Limits of the Glasgow Coma Scale When Assessing for Sepsis in Allogeneic Hematopoietic Cell Transplant Recipients.

BACKGROUND: The well-documented association between acute mental status changes and sepsis development and progression makes acute mental status an attractive factor for sepsis screening tools. However, the usefulness of acute mental status within these criteria is limited to the frequency and accuracy of its capture. The Glasgow Coma Scale (GCS) score-the acute mental status indicator in many clinical sepsis criteria-is infrequently captured among allogeneic hematopoietic cell transplant recipients with suspected infections, and its ability to serve as an indicator of acute mental status among this high-risk population is unknown. OBJECTIVE: We evaluated the GCS score as an indicator of acute mental status during the 24 hours after suspected infection onset among allogeneic hematopoietic cell transplant recipients. METHODS: Using data from the first 100 days posttransplant for patients transplanted at a single center between September 2010 and July 2017, we evaluated the GCS score as an indicator of documented acute mental status during the 24 hours after suspected infection onset. From all inpatients with suspected infections, we randomly selected a cohort based on previously published estimates of GCS score frequency among hematopoietic cell transplant recipients with suspected infections and performed chart review to ascertain documentation of clinical acute mental status within the 24 hours after suspected infection onset. RESULTS: A total of 773 patients had ≥1 suspected infections and experienced 1,655 suspected infections during follow-up-625 of which had an accompanying GCS score. Among the randomly selected cohort of 100 persons with suspected infection, 28 were accompanied with documented acute mental status, including 18 without a recorded GCS. In relation to documented acute mental status, the GCS had moderate to high sensitivity and high specificity. DISCUSSION: These data indicate that, among allogeneic hematopoietic cell transplant recipients with suspected infections, the GCS scores are infrequently collected and have a moderate sensitivity. If sepsis screening tools inclusive of acute mental status changes are to be used, nursing teams need to increase measurement of GCS scores among high sepsis risk patients or identify a standard alternative indicator.

High versus Low Intensity Summer Treatment for ADHD Delivered at Secondary School Transitions.

Spikes in symptom severity are noted for adolescents with attention deficit/hyperactivity disorder (ADHD) at the transitions to middle and high school that are attributed to developmental maladjustment. This study evaluated the effectiveness of high-intensity (HI; 412 hr, $4,373 per participant) versus low-intensity (LI; 24 hr, $97 per participant) skills-based summer intervention delivered to adolescents with ADHD by local school district staff. Participants were 325 ethnically diverse rising sixth and ninth graders with ADHD randomized to HI versus LI (n = 218) or recruited into an untreated comparison group (n = 107). Group × Time 1-year outcome trajectories were compared using linear mixed models. Both interventions possessed high fidelity and were viewed by families as enjoyable and beneficial. Youth attendance was higher for HI (~80%) versus LI (~45%). Parent training attendance was uniform across groups (~50%). Parent and student attendance did not impact trajectories. Primary benefits of HI over LI were to note taking (d = .50), parent contingency management (d = .43), and parent-rated ADHD symptoms (d = .40-.46; ninth grade only). Secondary analyses suggested that HI may produce additional benefits compared to no treatment for home organization skills (HI vs. untreated d = .54), parent-teen conflict (HI vs. untreated d = .39), and grade point average (HI vs. untreated d = .47, ninth grade only). Summer HI treatment was superior to LI in engagement and uptake of certain skills. However, the extent to which these medium benefits on a limited number of outcomes justify high costs compared to LI remains an open question. Delivering treatment during the summer instead of school year may limit generalizability.

A school consultation intervention for adolescents with ADHD: barriers and implementation strategies.

