Faculty Publications

Purpose This study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. Patients and Methods A single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. Results The low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (C-max) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and Cmax of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. Conclusion These large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.

OBJECTIVE: Lung cancer survivors commonly experience impairments in

Studies indicate that peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) can either attenuate or potentiate colon cancer. One hypothesis suggests that PPAR beta/delta is upregulated by the adenomatous polyposis coli (APC)/beta-CATENIN pathway and a related hypothesis suggests that PPAR beta/delta is downregulated by nonsteroidal antiinflammatory drugs (NSAIDs). The present study examined these possibilities using in vivo and in vitro models. While APC/beta-CATENIN-dependent expression of CYCLIN D1 was observed in vivo and in vitro, expression of PPAR beta/delta was not different in colon or intestinal polyps from wild-type or Apc(min) heterozygous mice or in human colon cancer cell lines with mutations in APC and/or beta-CATENIN. No difference in the level of PPAR beta/delta was found in colon from wild-type or Apc(min) heterozygous mice following treatment with NO-donating aspirin (NO-ASA). NSAIDs inhibited cell growth in RKO (wild-type APC) and DLD1 (mutant APC) human colon cancer cell lines but expression of PPAR beta/delta was not downregulated in these cell lines in response to a broad concentration range of celecoxib, indomethacin, NS-398, or nimesulide. However, indomethacin caused an increase in PPAR beta/delta mRNA and protein that was accompanied with increased expression of a known PPAR beta/delta target gene. Interestingly, expression of PPAR alpha was also increased in the human colon cancer cell lines by several NSAIDs at the highest concentration examined. Results from these studies provide additional evidence indicating that PPAR beta/delta is not upregulated by the APC/beta-CATENIN pathway. Further, these studies suggest that increased PPAR beta/delta and/or PPAR alpha by NSAIDs in human colon cancer cell lines could contribute to the mechanisms underlying the chemopreventive effects of NSAIDs. (C) 2009 Wiley-Liss, Inc.

alphabeta and gammadelta T cells arise from a common thymocyte progenitor during development in the thymus. Emerging evidence suggests that the pre-T cell receptor (pre-TCR) and gammadelta T cell receptor (gammadeltaTCR) play instructional roles in specifying the alphabeta and gammadelta T-lineage fates, respectively. Nevertheless, the signaling pathways differentially engaged to specify fate and promote the development of these lineages remain poorly understood. Here, we show that differential activation of the extracellular signal-related kinase (ERK)-early growth response gene (Egr)-inhibitor of DNA binding 3 (Id3) pathway plays a defining role in this process. In particular, Id3 expression served to regulate adoption of the gammadelta fate. Moreover, Id3 was both necessary and sufficient to enable gammadelta-lineage cells to differentiate independently of Notch signaling and become competent IFNgamma-producing effectors. Taken together, these findings identify Id3 as a central player that controls both adoption of the gammadelta fate and its maturation in the thymus.

Decrements in cognitive function are common in cancer patients and other clinical populations. As direct neuropsychological testing is often not feasible or affordable, there is potential utility in screening for deficits that may warrant a more comprehensive neuropsychological assessment. Furthermore, some evidence suggests that perceived cognitive function (PCF) is independently associated with structural and functional changes on neuroimagery, and may precede more overt deficits. To appropriately measure PCF, one must understand its components and the underlying dimensional structure. The purpose of this study was to examine the dimensionality of PCF in people with cancer. The sample included 393 cancer patients from four clinical trials who completed a questionnaire consisting of the prioritized areas of concerns identified by patients and clinicians: self-reported mental acuity, concentration, memory, verbal fluency, and functional interference. Each area contained both negatively worded (i.e., deficit) and positively worded (i.e., capability) items. Data were analyzed by using Cronbach's alpha, item-total correlations, one-factor confirmatory factor analysis, and a bi-factor analysis model. Results indicated that perceived cognitive problem items are distinct from cognitive capability items, supporting a two-factor structure of PCF. Scoring of PCF based on these two factors should lead to improved assessment of PCF for people with cancer.

A growing body of evidence indicates that early mitotic inhibitor 1 (Emi1) is essential for genomic stability, but how this function relates to embryonic development and cancer pathogenesis remains unclear. We have identified a zebrafish mutant line in which deficient emi1 gene expression results in multilineage hematopoietic defects and widespread developmental defects that are p53 independent. Cell cycle analyses of Emi1-depleted zebrafish or human cells showed chromosomal rereplication, and metaphase preparations from mutant zebrafish embryos revealed rereplicated, unsegregated chromosomes and polyploidy. Furthermore, EMI1-depleted mammalian cells relied on topoisomerase II alpha-dependent mitotic decatenation to progress through metaphase. Interestingly, the loss of a single emi1 allele in the absence of p53 enhanced the susceptibility of adult fish to neural sheath tumorigenesis. Our results cast Emi1 as a critical regulator of genomic fidelity during embryogenesis and suggest that the factor may act as a tumor suppressor.

