Citations

Background— The 2000 European Society of Cardiology/American College of Cardiology definition for myocardial infarction (MI) combines ischemic symptoms, electrocardiographic changes, and troponin rather than creatine kinase levels. The use of troponins will increase the detection of MI by a magnitude to be quantified, and the clinical acceptance of the new definition is unknown. Method and Results— Subjects presenting to an Olmsted County facility with a troponin T value ≥0.03 ng/mL between November 2002 and March 2005 were prospectively classified through the use of standardized MI criteria, relying on cardiac pain, Minnesota coding of the ECG, and troponin, creatine kinase, and its MB fraction measured simultaneously. Through the use of dynamic changes in troponin, 538 MIs were identified versus 327 with creatine kinase and 427 with only the MB fraction of creatine kinase. This represents a 74% (95% confidence interval [CI], 69% to 79%) increase above the number of MIs identified with creatine kinase and a 41% (95% CI, 37% to 46%) increase above the number identified with criteria including only its MB fraction. When relying on single values of troponin, increases in the number of MIs were always large but varied widely according to the threshold used for troponin. Cases meeting only troponin-based criteria were less likely to have electrocardiographic ST-segment elevation and had better survival than those identified with previous criteria. Clinician diagnoses mentioned MI in 42% (95% CI, 34% to 49%) of cases meeting only troponin-based criteria versus 74% (95% CI, 69% to 78%) for MIs meeting the previous criteria ( P <0.001). Conclusions— The prospective application of the new criteria in the community results in a large increase in the number of MIs and a change in case mix. The clinical acceptance of the new criteria is incomplete, and studies that rely exclusively on dismissal diagnoses to assess MI rates may underestimate the burden of disease as presently defined.

Abstract Cancer incidence for American Indians and Alaska Natives is typically reported as a single rate for all U.S. indigenous populations combined. Previously reported combined rates suggest that American Indians and Alaska Natives have lower cancer incidence rates compared with the U.S. population. Alaska Native people comprise three major ethnic groups: Eskimo, Indian, and Aleut people. We examined cancer incidence from only Alaska Indians and compared incidence rates with an American Indian population living in New Mexico. These data indicate striking differences in cancer patterns between two American Indian populations. Cancer data for the years 1993 to 2002 for American Indians of New Mexico and U.S. Whites are from the National Cancer Institute Surveillance, Epidemiology, and End Results Program Public-use data set. Data for Alaska Indians are from the Alaska Native Tumor Registry, which is also a Surveillance Epidemiology and End Results Program participant. Overall, cancer incidence rates for all sites combined in New Mexico Indian men and women were lower than U.S. White rates, whereas Alaska Indian men and women exceeded U.S. rates. In comparing Alaska and New Mexico Indians, we observed a 2.5-fold higher incidence of cancer among Alaska Indians. The largest differences between the two Indian populations were noted primarily in cancers associated with tobacco use, including cancers of the oral cavity/pharynx, esophagus (only in men), colon and rectum, pancreas, larynx (men), lung, prostate, and urinary bladder (men). Lung cancer rates in Alaska Indian men and women were 7 and 10 times those of New Mexico Indian men and women. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1515–9)

Purpose Previously, we reported results of Intergroup N9741, which compared standard bolus fluorouracil (FU), leucovorin, plus irinotecan (IFL) with infused FU, leucovorin, plus oxaliplatin (FOLFOX4) and irinotecan plus oxaliplatin in patients with untreated metastatic colorectal cancer. High rates of grade ≥ 3 toxicity on IFL (resulting in some deaths) led us to reduce the starting doses of both irinotecan and FU by 20% (rIFL). This article compares rIFL with FOLFOX4. Patients and Methods The primary comparison was time to progression, with secondary end points of response rate (RR), overall survival, and toxicity. Results Three hundred five patients were randomly assigned. The North Central Cancer Treatment Group Data Safety Monitoring Committee interrupted enrollment at a planned interim analysis when outcomes crossed predetermined stopping boundaries. The results were significantly superior for FOLFOX4 compared with rIFL for time to progression (9.7 v 5.5 months, respectively; P < .0001), RR (48% v 32%, respectively; P = .006), and overall survival (19.0 v 16.3 months, respectively; P = .026). Toxicity profiles were not significantly different between regimens for nausea, vomiting, diarrhea, febrile neutropenia, dehydration, or 60-day all-cause mortality. Sensory neuropathy and neutropenia were significantly more common with FOLFOX4. Approximately 75% of patients in both arms received second-line therapy; 58% of rIFL patients received oxaliplatin-based second-line therapy, and 55% of FOLFOX4 patients received irinotecan-based regimens as second-line therapy. Conclusion FOLFOX4 led to superior RR, time to progression, and overall survival compared with rIFL. The survival benefit for FOLFOX4 observed in the earlier stage of the study was preserved with equal use of either irinotecan or oxaliplatin as second-line therapy.

Abstract This multicenter, open-label, randomized phase 2 study evaluated 2 dose regimens of lenalidomide for relapsed, refractory myeloma. Seventy patients were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. Analysis of the first 70 patients showed increased grade 3/4 myelo-suppression in patients receiving 15 mg twice daily (41% versus 13%, P = .03). An additional 32 patients received 30 mg once daily. Responses were evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once-daily and 29% for twice-daily lenalidomide). Median overall survival in 30-mg once-daily and twice-daily groups was 28 and 27 months, respectively. Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2). Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of clinically significant grade 3/4 myelosuppression was shorter in the twice-daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred in only 3%. Lenalidomide is active and well tolerated in relapsed, refractory myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with dexamethasone.

AbstractThis article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials. We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.

The acetylcholine receptor from vertebrate skeletal muscle is a transmembrane channel that binds nerve-released acetylcholine to elicit rapid transport of small cations. Composed of two alpha subunits and one beta, one gamma, and one delta subunit, the receptor is a cooperative protein containing two sites that bind agonists, curariform antagonists, and snake alpha-toxins. Until recently the two binding sites were thought to reside entirely within each of the two alpha subunits, but affinity labeling and expression studies have demonstrated contributions by the gamma and delta subunits. Affinity labeling and mutagenesis studies have identified residues of the alpha subunit that contribute to the binding site, but the corresponding gamma- and delta-subunit residues remain unknown. By making gamma-delta chimeras and following the nearly 100-fold difference in curare affinity for the two binding sites, the present work identified residues of the gamma and delta subunits likely to be near the binding site. Two sets of binding determinants were identified in homologous positions of the gamma and delta subunits. The determinants lie on either side of a disulfide loop found within the major extracellular domain of the subunits. This loop is common to all acetylcholine, gamma-aminobutyrate, and glycine receptor subunits.