Citations

Abstract EGFR and EGFR ligand upregulation has been widely seen in both human chronic pancreatitis and pancreatic ductal adenocarcinoma (PDA) for many years; however the role of EGFR in PDA was poorly understood. Recently we and others have shown that genetic ablation of EGFR effectively prevents both spontaneous and cerulein induced tumorigenesis in the pancreas of the LSL-KrasG12D/+;Ptf1aCre/+ (KC) mouse model of pancreatic tumorigenesis. Pockets of EGFR upregulation localized in single acini of KC mice appear to precede pancreatic intraepithelial neoplasia (PanIN) formation in spontaneous tumorigenesis, coupled with a distinct spatially localized immune response. Ubiquitous EGFR upregulation is observed throughout the pancreas upon induction of pancreatitis in wild-type (WT) and KC mice, returning to normal levels in WT mice but continuing to increase along with the widespread tumorigenesis in cerulein treated KC mice. Comparison of cerulein treated KC mice with the EGFRf/f;LSL-KrasG12D/+;Ptf1aCre/+ mice (EKC), which are largely resistant to cerulein induced pancreatitis, offers an opportunity to identify signals in the KC mouse which could be responsible for the upregulation of EGFR and subsequent tumorigenesis. Citation Format: Christopher J. Halbrook, Kenneth K. Takeuchi, Howard C. Crawford. Regulation of EGFR in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3030. doi:10.1158/1538-7445.AM2013-3030

Abstract Background: Metaplastic breast carcinoma (MBC) accounts for <5% of all breast malignancies. This entity represents a heterogenous group of tumors in which the adenocarcinomatous element is admixed with one or more neoplastic mesenchymal (spindle, squamous, chondroid, or osseous) elements. Patients typically present with large triple negative tumors and have a poor prognosis. The likelihood of lymph node (LN) involvement has been reported to be low in MBC patients. Due to the paucity of data, we undertook this study to explore the role of axillary ultrasound (US) and sentinel LN biopsy (SLNB) in the management of MBC. Methods: With IRB approval, we retrospectively identified patients diagnosed with MBC from 2001–2011 from the surgical pathology database. Histopathology and imaging were reviewed. Demographic, treatment and outcome data were obtained by clinical chart review. Data were analyzed using JMP 9.0 software. Results: We identified 41 women with MBC. Median age was 60 years (range 33–90). Histologic subtypes were spindle cell (46%), mixed adenocarcinoma and mesenchymal elements (20%), squamous cell (17%) chondroid/osseous (10%) and adenosquamous (7%). Tumor stage was T1 (24%), T2 (44%), T3 (12%) and T4 (20%). 26 patients (63%) were treated by mastectomy and 15 (37%) by wide excision. Of the 38 patients who underwent LN surgery (6 low-grade MBC, 32 intermediate/high-grade MBC), 10 (26%) were LN positive. All low-grade MBC patients were LN negative while 10 of 32 intermediate/high-grade MBC patients (31%) had LN metastasis. 22 patients had a preoperative axillary US. 14 patients had a negative axillary US and none had LN metastasis. 4 of 8 patients with suspicious axillary US findings had a preoperative axillary LN fine needle aspiration biopsy (FNAB) and 3 were positive for cancer. These patients proceeded directly to axillary LN dissection (ALND). 24 patients had a SLNB of whom one was SLN positive and underwent completion ALND. LN metastasis was associated with larger tumor size (p = 0.003), higher tumor grade (p = 0.04), angioinvasion (p = 0.07) and abnormal axillary US (p = 0.003). Surviving patients were followed for a mean (median) of 41 (30) months during which 13 (32%) recurred at a median of 6 months (IQR 3–17 months) and 11 (27%) subsequently died of disease. One SLN negative patient developed an axillary recurrence at 8 months, was successfully treated by ALND and is disease-free at 38 months. There were no axillary LN relapses after ALND. Conclusions: For clinically node-negative MBC patients, our contemporary data series suggests the incidence of occult LN metastasis is sufficiently high to warrant LN staging especially for patients with intermediate and high-grade tumors. This can be accomplished in a minimally invasive fashion with reasonable accuracy (∼97%) with axillary US, FNAB of sonographically suspicious LNs, and SLNB for patients with negative axillary US or FNAB. Axillary LND should be performed for patients with clinically and/or FNAB-positive LN for enhanced disease control. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-22.

