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ABSTRACT: The use of p63 has been advocated for separating small cell lung carcinoma from poorly differentiated non-small cell lung carcinoma, in particular, squamous cell lung carcinoma. However, p63 is not entirely specific in this distinction, as several studies have demonstrated p63 immunoreactivity in a proportion of small cell lung carcinomas. p40 (ΔNp63) has recently been purported to be a highly specific marker for squamous cell lung carcinoma, but data regarding p40 (ΔNp63) in small cell lung carcinoma, a key differential diagnostic consideration in biopsy samples of squamous cell lung carcinoma, are lacking. In this study, a total of 34 previously confirmed small cell lung carcinomas (27 bronchoscopic biopsy samples and 7 large specimens) were immunostained for p40 (ΔNp63), p63, and keratin 34βE12. All 34 small cell lung carcinomas were negative for p40 (ΔNp63) and keratin 34βE12. Although none of the large small cell lung carcinoma specimens exhibited p63 immunoreactivity, 12 (44.4%) of 27 biopsy samples of small cell lung carcinoma were positive for p63. The rate of p63 staining in small cell lung carcinoma biopsy samples differed significantly from that of p40 (ΔNp63) and keratin 34βE12 (P = .005). Ten cases of squamous cell lung carcinoma were also tested, all of which were positive for all 3 markers. These findings confirm that p63 immunoexpression is not uncommon in biopsy samples of small cell lung carcinoma. Positive p63 staining may be mistakenly interpreted as supportive of squamous differentiation and result in misclassification of small cell lung carcinoma as squamous cell lung carcinoma, a diagnostic error that has important therapeutic and prognostic consequences. To provide greater diagnostic accuracy, p40 (ΔNp63) or keratin 34βE12 should be used instead of p63 in the distinction of small cell lung carcinoma from non-small cell lung carcinoma in biopsy samples.
Human pathology 03/2013; · 3.03 Impact Factor
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European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 07/2012; · 2.40 Impact Factor
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Sherrill L Macura,
Jedd M Hillegass,
Jeremy L Steinbacher,
Maximilian B MacPherson,
Arti Shukla,
Stacie L Beuschel,
Timothy N Perkins, Kelly J Butnor,
Melissa J Lathrop,
Mutlay Sayan,
Khan Hekmatyar,
Douglas J Taatjes,
Risto A Kauppinen,
Christopher C Landry,
Brooke T Mossman
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ABSTRACT: Pleural and peritoneal mesotheliomas (MMs) are chemoresistant tumors with no effective therapeutic strategies. The authors first injected multifunctional, acid-prepared mesoporous spheres (APMS), microparticles functionalized with tetraethylene glycol oligomers, intraperitoneally into rodents. Biodistribution of APMS was observed in major organs, peritoneal lavage fluid (PLF), and urine of normal mice and rats. After verification of increased mesothelin in human mesotheliomas injected into severe combined immunodeficient (SCID) mice, APMS were then functionalized with an antibody to mesothelin (APMS-MB) or bovine serum albumin (BSA), a nonspecific protein control, and tumor targeting was evaluated by inductively coupled plasma mass spectrometry and multifluorescence confocal microscopy. Some APMS were initially cleared via the urine over a 24 hr period, and small amounts were observed in liver, spleen, and kidneys at 24 hr and 6 days. Targeting with APMS-MB increased APMS uptake in mesenteric tumors at 6 days. Approximately 10% to 12% of the initially injected amount was observed in both spheroid and mesenteric MM at this time point. The data suggest that localized delivery of APMS-MB into the peritoneal cavity after encapsulation of drugs, DNA, or macromolecules is a novel therapeutic approach for MM and other tumors (ovarian and pancreatic) that overexpress mesothelin.
Journal of Histochemistry and Cytochemistry 06/2012; 60(9):658-74. · 2.72 Impact Factor
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ABSTRACT: Pulmonary carcinoid tumors are low-grade malignant neoplasms thought to arise primarily within the central airways in 85% of cases. The CT features of pulmonary carcinoid tumors that arise as solitary pulmonary nodules (SPNs) have not been well elucidated. We reviewed our experience with primary pulmonary carcinoid tumors to determine the distribution of lesions within the lung at diagnosis and to identify CT features that might aid in distinguishing these neoplasms from benign pulmonary nodules.
CT scans, if available, of all patients with a primary pulmonary carcinoid tumor diagnosed by biopsy or surgical resection over the previous 15 years were reviewed. The CT scans were reviewed for the following features: lesion location; order of bronchus involved; lesion size, contour, and density; contrast enhancement; and the presence of peripheral atelectasis, hyperlucency, and bronchiectasis. We defined central lesions as those involved with a segmental or larger bronchus. Subsegmental bronchial involvement and tumors surrounded by lung parenchyma without direct airway involvement were defined as peripheral lesions. The final pathologic diagnosis for all cases was confirmed by review of cytologic or histologic specimens.
Twenty-eight carcinoid tumors were identified in 28 patients: 24 typical carcinoids and four atypical carcinoids. The study group was composed of 23 females and five males with a mean age of 52.4 years (range, 14-83 years). Twelve of the 28 lesions (43%) were central (i.e., involved a segmental or larger bronchus), and the remaining 16 lesions (57%) were peripheral. The mean tumor diameter for the 16 peripheral tumors was 14 mm (range, 9-28 mm); the majority (14/16, 88%) had a lobulated contour. Of six peripheral lesions with unenhanced and contrast-enhanced CT nodule enhancement studies, the mean maximal enhancement was 55.2 HU (range, 34-73 HU). Thirteen of the 16 peripheral carcinoid tumors (81%) involved a subsegmental bronchus, with 10 (63%) showing peripheral hyperlucency, bronchiectasis, or atelectasis.