BACKGROUND: Academic impairment is among the most troubling domains of impairment for adolescents with Attention Deficit/Hyperactivity Disorder (ADHD). METHOD: This investigation presents results of a yearlong academic intervention delivered to adolescents with ADHD (N = 218) by engaging school staff as interventionists through behavioral consultation with an outside mental health professional. RESULTS: The intervention was coordinated successfully in some cases, but not in others. The principal challenge to intervention coordination was sustaining monthly contact between consultants and interventionists (38.5% success rate) and scheduling in-person consultation meetings with interventionists (40.0% success rate). Implementation of the intervention was enhanced when the student (a) attended a public (vs. private) school, (b) had an IEP or Section 504 plan in place, (c) was in middle school (vs. high school), (d) had a parent who communicated regularly with the school, and (e) had a special education support staff member or counselor (vs. teacher or administrator) as a school interventionist. CONCLUSIONS: Considering these data, recommendations are provided for effective coordination of academic interventions for adolescents with ADHD.

Analysis of health care facility-onset Clostridioides difficile infection (CDI) in a hematopoietic cell transplant (HCT) unit: A call for diagnostic stewardship in a complex patient population.

Nearly half the patients identified as having health care facility-onset Clostridioides difficile infections on a hematopoietic cell transplant unit had an alternative clinical explanation for diarrhea, including conditioning regimen toxicity or other medications. Our study supports that targeted diagnostic stewardship interventions should be explored and that additional risk-adjustments considered for facilities with oncology hematopoietic cell transplant wards in the National Healthcare Safety Network LabID Clostridioides difficile infection standardized infection ratio model.

ALDH7A1 expression is associated with recurrence in patients with surgically resected non-small-cell lung carcinoma.

AIM: The purpose of this study was to describe the prognostic significance of ALDH7A1 in surgically treated non-small-cell lung carcinoma. (NSCLC). MATERIALS & METHODS: We immunohistochemically analyzed ALDH7A1 expression in surgically resected NSCLC from 89 patients using a tissue microarray. RESULTS: ALDH7A1 staining was positive in 43 patients and negative in 44 patients, with two tumor sections missing. For stage I NSCLC patients, ALDH7A1 positivity was associated with decreased recurrence-free and overall survival. Multivariate analysis demonstrated that ALDH7A1-expressing NSCLC tumors had a significantly higher incidence of lung cancer recurrence compared with patients with ALDH7A1-negative tumors, although there was no association with overall survival. CONCLUSION: For patients with NSCLC, low ALDH7A1 expression was associated with a decreased incidence of cancer recurrence. Specifically in stage I patients, negative staining for ALDH7A1 was associated with improved recurrence-free and overall survival, suggesting a predictive role in surgically treated patients.

IgG4 plasma cells in inflammatory myofibroblastic tumor: inflammatory marker or pathogenic link?

Inflammatory myofibroblastic tumor is a rare mesenchymal neoplasm that harbors an anaplastic lymphoma kinase (ALK) gene rearrangement in the majority of cases. It is composed of fibroblastic-myofibroblastic cells with a characteristic inflammatory infiltrate that consists predominantly of plasma cells. In contrast, IgG4-related sclerosing disease is a recently described multisystem disorder with a histological appearance similar to inflammatory myofibroblastic tumor. The plasma cell infiltrate is characteristic in IgG4-related sclerosing disease and has been studied as a tool to render this diagnosis. Histologically, the two disorders overlap, although there are significant clinical differences. This study analyzes the histological appearance of 36 inflammatory myofibroblastic tumors, compares them with IgG4-related sclerosing disease, and assesses the plasma cell profile using immunohistochemistry to determine the range and proportion of IgG4 plasma cells. The majority of patients were children and young adults, mainly with solitary masses and no clinical manifestations of IgG4-related sclerosing disease. ALK-1 positivity was present in 23 cases (64%). None showed obliterative phlebitis or prominent lymphoid aggregates. Of 36 inflammatory myofibroblastic tumors, 15 cases showed an IgG4/IgG ratio ≥0.10, a cutoff described in the literature as supportive of IgG4-related sclerosing disease and up to 33 IgG4-positive plasma cells per high-power field indicating a mild-to-moderate increase as compared with IgG4-related sclerosing disease. Currently, the diagnostic recognition of inflammatory myofibroblastic tumor is based on clinicopathological features and diagnostic adjuncts, such as ALK-1 reactivity and genetic tests. Although inflammatory myofibroblastic tumor and IgG4-related sclerosing disease are distinct entities, a subset of inflammatory myofibroblastic tumors exhibit an IgG4/IgG ratio that is within the range for IgG4-related sclerosing disease. Therefore, the ratio alone cannot be used as a reliable discriminator between these two entities and other clinical and pathologic features must always be taken into account.