Abstract Background- The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. Studies of cell-free DNA in the peripheral blood of breast cancer patients suggest that methylated DNA markers in serum or plasma could be used for detection of advanced disease, monitoring of therapeutic response, and for early detection of disease recurrence. Methods- A genome-wide serum DNA methylome array (Illumina HumanMethylation27 BeadChip) analysis was conducted on cell-free circulating DNA in serum from women with stage IV recurrent breast cancer, and 232 key CpG loci were identified. Methylation for this panel of 10 gene loci was evaluated using our newly developed cMethDNA assay to detect miniscule amounts of methylated DNA in Training and Test sets of sera from a total of 112 women (n = 55 normal, n = 57 metastatic breast cancer). The clinical sensitivity and specificity of the assay, along with technical reproducibility, was determined. To evaluate the concordance of DNA methylation patterns, the 10 gene panel was tested on 22 DNA sets of primary tumor, metastases and serum from the same patient. Finally, the ability of cMethDNA to monitor response to therapy was evaluated in 28 patients with metastatic disease. Results- A normal laboratory threshold of 7 cumulative methylation units was set and assay parameters were locked, based on Receiver Operating Characteristic (ROC) analyses of DNA from 300 ul of patient sera in the Training set (normal, n = 28; cancer, n = 24; 92% sensitivity, 96% specificity, and AUC = 0.950). Evaluation of the Test set of patient sera (normal, n = 27; cancer n = 33) resulted in detection of metastatic breast cancer with 91% sensitivity, 100% specificity, and AUC = 0.994 (0.984-1.005, p<0.0001). Reproducibility of the cMethDNA assay increased with copy number; with the highest variation at 50 copies (CV = 29.1%) and the lowest at 3,200 copies (CV = 2.5%) of methylated DNA. The test was shown to be operator independent (ICC = 0.99). Evaluation of concordance between primary and disseminated tumor methylation showed that the methylation pattern from any given individual is highly conserved between serum, primary tissue and their metastases, and poorly conserved between different individuals. cMethDNA analysis of 28 patients before and after initiation of therapy showed a decrease in cumulative methylation in women with stable/responsive disease and a correlation with disease progression free survival (p<0.0001). Conclusion- Together, our data suggest that the cMethDNA test 1) can detect tumor DNA shed into blood, 2) reflect the methylation alterations typical of the primary tumor and its metastatic lesions, and 3) reflect response to treatment after chemotherapy. Next, we will test the clinical utility of cMethDNA in independent clinical trial sample sets where it's complementary and independent roles will be examined against CA15.3 and CTC assays. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-06-01.

Targeting a kinase common to both the EGFR and TNFα signaling pathways may prevent drug resistance in glioblastoma.

AbstractObjectivesWith clinical use of high‐sensitivity troponin I (hsTnI), more frequent troponin elevations will occur. However, the burden and implications of these elevations are not well understood. The authors quantified the prevalence of elevated hsTnI in patients presenting with possible acute coronary syndrome (ACS) who do not have elevated troponin with a current generation assay (cardiac troponin I [cTnI]) and determined the association of these newly detected elevations with a composite of all‐cause mortality and subsequent cardiac hospitalization.MethodsThis was a prospective observational study of 808 subjects evaluated for possible ACS and followed for up to 1 year. Troponin values were measured with hsTnI (Abbott Laboratories) and cTnI (Abbott and Beckman Coulter). Cardiac hospitalization was defined as hospitalization for ACS, revascularization, acute heart failure (AHF), or tachy/brady arrhythmia that occurred after the index emergency department (ED) visit or hospital discharge.ResultsForty subjects (5%) were diagnosed with ACS (26 myocardial infarction and 14 unstable angina). On the initial sample, the prevalence of elevated hsTnI among subjects with nonelevated cTnI was 9.2% using a gender‐neutral cutoff (95% confidence interval [CI] = 7.1% to 11.4%) and 11.1% using a gender‐specific cutoff (95% CI = 8.8% to 13.4%). Adjudicated diagnoses for subjects whose initial samples had elevated hsTnI but nonelevated cTnI (gender‐neutral cutoff) were as follows: three (4.6%) ACS, 15 (23.1%) AHF, three (4.6%) volume overload etiology unclear/noncardiac, three (4.6%) cardiac (non‐ACS), and 41 (63.1%) other. Of the 65 patients whose initial samples had hsTnI but nonelevated cTnI, eight developed cTnI elevation on subsequent serial sampling. After traditional cardiovascular risk factors and renal function were adjusted for, subjects with elevated initial hsTnI but nonelevated cTnI (initial and serial sampling) had a higher risk of all‐cause mortality and subsequent cardiac hospitalization than subjects with both nonelevated hsTnI and nonelevated cTnI (hazard ratio [HR] = 1.91, 95% CI = 1.14 to 3.19).ConclusionsOn the initial sample, 9% to 11% of subjects without cTnI elevation had hsTnI elevation. Although the majority of the patients with these newly detected hsTnI elevations did not have ACS, they had a higher risk for all‐cause mortality and subsequent cardiac hospitalization.

