Citations

AbstractRunx2 is the master transcription factor for bone formation. Haploinsufficiency of RUNX2 is the genetic cause of cleidocranial dysplasia (CCD) that is characterized by hypoplastic clavicles and open fontanels. In this study, we found that Pin1, peptidyl prolyl cis–trans isomerase, is a critical regulator of Runx2 in vivo and in vitro. Pin1 mutant mice developed CCD‐like phenotypes with hypoplastic clavicles and open fontanels as found in the Runx2+/− mice. In addition Runx2 protein level was significantly reduced in Pin1 mutant mice. Moreover Pin1 directly interacts with the Runx2 protein in a phosphorylation‐dependent manner and subsequently stabilizes Runx2 protein. In the absence of Pin1, Runx2 is rapidly degraded by the ubiquitin‐dependent protein degradation pathway. However, Pin1 overexpression strongly attenuated uniquitin‐dependent Runx2 degradation. Collectively conformational change of Runx2 by Pin1 is essential for its protein stability and possibly enhances the level of active Runx2 in vivo. J. Cell. Physiol. 228: 2377–2385, 2013. © 2013 Wiley Periodicals, Inc.

Purpose There is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. We determined the frequency and prognostic impact of heterogeneous HER2 gene amplification and polysomy 17 in patients with esophageal adenocarcinoma (EAC). Patients and Methods HER2 amplification (by fluorescence in situ hybridization) was examined in surgical EAC specimens (n = 675). HER2 heterogeneity was defined according to consensus guidelines as gene amplification (HER2/CEP17 ratio ≥ 2.0) in more than 5% but less than 50% of cancer cells. No patient received neoadjuvant or HER2-targeted therapy. Cox models were used to assess disease-specific survival (DSS) and overall survival (OS). Results Overall, 117 EACs (17%) demonstrated HER2 amplification, of which 20 (17%) showed HER2 heterogeneity. All HER2-heterogeneous tumors were amplified. Among HER2-amplified tumors, heterogeneous tumors had significantly higher frequency of poor histologic grade and polysomy 17. In multivariable models that included number of metastatic lymph nodes, grade, tumor stage, and polysomy 17, only HER2 heterogeneity and node number were prognostic among HER2-amplified tumors, with heterogeneity showing worse DSS (hazard ratio, 2.04; 95% CI, 1.09 to 3.79; P = .025) and OS (P = .026). Among HER2-nonamplified EACs, polysomy 17 was independently associated with worse DSS (P = .012) and OS (P = .023). Conclusion Among HER2-amplified EACs, 17% show HER2 heterogeneity, which independently predicts for worse cancer-specific death. Among HER2-nonamplified EACs, polysomy 17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and determination of benefit from HER2-targeted therapy.