The phosphatidylinositol 3' kinase-Akt-mammalian target of rapamycin pathway in smooth muscle tumors of the uterus: selected protein expression patterns and their clinicopathologic implications.

Preclinical analyses strongly implicate the phosphatidylinositol 3' kinase-Akt-mammalian target of the rapamycin (P13K-Akt-mTOR) signaling pathway in smooth muscle tumorigenesis and differentiation, indicating that this pathway may be a suitable molecular target for the development of anticancer chemotherapeutic agents. The purpose of this study is to define the frequency and patterns of expression of 3 proteins in this pathway (mTOR, Akt, and PI3-K) in smooth muscle tumors of the uterine corpus, and to establish whether the expression of any of these proteins has independent prognostic significance. The expression patterns of mTOR, pan-Akt, and PI3-K were evaluated by immunohistochemistry in 31 uterine leiomyosarcomas and 10 leiomyomata, and the results were correlated with clinicopathologic parameters. Cases were scored by multiplication of staining intensity (on a 0 to 3+scale) and the extent/distribution of immunoreactivity (on a 0 to 4+ scale) for potential scores that ranged from 0 to a maximum of 12. Cases with scores of 4+to 12+(moderate, 4+ to 8+; high, 9+ to 12+ immunoreactivity) were considered positive. Associated peritumoral normal myometrium was present in 27 cases. All 31 leiomyosarcomas were pan-Akt positive, with 80.6% of the positive cases displaying high scores, whereas all 10 leiomyomata and 27 normal myometria were entirely pan-Akt negative. High pan-Akt scores were associated with high tumor grade but not with advanced stage or outcome. Every tumoral and nontumoral sample that was evaluated showed immunoreactivity for mTOR. PI3-K was positive in 20 (64.5%) of the 31 leiomyosarcomas but in none of the leiomyomata. High scores of PI3-K were associated with late pathologic stage (P=0.0022). High PI3-K scores, high pan-Akt scores, and PI3-K positivity were not independently associated with reduced disease-specific survival on multivariate analysis. Our findings suggest that relative to the normal myometrium, there is indeed dysregulation of the P13K-Akt-mTOR pathway in uterine smooth muscle tumors and especially in uterine leiomyosarcomas. Pan-Akt, mTOR, and PI3-K expression lacked independent prognostic significance in this pilot study, but additional and larger analyses are required. If corroborated in other laboratories, the expression patterns of proteins in this pathway, especially pan-Akt, may be of diagnostic use.

The Effect of Gravity on Flame Spread over PMMA Cylinders.

Fire safety is a concern in space travel, particularly with the current plans of increasing the length of the manned space missions, and of using spacecraft atmospheres different than in Earth, such as microgravity, low-velocity gas flow, low pressure and elevated oxygen concentration. In this work, the spread of flame over a thermoplastic polymer, polymethyl methacrylate (PMMA), was conducted in the International Space Station and on Earth. The tests consisted of determining the opposed flame spread rate over PMMA cylinders under low-flow velocities ranging from 0.4 to 8 cm/s and oxygen concentrations from 15% to 21%. The data show that as the opposed flow velocity is increased, the flame spread rate first increases, and then decreases, different from that on Earth. The unique data are significant because they have only been predicted theoretically but not been observed experimentally before. Results also show that flame spread in microgravity could be faster and sustained at lower oxygen concentration (17%) than in normal gravity (18%). These findings suggest that under certain environmental conditions there could be a higher fire risk and a more difficult fire suppression in microgravity than on Earth, which would have significant implications for spacecraft fire safety.

