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American Journal of Respiratory and Critical Care Medicine 07/2012; 186(1):7-8. · 11.08 Impact Factor
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ABSTRACT: Acute lung injury (ALI) is a syndrome marked by increased permeability across the pulmonary epithelium resulting in pulmonary edema. Recent evidence suggests that members of the human epidermal growth factor receptor (HER) family are activated in alveolar epithelial cells during ALI and regulate alveolar epithelial barrier function. These tyrosine kinase receptors, which also participate in the pathophysiology of pulmonary epithelial malignancies, regulate cell growth, differentiation, and migration as well as cell-cell adhesion, all processes that influence epithelial injury and repair. In this review we outline mechanisms of epithelial injury and repair in ALI, activation patterns of this receptor family in pulmonary epithelial cells as a consequence injury, how receptor activation alters alveolar permeability, and the possible intracellular signaling pathways involved. Finally, we propose a theoretical model for how HER-mediated modulation of alveolar permeability might affect lung injury and repair. Understanding how these receptors signal has direct therapeutic implications in lung injury and other diseases characterized by altered epithelial barrier function.
American Journal of Respiratory Cell and Molecular Biology 05/2012; 47(4):395-404. · 5.13 Impact Factor
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ABSTRACT: Shedding of neuregulin-1 (NRG-1) from pulmonary epithelium leads to activation of the epithelial HER2 receptor and increased pulmonary epithelial permeability and acute lung injury (ALI). We sought to determine if NRG-1 was detectable and elevated in bronchoalveolar lavage (BAL) and plasma from patients with ALI compared with controls and to determine whether a correlation exists between NRG-1 and inflammation and outcome in ALI.Matched BAL and plasma samples were obtained from 23 ALI patients requiring intubation and mechanical ventilation. Control patients (n=5) included healthy volunteers. NRG-1 and indices of inflammation were measured in BAL and plasma via ELISA.The mean BAL NRG-1 concentration in ALI patients was 187.0±21.35 pg/mL compared to 85.50±9.2 pg·mL(-1) in controls (P=0.001). Increased BAL NRG-1 was associated with markers of inflammation, and inversely correlated with ventilator free days (VFDs; r= -0. 51, P=0.015). Plasma NRG-1 was elevated in ALI patients compared to controls (611.7±354.2 pg·mL(-1) vs. 25.17±19.33 pg·mL(-1), P < 0.001) and inversely correlated with VFDs (r= -0.51, P=0.04).These results confirm shedding of NRG-1 in ALI and suggest that the NRG-1-HER2 pathway is active in patients with ALI.
European Respiratory Journal 05/2012; · 5.89 Impact Factor
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ABSTRACT: Lung cancer is the most common cause of cancer-related death in the United States; however, recent clinical advances may change this outcome. New data on low-dose computed tomography for lung cancer screening, and technologic advances in surgery and radiation, have improved outcomes for those with early-stage disease. Identification of driver mutations in lung cancer has led to the development of molecular targeted therapy to improve survival of subsets of patients with metastatic disease. These advances now allow for treatment of many patients with lung cancer with comorbidities or poor performance status who would have had limited options in the past.
The Medical clinics of North America 11/2011; 95(6):1041-54. · 2.18 Impact Factor
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James H Finigan,
Jihane A Faress,
Emily Wilkinson,
Rangnath S Mishra,
David E Nethery,
David Wyler,
Mohammad Shatat,
Lorraine B Ware,
Michael A Matthay,
Robert Mason,
Richard F Silver, Jeffrey A Kern
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ABSTRACT: The mechanisms behind the loss of epithelial barrier function leading to alveolar flooding in acute lung injury (ALI) are incompletely understood. We hypothesized that the tyrosine kinase receptor human epidermal growth factor receptor-2 (HER2) would be activated in an inflammatory setting and participate in ALI. Interleukin-1β (IL-1β) exposure resulted in HER2 activation in human epithelial cells and markedly increased conductance across a monolayer of airway epithelial cells. Upon HER2 blockade, conductance changes were significantly decreased. Mechanistic studies revealed that HER2 trans-activation by IL-1β required a disintegrin and metalloprotease 17 (ADAM17)-dependent shedding of the ligand neuregulin-1 (NRG-1). In murine models of ALI, NRG-1-HER2 signaling was activated, and ADAM17 blockade resulted in decreased NRG-1 shedding, HER2 activation, and lung injury in vivo. Finally, NRG-1 was detectable and elevated in pulmonary edema fluid from patients with ALI. These results suggest that the ADAM17-NRG-1-HER2 axis modulates the alveolar epithelial barrier and contributes to the pathophysiology of ALI.
