High-dose chemotherapy and hematopoietic support for patients with high-risk primary breast cancer and involvement of 4 to 9 lymph nodes.

Despite modern chemotherapy, advanced breast cancer remains a significant cause of cancer morbidity and mortality in women. Patients with disease involvement of multiple lymph nodes represent a subgroup with a high risk of relapse. In particular, 50% of patients with 4 to 9 axillary lymph nodes involved will relapse after standard chemotherapy. In an effort to improve the survival of patients with 4 to 9 involved nodes, we performed a phase II study in which 61 patients with surgically diagnosed stage II or III breast cancer and 4 to 9 positive lymph nodes received 3 cycles of doxorubicin and 5-fluorouracil followed by high-dose chemotherapy consisting of cisplatin, cyclophosphamide, and carmustine and infusion of autologous hematopoietic progenitor cells. All patients received posttransplantation localized radiotherapy unless contraindicated, and all patients with hormone receptor-positive disease received tamoxifen. After a median patient follow-up of 6.7 years (range, 4.6-8.6 years), the 5-year overall survival rate was 79% (95% CI, 69%-90%), with relapse-free survival of 73% (95% CI, 62%-85%). Treatment-related mortality was 3%. Interstitial pneumonitis occurred in 69% of patients but did not contribute to mortality. Our study presents long-term favorable results regarding the use of consolidative HDC with autologous hematopoietic support in previously untreated patients with high-risk primary breast cancer.     

In vitro and in vivo characterization of TC‐1827, a novel brain α4β2 nicotinic receptor agonist with pro‐cognitive activity

Nicotine activates specific receptors that are cation‐permeable ionic channels located in the central and autonomous nervous systems, as well as at the neuromuscular junction. Administration of nicotine to animals and humans has been shown to enhance cognitive processes. However, side effects linked to the activation of peripheral nicotinic receptors limit the usefulness of nicotine for the treatment of cognitive disorders such as Alzheimer's disease (AD) or mild cognitive impairments (MCI). The synthesis and properties of TC‐1827, a novel metanicotine derivative that activates brain α₄β₂ nicotinic receptors is described. TC‐1827 has high affinity for nicotine‐labeled receptors in the cortex (K_i=34 nM), full‐agonist intrinsic activity in α₄β₂‐mediated neurotransmitter release studies in synaptosomes, and has no functional activity at nicotinic receptors in ganglionic or muscular cell lines. The compound enhances long‐term potentiation in hippocampal slices, a form of synaptic plasticity thought to be involved in information storage at the cellular level. In vivo studies demonstrate that TC‐1827 dose‐dependently occupies thalamic nicotinic receptors labeled with [³H]‐cytisine, increases cortical extracellular acetylcholine levels following oral administration, and enhances cognitive performance in rat and mice behavioral procedures of learning and memory. Pharmacokinetic studies in mice, rats, and monkeys indicated that TC‐1827 has good oral absorption with a first pass effect resulting in bioavailabilities of 13–65% across dose/species. Cardiovascular safety studies indicate good cardiovascular tolerability for this compound. The present data demonstrate that TC‐1827 is a selective and potent activator of brain α₄β₂ nicotinic receptors and is a prototypical member of a new class of compounds with potential utility in the symptomatic treatment of cognitive disorders including AD and MCI. Drug Dev. Res. 62:26–40, 2004. © 2004 Wiley‐Liss, Inc.     

Synthesis of diketopiperazines with on‐resin N‐methylation and cyclative release

Abstract: Enantiomerically pure N‐methylated diketopiperazines (DKP) can be obtained by treating a N‐methylated resin‐bound dipeptide with 20% piperidine in dimethylformamide via a process known as cyclative release. N‐methylated resin‐bound dipeptides can be formed from N‐methylated precursors or N‐methylation can be selectively performed on the resin. When on‐resin N‐methylation was performed on the C‐terminal side of the dipeptide, diastereomers were formed. Yet the cyclative release is shown to be a stereoselective process, as seen using preformed N‐methylated amino acids. The procedure was also applied to synthesize the pseudodiketopiperazine cyclo(Pheψ[CH₂NH]Leu). When comparing nonmethylated, monomethylated and bismethylated derivatives, we find that N‐methylation results in a dramatic increase in solubility.     

Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small cell lung cancer: Focus on epidermal growth factor receptor mutation testing and mutation-positive patients

Activation of the epidermal growth factor receptor (EGFR) pathway has been implicated in tumorigenesis in non-small cell lung cancer (NSCLC), the most common type of lung cancer. As a result, EGFR has become a key focus for the development of personalized therapy, with several molecular biomarkers having been investigated as potential predictors of response with EGFR tyrosine kinase inhibitors (TKIs) in NSCLC (e.g., EGFR expression, EGFR gene copy gain, and EGFR mutations). Of these, activating mutations in EGFR have thus far given the most consistent results based on the available evidence from preclinical studies and clinical trials. In an attempt to identify patients who are most likely to benefit from treatment with EGFR TKIs, EGFR mutation testing is being increasingly utilized in clinical practice. Currently in the United States, no EGFR TKI or accompanying mutational test is approved for the identification and first-line treatment of patients with advanced NSCLC. However, the first-generation EGFR TKIs, erlotinib and gefitinib, as well as investigational ErbB family TKIs and EGFR mutation testing methods are being evaluated in this setting. This review will discuss EGFR mutation testing as a biomarker of response to EGFR TKIs and the evolution of EGFR mutational analysis in NSCLC. Completed and ongoing clinical trials evaluating currently available or investigational EGFR TKIs as first-line therapy in molecularly and clinically selected patients with NSCLC, with a focus on trials in patients whose tumors have EGFR mutations, will also be reviewed.     

Copper Substitution and Noise Reduction in Brake Pads: Graphite Type Selection

Graphite is commonly used in brake pads. The use of graphite powder has the main goal of solid state lubrication and friction coefficient stabilization. In this article results on resin bonded brake pads with focus on noise performance and heat dissipation are presented. Experimental tests are based on model friction materials with a known formulation and a reduced number of components for a better identification of the role of the graphite type. Results clearly indicate that both noise performance and thermal conductivity are strongly affected by the type of graphite. Guidelines for the selection of graphite types for optimized friction materials are given.     

HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies

A hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.     

MRI of the intracranial corticospinal tracts in amyotrophic and primary lateral sclerosis

Our aim was to investigate the corticospinal tracts (CST) in motor neurone disease, using MRI, and to correlate findings with clinical data. We studied 31 patients with amyotrophic (ALS) and eight with primary lateral sclerosis (PLS). The signal from the CST was classified into four grades on T2-weighted images, and compared to T2-weighted images of 37 age-matched control subjects. No abnormalities were seen in the CST on T1-weighted images and were rarely evident on proton-density weighting. Variable high signal in the CST was found on T2-weighted images in 35 patients, and in 29 control subjects. Our grades 0 and 1 were more frequent in control subjects, grades 2 and 3 more frequent in patients. We found no correlation between the high signal and clinical data, including the duration of the illness. We therefore conclude that this technique is neither sensitive nor specific except in grade 3 which is quite specific for ALS. In half the patients we found atrophy of the superior parietal gyrus, which merits further study. Received: 10 August 1998 Accepted: 23 February 1999