On Simulating Concurrent Flame Spread in Reduced Gravity by Reducing Ambient Pressure.

The flammability of combustible materials in spacecraft environments is of importance for fire safety applications because the environmental conditions can greatly differ from those on earth, and a fire in a spacecraft could be catastrophic. Moreover, experimental testing in spacecraft environments can be difficult and expensive, so using ground-based tests to inform microgravity tests is vital. Reducing buoyancy effects by decreasing ambient pressure is a possible approach to simulate a spacecraft environment on earth. The objective of this work is to study the effect of pressure on material flammability, and by comparison with microgravity data, determine the extent to which reducing pressure can be used to simulate reduced gravity. Specifically, this work studies the effect of pressure and microgravity on upward/concurrent flame spread rates and flame appearance of a burning thin composite fabric made of 75% cotton and 25% fiberglass (Sibal). Experiments in normal gravity were conducted using pressures ranging between 100 and 30 kPa and a forced flow velocity of 20 cm/s. Microgravity experiments were conducted during NASA's Spacecraft Fire Experiment (Saffire), on board of the Orbital Corporation Cygnus spacecraft at 100 kPa and an air flow velocity of 20 cm/s. Results show that reductions of ambient pressure slow the flame spread over the fabric. As pressure is reduced, flame intensity is also reduced. Comparison with the concurrent flame spread rates in microgravity show that similar flame spread rates are obtained at around 30 kPa. The normal gravity and microgravity data is correlated in terms of a mixed convection non-dimensional parameter that describes the heat transferred from the flame to the solid surface. The correlation provides information about the similitudes of the flame spread process in variable pressure and reduced gravity environments, providing guidance for potential on-earth testing for fire safety design in spacecraft and space habitats.

Cytoplasmic clusterin expression is associated with longer survival in patients with resected non small cell lung cancer.

BACKGROUND: Clusterin is a glycoprotein that has been implicated in many processes, including apoptosis, cell cycle regulation, and DNA repair. Previous studies have examined the prognostic value of clusterin expression in various malignancies. In the present study, we examined clusterin staining in tumors resected from patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Tumor specimens were obtained for 113 patients with completely resected NSCLC from paraffin-embedded tissue microarrays and stained with an antibody specific for clusterin. Staining patterns were observed and graded based on intensity and then correlated with clinical data. RESULTS: Positive cytoplasmic clusterin staining was observed in 44 patients, and weak/negative staining was observed in 62 patients. Patients who had tumors that stained positive for cytoplasmic clusterin had significantly longer survival in multivariate analysis (hazard ratio 0.487, 95% confidence interval 0.27-0.89). A correlation was also observed for recurrence-free survival, which approached statistical significance (hazard ratio 0.345, 95% confidence interval 0.12-1.02). In univariate analysis, patients with clusterin-positive tumors had a 63% 3-year survival, whereas patients with clusterin-negative tumors had a 42% 3-year survival (P = 0.0108); clusterin-positive tumors also had significantly less recurrence (P = 0.0231). CONCLUSIONS: Cytoplasmic clusterin staining is present in a substantial number of NSCLC tumors and may be a biomarker for longer survival in patients with surgically resected NSCLC.

PDGFR-beta expression in small cell lung cancer patients.