Journal of Biological Chemistry 01/2011; 286(12):10660-70. · 4.77 Impact Factor
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ABSTRACT: Idiopathic pulmonary fibrosis is characterized by myofibroblast accumulation, extracellular matrix (ECM) remodeling, and excessive collagen deposition. ECM-producing myofibroblasts may originate from epithelial cells through epithelial to mesenchymal transition (EMT). TGF-β1 is an inducer of EMT in pulmonary epithelial cells in vitro and in vivo, though the mechanisms are unclear. We hypothesized that TGF-β1 induced EMT through Smad-dependent and -independent processes. To test this hypothesis, we studied the roles and mechanisms of TGF-β1-induced Smad and p38 mitogen-activated protein kinase (MAPK) signaling in EMT-related changes in pulmonary epithelial cells. Exposure of pulmonary epithelial 1HAEo(-) cells to TGF-β1 resulted in morphological and molecular changes of EMT over a 96-h period; loss of cell-cell contact, cell elongation, down-regulation of E-cadherin, up-regulation of fibronectin, and up-regulation of collagen I. Both Smad2/3 and p38 MAPK signaling pathways were activated by TGF-β1. However, neither Smad2/3 nor p38 MAPK were required for the down-regulation of E-cadherin, yet p38 MAPK was associated with fibronectin up-regulation. Both Smad2/3 and p38 MAPK had a role in regulation of TGF-β1-induced collagen expression. Furthermore, these data demonstrate that Smads and p38 MAPK differentially regulate EMT-related changes in pulmonary epithelial cells.
Journal of Cellular Physiology 10/2010; 226(5):1248-54. · 3.87 Impact Factor
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ABSTRACT: Anatomic right-to-left shunt causes hypoxemia that can pose a diagnostic challenge to clinicians. Among the many possible causes of right-to-left shunt, persistent left-sided superior vena cava (PLSVC) with an "unroofed" coronary sinus represents an uncommon congenital anomaly in which detection by saline-contrast echocardiogram (bubble echo) or contrast-enhanced CT scan requires injection of contrast in the left arm. We present the case of an elderly man with hypoxemia on the basis of a right-to-left shunt accompanying a PLSVC with unroofed coronary sinus in whom the shunt escaped initial detection following a bubble echo with contrast injected into the right arm. This case reminds pulmonary clinicians, who are frequently called on to assess the cause of hypoxemia, that specifying a contrast injection into the left arm is required in the pursuit of this specific shunt-producing anomaly.
Chest 09/2009; 136(2):617-20. · 5.25 Impact Factor
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ABSTRACT: The molecular mechanisms of oncogenesis in mesothelioma involve the loss of negative regulators of cell growth including p16INK4a. Absence of expression of the p16INK4a gene product is exhibited in virtually all mesothelioma tumors and cell lines examined to date. Loss of p16INK4a expression has also been frequently observed in more common neoplasms such as lung cancer as well. In a wide variety of these malignancies, including lung cancer, p16INK4a expression is known to be inactivated by hypermethylation of the first exon. This project (CALGB 159904) intended to test the hypothesis that in mesothelioma loss of p16INK4a via methylation would correlate with response to the cytidine analog and methylation inhibitor dihydro-5-azacytidine (DHAC).
Using tissue samples from CALGB 8833 and 9031, two clinical studies which used DHAC based therapy in mesothelioma, this study tested the hypothesis that tumors possessing methylation of p16INK4a would have a better response and survival following DHAC treatment than their nonmethylated counterparts.
Methylation of p16INK4a was identified in 4 of the 20 specimens. Although there was a trend towards improved survival the result was not statistically significant.