Background: The National Comprehensive Cancer Network (NCCN) Outcomes Database was created to assess concordance to evidence- and consensus-based guidelines and to measure adherence to quality measures on an ongoing basis. The Colorectal Cancer Database began in 2005 as a collaboration among 8 NCCN centers. Methods: Newly diagnosed colon and rectal cancer patients presenting to 1 of 8 NCCN centers between September 1, 2005, and May 21, 2008, were eligible for analysis of concordance with NCCN treatment guidelines for colorectal cancer and with a set of quality metrics jointly developed by ASCO and NCCN in 2007. Adherence rates were determined for each metric. Center-specific rates were benchmarked against mean concordance rates for all participating centers. Results: A total of 3443 patients were evaluable. Mean concordance rates with NCCN colorectal cancer guidelines and ASCO/NCCN quality measures were generally high (>= 90%). However, relatively low mean concordance rates were noted for adjuvant chemotherapy treatment recommendations within 9 months of diagnosis of stage II to III rectal cancer (81%), and neoadjuvant chemoradiation in clinical T4 rectal primaries (83%). These low rates of concordance seemed to be consistent across centers. Conclusions: Adherence to guidelines and quality measures is generally high at institutions participating in the NCCN colorectal cancer database. Lack of documentation, patient refusal, delayed treatment initiation, and lack of consensus about whether treatment was essential were the primary reasons for nonconcordance. Measurement of concordance and the reasons for nonconcordance enable participating centers to understand and improve their care delivery systems. (JNCCN 2009;7:895-904)

Context: Family history is a risk factor for many common chronic diseases, yet it remains underutilized in primary care practice. Background: Family Healthware (TM) is a self-administered, web-based tool that assesses familial risk for CHD; stroke; diabetes; and colorectal, breast, and ovarian cancer, and provides a personalized prevention plan based on familial risk. The Family Healthware Impact Trial evaluated the tool. Design: In this cluster RCT, participants completed baseline and 6-month follow-up surveys. The intervention group used Family Healthware directly after the baseline survey. Controls used the tool after completing the follow-up survey. Setting/participants: Patients aged 35-65 years with no known diagnosis of these six diseases were enrolled from 41 primary care practices. Main outcome measures: The prevalence of family-history-based risk for coronary heart disease (CHD); stroke; diabetes; and colorectal, breast, and ovarian cancer was determined in a primary care population. Results: From 2005 to 2007, 3786 participants enrolled. Data analysis was undertaken from September 2007 to March 2008. Participants had a mean age of 50.6 years and were primarily white (91%) women (70%). Of the 3585 participants who completed the risk assessment tool, 82% had a strong or moderate familial risk for at least one of the diseases: CHD (strong=33%, moderate=26%); stroke (strong=15%, moderate=34%); diabetes (strong=11%, moderate=26%); colorectal cancer (strong=3%, moderate=11%); breast cancer (strong=10%, moderate=12%); and ovarian cancer (strong=4%, moderate=6%). Women had a significantly (p<0.04) higher familial risk than men for all diseases except colorectal and ovarian cancer. Overweight participants were significantly (p <= 0.02) more likely to have a strong family history for CHD, stroke, and diabetes. Older participants were significantly (p <= 0.02) more likely to report a strong family history for CHD and stroke as well as colorectal and breast cancer. Conclusions: This self-administered, online tool delineated a substantial burden of family-history-based risk for these chronic diseases in an adult, primary care population. Trial registration: NCT00164658. (Am J Prev Med 2009;36(6):506-514) (C) 2009 American journal of Preventive Medicine

Protein structure determination and predictive modeling have long been guided by the paradigm that the peptide backbone has a single, context-independent ideal geometry. Both quantum-mechanics calculations and empirical analyses have shown this is an incorrect simplification in that backbone covalent geometry actually varies systematically as a function of the Phi and Psi backbone dihedral angles. Here, we use a nonredundant set of ultrahigh-resolution protein structures to define these conformation-dependent variations. The trends have a rational, structural basis that can be explained by avoidance of atomic clashes or optimization of favorable electrostatic interactions. To facilitate adoption of this paradigm, we have created a conformation-dependent library of covalent bond lengths and bond angles and shown that it has improved accuracy over existing methods without any additional variables to optimize. Protein structures derived from crystallographic refinement and predictive modeling both stand to benefit from incorporation of the paradigm.

Purpose To evaluate the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with one to three hepatic metastases. Patients and Methods Patients with one to three hepatic lesions and maximum individual tumor diameters less than 6 cm were enrolled and treated on a multi-institutional, phase I/II clinical trial in which they received SBRT delivered in three fractions. During phase I, the total dose was safely escalated from 36 Gy to 60 Gy. The phase II dose was 60 Gy. The primary end point was local control. Lesions with at least 6 months of radiographic follow-up were considered assessable for local control. Secondary end points were toxicity and survival. Results Forty-seven patients with 63 lesions were treated with SBRT. Among them, 69% had received at least one prior systemic therapy regimen for metastatic disease (range, 0 to 5 regimens), and 45% had extrahepatic disease at study entry. Only one patient experienced grade 3 or higher toxicity (2%). Forty-nine discrete lesions were assessable for local control. Median follow-up for assessable lesions was 16 months (range, 6 to 54 months). The median maximal tumor diameter was 2.7 cm (range, 0.4 to 5.8 cm). Local progression occurred in only three lesions at a median of 7.5 months (range, 7 to 13 months) after SBRT. Actuarial in-field local control rates at one and two years after SBRT were 95% and 92%, respectively. Among lesions with maximal diameter of 3 cm or less, 2-year local control was 100%. Median survival was 20.5 months. Conclusion This multi-institutional, phase I/II trial demonstrates that high-dose liver SBRT is safe and effective for the treatment of patients with one to three hepatic metastases.

