Expression of CAAT Enhancer Binding Protein Beta (C/EBP β) in Cervix and Endometrium

BACKGROUND: The CCAAT element binding protein family of transcriptional factors consists of at least six members of the basic leucine zipper DNA binding proteins that bind to the same CCAAT palindromic DNA sequence through homo- or hetero-dimerization with the same family members. C/EBP β has been shown to play an important role in mediating the effects of the LH/hCG in ovarian development. C/EBP β was also found increased in ovarian cancer and correlated to ovarian cancer progression. DESIGN: We assessed the C/EBP β expression pattern in the normal and neoplastic conditions of the female genital tract by immunostaining the normal cervix – 10 cases, squamous intraepithelial lesion (SIL)-10, invasive squamous carcinomas of cervix – 10 cases, normal endometrial tissue – 10 cases, and invasive endometrial adenocarcinomas carcinomas-10 cases. The staining pattern and intensity were graded from 0 to 2+. Results were statistically analyzed utilizing JMP 4.1. RESULTS: C/EPB β expression was detected in the normal proliferative squamous, dysplastic and malignant squamous epithelial cells. There was no statistical correlation between C/EPB β staining in benign squamous, endocervical tissue, SIL, and squamous cancer, as the majority of all stained positively (91%, 79%, 71% and 89%, respectively, p = 0.3448). However, endometrial carcinoma was significantly more likely to stain positively with C/EPB β than benign endometrial glands (92% versus 3% respectively, p < 0.0001, Fisher's exact test). CONCLUSION: C/EBP β is more likely to be preferentially expressed in endometrial adenocarcinoma as compared to benign endometrial tissue. There is no difference of C/EPB β expression in squamous neoplasia of the cervix

Gleevec (STI-571) inhibits lung cancer cell growth (A549) and potentiates the cisplatin effect in vitro

BACKGROUND: Gleevec (aka STI571, Imatinib) is a recently FDA approved anti-tumor drug for chronic myelogenous leukemia. Gleevec binds specifically to BCR-ABL tyrosine kinase and inhibit the tyrosine kinase activity. It cross-reacts with another two important membrane tyrosine kinase receptors, c-kit and PDGF receptors. We sought to investigate if Gleevec has a potential role in treatment of non-small cell lung cancer. RESULTS: We have shown that Gleevec alone can inhibit the A549 lung cancer cell growth in dose-dependent manner, and the optimal concentration of Gleevec inhibition of A549 cell growth is at the range of 2–3 μM (IC50). We have also shown that A549 cells are resistant to cisplatin treatment (IC50 64 μM). Addition of Gleevec to the A549 cells treated with cisplatin resulted in a synergistic cell killing effect, suggesting that Gleevec can potentiate the effect of cisplatin on A549 cells. We also showed that the A549 lung cancer cells expresses the platelet derived growth factor receptor α, and the inhibitory effects of Gleevec on A549 cells is likely mediated through inhibition of PDGFR α phosphorylation. We further tested 33 lung cancer patients' tumor specimens to see the frequency of PDGFR-α expression by tissue micro-arrays and immunohistochemistry. We found that 16 of the 18 squamous carcinomas (89%), 11 of the 11 adenocarcinomas (100%), and 4 of the 4 small cell lung cancers (100%) expressed PDGFR-α. CONCLUSION: These results suggest a potential role of Gleevec as adjuvant therapeutic agent for treatment of non-small cell lung cancer