There was no significant correlation between the presence of p16INK4a methylation and response to DHAC therapy or overall survival.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2008; 3(4):417-21. · 4.55 Impact Factor
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ABSTRACT: Signal transducer and activators of transcription 3 (STAT3) is an important transcription factor that is essential for lung cancer cell survival. STAT3 is activated by diverse upstream receptor and nonreceptor tyrosine kinases, and blockade of STAT3 results in tumor growth inhibition. Therefore, a search for STAT3 inhibitors is under way. We demonstrate that SCH66336, at 4 mumol/l, completely blocks STAT3 phosphorlyation in a variety of nonsmall cell lung carcinoma (NSCLC) cell lines, whereas the effect on AKT and extracellular signal-regulated kinase activation is variable. Furthermore, SCH66336 has antiproliferative effects on NSCLC cells. When NSCLC cells are exposed sequentially to SCH66336 and a small molecule dual tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2, synergistic activity is observed with an increase in the fraction of cells undergoing apoptosis. Concurrent exposure to both agents is, however, associated with antagonism and decreased apoptosis. We conclude that blockade of STAT3 phosphorylation might be one of the mechanisms by which SCH66336 exerts its antitumor activity, and that this can be synergistic in vitro when administered sequentially with epidermal growth factor receptor inhibitors.
Anti-Cancer Drugs 02/2008; 19(1):9-16. · 2.41 Impact Factor
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ABSTRACT: The importance of HER2/HER3 signaling in decreasing the effects of lung injury was recently demonstrated. Transgenic mice unable to signal through HER2/HER3 had significantly less bleomycin-induced pulmonary fibrosis and showed a survival benefit. Based on these data, we hypothesized that pharmacological blockade of HER2/HER3 in vivo in wild-type mice would have the same beneficial effects. We tested this hypothesis in a bleomycin lung injury model using 2C4, a monoclonal antibody directed against HER2 that blocks HER2/HER3 signaling. The administration of 2C4 before injury decreased the effects of bleomycin at days 15 and 21 after injury. HER2/HER3 blockade resulted in less collagen deposition (362.8 +/- 37.9 compared with 610.5 +/- 27.1 microg/mg; P = 0.03) and less lung morphological changes (injury score of 1.99 +/- 1.55 vs. 3.90 +/- 0.76; P < 0.04). In addition, HER2/HER3 blockade resulted in a significant survival advantage with 50% vs. 25% survival at 30 days (P = 0.04). These results confirm that HER2 signaling can be pharmacologically targeted to reduce lung fibrosis and remodeling after injury.
Journal of Applied Physiology 12/2007; 103(6):2077-83. · 3.75 Impact Factor
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ABSTRACT: Patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer derive significant clinical benefit from treatment with the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Secondary EGFR mutations such as EGFR T790M commonly lead to resistance to these agents, limiting their long-term efficacy. Irreversible EGFR inhibitors such as CL-387,785 can overcome resistance and are in clinical development, yet acquired resistance against these agents is anticipated. We carried out a cell-based, in vitro random mutagenesis screen to identify EGFR mutations that confer resistance to CL-387,785 using T790M-mutant H1975 lung adenocarcinoma cells. Mutations at several residues occurred repeatedly leading to functional resistance to CL-387,785. These variants showed uninhibited cell growth, reduced apoptosis, and persistent EGFR activation in the presence of CL-387,785 as compared with parental H1975 cells, thus confirming their role in resistance. A screen of alternative agents showed that both an alternative EGFR inhibitor and a cyclin-dependent kinase 4 inhibitor led to significant inhibition of cell growth of the resistant mutants, suggestive of potential alternative treatment strategies. These results identify novel mutations mediating resistance to irreversible EGFR inhibitors and reveal alternative strategies to overcome or prevent the development of resistance in EGFR-mutant non-small cell lung cancers.
Cancer Research 12/2007; 67(21):10417-27. · 7.86 Impact Factor
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Journal of Thoracic Oncology 07/2007; 2(8):S546. · 3.66 Impact Factor
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ABSTRACT: Nitration is a posttranslational modification that can compromise protein function. We hypothesized that nitration of growth factors secreted in the lung may alter their interaction with their respective receptors and modulate the normal growth and differentiation program induced by ligand-receptor interaction. We tested this hypothesis in vitro by nitration of neuregulin-1's (NRG-1) EGF-like domain and studying the effect on NRG-1's activity. Nitration of NRG-1's (nNRG-1) EGF-like domain resulted in an inability to activate its receptor, the human epidermal growth factor receptors 2 and 3 (HER2/HER3) heterodimer, as defined by loss of HER2 tyrosine phosphorylation induced by nNRG-1 in MCF-7 cells. Receptor activation was not restored with increasing nNRG-1 concentration or exposure times. nNRG-1 did not compete with NRG-1 for HER2/HER3 binding in competition assays. In addition, nNRG-1 no longer induced proliferation of the MCF-7 cell line, as MCF-7 cells exposed to nNRG-1 and NRG-1 concurrently had the same proliferation rate as that induced by NRG-1 alone. Thus nitration of NRG-1's EGF-like domain caused it to lose its ability to bind and activate its receptor with loss of ligand-induced proliferation. Posttranslational nitration of growth factors in states where reactive nitrogen species are increased may be an important means of regulating growth factor receptor effects in the lung.