Abstract Background: Esophageal adenocarcinoma (EAC) is a lethal cancer, and the incidence is increasing. Our group demonstrated that over-expression of the epidermal growth factor receptor (EGFR) correlated with reduced survival in EAC. Panitumumab (P) is a fully human IgG2 monoclonal antibody against human EGFR. Cetuximab combined with irinotecan (I) has shown activity for second-line treatment of advanced colorectal cancer (CRC). P alone is active in EGFR expressing CRC as well. Our group has empiric evidence for the activity of cetuximab + I as third-line treatment for advanced EAC. As such, a phase II study was designed to evaluate P + I as second-line therapy for advanced EAC. Trial Design: The primary endpoint is overall response (OR) as measured by RECIST (cross-sectional imaging every 2 cycles). Secondary endpoints include overall survival, safety/toxicity and correlative studies. Patients with confirmed EAC with history of one prior treatment are treated with P 9 mg/m2 on day 1 and I 125 mg/m2 on days 1 and 8 of each 21 day cycle to a maximum of 6 cycles. Inclusion criteria include confirmed EAC, measurable disease, no prior I or P, PS <2 and normal organ function. A Simon two-stage design is used with power of 80% and a type I error of 0.05. 18 patients will be tested in the first stage and will terminate the trial if 2 or fewer respond. A total of 43 patients will be studied. Blood and tissue are obtained to analyse the role of FCα-R receptors as well EGFR pathway components and kras mutations. Enrollment: The 1st patient was enrolled in May 2009. Through August 2011, 7 patients received treatment. Preliminary results: Of the 7 patients treated, all are white males, median age 62. 2 patients completed 6 cycles. 1 patient received 3 cycles, 3 received 2 cycles and 1 patient completed 1 cycle. 3 patients are still alive. However, only 1 patient is still in the trial. 4 patients received dose reductions due to grade 3 or 4 side effects, including GI disturbances (5), fatigue(1), skin rash(1), electrolyte imbalances(2) and hematologic abnormalities (5). Reasons for discontinuation included progressive disease (PD, 5 patients) and patient refusal (2). The longest survival was 338 days–1 of the 2 patients who completed 6 cycles. The second patient who completed 6 cycles is alive at 307 days. 1 patient completed 3 cycles and survived 213 days after PD. 1 patient survived 174 days followed PD after 2 cycles. 2 patients completed 2 cycles and are still alive, surviving 151 (pt refusal) and 103 days respectively. The shortest survival was 85 days who completed only 1 cycle. Conclusion: Preliminary data from this Phase II trial suggests that patients with advanced EAC might benefit from P+I regimen as 2nd line therapy. 3 additional centers will open the trial. Accrual is ongoing, and correlative studies will follow. This project used the University of Pittsburgh Cancer Institute and was supported in part by award P30CA047904 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 3708. doi:1538-7445.AM2012-3708

Background— Coronary stents, drug-eluting stents in particular, have been linked to coronary epicardial endothelial dysfunction after implantation. However, less is known about their impact on coronary microvascular function and their long-term effects on the vasculature. Methods and Results— We evaluated 71 patients (mean age, 53.0±10.1 years) with chest pain and angiographically nonsignificant coronary artery disease 17.1±17.1 months after left anterior descending coronary artery stenting. Seventy-one age- and sex-matched patients (mean age, 53.0±10.3 years) with chest pain but no prior coronary intervention served as controls. Coronary blood flow in response to the endothelium-dependent vasodilator acetylcholine as well as the microvascular (endothelium-independent) coronary flow reserve in response to intracoronary adenosine were evaluated. Quantitative coronary angiography was used to study epicardial diameter changes to acetylcholine. Microcirculatory function was not significantly different between the stenting and control groups (median [interquartile range] coronary flow reserve, 2.9 [2.5–3.4] versus 3.0 [2.4–3.4] mL/min, P =0.24; change of coronary blood flow, 34.9% [−34.4% to 90.0%] versus 54.7% [−5.6% to 104.6%], P =0.18). Both groups exhibited epicardial endothelial dysfunction (−23.0% [−47.4% to −7.6%] versus −20.0% [−40.0% to 0.0%], P =0.4). Results did not differ between patients with drug-eluting stents (n=46) and patients with bare-metal stents (n=24). Conclusions— This study demonstrates that in patients with coronary arteries in which a stent has been placed, coronary microcirculatory and epicardial vascular function are not significantly different from that of an age- and sex-matched population with similar symptoms but nonsignificant coronary artery disease.

The zona conoidea comprises the area of the lateral trochlear ridge of the humerus. The purpose of this study is to reintroduce this term ‘zona conoidea’ to the discussion of the human elbow and to investigate its significance in the development of osteoarthritis of the elbow. The upper extremities of 12 cadavers were prepared. With the forearm in neutral, pronation and supination, the distance between the bevel of the radial head and zona conoidea was inspected. A total of 12 healthy volunteers had a CT scan. The distance between the zona conoidea and the bevelled rim of the radial head was measured in these positions. In the anatomical specimens, early osteo-arthritic changes were identified in the posteromedial bevelled rim of the radial head, and the corresponding zona conoidea in supination. Measurement in the CT study showed that in full supination, the distance between the bevel of the radial head and the zona conoidea was at a minimum. This study suggests that the significant contact between the bevel of the radial head and the zona conoidea in supination is associated with the initiation of osteoarthritis of the elbow in this area.

