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Background— The clinical profiles and outcomes of patients treated surgically for acute type B aortic dissection (ABAD) are often reported for those in small series or for those cared for at a single institution over a long time period, during which a continuous evolution in techniques has occurred. Accordingly, we sought to evaluate the clinical features and surgical results of patients enrolled in the International Registry of Acute Aortic Dissection by identifying primary factors that influenced surgical outcome and estimating average surgical mortality for ABAD in the current era. Methods and Results— A comprehensive analysis of 290 clinical variables and their relation to surgical outcomes for 82 patients who required surgery for ABAD (from a population of 1256 patients; mean±SD age, 60.6±15.0 years; 82.9% male) and who were enrolled in the International Registry of Acute Aortic Dissection was performed. The overall in-hospital mortality was 29.3%. Factors associated with increased surgical mortality based on univariate analysis were preoperative coma or altered consciousness, partial thrombosis of the false lumen, evidence of periaortic hematoma on diagnostic imaging, descending aortic diameter >6 cm, right ventricle dysfunction at surgery, and shorter time from the onset of symptoms to surgery. Factors associated with favorable outcomes included radiating pain, normotension at surgery (systolic blood pressure 100 to 149 mm Hg), and reduced hypothermic circulatory arrest time. The 2 independent predictors of surgical mortality were age >70 years (odds ratio, 4.32; 95% confidence interval, 1.30 to 14.34) and preoperative shock/hypotension (odds ratio, 6.05; 95% confidence interval, 1.12 to 32.49). Conclusions— The present study provides insights into current-day clinical profiles and surgical outcomes of ABAD. Knowledge about different preoperative clinical conditions may help surgeons in making treatment decisions among these high-risk patients.

Purpose Palliation of bone pain can be achieved in men with androgen-independent prostate cancer treated with docetaxel and estramustine (DE) or mitoxantrone and prednisone (MP). While Southwest Oncology Group trial 99-16 demonstrated a survival improvement of DE over MP, the study also was designed to compare the palliation of disease-related symptoms. Methods Pain palliation and global quality of life (QOL) were the two primary patient-reported outcomes. Pain was measured with the Present Pain Intensity scale of the McGill Pain Questionnaire-Short Form. The European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (QLQ-C30) and its Prostate Cancer Module (PR25) measured QOL and symptom status. Pain and analgesic use were measured at random assignment, every cycle for eight cycles, and 1 year from random assignment; the QLQ-C30 and the PR25 were administered at random assignment, before cycle four (week 10) and cycle eight (month 6) and at 1 year. In addition to the primary intent-to-treat, missing at random analysis, sensitivity analyses were performed to assess robustness of global QOL conclusions under alternative informative missing data assumptions. Results Six hundred seventy four eligible patients received DE (n = 338) or MP (n = 336). In an intention-to-treat analysis, median overall survival was 17.5 months for the DE arm and 15.6 months for the MP arm (P = .02). There were no statistically significant differences in pain palliation between the treatment arms. The sensitivity analyses showed a consistent lack of statistically significant global QOL differences for the two arms. Conclusion DE had superior clinical efficacy (overall survival, time-to-progression, and prostate-specific antigen declines) with similar global QOL and pain palliation in the MP arm.

Abstract Despite numerous studies showing that mutagen sensitivity is a cancer predisposition factor, the heritability of mutagen sensitivity has not been clearly established. In this report, we used a classic twin study design to examine the role of genetic and environmental factors on the mutagen sensitivity phenotype. Mutagen sensitivity was measured in peripheral blood lymphocytes from 460 individuals [148 pairs of monozygotic (MZ) twins, 57 pairs of dizygotic (DZ) twins, and 50 siblings]. The intraclass correlation coefficients were all significantly higher in MZ twins than in dizygotes (DZ pairs and MZ-sibling pairs combined) for sensitivity to four different mutagen challenges. Applying biometric genetic modeling, we calculated a genetic heritability of 40.7%, 48.0%, 62.5%, and 58.8% for bleomycin, benzo[a]pyrene diol epoxide, γ-radiation, and 4-nitroquinoline-1-oxide sensitivity, respectively. This study provides the strongest and most direct evidence that mutagen sensitivity is highly heritable, thereby validating the use of mutagen sensitivity as a cancer susceptibility factor. (Cancer Res 2006; 66(12): 5993-6)

