Citations

Abstract Activating epidermal growth factor receptor (EGFR) mutations are common in many cancers including glioblastoma. However, clinical responses to EGFR inhibitors are infrequent and short-lived. We show that the Src family kinases (SFK) Fyn and Src are effectors of oncogenic EGFR signaling, enhancing invasion and tumor cell survival in vivo. Expression of a constitutively active EGFR mutant, EGFRvIII, resulted in activating phosphorylation and physical association with Src and Fyn, promoting tumor growth and motility. Gene silencing of Fyn and Src limited EGFR- and EGFRvIII-dependent tumor cell motility. The SFK inhibitor dasatinib inhibited invasion, promoted tumor regression, and induced apoptosis in vivo, significantly prolonging survival of an orthotopic glioblastoma model expressing endogenous EGFRvIII. Dasatinib enhanced the efficacy of an anti-EGFR monoclonal antibody (mAb 806) in vivo, further limiting tumor growth and extending survival. Examination of a large cohort of clinical samples showed frequent coactivation of EGFR and SFKs in glioblastoma patients. These results establish a mechanism linking EGFR signaling with Fyn and Src activation to promote tumor progression and invasion in vivo and provide rationale for combined anti-EGFR and anti-SFK targeted therapies. [Cancer Res 2009;69(17):6889–98]

The treatment options currently available in the medical therapy of advanced colorectal cancer (CRC) appear to be an abundance of riches. The integration of oxaliplatin and irinotecan as conventional cytotoxic agents as well as bevacizumab and the epidermal growth factor receptor (EGFR) antibodies, cetuximab and panitumumab, as novel targeted agents into standard medical therapy have improved median overall survival in metastatic CRC beyond 2 years. It cannot be overemphasized that these significant improvements in outcome of patients with CRC are closely linked to the number of active drugs available to treat this disease. The abundance of treatment options, however, comes with specific challenges for the practical management of palliative medical therapy in advanced CRC, in particular with regard to the utilization of targeted agents. In this context, bevacizumab has established itself as the standard component of first-line chemotherapy. It is of interest for clinical practice that so far no predictive marker for the activity of bevacizumab in metastatic CRC has been identified. The key questions surrounding the use of bevacizumab in the palliative setting are whether its continuation beyond tumor progression provides clinical benefit, and which patient group is at higher risk for bevacizumab-related toxicities. Cetuximab and panitumumab have demonstrated efficacy both in combination with chemotherapy or — in contrast to bevacizumab — as single agent. In unselected patients, the effect of both EGFR antibodies on time-related parameters, progression free survival and overall survival, is moderate at best with emphasis more on the induction of tumor responses in a select group of patients. Therefore, until recently, EGFR antibodies were mainly regarded as salvage therapy options, in particular, since there did not appear to be a loss of activity when used in later lines of therapy. The finding that CRC harboring KRAS (and BRAF) mutations are resistant to EGFR antibodies, has allowed us to enrich the patient population with CRC that have a chance to benefit from cetuximab or panitumumab therapy. Biomarker-based treatment decisions are therefore now an integral part of clinical practice and trial design in CRC. In conclusion, targeted agents have become an integral part of medical therapy for advanced CRC. The challenge for current oncologic practice is to develop a rationale and biomarker-based treatment algorithm utilizing all potentially active agents as individualized therapy.

Background Golf provides an opportunity for relatively low-impact exercise for nearly all age groups and is considered a recommended activity for patients after total knee arthroplasty. Hypothesis We hypothesized that total knee arthroplasty would afford patients increased ability to participate in and enjoy golf, allowing a large percentage of these patients to walk the golf course. Study Design Case series; Level of evidence, 4. Methods Surveys were sent to 151 golfers who had undergone primary total knee arthroplasty from 1995 to 2000. The detailed survey included 33 questions specific to the patients’ golf performance, enjoyment of golf, frequency of participation, timing of return to play, presence of pain, use of a cart, and related golf-specific issues. Results We received and evaluated 93 responses (62%). Fifty-seven percent reported they had returned to golf within 6 months after total knee arthroplasty. Eighty-one percent of respondents reported golfing as frequently, or more frequently, than before knee replacement. Notably, golfers reported less pain while golfing after total knee arthroplasty than before (13% vs 83%; P < .0001), and 94% of respondents reported currently enjoying golf as much as or more than before surgery. Twenty-eight percent of respondents stated that they walked the course, rather than using a motorized golf cart, before surgery, while only 14% walked the course after surgery ( P = .02). Conclusion In this population of golfers, total knee arthroplasty reliably relieved pain that had been previously experienced while golfing, and increased or maintained this group’s enjoyment of playing golf. However, 86% of these patients reported using a cart while golfing. Further patient education is needed regarding the potential health benefits of walking during golf after total knee arthroplasty.

Abstract Objective Emerging data demonstrate that a large fraction of the global burden of disease is amenable to surgical intervention. There is a paucity of data related to delivery of surgical care in low‐ and middle‐income countries, and no aggregate data describe the efforts of international organizations to provide surgical care in these settings. This study was designed to describe the roles and practices of international organizations delivering surgical care in developing nations with regard to surgical types and volume, outcomes tracking, and degree of integration with local health systems. Methods Between October 2008 and December 2008, an Internet‐based confidential questionnaire was distributed to 99 international organizations providing humanitarian surgical care to determine their size, scope, involvement in surgical data collection, and integration into local systems. Results Forty‐six international organizations responded (response rate 46%). Findings reveal that a majority of organizations that provide surgery track numbers of cases performed and immediate outcomes, such as mortality. In general, these groups have mechanisms in place to track volume and outcomes, provide for postintervention follow‐up, are committed to providing education, and work in conjunction with local health organizations and providers. Whereas most organizations surveyed provided fewer than 500 surgical procedures annually, more than half had the capacity to provide emergency services. In addition, a great diversity of specialized surgical care was provided, including obstetrics, orthopedic, plastic, and ophthalmologic surgery. Conclusions International organizations providing surgical services are diverse in size and breadth of surgical services provided yet, with consistency, provide rudimentary analysis, postoperative follow‐up care, and both education and integration of health services at the local level. The role of international organizations in the delivery of surgery is an important index, worthy of further evaluation.