Quality Improvement Intervention for Reduction of Redundant Testing

Laboratory data are critical to analyzing and improving clinical quality. In the setting of residual use of creatine kinase M and B isoenzyme testing for myocardial infarction, we assessed disease outcomes of discordant creatine kinase M and B isoenzyme +/troponin I (−) test pairs in order to address anticipated clinician concerns about potential loss of case-finding sensitivity following proposed discontinuation of routine creatine kinase and creatine kinase M and B isoenzyme testing. Time-sequenced interventions were introduced. The main outcome was the percentage of cardiac marker studies performed within guidelines. Nonguideline orders dominated at baseline. Creatine kinase M and B isoenzyme testing in 7496 order sets failed to detect additional myocardial infarctions but was associated with 42 potentially preventable admissions/quarter. Interruptive computerized soft stops improved guideline compliance from 32.3% to 58% (P \u3c .001) in services not receiving peer leader intervention and to \u3e80% (P \u3c .001) with peer leadership that featured dashboard feedback about test order performance. This successful experience was recapitulated in interrupted time series within 2 additional services within facility 1 and then in 2 external hospitals (including a critical access facility). Improvements have been sustained postintervention. Laboratory cost savings at the academic facility were estimated to be ≥US$635 000 per year. National collaborative data indicated that facility 1 improved its order patterns from fourth to first quartile compared to peer norms and imply that nonguideline orders persist elsewhere. This example illustrates how pathologists can provide leadership in assisting clinicians in changing laboratory ordering practices. We found that clinicians respond to local laboratory data about their own test performance and that evidence suggesting harm is more compelling to clinicians than evidence of cost savings. Our experience indicates that interventions done at an academic facility can be readily instituted by private practitioners at external facilities. The intervention data also supplement existing literature that electronic order interruptions are more successful when combined with modalities that rely on peer education combined with dashboard feedback about laboratory order performance. The findings may have implications for the role of the pathology laboratory in the ongoing pivot from quantity-based to value-based health care

Raw Single-Wall Carbon Nanotubes Induce Oxidative Stress and Activate MAPKs, AP-1, NF-κB, and Akt in Normal and Malignant Human Mesothelial Cells

Background Single-wall carbon nanotubes (SWCNTs), with their unique physicochemical and mechanical properties, have many potential new applications in medicine and industry. There has been great concern subsequent to preliminary investigations of the toxicity, biopersistence, pathogenicity, and ability of SWCNTs to translocate to subpleural areas. These results compel studies of potential interactions of SWCNTs with mesothelial cells. Objective Exposure to asbestos is the primary cause of malignant mesothelioma in 80–90% of individuals who develop the disease. Because the mesothelial cells are the primary target cells of asbestos-induced molecular changes mediated through an oxidant-linked mechanism, we used normal mesothelial and malignant mesothelial cells to investigate alterations in molecular signaling in response to a commercially manufactured SWCNT. Methods In the present study, we exposed mesothelial cells to SWCNTs and investigated reactive oxygen species (ROS) generation, cell viability, DNA damage, histone H2AX phosphorylation, activation of poly(ADP-ribose) polymerase 1 (PARP-1), stimulation of extracellular signal-regulated kinase (ERKs), Jun N-terminal kinases (JNKs), protein p38, and activation of activator protein-1 (AP-1), nuclear factor κB (NF-κB), and protein serine-threonine kinase (Akt). Results Exposure to SWCNTs induced ROS generation, increased cell death, enhanced DNA damage and H2AX phosphorylation, and activated PARP, AP-1, NF-κB, p38, and Akt in a dose-dependent manner. These events recapitulate some of the key molecular events involved in mesothelioma development associated with asbestos exposure. Conclusions The cellular and molecular findings reported here do suggest that SWCNTs can cause potentially adverse cellular responses in mesothelial cells through activation of molecular signaling associated with oxidative stress, which is of sufficient significance to warrant in vivo animal exposure studies

Breast Cancer Pathology, Receptor Status, and Patterns of Metastasis in a Rural Appalachian Population

Breast cancer patients in rural Appalachia have a high prevalence of obesity and poverty, together with more triple-negative phenotypes. We reviewed clinical records for tumor receptor status and time to distant metastasis. Body mass index, tumor size, grade, nodal status, and receptor status were related to metastatic patterns. For 687 patients, 13.8% developed metastases to bone (n=42) or visceral sites (n=53). Metastases to viscera occurred within five years, a latent period which was shorter than that for bone (P=0.042). More women with visceral metastasis presented with grade 3 tumors compared with the bone and nonmetastatic groups (P=0.0002). There were 135/574 women (23.5%) with triple-negative breast cancer, who presented with lymph node involvement and visceral metastases (68.2% versus 24.3%; P=0.033). Triple-negative tumors that metastasized to visceral sites were larger (P=0.007). Developing a visceral metastasis within 10 years was higher among women with triple-negative tumors. Across all breast cancer receptor subtypes, the probability of remaining distant metastasis-free was greater for brain and liver than for lung. The excess risk of metastatic spread to visceral organs in triple-negative breast cancers, even in the absence of positive nodes, was combined with the burden of larger and more advanced tumors

