with CT. CT and MR measurements were compared with Bland-Altman plots.Intra- and inter-observer agreement for SMA was high for CT and MR. For MR, the measurements on T2w images showed the highest inter-observer agreement (ICC=0.96). CT SMA correlated closely with MR, with T2w images showing the highest correlation (r=0.98; P0.01). Bland-Altman plots showed a 1.7%-3.9% bias between CT and MR measurements, lowest for T2w images.MR SMA measurements are reproducible and correlate closely with CT. The T2w sequence is recommended to quantify SMA on MR images.

A mild and efficient method for the palladium-catalyzed reductive cyclization of ortho-nitrostyrenes to afford indoles is reported. Treatment of ortho-nitrostyrenes with 0.1 mol% palladium (II) trifluoroacetate [Pd(TFA)2] and 0.7 mol% 3,4,7,8-tetramethyl-1,10-phenanthroline (tm-phen) in DMF at 15 psig CO and 80 °C afforded indoles in good to excellent yields. When the reaction was conducted in toluene, the corresponding N-hydroxyindole was isolated. A mechanism that accounts for the formation of N-hydroxyindole is proposed.

A series of highly potent second-generation taxoids bearing a 2-methylprop-1-enyl or a 2-methylpropyl group at C-3′ with modifications at the C-2, C-10, and C-14 positions was synthesized through the coupling of racemic cis-β-lactams with properly protected/modified baccatin and 14-OH-baccatin. A high level of kinetic resolution was observed for all cases examined. The observed highly efficient enantiomer differentiation is ascribed to the markedly different chiral environment between the (+)- and (−)-β-lactams in their approach to the chiral framework of the enantiopure lithium alkoxide of a baccatin in the ring-opening coupling process. It was also observed that substantially higher selectivity was achieved when 14-OH-baccatin-1,14-carbonate was used. Analysis of the transition state models revealed that the repulsive interactions between the 3-TIPS group of a (−)-β-lactam with 1,14-carbonate group of the baccatin substantially increases the asymmetric bias in the kinetic resolution process, favoring the reaction of a (+)-β-lactam, which leads to the observed excellent selectivity. Chirality 12:431–441, 2000. © 2000 Wiley-Liss, Inc.

The asymmetric Michael reaction of pseudoephedrine amides is reported. The 1,5-dicarbonyl products are converted to 3-aryl-δ-lactones in a two-step reduction/lactonization sequence. This method pro...

A novel high-yielding Zn/CuI-mediated coupling method of alkyl halides with vinyl sulfones, vinyl sulfonates, and vinyl sulfonamides is described. This protocol is applicable for primary, secondary, and tertiary alkyl iodides and bromides. Alkyl chlorides and aryl and vinyl halides were unreactive under the reaction conditions. Formamide was found to be a superior solvent for obtaining high yields.

Two asymmetric syntheses of the NK(1) receptor antagonist 1-[2-(R)-{1-(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(R)-(3,4-difluorophenyl)-4-(R)-tetrahydro-2H-pyran-4-ylmethyl]-3-(R)-methylpiperidine-3-carboxylic acid (1) were developed. In both routes, the core tetrahydropyran stereochemistry was established by asymmetric conjugate addition to an alpha,beta-unsaturated ester (6), using an amide of the chiral auxiliary pseudoephedrine. Selective ester reduction then allowed formation of lactone 2 with the thermodynamically preferred trans geometry. The chiral ether side chain (3) was attached by stereoselective acetal substitution. In the first route, the chiral piperidine ester fragment was installed at the end by N-alkylation. In the shorter second synthesis, this piece was appended to the Michael acceptor at the beginning.

[reaction: see text] A number of approaches for the synthesis of the 1H-indol-2-yl-1H-quinolin-2-one ring system found in the potent and selective KDR kinase inhibitor 1 are described. The preparation and reaction of trimethylsilylnitrobenzene 26 with 2-methoxy-3-quinolinecarboxaldehyde 28 afforded alcohol 30, which was the key intermediate for the preparation of the target compounds. Conversion of alcohol 30 to either nitroketone 36 or nitrostyrene 45 set the stage for reductive cyclization and the formation of indole 25. The quinolin-2-one functionality was unmasked in the last step to provide compound 1 in 56-60% overall yield from readily available starting materials.

The stereochemical outcome of the asymmetric Michael reaction of pseudoephedrine amide enolates changes dramatically in the presence of LiCl. Reaction of the enolate in the absence of LiCl results in formation of the anti Michael adduct with high selectivity, whereas in the presence of lithium chloride the syn adduct is favored. This method provides access to enantiomerically enriched trans-3,4-disubstituted delta-lactones from the anti Michael adducts by a two step reduction/lactonization sequence. Information obtained from NMR studies indicates that, under both enolization conditions, the (Z)-enolate is formed. A model to explain the turnover in selectivity based on NMR evidence is presented.

Taxoids bearing methyldisulfanyl(alkanoyl) groups for taxoid-antibody immunoconjugates were designed, synthesized and their activities evaluated. A highly cytotoxic C-10 methyldisulfanylpropanoyl taxoid was conjugated to monoclonal antibodies recognizing the epidermal growth factor receptor (EGFR) expressed in human squamous cancers. These conjugates were shown to possess remarkable target-specific antitumor activity in vivo against EGFR-expressing A431 tumor xenografts in severe combined immune deficiency mice, resulting in complete inhibition of tumor growth in all the treated mice.

[reaction: see text] The asymmetric Michael reaction of pseudoephedrine amides is reported. The 1,5-dicarbonyl products are converted to 3-aryl-delta-lactones in a two-step reduction/lactonization sequence. This method provides access to enantiomerically enriched trans-3,4-disubstituted delta-lactones.