Abstract Background: Natriuretic peptide concentrations in adults require age- and sex-specific reference intervals for optimal interpretation. Females have higher natriuretic peptide concentrations, and hypotheses suggest that estrogen may be responsible. This study sought to determine the influence of hormone modulation on N-terminal probrain natriuretic peptide (NT-proBNP) by using a pediatric cohort. Children/adolescents typically have rapid hormone changes during puberty, making them an ideal group to study. Methods: We selected 759 specimens (303 male, 456 female; ages 2 months to 18 years, mean 13 years) obtained from the Mayo Clinic Pediatric Residual Specimen Bank. We measured NT-proBNP, sex hormone–binding globulin (SHBG), estradiol, and testosterone by immunoassays or LC-MS/MS and calculated free testosterone. We performed univariate and multivariate analyses to investigate the significance of NT-proBNP with each hormone. Results: Reference values demonstrated a sex difference and sequential age differences in females. Univariate modeling of the hormones with NT-proBNP revealed an independent inverse association of NT-proBNP with testosterone, a direct association with SHBG, and no significant association with estradiol. Multivariate modeling confirmed a strong association of testosterone and SHBG with NT-proBNP. Correlation of hormones with NT-proBNP retained greater significance than either age or sex. Conclusions: In pediatric patients, NT-proBNP is independently associated with both testosterone and SHBG hormone concentrations. Measurements of testosterone are inversely associated with NT-proBNP, and estrogens are marginally associated with NT-proBNP in males but not females, suggesting that androgens and not estrogens modulate sex differences notable in natriuretic peptides. Children and adolescents may require an objective assessment of hormones if optimal interpretation of natriuretic peptide concentrations is desired or the concentrations are confounded. .

Abstract Background: The next-generation, high-sensitivity cardiac troponin assays can measure quantifiable concentrations of cTn in a majority of individuals, but there are few studies assessing these assays for risk stratification. The present study was undertaken to determine if a research hs-cTnI assay can be useful for predicting death/myocardial infarction (MI), both short- and long-term, in an emergency department acute coronary syndrome (ACS) population. Methods: In a cohort of 383 subjects, originally recruited in 1996, presenting to the emergency department with symptoms suggestive of ACS, the heparin plasma obtained at initial presentation was thawed and measured in 2007 with a research hs-cTnI assay. AccuTnI (Beckman Coulter) measurements were made on these same samples in 2003. The population was divided into 4 groups by hs-cTnI: &lt;5.00, 5.00–9.99, 10.00–40.00, and &gt;40.00 ng/L. Kaplan–Meier, Cox proportional hazards, ROC curves, and logistic regression analyses were used to identify which hs-cTnI concentrations were predictive of death/MI within 10 years after presentation. Results: There were significant differences between the hs-cTnI groups for the probability of death/MI up to 10 years after presentation (P &lt; 0.05). At 6 months, patients with hs-cTnI ≥10.00 ng/L were at higher risk for death/MI (hazard ratio &gt;3.7; P &lt; 0.05) compared with those having hs-cTnI &lt;5.00 ng/L. ROC curve analysis for death/MI at 30 days with the hs-cTnI assay had an area under the curve of 0.74 (95% CI 0.65–0.82), with logistic models yielding an optimal assay threshold of 12.68 ng/L. Conclusions: This research hs-cTnI assay appears useful for risk stratification for death/MI in an ACS population.

OBJECTIVE Transgenic expression of diacylglycerol acyltransferase-1 (DGAT1) in skeletal muscle leads to protection against fat-induced insulin resistance despite accumulation of intramuscular triglyceride, a phenomenon similar to what is known as the “athlete paradox.” The primary objective of this study is to determine how DGAT1 affects muscle fatty acid oxidation in relation to whole-body energy metabolism and insulin sensitivity. RESEARCH DESIGN AND METHODS We first quantified insulin sensitivity and the relative tissue contributions to the improved whole-body insulin sensitivity in muscle creatine kisase (MCK)-DGAT1 transgenic mice by hyperinsulinemic-euglycemic clamps. Metabolic consequences of DGAT1 overexpression in skeletal muscles were determined by quantifying triglyceride synthesis/storage (anabolic) and fatty acid oxidation (catabolic), in conjunction with gene expression levels of representative marker genes in fatty acid metabolism. Whole-body energy metabolism including food consumption, body weights, oxygen consumption, locomotor activity, and respiration exchange ratios were determined at steady states. RESULTS MCK-DGAT1 mice were protected against muscle lipoptoxicity, although they remain susceptible to hepatic lipotoxicity. While augmenting triglyceride synthesis, DGAT1 overexpression also led to increased muscle mitochondrial fatty acid oxidation efficiency, as compared with wild-type muscles. On a high-fat diet, MCK-DGAT1 mice displayed higher basal metabolic rates and 5–10% lower body weights compared with wild-type littermates, whereas food consumption was not different. CONCLUSIONS DGAT1 overexpression in skeletal muscle led to parallel increases in triglyceride synthesis and fatty acid oxidation. Seemingly paradoxical, this phenomenon is characteristic of insulin-sensitive myofibers and suggests that DGAT1 plays an active role in metabolic “remodeling” of skeletal muscle coupled with insulin sensitization.