AbstractPurpose: To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule.Experimental Design: Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase (ALT): Group 1 (n = 19): total bilirubin 1.5 to 3.0 × institutional upper limit of normal (IULN) and ALT/AST ≤5.0 × IULN; Group 2 (n = 7): total bilirubin 3.1 to 5.0 × IULN and ALT/AST ≤5.0 × IULN; Group 3 (n = 6): total bilirubin ≤1.5 × IULN and ALT/AST 5.1 to 20.0 × IULN; Group 4 (n = 10): total bilirubin 1.5 to 3.0 × IULN and ALT/AST 5.1 to 20.0 × IULN. Irinotecan was given as a 90-minute i.v. infusion weekly for the first 4 weeks in each 6-week cycle at starting doses which escalated from 40 to as much as 75 mg/m2. After the first treatment, doses were adjusted based on individual patient toxicities. Starting doses for patients with hepatic dysfunction were derived from the maximum tolerated doses noted in the four hepatic dysfunction groups.Results: Forty-two patients were treated. Among the most frequent adverse events were neutropenia (41%, grades 3/4), diarrhea (15%, grades 3/4), nausea (10%, grade 3), and vomiting (5%, grades 3/4). Two patients died from drug-induced neutropenic sepsis. Two patients had objective tumor responses (complete response, liver metastases from unknown primary; partial response, colon cancer). Hepatic dysfunction reduced irinotecan clearance while increasing relative exposure to the active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). SN-38 exposures in patients receiving doses of 40 to 75 mg/m2 were comparable to exposures in patients with normal liver function treated with a starting dose of 125 mg/m2.Conclusions: Irinotecan starting doses that seem to be safe for hepatically impaired patients treated with the weekly schedule are 60, 50, 60, and 40 mg/m2 for groups 1 to 4, respectively. At these starting doses, exposure to SN-38 and the adverse event profile are similar to that observed in patients with normal liver function and antitumor activity can be observed.

The biological changes that occur in the brains of Alzheimer's disease (AD) patients are thought to begin long before the onset of clinical symptoms. Although current therapeutic agents have been approved only for patients with mild to moderate AD, Alzheimer‐type pathology in patients with mild to moderate AD is already quite advanced. One impetus for the development of the concept of mild cognitive impairment (MCI) was the attempt to recognize AD early in its clinical expression and to determine whether it is possible through therapeutic interventions to improve the memory impairment at this stage or delay further progression to dementia. To this end, several clinical trials have been conducted in patients with MCI. On September 8 and 9, 2004 a meeting of the Alzheimer's Association Research Roundtable was held at which experts in the field of MCI convened to review the collective experience from these trials and to consider potential approaches that might improve MCI clinical trials in the future. This article summarizes the presentations and discussions of that meeting.

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.

Abstract Aberrant crypt foci (ACF) are collections of abnormal colonic crypts with heterogeneous molecular and pathologic characteristics. Large and dysplastic ACF are putative precursors of colon cancer with neoplastic risk related to increased proliferation. In this study, we examined the role of epidermal growth factor receptor (EGFR) signaling in regulating ACF proliferation. Using magnification chromoendoscopy, we collected large ACF with endoscopic features of dysplasia and separately biopsied adjacent mucosa. Transcript levels were measured by real-time PCR, proteins were assessed by Western blotting, and levels were expressed as fold changes of adjacent mucosa. K-ras and B-Raf mutations were assessed by PCR and Ras activation by the ratio Ras-GTP / (Ras-GTP + Ras-GDP). At the RNA level, 38% of ACF were hyperproliferative, with proliferating cell nuclear antigen (PCNA) mRNA ≥2-fold of adjacent mucosa. Hyperproliferative ACF had significantly increased mRNA levels of EGFR (6.0 ± 1.7–fold), transforming growth factor-α (14.4 ± 5.0–fold), heparin-binding EGF-like growth factor (4.5 ± 1.4–fold), cyclin D1 (4.6 ± 0.7–fold), and cyclooxygenase-2 (COX-2; 9.3 ± 4.2–fold; P < 0.05). At the protein level, 46% of ACF were hyperproliferative (PCNA, 3.2 ± 1.2–fold). In hyperproliferative ACF, 44% possessed significant increases in four EGFR signaling components: EGFR (9.5 ± 1.3–fold), phosphoactive ErbB2 (2.6 ± 0.4–fold), phosphoactive extracellular signal-regulated kinase (3.7 ± 1.1–fold), and cyclin D1 (3.4 ± 0.8–fold; P < 0.05). Ras was activated in 46% of ACF (3.2 ± 0.4–fold; P < 0.05), but K-ras mutations were present in only 7% of ACF. In contrast to COX-2 mRNA, the protein was not increased in hyperproliferative ACF. In summary, we have shown that ACF with up-regulated PCNA possess increased EGFR signaling components that likely contribute to the enhanced proliferative state of dysplastic-appearing ACF. (Cancer Res 2006; 66(11): 5656-64)