BACKGROUND: Platelet derived growth factor (PDGF) and PDGFR-beta are expressed and have been found to have prognostic value in several human cancers. Data in non-small-cell cancer cell lines have suggested that PDGFR is a therapeutic target for drug development. In the current study PDGFR-beta expression and prognostic value in small cell lung cancer (SCLC) was investigated. METHODS AND MATERIALS: Paraffin-embedded tissue blocks from 53 patients with limited and extensive stage SCLC were obtained for immunohistochemical staining. Tumors from each patient were sampled 3 times and stained with PDGFR-beta specific antibody. Patients were divided into low and high staining groups based on intensity. RESULTS: There was high intensity PDGFR-beta staining in 20 patients with SCLC. Another 29 expressed low intensity PDGFR-beta staining, with only 4 patients showing no PDGFR-beta staining. There was no statistically significant difference in 5 year overall survival between patients with low levels of PDGFR-beta staining vs. those with high level staining SCLC tumors (p = 0.538). CONCLUSIONS: The present study found that the majority of SCLC patients express, at least, a low level of PDGF-beta. However, the level of PDGFR-beta expression was not a statistically significant predictor of 5 year overall survival in SCLC.

Expression of ABCA3 in developing lung and other tissues.

ABCA3 is a member of the ATP-binding cassette (ABC) family of transport proteins and is required for perinatal respiratory adaptation. Monoclonal and polyclonal antibodies were generated against a recombinant human ABCA3 peptide and used to assess its expression in the developing lung and adult tissues. Immunostaining for ABCA3 was detected at highest levels in type II epithelial cells of the lung but was also noted in other organs including liver, stomach, kidney, adrenal, pancreas, trachea, and brain. In the fetal lung, ABCA3 staining and mRNA increased prior to birth. Like other surfactant protein genes, ABCA3 expression was induced by thyroid transcription factor-1 in vitro. ABCA3 was coexpressed with SP-B and proSP-C in type II epithelial cells. ABCA3 staining was detected surrounding large, intracellular organelles consistent with its association with lamellar bodies. In the human fetal lung, ABCA3 staining was not detected prior to 22-23 weeks of gestation, except in the presence of pulmonary inflammation. ABCA3 was detected in type II epithelial cells of the human lung from 28 weeks of gestation and thereafter. Postnatally, intense ABCA3 staining was observed in hyperplastic epithelial cells relining injured airways in infants with chronic lung disease. Localization and regulation of ABCA3 in the respiratory epithelium is consistent with its proposed role in surfactant homeostasis. The role of ABCA3 in extrapulmonary tissues and organs remains to be elucidated. This manuscript contains online supplemental material at (www.jhc.org). Please visit this article online to view these materials.

Steroid hormone receptor and COX-2 expression in chordoma.

Reports of sex steroid receptor expression in chordoma suggest that these tumors may be responsive to hormone manipulation therapy. Immunohistochemical stains for estrogen receptor (ER)-alpha, ER-beta, progesterone receptor (PR), androgen receptor (AR), and cyclooxygenase 2 (COX-2), were performed on a tissue microarray containing 21 samples of chordoma. Most chordomas expressed COX-2, ER-beta, and AR, whereas ER-alpha and PR stains were negative in all cases. ER-beta expression did not correlate with AR expression (P = .4142; McNemar test). There were no statistically significant correlations between the expression of any of these markers and anatomic location of tumor, patient sex, patient age, or disease-free survival. Chordomas commonly express COX-2, AR, and ER-beta. These findings may have therapeutic implications concerning the use of agents that inhibit or modulate these signaling molecules.

Dominant-negative Notch3 receptor inhibits mitogen-activated protein kinase pathway and the growth of human lung cancers.

