Paul A. VanderLaan

Site Specificity of Atherosclerosis: Site-Selective Responses to Atherosclerotic Modulators

Abstract—Atherosclerosis is a complex disease process that affects very specific sites of the vasculature. It is recognized that hemodynamic forces are largely responsible for dictating which vascular sites are either susceptible or resistant to developing atherosclerosis. In addition, a number of systemic and local factors also modulate the pathogenesis of the disease. By studying the development of atherosclerosis in mice, investigators have gained insights into the molecular mechanisms of this disease, although studies have largely focused on a single vascular site. Here, we review those recent studies in which vascular site-specific effects on atherosclerosis were reported when more than 1 site was examined. We assess the hypothesis that regional differences in the hemodynamic profile prime the endothelial phenotype to respond distinctly to such systemic risk factors as hypercholesterolemia, genetics, immune status, gender, and oxidative stress. Because a given treatment may differentially affect the development of atherosclerotic lesions throughout the vasculature, the sites chosen for study are critically important. By accounting for the complex interplay of factors that may operate at these different sites, a more complete understanding of the overriding mechanisms that control the initiation and progression of the atherosclerotic lesion may be realized.

RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.

Clinical outcome for atypia of undetermined significance in thyroid fine-needle aspirations: should repeated fna be the preferred initial approach?

In the Bethesda System for reporting thyroid fine-needle aspirations (FNAs), atypia of undetermined significance (AUS) is a category with limited reported follow-up and outcome data. We report a retrospective analysis of our institutions experience during nearly 4.5 years with a tiered classification scheme conforming to the Bethesda System in which repeated FNA was recommended for most patients with an initial AUS diagnosis. Of 4,691 thyroid FNAs, 512 (10.9%) had a diagnosis of AUS. Cytologic or histologic outcome data were available for 331 cases (64.6%), of which 240 (72.5%) were benign and 91 (27.5%) were malignant. Of patients with a surgical diagnosis, there was no statistically significant difference in malignancy rate among patients who went directly to surgery after a single AUS diagnosis (37/90 [41%]), patients having 2 successive AUS FNA diagnoses (22/51 [43%]), and patients with a benign aspirate after AUS (2/7 [29%]). Although AUS confers an intermediate risk of malignancy, guidelines recommending repeated FNA for most cases should be reevaluated.

Thematic review series: the immune system and atherogenesis. The unusual suspects:an overview of the minor leukocyte populations in atherosclerosis.

Atherosclerosis is a complex inflammatory disease process involving an array of cell types and interactions. Although macrophage foam cells and vascular smooth muscle cells constitute the bulk of the atherosclerotic lesion, other cell types have been implicated in this disease process as well. These cellular components of both innate and adaptive immunity are involved in modulating the response of macrophage foam cells and vascular smooth muscle cells to the retained and modified lipids in the vessel wall as well as in driving the chronic vascular inflammation that characterizes this disease. In this review, the involvement of a number of less prominent leukocyte populations in the pathogenesis of atherosclerosis is discussed. More specifically, the roles of natural killer cells, mast cells, neutrophils, dendritic cells, γδ T-cells, natural killer T-cells, regulatory T-cells, and B-cells are addressed.

Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers

INTRODUCTION Brain metastases (BM) are common in non-small-cell lung cancer (NSCLC). However, the baseline incidence and evolution of BM over time in oncogene-driven NSCLCs are seldom reported. In this study, we evaluated the frequency of BM in patients with epidermal growth factor receptor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged NSCLC. METHODS The presence of BM, clinicopathologic data, and tumor genotype were retrospectively compiled and analyzed from a cohort of 381 patients. RESULTS We identified 86 EGFR-mutated (90.7% with metastatic disease; 85.9% received an EGFR inhibitor) and 23 ALK-rearranged (91.3% with metastatic disease; 85.7% received an ALK inhibitor) NSCLCs. BM were present in 24.4% of EGFR-mutated and 23.8% of ALK-rearranged NSCLCs at the time of diagnosis of advanced disease. This study did not demonstrate a difference in the cumulative incidence of BM over time between the two cohorts (EGFR/ALK cohort competing risk regression [CRR] coefficient of 0.78 [95% CI 0.44-1.39], p=0.41). In still living patients with advanced EGFR-mutated NSCLC, 34.2% had BM at 1 year, 38.4% at 2 years, 46.7% at 3 years, 48.7% at 4 years, and 52.9% at 5 years. In still living patients with advanced ALK-rearranged NSCLC, 23.8% had BM at 1 year, 45.5% at 2 years, and 58.4% at 3 years. CONCLUSIONS BM are frequent in advanced EGFR-mutated or ALK-rearranged NSCLCs, with an estimated >45% of patients with CNS involvement by three years of survival with the use of targeted therapies. These data point toward the CNS as an important unmet clinical need in the evolving schema for personalized care in NSCLC.

The atypia of undetermined significance/follicular lesion of undetermined significance:malignant ratio: a proposed performance measure for reporting in The Bethesda System for thyroid cytopathology.

The Bethesda System (TBS) for reporting thyroid cytopathology introduced the atypia of undetermined significance/follicular lesion of undetermined significance (AUS) category, but did not provide adequate guidance for the appropriate use of this diagnosis. In the current study, the authors sought to identify an appropriate measure for AUS use based on experience to date with TBS.

