Citations

Abstract A circulating isoform of EGFR has been identified as an emerging serum biomarker in cancer patients. Serum concentrations of EGFR have been evaluated as screening, diagnostic, prognostic, and theragnostic markers for diverse human malignancies, including breast, ovarian, endometrial, colorectal, and lung cancer. Yet full-length EGFR is rarely shed from normal or malignant cells. Here we demonstrate that an alternately spliced EGFR isoform, termed ‘sEGFR,’ gives rise to the circulating sEGFR protein through proteolytic cleavage of a cell surface precursor. This cleavage event is inhibited by fibronectin and stimulated by both an anti-Δ5/α1 integrin antibody and the metalloprotease activator 4-aminophenylmercuric acetate. Preliminary results identify ADAM17/TACE as at least one mediator of sEGFR shedding. Shed sEGFR binds to EGF with high affinity. Two FDA-approved therapeutic anti-EGFR antibodies, cetuximab (Erbitux) and panitumumab (Vectibix), inhibit shedding of sEGFR, implicating sEGFR as a potential alternative target for these antibodies, consistent with previous studies indicating that baseline serum sEGFR concentrations may predict responsiveness to anti-EGFR-targeted therapy. These observations bear striking similarity to aspects of trastuzumab regulation of HER2, shedding, and, by analogy, may have implications for the design of future clinical trials using EGFR-directed therapeutics, including cetuximab and panitumimab. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3624. doi:1538-7445.AM2012-3624

Rationale: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1–dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. Objective: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. Methods and Results: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P =0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. Conclusions: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain.

The antihypertensive influence of fish oil is controversial, and the mechanisms remain unclear. Because the inverse relation between fish oil and hypertension appears to be partially dependent on the degree of hypertension, we tested the hypothesis that fish oil would elicit more dramatic reductions in mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA) in prehypertensive (PHT) compared with normotensive (NT) subjects. Resting MAP, MSNA, and heart rate (HR) were examined before and after 8 wk of fish oil (9 g/day; 1.6 g eicosapentaenoic acid and 1.1 g docosahexaenoic acid) or placebo (olive oil; 9 g/day) in 38 NT (19 fish oil; 19 placebo) and 29 PHT (15 fish oil; 14 placebo) volunteers. Fish oil did not alter resting MAP, MSNA, or HR in either NT (80 ± 1 to 80 ± 1 mmHg; 11 ± 2 to 10 ± 1 bursts/min; 71 ± 2 to 71 ± 2 beats/min) or PHT (88 ± 2 to 87 ± 1 mmHg; 11 ± 2 to 10 ± 2 bursts/min; 73 ± 2 to 73 ± 2 beats/min) subjects. When NT and PHT groups were consolidated, analysis of covariance confirmed that pretreatment resting MAP was not associated with changes in MSNA after fish oil. In contrast, pretreatment resting HR was correlated with changes in MSNA ( r = 0.47; P = 0.007) and MAP ( r = 0.42; P < 0.007) after fish oil but not placebo. In conclusion, fish oil did not alter sympathetic neural control in NT or PHT subjects. However, our findings suggest that fish oil is associated with modest sympathoinhibition in individuals with higher resting heart rates, a finding that is consistent with a recent meta-analysis examining the relations among fish oil, HR, and the risk of cardiovascular disease.

Abstract —The present study was performed to determine whether physiologically relevant doses of angiotensin II (Ang II), which do not affect renal hemodynamics but do cause slow response hypertension, result in oxidative stress as measured by production of vasoconstrictor F 2 -isoprostane, a prostaglandin-like non–cyclooxygenase-produced arachidonic acid metabolite that is the end product of lipid peroxidation. Rats were instrumented with abdominal aortic and left femoral venous catheters, and before and throughout Ang II (or saline) infusion, all rats received enalapril (250 mg/L). Four days after the initiation of enalapril, rats were infused with Ang II (10 ng · kg −1 · min −1 , n=6) or saline (n=6) for 14 days. Mean arterial pressure was measured 24 hours per day, and on day 12, glomerular filtration rate and renal plasma flow were measured. Mean arterial pressure in control rats averaged 85±1 mm Hg, and with Ang II infusion, mean arterial pressure increased slowly and reached a plateau on day 3, averaging 117±2 mm Hg ( P <0.0001 compared with enalapril alone). Glomerular filtration rate and renal plasma flow were not affected by Ang II. Free F 2 -isoprostanes in plasma increased by 54% with Ang II ( P <0.01), and the production of F 2 -isoprostanes esterified in plasma lipids tended to be higher with Ang II also but did not reach significance ( P =0.1). These studies suggest that low doses of Ang II are capable of producing oxidative stress in animals. Whether oxidative stress plays a causative role in Ang II–mediated slow-response hypertension or is secondary to the hypertension is not clear from these data and will require further study.