Notch3 is a member of an evolutionarily conserved family of cell surface receptors important in cell-fate determination in both vertebrates and invertebrates. Significant data support the role of Notch pathway in cancer development, although the conflicting role of Notch signaling pathways in tumorigenesis suggests that its action is highly context-dependent. Furthermore, although Notch receptors signal primarily through the regulation of hairy enhancer of split (HES) and HES-related (HRT) genes, they are known to crosstalk with other signaling pathways, including the epidermal growth factor (EGF) and the mitogen-activated protein kinase pathways. Whereas much is known about the role of Notch1 in human cancer, the role of Notch3 in epithelial tumors, such as lung carcinomas, has not been well established. In this study, we show that Notch3 is expressed in 80 of 207 (39%) resected human lung tumors and that its expression is positively correlated with EGF receptor expression. Inhibition of the Notch3 pathway using a dominant-negative receptor dramatically reduces growth in soft agar and increases growth factor dependence. We also find that Notch inhibition increases sensitivity to EGF receptor tyrosine kinase inhibition and decrease in phosphorylation of the mitogen-activated protein kinase. These observations support a role for Notch3 signaling in lung cancer, and one potential mechanism of maintaining the neoplastic phenotype is through the modulation of the EGF pathway.

Selecting antibodies to detect HER2 overexpression by immunohistochemistry in invasive mammary carcinomas.

There is an increasing clinical demand for HER2 analysis in breast cancer, especially since the release of trastuzumab. The authors assessed the ability of immunohistochemistry to detect HER2 overexpression in invasive mammary carcinomas (IMC) using five antibodies. Paraffin-embedded samples of 86 IMCs (T2N0) were used to compare the immunohistochemical overexpression of HER2 using two polyclonal antibodies (HercepTest [DAKO] and A0485 [DAKO]) and three monoclonal antibodies (CB11 from two different laboratories, Biogenex and Novocastra, and 4D5 [Genentech]). All immunostainings were scored according to the FDA-approved HercepTest recommendations. The HercepTest-positive cases were compared with gene amplification by FISH (Oncor Inform, Ventana). The HercepTest was positive in 31 of the 86 cases (36.1%). The DAKO antibody A0485 was positive in 25 of the 66 (37.8%). Monoclonal antibody 4D5 was positive in only 15 of the 86 cases (17.4%). There was almost total agreement in results between the two CB11 antibodies: 25 of the 86 positive cases (29.1%). All cases positive for CB11 or 4D5 were HercepTest positive. Most of the HercepTest 2+ cases were negative when using either monoclonal antibody. FISH was positive in 19 of the 20 HercepTest 3+ cases and negative in 5 HercepTest 2+ cases. Three CB11-2+ cases showed no amplification by FISH. In three FISH-positive cases the immunohistochemistry showed no overexpression by all antibodies used. These findings suggest that immunohistochemistry may be used reliably as a primary methodology for evaluating HER2; however, the use of polyclonal antibodies may not be adequate to assess HER2 overexpression. CB11, regardless of the manufacturer (Biogenex or Novocastra), showed better concordance with FISH (kappa=0.83) than did the polyclonal antibodies.

Elevated expression of 12/15-lipoxygenase and cyclooxygenase-2 in a transgenic mouse model of prostate carcinoma.