AJP Lung Cellular and Molecular Physiology 02/2007; 292(1):L287-93. · 3.66 Impact Factor
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ABSTRACT: Neuregulin-1 (NRG-1), binding to the human epidermal growth factor receptor HER2/HER3, plays a role in pulmonary epithelial cell proliferation and recovery from injury in vitro. We hypothesized that activation of HER2/HER3 by NRG-1 would also play a role in recovery from in vivo lung injury. We tested this hypothesis using bleomycin lung injury of transgenic mice incapable of signaling through HER2/HER3 due to lung-specific dominant-negative HER3 (DNHER3) expression. In animals expressing DNHER3, protein leak, cell infiltration, and NRG-1 levels in bronchoalveolar lavage fluid increased after injury, similar to that in nontransgenic littermate control animals. However, HER2/HER3 was not activated, and DNHER3 animals displayed fewer lung morphological changes at 10 and 21 days after injury (P = 0.01). In addition, they contained 51% less collagen in injured lungs (P = 0.04). Transforming growth factor-beta1 did not increase in bronchoalveolar lavage fluid from DNHER3 mice compared with nontransgenic littermate mice (P = 0.001), suggesting that a mechanism for the decreased fibrosis was lack of transforming growth factor-beta1 induction in DNHER3 mice. Severe lung injury (0.08 units bleomycin) resulted in 80% mortality of nontransgenic mice, but only 35% mortality of DNHER3 transgenic mice (P = 0.04). Thus inhibition of HER2/HER3 signaling protects against pulmonary fibrosis and improves survival.
Journal of Applied Physiology 08/2005; 99(1):298-307. · 3.75 Impact Factor
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Jonathan D'Cunha,
James E Herndon,
Debra L Herzan,
G Alexander Patterson,
Leslie J Kohman,
David H Harpole,
Kemp H Kernstine, Jeffrey A Kern,
Mark R Green,
Michael A Maddaus,
Robert A Kratzke
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ABSTRACT: A major problem with the staging system for non-small cell lung cancer (NSCLC) is clinical underestimation of the extent of disease. Many patients with clinical stage 1 disease do not retain that designation following surgical resection. Herein, we present data from Cancer and Leukemia Group B (CALGB) protocol 9761 evaluating the correspondence between clinical and pathologic analysis in early stage NSCLC.
Five hundred and two patients with suspected or biopsy-proven NSCLC classified as clinical stage 1 (T1-2, N0) by computed tomography (CT) scan or cervical mediastinoscopy were prospectively enrolled in CALGB 9761. The purpose of CALGB 9761 was to prospectively evaluate molecular markers of micrometastatic disease in stage 1 NSCLC. Enrollment occurred at 11 selected institutions within the CALGB. Patients with clinically suspected resectable early stage lung cancer were eligible for enrollment if they had no evidence of mediastinal or hilar adenopathy on CT scan or if they had CT evidence of potential N2 or N3 disease (lymph node > or =1.0 cm) but with negative mediastinoscopy. No prior chemotherapy or radiotherapy was permitted.
Of the 502 patients felt to have clinical stage 1 NSCLC enrolled in CALGB 9761, 489 underwent resection with complete surgical staging and routine histopathologic analysis. From these 489 patients, only 422 (86.3%) turned out to have pathologically documented NSCLC. Of these 422 patients, 302 (71.6%) had pathologic stage 1 disease (173 stage 1A and 129 stage 1B). Despite clinical assessment of stage 1 disease, 59 (14%) patients had pathologic stage 2 disease, 57 (13.5%) had stage 3 disease, and four (0.9%) patients had stage 4 disease. Of the patients undergoing resection for clinical stage 1 NSCLC, 65 patients did not have NSCLC (44 had benign disease and 21 had malignancies other than NSCLC) and two additional patients had dual synchronous primary NSCLC tumors and were not eligible for the study. Overall, only 61.7% (302 of 489) of patients with suspected stage 1 NSCLC disease retained that stage and diagnosis after complete surgical staging, while 38.3% had an inaccurate pre-operative clinical stage or diagnosis.