Usefulness of Diagnostic Qualifiers for Thyroid Fine-Needle Aspirations With Atypia of Undetermined Significance

The diagnostic category of atypia of undetermined significance (AUS) in the Bethesda System for reporting the results of thyroid fine-needle aspirations (FNAs) is intended to encompass findings associated with a low risk of malignancy. It is unclear if there are patterns within this evolving, heterogeneous category associated with differing risk of malignancy that might warrant alternative classification or clinical management. Therefore, a retrospective review of 512 AUS FNAs from January 2005 to May 2009 was done. Most malignancies associated with AUS were papillary carcinoma (86/96 [90%]), of which 85% (73/86) were follicular variants. Atypia qualifiers were correlated with the follow-up rate of malignancy. The risk of malignancy for architectural atypia alone was approximately half that observed for cytologic, both cytologic and architectural, or unspecified atypia. Architectural atypia alone was less likely to be papillary carcinoma and more likely to be follicular adenoma. The lower risk of malignancy associated with isolated architectural atypia compared with other patterns of AUS should be considered in clinical decision making and in future management guidelines.

Success and failure rates of tumor genotyping techniques in routine pathological samples with non-small-cell lung cancer

INTRODUCTION Identification of some somatic molecular alterations in non-small-cell lung cancer (NSCLC) has become evidence-based practice. The success and failure rate of using commercially available tumor genotyping techniques in routine day-to-day NSCLC pathology samples is not well described. We sought to evaluate the success and failure rate of EGFR mutation, KRAS mutation, and ALK FISH in a cohort of lung cancers subjected to routine clinical tumor genotype. METHODS Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 381 patient-tumor samples. RESULTS From these 381 patients with lung cancer, the mean age was 65 years, 61.2% were women, 75.9% were white, 27.8% were never smokers, 73.8% had advanced NSCLC and 86.1% had adenocarcinoma histology. The tumor tissue was obtained from surgical specimens in 48.8%, core needle biopsies in 17.9%, and as cell blocks from aspirates or fluid in 33.3% of cases. Anatomic sites for tissue collection included lung (49.3%), lymph nodes (22.3%), pleura (11.8%), bone (6.0%), brain (6.0%), among others. The overall success rate for EGFR mutation analysis was 94.2%, for KRAS mutation 91.6% and for ALK FISH 91.6%. The highest failure rates were observed when the tissue was obtained from image-guided percutaneous transthoracic core-needle biopsies (31.8%, 27.3%, and 35.3% for EGFR, KRAS, and ALK tests, respectively) and bone specimens (23.1%, 15.4%, and 23.1%, respectively). In specimens obtained from bone, the failure rates were significantly higher for biopsies than resection specimens (40% vs. 0%, p=0.024 for EGFR) and for decalcified compared to non-decalcified samples (60% vs. 5.5%, p=0.021 for EGFR). CONCLUSIONS Tumor genotype techniques are feasible in most samples, outside small image-guided percutaneous transthoracic core-needle biopsies and bone samples from core biopsies with decalcification, and therefore expansion of routine tumor genotype into the care of patients with NSCLC may not require special tissue acquisition or manipulation.

Mammary analogue secretory carcinoma: Update on a new diagnosis of salivary gland malignancy

To review the known histopathologic findings and clinical behavior of mammary analogue secretory carcinoma (MASC).

Adequacy of lymph node transbronchial needle aspirates using convex probe endobronchial ultrasound for multiple tumor genotyping techniques in non-small-cell lung cancer.

Introduction: Adequate tumor acquisition is essential to identify somatic molecular alterations in non–small-cell lung cancer (NSCLC), such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations. The success and failure rates for tumor genotyping of tissue obtained from fine-needle aspirates of nodal tissue using a convex probe endobronchial ultrasound (CP-EBUS) and other diagnostic modalities in routine NSCLC care have not been described. Methods: Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 207 patient-tumor samples sent for routine tumor genotype in clinical practice, including 42 patient-tumor samples obtained from hilar or mediastinal lymph nodes using CP-EBUS. Results: The median age of the patients was 65 years, 62.3% were women, 77.8% were white, 26.6% were never smokers, 73.9% had advanced NSCLC, and 84.1% had adenocarcinoma histology. Tumor tissue was obtained from CP-EBUS–derived hilar or mediastinal nodes in 42 cases (20.2% of total). In this latter cohort, the overall success rate for EGFR mutation analysis was 95.2%, for Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation 90.5%, and for ALK fluorescence in situ hybridization 90.5%. In the complete 207 tumors, the success rate for EGFR was 92.3%, for KRAS 91.8%, and for ALK 89.9%. The failure rates were not significantly different when comparing CP-EBUS–derived nodal tissue versus all other samples or versus surgical biopsies of mediastinal nodes, but were significantly lower than image-guided percutaneous transthoracic core-needle biopsies. Conclusions: The success rate of multiple tumor genomic analyses techniques for EGFR, KRAS, and ALK gene abnormalities using routine lung cancer tissue samples obtained from hilar or mediastinal lymph nodes by means of CP-EBUS exceeds 90%, and this method of tissue acquisition is not inferior to other specimen types. Tumor genotype techniques are feasible in most CP-EBUS–derived samples and therefore further expansion of routine tumor genotype for the care of patients with NSCLC may be possible using targeted sample acquisition through CP-EBUS.