Changes in expression of arachidonic acid (AA) metabolizing enzymes are implicated in the development and progression of human prostate carcinoma (Pca). Transgenic mouse models of Pca that progress from high-grade prostatic intraepithelial neoplasia (HGPIN) to invasive and metastatic carcinoma could facilitate study of the regulation and function of these genes in Pca progression. Herein we characterize the AA-metabolizing enzymes in transgenic mice established with a prostate epithelial-specific long probasin promoter and the SV40 large T antigen (LPB-Tag mice) that develop extensive HGPIN and invasive and metastatic carcinoma with neuroendocrine (NE) differentiation. Murine 8-lipoxygenase (8-LOX), homologue of the 15-LOX-2 enzyme that is expressed in benign human prostatic epithelium and reduced in Pca, was not detected in wild-type or LPB-Tag prostates as determined by enzyme assay, reverse transcription-PCR, and immunohistochemistry. The most prominent AA metabolite in mouse prostate was 12-HETE. Wild-type prostate (dorsolateral lobe) converted 1.6 +/- 0.5% [(14)C]AA to 12-HETE (n = 7), and this increased to 8.0 +/- 4.4% conversion in LPB-Tag mice with HGPIN (n = 13). Quantitative real-time reverse transcription-PCR and immunostaining correlated the increased 12-HETE synthesis with increased neoplastic epithelial expression of 12/15-LOX, the leukocyte-type (L) of 12-LOX and the murine homologue of human 15-LOX-1. Immunostaining showed increased L12-LOX in invasive carcinoma and approximately one-half of metastatic foci. COX-2 mRNA was detectable in neoplastic prostates with HGPIN but not in wild-type prostate. By immunostaining, COX-2 was increased in the neoplastic epithelium of HGPIN but was absent in foci of invasion and metastases. We conclude that (a) AA metabolism in wild-type mouse prostate differs from humans in the basal expression of LOXs (15-LOX-2 in human, absence of its 8-LOX homologue in mouse prostate); (b) increased expression of 12/15-LOX in HGPIN and invasive carcinoma of the LPB-Tag model is similar to the increased 15-LOX-1 in high-grade human Pca; and (c) the LPB-Tag model shows increased COX-2 in HGPIN, and therefore, it may allow additional definition of the role of this enzyme in the subset of human HGPINs or other precursor lesions that are COX-2 positive, as well as investigation of its contribution to neoplastic cell proliferation and tumor angiogenesis in Pca.

Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice.

Notch3 is a transmembrane receptor and a member of the Notch signaling pathway essential for cellular differentiation in a variety of developing tissues in both invertebrates and vertebrates. Emerging data support the role of the Notch signaling pathway in tumorigenesis. We have previously demonstrated the expression of Notch3 in a subset of lung adenocarcinomas. To further elucidate the role of Notch3 in development of lung cancer, we established a transgenic mouse model in which the intracellular domain of Notch3 is expressed using the surfactant protein C promoter/enhancer. Constitutive expression of Notch3 in the peripheral epithelium in the developing lung resulted in altered lung morphology and delayed development, leading to perinatal lethality in these transgenic mice. Cell-specific markers and electron microscopy examination showed that the majority of the epithelial cells are undifferentiated, with some maturation of type II pneumocytes. No type I alveolar cells were evident. Metaplasia of undifferentiated cells in the terminal airways was also observed. Although the mice did not live long enough to assess tumor development, these findings demonstrate that ectopic expression of Notch3 in airway epithelium potentially contributes to the multistep evolution of lung cancer through the inhibition of terminal differentiation.

Immunohistochemical expression of estrogen receptor in enlarged lobular units with columnar alteration in benign breast biopsies: a nested case-control study.

The prognostic and therapeutic implications of estrogen receptor (ER) status in breast cancer are well known. Whether ER status plays a role in benign breast lesions and the progression to malignancy has not been proven. Enlarged lobular units with columnar alteration (ELUCA), also known as unfolded lobular units, have been associated with mild elevations in subsequent breast cancer risk. We examined the association of ERalpha expression in ELUCA with invasive breast cancer risk. A nested case-control study was performed of women with ELUCA who had undergone benign breast surgery. Eighty-two women who developed invasive breast cancer on follow-up were matched by age and year of biopsy with 166 women who did not develop invasive breast cancer. Entry biopsies were stained for ERalpha (clone 6F11) without knowledge of subsequent cancer outcome. ELUCA lesions were scored as positive if greater than 10% of epithelial nuclei stained with ERalpha and at least one ELUCA contained >50% of cells staining for ERalpha. Relative risks of breast cancer were estimated by odds ratios derived from conditional logistic regression analyses. Thirty-nine percent of cases and 56% of controls had positive ERalpha staining in ELUCA. The relative risk of invasive breast cancer in women with ERalpha-negative ELUCA was 1.85 times that of women with ERalpha-positive lesions (95% confidence interval, 1.0-3.4, P=0.04). The presence of ERalpha staining in women with ELUCA is associated with a lower risk of developing subsequent invasive carcinoma. These findings have implications for risk assessment in benign breast biopsies and are of particular interest given the controversy currently surrounding hormone replacement therapy.