The results from this prospective trial demonstrate the poor predictive value of current clinical staging techniques in early stage NSCLC. These findings will serve as a benchmark for comparison of future clinical imaging modalities and other tests evaluating early stage NSCLC.
Lung Cancer 05/2005; 48(2):241-6. · 3.43 Impact Factor
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ABSTRACT: Neuregulin-1 (NRG-1) induces signal transduction through the activation of its receptor, a heterodimer of human epidermal growth factor receptors 2 and 3 (HER2/HER3). Signal transduction through this receptor/ligand system plays a critical role in the developing heart, mammary gland, and nervous systems. Previous studies showed that NRG-1-induced HER2 activation resulted in pulmonary epithelial cell proliferation in the human fetal lung. The authors hypothesized that NRG-1 further contributes to lung development and maturation by inducing branching morphogenesis. In the present study, the authors show that NRG-1, HER2, and HER3, but not HER4, are expressed in the developing mouse lung. Addition of NRG-1 to fetal lung explants increased lung branching morphogenesis by 32% (P < .05). This increase in branching was blocked by 2C4, an antibody directed against HER2 that inhibits its dimerization and subsequent NRG-1-induced signal transduction. To gain an understanding of the intracellular signaling pathways involved in NRG-1-induced branching morphogenesis, the authors specifically blocked the phosphatidylinositol-3 kinase (PI3K) and mitogen activation protein kinase (MAPK) pathways. Inhibition of PI3K signaling significantly decreased NRG-1-induced branching morphogenesis (P < .05). Inhibition of NRG-1-induced MAPK activation had no effect on explant branching morphogenesis. These data suggest that NRG-1, binding to the HER2/HER3 heterodimer receptor complex, induces pulmonary branching morphogenesis through HER2 activation of the PI3K pathway.
Experimental Lung Research 09/2004; 30(6):465-78. · 1.22 Impact Factor
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ABSTRACT: Epidermal growth factor receptor (EGFR) inhibition with small molecule tyrosine kinase inhibitors results in antitumor activity in only a minority of patients whose tumors express EGFR. One hypothesis to explain this suboptimal clinical activity is that multiple growth regulatory pathways are abnormal in most EGFR-expressing cancers. Given the importance of Stat-3 signaling pathway in epidermoid tumors, we hypothesized that blocking complementary pathways in an epidermal growth factor (EGF)-driven model of proliferation in the A431 cell line would demonstrate improved antiproliferative activity. Exposure of A431 cells to the EGF results in a significant increase in EGFR and Stat-3 phosphorylation. However, inhibition of EGFR by AG1478 fails to decrease EGF-induced Stat-3 phosphorylation. This suggests that EGF continues to drive Stat-3 phosphorylation through other receptors. Our study suggests that residual ErbB2 activation by EGF, despite EGFR blockade, is responsible for persistent downstream activation of Stat-3. In this setting, combined exposure to an EGFR blocker and Stat-3 blocker (AG490) results in significantly greater tumor growth inhibition than either agent alone. We conclude that targeting multiple pathways (EGFR and JAK/STAT pathways) in EGF-driven tumors may result in greater antiproliferative activity than blocking EGFR alone.