Use of Pathology Data to Improve High-Value Treatment of Cervical Neoplasia

We investigated the influence of pathology data to improve patient outcomes in the treatment of high-grade cervical neoplasia in a joint pathology and gynecology collaboration. Two of us (B.S.D. and M.D.) reviewed all cytology, colposcopy and surgical pathology results, patient history, and pregnancy outcomes from all patients with loop electrosurgical excision procedure specimens for a 33-month period (January 2011-September 2013). We used this to determine compliance to 2006 consensus guidelines for the performance of loop electrosurgical excision procedure and shared this information in 2 interprofessional and interdisciplinary educational interventions with Obstetrics/Gynecology and Pathology faculty at the end of September 2013. We simultaneously emphasized the new 2013 guidelines. During the postintervention period, we continued to provide follow-up using the parameters previously collected. Our postintervention data include 90 cases from a 27-month period (October 2013- December 2015). Our preintervention data include 331 cases in 33 months (average 10.0 per month) with 76% adherence to guidelines. Postintervention, there were 90 cases in 27 months (average 3.4 per month) and 96% adherence to the 2013 (more conservative) guidelines (P \u3c .0001, w2 test). Preintervention, the rate of high-grade squamous intraepithelial lesion in loop electrosurgical excision procedures was 44%, whereas postintervention, there was a 60% high-grade squamous intraepithelial lesion rate on loop electrosurgical excision procedure (P \u3c .0087 by 2-tailed Fisher exact test). The duration between diagnosis of low-grade squamous intraepithelial lesion and loop electrosurgical excision procedure also increased significantly from a median 25.5 months preintervention to 54 months postintervention (P \u3c .0073; Wilcoxon Kruskal-Wallis test). Postintervention, there was a marked decrease of loop electrosurgical excision procedure cases as well as better patient outcomes. We infer improved patient safety, and higher value can be achieved by providing performance-based pathologic data

Benchmarking Academic Anatomic Pathologists: The Association of Pathology Chairs Survey

The most common benchmarks for faculty productivity are derived from Medical Group Management Association (MGMA) or Vizient-AAMC Faculty Practice Solutions Center1 (FPSC) databases. The Association of Pathology Chairs has also collected similar survey data for several years. We examined the Association of Pathology Chairs annual faculty productivity data and compared it with MGMA and FPSC data to understand the value, inherent flaws, and limitations of benchmarking data. We hypothesized that the variability in calculated faculty productivity is due to the type of practice model and clinical effort allocation. Data from the Association of Pathology Chairs survey on 629 surgical pathologists and/or anatomic pathologists from 51 programs were analyzed. From review of service assignments, we were able to assign each pathologist to a specific practice model: general anatomic pathologists/surgical pathologists, 1 or more subspecialties, or a hybrid of the 2 models. There were statistically significant differences among academic ranks and practice types. When we analyzed our data using each organization’s methods, the median results for the anatomic pathologists/surgical pathologists general practice model compared to MGMA and FPSC results for anatomic and/or surgical pathology were quite close. Both MGMA and FPSC data exclude a significant proportion of academic pathologists with clinical duties. We used the more inclusive FPSC definition of clinical ‘‘full-time faculty’’ (0.60 clinical full-time equivalent and above). The correlation between clinical full-time equivalent effort allocation, annual days on service, and annual work relative value unit productivity was poor. This study demonstrates that effort allocations are variable across academic departments of pathology and do not correlate well with either work relative value unit effort or reported days on service. Although the Association of Pathology Chairs–reported median work relative value unit productivity approximated MGMA and FPSC benchmark data, we conclude that more rigorous standardization of academic faculty effort assignment will be needed to improve the value of work relative value unit measurements of faculty productivity