Overexpression of 12/15-lipoxygenase, an ortholog of human 15-lipoxygenase-1, in the prostate tumors of TRAMP mice.

Changes in the expression and activity of lipid-metabolizing enzymes, including the linoleic acid (LA)-metabolizing enzyme 15-lipoxygenase-1 (15-LO-1), may play a role in the development and progression of human prostate carcinoma (PCa). We reported that human 15-LO-1 (designated as leukocyte type 12-LO or 12/15-LO in mouse) is expressed in human prostate and increased in PCa, particularly high-grade PCa. Genetically engineered mouse (GEM) models of PCa could facilitate the study of this gene and its regulation and function in PCa progression. In this study, we examine the protein expression and enzyme activity levels of 12/15-LO associated with PCa progression in the TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) model of PCa. This GEM model develops prostatic intraepithelial neoplasia (PIN), followed by invasive gland-forming PCa and invasive and metastatic less differentiated PCa, with neuroendocrine (NE) differentiation (NE Ca). In the wild-type and TRAMP prostates, the most prominent LA metabolite was 13-hydroxyoctadecadienoic acid (13-HODE). Lesser amounts of 12-hydroxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid (HETE) were made from arachidonic acid (AA). In TRAMP prostates, 12/15-LO activity was increased compared to wild type at 20, 29, 39, and 49 weeks, as assessed by LA conversion to 13-HODE, and by AA conversion to 12/15-HETE, respectively. Immunostaining demonstrated that the increased capacity to generate 13-HODE was paralleled by an increase in neoplastic epithelial expression of 12/15-LO in PIN and invasive carcinomas. In conclusion, although there is a basal 12/15-LO activity in the wild-type mouse prostate, there is a marked increase in the expression of 12/15-LO with TRAMP PCa progression, paralleling our previously reported increased expression of the ortholog 15-LO-1 in high-grade human PCa. Thus, 12/15-LO and LA metabolism in the TRAMP model shares similarities to human PCa, and may allow to confirm a role for LA metabolism and other biologic functions of 15-LO-1 in human PCa. In addition, the TRAMP model will serve as a tool for testing the suitability of 12/15-LO-and ultimately human 15-LO--as a therapeutic target during PCa progression.

Forkhead box A2 transcription factor is expressed in all types of neuroendocrine lung tumors.

Forkhead box A2 (Foxa2) is a winged helix nuclear transcription protein that regulates the expression of genes that are critical to lung morphogenesis, differentiation, and function, including thyroid transcription factor-1, surfactant proteins, and Clara cell secretory protein. We examined the immunoreactivity of Foxa2 in paraffin sections of 75 lung tumors: 17 typical carcinoids, 2 atypical carcinoids, 4 large cell neuroendocrine (NE) carcinomas, 23 small cell carcinomas, 19 adenocarcinomas, 7 squamous cell carcinomas, and 3 (non-NE) large cell carcinomas, using a polyclonal rabbit Foxa2 antibody and a biotin-streptavidin detection system. In the adjacent lung, Foxa2 was detected in normal and hyperplastic type II cells. Foxa2 immunoreactivity was detected in 13 typical carcinoids (76%), 2 atypical carcinoids (100%), 2 large cell NE carcinomas (50%), 11 small cell carcinomas (48%), and 1 adenocarcinoma (5%). Squamous cell carcinomas and (non-NE) large cell carcinomas uniformly lacked Foxa2 staining. Expression of Foxa2 in the entire spectrum of NE lung tumors is another indication of differentiation shared by typical carcinoid, atypical carcinoid, large cell NE carcinoma, and small cell carcinoma.