Molecular Cancer Therapeutics 05/2004; 3(4):459-63. · 5.23 Impact Factor
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ABSTRACT: Our prior studies identified co-expression of the human epidermal growth factor-like receptors 2 (ErbB2) and 3 (ErbB3), as well as the growth factor neuregulin-1 (NRG-1) in normal lung epithelium and lung cancers. As ErbB2 and ErbB3 dimerize to produce a high affinity receptor for NRG-1, we postulated that an autocrine growth loop was present in transformed and non-transformed pulmonary epithelial cells. To test this hypothesis, we examined four cell lines derived from human non-small cell carcinomas for: (1) ErbB2 and ErbB3 expression and endogenous activation; (2) NRG-1 expression and secretion/shedding; and (3) the effect of receptor blockade on autocrine receptor activation. Our studies found that ErbB2 and ErbB3 were expressed by each of these cell lines. In addition, the NRG-1 gene was also expressed with both major isoforms of NRG-1 (NRG-1alpha and NRG-1beta) found intracellularly. Only the NRG-1alpha isoform, however, was found secreted/shed into the culture medium. The secreted/shed NRG-1alpha was capable of activating the ErbB2/ErbB3 receptor complex expressed on the breast adenocarcinoma cell line MCF-7. Basal ErbB2 phosphorylation was identified in all lung cancer cell lines and was inhibited with an antibody that blocked the NRG-1 binding site on ErbB3. Taken together, these data show that secreted NRG-1alpha can activate the ErbB2/ErbB3 heterodimer in an autocrine fashion. The identification of a NRG-1alpha/ErbB2/ErbB3 autocrine loop raises the possibility that interruption of this loop may have therapeutic potential in lung cancer.
Lung Cancer 03/2004; 43(2):135-43. · 3.43 Impact Factor
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Robin T Vollmer,
James E Herndon,
Jonathan D'Cunha,
Naif Z Abraham,
Joette Solberg,
Mitra Fatourechi,
Ann Maruska, Jeffrey A Kern,
Mark R Green,
Robert A Kratzke,
Michael A Maddaus
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ABSTRACT: Our purpose was to study the detection of occult metastases (OM) in regional lymph nodes using immunohistochemical stain for cytokeratin, and for this study we targeted clinical stage I patients with non-small cell lung cancer.
The study comprised the first 193 patients entered onto Cancer and Leukemia Group B protocol 9761. All had clinically staged T(1-2)N(0)M(0) non-small cell lung cancer, and all underwent curative resections of their primary tumors. Samples of the primary tumor and lymph nodes were taken from lymph node stations 2-12 and shipped to a central laboratory, where each lymph node was histologically processed and stained with H&E as well as with immunohistochemical stain using antibodies to cytokeratin (AE1/3).
Altogether, we examined 825 lymph nodes. Whereas routine H&E staining allowed us to detect 18 positive lymph nodes, immunohistochemical staining allowed us to detect 45 positive lymph nodes (P < 0.0001). There were 28 OM [i.e., those detectable only by immunohistochemistry (IHC)], and there was 1 metastasis detected only by H&E staining. The OM included 9 OM in N1 stations and 19 OM in N2 stations. Twelve patients with OM had skip metastases. Routine H&E staining upstaged six patients to N1, and IHC added another five. Routine H&E upstaged 9 patients to N2, and IHC added another 11. We also uncovered new details about the way in which H&E detection depends on metastatic tumor burden. Specifically, for the probability of detecting metastases by H&E to exceed 0.50, the maximum diameter of the metastasis must be greater than 0.23 mm.
IHC detects greater than twice as many positive regional lymph nodes as does H&E staining, and the foci of tumor it detects are significantly smaller than those detected by H&E staining.
Clinical Cancer Research 11/2003; 9(15):5630-5. · 7.74 Impact Factor
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ABSTRACT: Interactions between ligands and receptors are central to communication between cells and tissues. Human airway epithelia constitutively produce both a ligand, the growth factor heregulin, and its receptors--erbB2, erbB3 and erbB4 (refs 1-3). Although heregulin binding initiates cellular proliferation and differentiation, airway epithelia have a low rate of cell division. This raises the question of how ligand-receptor interactions are controlled in epithelia. Here we show that in differentiated human airway epithelia, heregulin-alpha is present exclusively in the apical membrane and the overlying airway surface liquid, physically separated from erbB2-4, which segregate to the basolateral membrane. This physical arrangement creates a ligand-receptor pair poised for activation whenever epithelial integrity is disrupted. Indeed, immediately following a mechanical injury, heregulin-alpha activates erbB2 in cells at the edge of the wound, and this process hastens restoration of epithelial integrity. Likewise, when epithelial cells are not separated into apical and basolateral membranes ('polarized'), or when tight junctions between adjacent cells are opened, heregulin-alpha activates its receptor. This mechanism of ligand-receptor segregation on either side of epithelial tight junctions may be vital for rapid restoration of integrity following injury, and hence critical for survival. This model also suggests a mechanism for abnormal receptor activation in diseases with increased epithelial permeability.
Nature 04/2003; 422(6929):322-6. · 36.28 Impact Factor