Object Glomus tumors are rare skull base neoplasms that frequently involve critical cerebrovascular structures and lower cranial nerves. Complete resection is often difficult and may increase cranial nerve deficits. Stereotactic radiosurgery has gained an increasing role in the management of glomus tumors. The authors of this study examine the outcomes after radiosurgery in a large, multicenter patient population. Methods Under the auspices of the North American Gamma Knife Consortium, 8 Gamma Knife surgery centers that treat glomus tumors combined their outcome data retrospectively. One hundred thirty-four patient procedures were included in the study (134 procedures in 132 patients, with each procedure being analyzed separately). Prior resection was performed in 51 patients, and prior fractionated external beam radiotherapy was performed in 6 patients. The patients' median age at the time of radiosurgery was 59 years. Forty percent had pulsatile tinnitus at the time of radiosurgery. The median dose to the tumor margin was 15 Gy. The median duration of follow-up was 50.5 months (range 5–220 months). Results Overall tumor control was achieved in 93% of patients at last follow-up; actuarial tumor control was 88% at 5 years postradiosurgery. Absence of trigeminal nerve dysfunction at the time of radiosurgery (p = 0.001) and higher number of isocenters (p = 0.005) were statistically associated with tumor progression–free tumor survival. Patients demonstrating new or progressive cranial nerve deficits were also likely to demonstrate tumor progression (p = 0.002). Pulsatile tinnitus improved in 49% of patients who reported it at presentation. New or progressive cranial nerve deficits were noted in 15% of patients; improvement in preexisting cranial nerve deficits was observed in 11% of patients. No patient died as a result of tumor progression. Conclusions Gamma Knife surgery was a well-tolerated management strategy that provided a high rate of long-term glomus tumor control. Symptomatic tinnitus improved in almost one-half of the patients. Overall neurological status and cranial nerve function were preserved or improved in the vast majority of patients after radiosurgery.

Abstract Purpose: To explore the effects of single-nucleotide polymorphisms (SNP) on pancreatic cancer risk and overall survival (OS). Experimental Design: The germ line DNA of 531 pancreatic cancer cases and 305 healthy controls from a hospital-based study was genotyped at SNPs previously reported to be associated with pancreatic cancer risk or clinical outcome. We analyzed putative risk SNPs for replication of their reported effects on risk and tested for novel effects on OS. Similarly, we analyzed putative survival-associated SNPs for replication of their reported effects on OS and tested for novel effects on risk. Finally, we conducted a genome-wide association study (GWAS) of OS using a subset of 252 cases, with two subsequent validation sets of 261 and 572 patients, respectively. Results: Among seven risk SNPs analyzed, two (rs505922 and rs9543325) were associated with risk (P &lt; 0.05). Among 24 survival-associated SNPs analyzed, one (rs9350) was associated with OS (P &lt; 0.05). No putative risk SNPs or putative survival-associated SNPs were found to be associated with OS or risk, respectively. Furthermore, our GWAS identified a novel SNP [rs1482426, combined stage I and II, P = 1.7 × 10−6, per-allele HR, 1.74; 95% confidence interval (CI), 1.38–2.18] to be putatively associated with OS. Conclusions: The effects of SNPs on pancreatic cancer risk and OS were replicated in our study, although further work is necessary to understand the functional mechanisms underlying these effects. More importantly, the putative association with OS identified by GWAS suggests that GWAS may be useful in identifying SNPs associated with clinical outcome in pancreatic cancer. Clin Cancer Res; 18(14); 3942–51. ©2012 AACR.