Purpose: Men with a family history of prostate cancer and black men are at higher risk for prostate cancer. Recruitment and retention of these men at high risk into early detection programs is challenging. We report a comprehensive analysis of recruitment methods, show rates and participant factors from the Prostate Cancer Risk Assessment Program, a prospective, longitudinal prostate cancer screening study. Materials and Methods: Men 35 to 69 years old were eligible for recruitment if they had a family history of prostate cancer, were black or had a BRCA1/2 mutation. Recruitment methods were analyzed using standard statistical methods with respect to participant demographics and presentation to the first program appointment. Results: Of 707 men recruited 64.9% presented to the initial program appointment. More men were recruited via radio than via referral or other methods (chi-square = 298.13, p<0.0001). Men recruited by radio were more likely to be black (p<01.001), less educated (p = 0.003) and not married or partnered (p = 0.007), and have no prostate cancer family history (p <0.001). Men recruited by referral had a higher income (p = 0.007) and were more likely to attend the initial program visit than those recruited by radio or other methods (chi-square = 27.08, p <0.0001). Conclusions: This comprehensive analysis shows that radio led to higher recruitment of black men with lower socioeconomic status. However, these men at high risk have a lower presentation rate for prostate cancer screening. Targeted motivational measures must be studied to improve the show rate for prostate cancer risk assessment in these men at high risk.

Because there have been no RCTs of preoperative and postoperative AT sequencing in the treatment of resectable and borderline resectable pancreatic cancer, it is impossible to assess their relative values with confidence. Three nonrandomized experiences of both treatment approaches from single institutions provide some assurance that preoperative AT is not inferior to postoperative AT. Phase II trials for both resectable and borderline resectable tumors suggest that longer median survival can be obtained by a policy of preoperative AT. We will watch the European RCT with great interest.

We report results from a computational investigation of the oxidative deboronation of boroglycine, H2N-CH2-B(OH)(2), using H2O and H2O2 as the reactive oxygen species (ROS) to yield aminomethanol, H2N-CH2-OH; these results complement Our study on the protodeboronation of boroglycine to produce methylamine, H2N-CH3 (Larkin et al. J. Phys. Chem. A 2007, 111, 6489-6500). Second-order Moller-Plesset (MP2) perturbation theory with Dunning-Woon correlation-consistent (cc) basis sets were used for the calculations with comparisons made to results from density functional theory (DFT) at the PBE1PBE/6-311++G(d,p)(cc-pVDZ) levels. The effects of a bulk aqueous environment were also incorporated into the calculations employing PCM and CPCM methodology. Using H2O as the ROS, the reaction H2O + H2N-CH2-B(OH)(2) -> H2N-CH2-OH + H-B(OH)(2) was calculated to be endothermic; the value of Delta H-298(0) was + 12.0 kcal/mol at the MP2(FC)/cc-pVTZ computational level in vacuo and + 13.7 kcal/mol in PCM aqueous media; the corresponding value for the activation barrier, Delta H double dagger, was +94.3 kcal/mol relative to the separated reactants in vacuo and +89.9 kcal/mol in PCM aqueous media. In contrast, the reaction H2O2 + H2N-CH2-B(OH)(2) -> H2N-CH2-OH + B(OH)(3) was calculated to be highly exothermic with an Delta H-298(0) value of -100.9 kcal/mol at the MP2(FC)/cc-pVTZ computational level in vacuo and -99.6 kcal/mol in CPCM aqueous media; the highest-energy transition state for the multistep process associated with this reaction involved the rearrangement of H2N-CH2-B(OH)(OOH) to H2N-CH2-O-B(OH)(2) with a Delta H double dagger value of +23.2 kcal/mol in vacuo relative to the separated reactants. These computational results for boroglycine are in accord with the experimental observations for the deboronation of the FDA approved anticancer drug bortezomib (Velcade, PS-341), where it was found to be the principle deactivation pathway (Labutti et al. Chem. Res. Toxicol. 2006, 19, 539-546).

It is shown that the energy of protons accelerated in laser matter inter-action experiments may be significantly increased through the process of splitting the incoming laser pulse into multiple interaction stages of equal intensity. From a thermodynamic point of view, the splitting procedure can be viewed as an effective way of increasing the efficiency of energy transfer from the laser light to protons, which peaks for processes having the least amount of entropy gain. It is predicted that it should be possible to achieve at least a 100% increase in the energy efficiency in a six-stage laser proton accelerator compared with a single laser target interaction scheme.