Object Rates of complications associated with the surgical treatment of cervical spondylotic myelopathy (CSM) are not clear. Appreciating these risks is important for patient counseling and quality improvement. The authors sought to assess the rates of and risk factors associated with perioperative and delayed complications associated with the surgical treatment of CSM. Methods Data from the AOSpine North America Cervical Spondylotic Myelopathy Study, a prospective, multicenter study, were analyzed. Outcomes data, including adverse events, were collected in a standardized manner and externally monitored. Rates of perioperative complications (within 30 days of surgery) and delayed complications (31 days to 2 years following surgery) were tabulated and stratified based on clinical factors. Results The study enrolled 302 patients (mean age 57 years, range 29–86) years. Of 332 reported adverse events, 73 were classified as perioperative complications (25 major and 48 minor) in 47 patients (overall perioperative complication rate of 15.6%). The most common perioperative complications included minor cardiopulmonary events (3.0%), dysphagia (3.0%), and superficial wound infection (2.3%). Perioperative worsening of myelopathy was reported in 4 patients (1.3%). Based on 275 patients who completed 2 years of follow-up, there were 14 delayed complications (8 minor, 6 major) in 12 patients, for an overall delayed complication rate of 4.4%. Of patients treated with anterior-only (n = 176), posterior-only (n = 107), and combined anterior-posterior (n = 19) procedures, 11%, 19%, and 37%, respectively, had 1 or more perioperative complications. Compared with anterior-only approaches, posterior-only approaches had a higher rate of wound infection (0.6% vs 4.7%, p = 0.030). Dysphagia was more common with combined anterior-posterior procedures (21.1%) compared with anterior-only procedures (2.3%) or posterior-only procedures (0.9%) (p < 0.001). The incidence of C-5 radiculopathy was not associated with the surgical approach (p = 0.8). The occurrence of perioperative complications was associated with increased age (p = 0.006), combined anterior-posterior procedures (p = 0.016), increased operative time (p = 0.009), and increased operative blood loss (p = 0.005), but it was not associated with comorbidity score, body mass index, modified Japanese Orthopaedic Association score, smoking status, anterior-only versus posterior-only approach, or specific procedures. Multivariate analysis of factors associated with minor or major complications identified age (OR 1.029, 95% CI 1.002–1.057, p = 0.035) and operative time (OR 1.005, 95% CI 1.002–1.008, p = 0.001). Multivariate analysis of factors associated with major complications identified age (OR 1.054, 95% CI 1.015–1.094, p = 0.006) and combined anterior-posterior procedures (OR 5.297, 95% CI 1.626–17.256, p = 0.006). Conclusions For the surgical treatment of CSM, the vast majority of complications were treatable and without long-term impact. Multivariate factors associated with an increased risk of complications include greater age, increased operative time, and use of combined anterior-posterior procedures.

Abstract Purpose: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC). Experimental Design: HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3–4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used. Results: Overall, 17% of EACs were HER2 positive (i.e., IHC3+ or IHC2+ with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio ≥2) and expression (κ = 0.83). HER2 positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barrett's esophagus (BE). EACs with BE had higher odds of HER2 positivity than EACs without BE, independent of pathologic features [OR = 1.8 (95% CI: 1.1–2.8), P = 0.014]. Among all cases, HER2 positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (Pinteraction = 0.0047). In EACs with BE, HER2 positivity was significantly associated with improved DSS [HR = 0.54 (95% CI: 0.35–0.84), P = 0.0065] and overall survival (P = 0.0022) independent of pathologic features, but was not prognostic among EACs without BE. Conclusions: HER2 positivity was shown in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2 positive and, within this subgroup, HER2 positivity was independently associated with improved survival. Clin Cancer Res; 18(2); 546–54. ©2012 AACR.