Abstract Transmission of pathogens from donor to recipient is a potential complication of organ transplantation. Herein, we describe the clinical course and outcomes of 4 transplant recipients who received tissues from a donor with multi‐organ infection with Klebsiella pneumoniae carbapenemase ( KPC )‐producing K. pneumoniae . Recipient 1 underwent simultaneous liver and kidney transplantation for alpha‐1 antitrypsin deficiency and alcohol‐related cirrhosis, and acute tubular necrosis, respectively. Soon after transplantation, he developed an infected hematoma and peritonitis due to KPC ‐producing K. pneumoniae despite receiving tigecycline prophylaxis. He was treated with a prolonged course of tigecycline, amikacin, and meropenem, in conjunction with surgical evacuation and percutaneous drainage of the infected fluid collections. Recipient 2 underwent living‐donor liver transplantation for cholangiocarcinoma and primary sclerosing cholangitis using vein graft from the donor infected with KPC ‐producing K. pneumoniae . Culture of the preservation fluid containing the vein graft was positive for KPC ‐producing K. pneumoniae . The patient received preemptive amikacin and tigecycline, and he did not develop any infection (as evidenced by negative surveillance blood cultures). The isolates from the donor and Recipients 1 and 2 were indistinguishable by pulsed‐field gel electrophoresis. Recipients 3 and 4 underwent kidney and heart transplantation, respectively; both patients received perioperative tigecycline prophylaxis and did not develop infections due to KPC ‐producing K. pneumoniae . All transplant recipients had good short‐term outcomes. These cases highlight the importance of inter‐institutional communication and collaboration to ensure the successful management of recipients of organs from donors infected with multidrug‐resistant organisms.

Object Familial predisposition is a recognized nonmodifiable risk factor for the formation and rupture of intracranial aneurysms (IAs). However, data regarding the characteristics of familial IAs are limited. The authors sought to describe familial IAs more fully, and to compare their characteristics with a large cohort of nonfamilial IAs. Methods The Familial Intracranial Aneurysm (FIA) study is a multicenter international study with the goal of identifying genetic and other risk factors for formation and rupture of IAs in a highly enriched population. The authors compared the FIA study cohort with the International Study of Unruptured Intracranial Aneurysms (ISUIA) cohort with regard to patient demographic data, IA location, and IA multiplicity. To improve comparability, all patients in the ISUIA who had a family history of IAs or subarachnoid hemorrhage were excluded, as well as all patients in both cohorts who had a ruptured IA prior to study entry. Results Of 983 patients enrolled in the FIA study with definite or probable IAs, 511 met the inclusion criteria for this analysis. Of the 4059 patients in the ISUIA study, 983 had a previous IA rupture and 657 of the remainder had a positive family history, leaving 2419 individuals in the analysis. Multiplicity was more common in the FIA patients (35.6% vs 27.9%, p < 0.001). The FIA patients had a higher proportion of IAs located in the middle cerebral artery (28.6% vs 24.9%), whereas ISUIA patients had a higher proportion of posterior communicating artery IAs (13.7% vs 8.2%, p = 0.016). Conclusions Heritable structural vulnerability may account for differences in IA multiplicity and location. Important investigations into the underlying genetic mechanisms of IA formation are ongoing.

Abstract High BAALC expression levels are associated with poor outcome in cytogenetically normal acute myeloid leukemia (CN-AML) patients. Recently, miR-3151 was discovered in intron 1 of BAALC. To evaluate the prognostic significance of miR-3151 expression levels and to gain insight into the biologic and prognostic interplay between miR-3151 and its host, miR-3151 and BAALC expression were measured in pretreatment blood of 179 CN-AML patients. Gene-expression profiling and miRNA-expression profiling were performed using microarrays. High miR-3151 expression was associated with shorter disease-free and overall survival, whereas high BAALC expression predicted failure of complete remission and shorter overall survival. Patients exhibiting high expression of both miR-3151 and BAALC had worse outcome than patients expressing low levels of either gene or both genes. In gene-expression profiling, high miR-3151 expressers showed down-regulation of genes involved in transcriptional regulation, posttranslational modification, and cancer pathways. Two genes, FBXL20 and USP40, were validated as direct miR-3151 targets. The results of the present study show that high expression of miR-3151 is an independent prognosticator for poor outcome in CN-AML and affects different outcome end points than its host gene, BAALC. The combination of both markers identified a patient subset with the poorest outcome. This interplay between an intronic miR and its host may have important biologic implications.