AbstractThe histopathology of cardiac xenograft rejection has evolved over the last 20 yr with the development of new modalities for limiting antibody‐mediated injury, advancing regimens for immune suppression, and an ever‐widening variety of new donor genetics. These new technologies have helped us progress from what was once an overwhelming anti‐Gal‐mediated hyperacute rejection to a more protracted anti‐Gal‐mediated vascular rejection to what is now a more complex manifestation of non‐Gal humoral rejection and coagulation dysregulation. This review summarizes the changing histopathology of Gal‐ and non‐Gal‐mediated cardiac xenograft rejection and discusses the contributions of immune‐mediated injury, species‐specific immune‐independent factors, transplant and therapeutic procedures, and donor genetics to the overall mechanism(s) of cardiac xenograft rejection.

Purpose The purpose of this study was to determine failure rates, functional outcomes, and risk factors for failure after revision anterior shoulder stabilization surgery in high‐risk adolescent athletes. Methods Adolescent athletes who underwent primary anterior shoulder stabilization were reviewed. Patients undergoing subsequent revision stabilization surgery were identified and analyzed. Failure rates after revision surgery were assessed by Kaplan‐Meier analysis. Failure was defined as recurrent instability requiring reoperation. Functional outcomes included the Marx activity score; American Shoulder and Elbow Surgeons score; and University of California, Los Angeles score. The characteristics of patients who required reoperation for recurrent instability after revision surgery were compared with those of patients who required only a single revision to identify potential risk factors for failure. Results Of 90 patients who underwent primary anterior stabilization surgery, 15 (17%) had failure and underwent revision surgery (mean age, 16.6 years; age range, 14 to 18 years). The mean follow‐up period was 5.5 years (range, 2 to 12 years). Of the 15 revision patients, 5 (33%) had recurrent dislocations and required repeat revision stabilization surgery at a mean of 50 months (range, 22 to 102 months) after initial revision. No risk factors for failure were identified. The Kaplan‐Meier reoperation‐free estimates were 86% (95% confidence interval, 67% to 100%) at 24 months and 78% (95% confidence interval, 56% to 100%) at 48 months after revision surgery. The mean final Marx activity score was 14.8 (range, 5 to 20); American Shoulder and Elbow Surgeons score, 82.1 (range, 33 to 100); and University of California, Los Angeles score, 30.8 (range, 16 to 35). Conclusions At 5.5 years' follow‐up, adolescent athletes had a high failure rate of revision stabilization surgery and modest functional outcomes. We were unable to convincingly identify specific risk factors for failure of revision surgery. Level of Evidence Level IV, retrospective therapeutic case series.

Cochlear and neural auditory function for a series of 30 patients with acoustic neuroma was assessed pre- and postoperatively by transiently evoked otoacoustic emission (TEOAE), auditory brain stem response (ABR), and acoustic reflex measures. Employing a retrosigmoid surgical approach, physical integrity of the acoustic nerve was preserved for 22 patients. TEOAEs were observed preoperatively for 13 patients and postoperatively for 6 of them. Postoperative neural function remained unchanged or improved following surgery for 7 patients, and cochlear function decreased. TEOAE, ABR, and acoustic reflex measurements were considered valuable in providing information about site of lesion and probable mechanisms of injury associated with tumor removal.