In our series, primary pulmonary carcinoid tumors presenting as peripheral SPNs were more common than central endobronchial lesions in contrast to the published literature. The CT features of peripheral carcinoid tumors presenting as SPNs that suggest the diagnosis include lobulated nodules of high attenuation on contrast-enhanced CT; nodules that densely enhance with contrast administration; the presence of calcification; subsegmental airway involvement on thin-section analysis; and nodules associated with distal hyperlucency, bronchiectasis, or atelectasis.
American Journal of Roentgenology 11/2011; 197(5):1073-80. · 2.78 Impact Factor
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Arti Shukla,
Jedd M Hillegass,
Maximilian B MacPherson,
Stacie L Beuschel,
Pamela M Vacek, Kelly J Butnor,
Harvey I Pass,
Michele Carbone,
Joseph R Testa,
Nicholas H Heintz,
Brooke T Mossman
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ABSTRACT: Members of the extracellular signal-regulated kinase (ERK) family may have distinct roles in the development of cell injury and repair, differentiation and carcinogenesis. Here, we show, using a synthetic small-molecule MEK1/2 inhibitor (U0126) and RNA silencing of ERK1 and 2, comparatively, that ERK2 is critical to transformation and homeostasis of human epithelioid malignant mesotheliomas (MMs), asbestos-induced tumors with a poor prognosis. Although MM cell (HMESO) lines stably transfected with shERK1 or shERK2 both exhibited significant decreases in cell proliferation in vitro, injection of shERK2 cells, and not shERK1 cells, into immunocompromised severe combined immunodeficiency (SCID) mice showed significant attenuated tumor growth in comparison to shControl (shCon) cells. Inhibition of migration, invasion and colony formation occurred in shERK2 MM cells in vitro, suggesting multiple roles of ERK2 in neoplasia. Microarray and quantitative real-time PCR analyses revealed gene expression that was significantly increased (CASP1, TRAF1 and FAS) or decreased (SEMA3E, RPS6KA2, EGF and BCL2L1) in shERK2-transfected MM cells in contrast to shCon-transfected MM cells. Most striking decreases were observed in mRNA levels of Semaphorin 3 (SEMA3E), a candidate tumor suppressor gene linked to inhibition of angiogenesis. These studies demonstrate a key role of ERK2 in novel gene expression critical to the development of epithelioid MMs. After injection of sarcomatoid human MM (PPMMill) cells into SCID mice, both shERK1 and shERK2 lines showed significant decreased tumor growth, suggesting heterogeneous effects of ERKs in individual MMs.
International Journal of Cancer 09/2011; 129(5):1075-86. · 5.44 Impact Factor
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Jedd M Hillegass,
Steven R Blumen,
Kai Cheng,
Maximilian B MacPherson,
Vlada Alexeeva,
Sherrill A Lathrop,
Stacie L Beuschel,
Jeremy L Steinbacher, Kelly J Butnor,
Maria E Ramos-Niño,
Arti Shukla,
Ted A James,
Daniel J Weiss,
Douglas J Taatjes,
Harvey I Pass,
Michele Carbone,
Christopher C Landry,
Brooke T Mossman
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ABSTRACT: New and effective treatment strategies are desperately needed for malignant mesothelioma (MM), an aggressive cancer with a poor prognosis. We have shown previously that acid-prepared mesoporous microspheres (APMS) are nontoxic after intrapleural or intraperitoneal (IP) administration to rodents. The purpose here was to evaluate the utility of APMS in delivering chemotherapeutic drugs to human MM cells in vitro and in two mouse xenograft models of MM. Uptake and release of doxorubicin (DOX) alone or loaded in APMS (APMS-DOX) were evaluated in MM cells. MM cell death and gene expression linked to DNA damage/repair were also measured in vitro. In two severe combined immunodeficient mouse xenograft models, mice received saline, APMS, DOX or APMS-DOX injected directly into subcutaneous (SC) MM tumors or injected IP after development of human MMs peritoneally. Other mice received DOX intravenously (IV) via tail vein injections. In comparison to DOX alone, APMS-DOX enhanced intracellular uptake of DOX, MM death and expression of GADD34 and TP73. In the SC MM model, 3× weekly SC injections of APMS-DOX or DOX alone significantly inhibited tumor volumes, and systemic DOX administration was lethal. In mice developing IP MMs, significant (p < 0.05) inhibition of mesenteric tumor numbers, weight and volume was achieved using IP administration of APMS-DOX at one-third the DOX concentration required after IP injections of DOX alone. These results suggest APMS are efficacious for the localized delivery of lower effective DOX concentrations in MM and represent a novel means of treating intracavitary tumors.
International Journal of Cancer 07/2011; 129(1):233-44. · 5.44 Impact Factor
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ABSTRACT: Inflammation and lung remodeling are hallmarks of asbestos-induced fibrosis, but the molecular mechanisms that control these events are unclear. Using laser capture microdissection (LCM) of distal bronchioles in a murine asbestos inhalation model, we show that osteopontin (OPN) is up-regulated by bronchiolar epithelial cells after chrysotile asbestos exposures. In contrast to OPN wild-type mice (OPN(+/+)) inhaling asbestos, OPN null mice (OPN(-/-)) exposed to asbestos showed less eosinophilia in bronchoalveolar lavage fluids, diminished lung inflammation, and decreased mucin production. Bronchoalveolar lavage fluid concentrations of inflammatory cytokines (IL-1β, IL-4, IL-6, IL-12 subunit p40, MIP1α, MIP1β, and eotaxin) also were significantly less in asbestos-exposed OPN(-/-) mice. Microarrays performed on lung tissues from asbestos-exposed OPN(+/+) and OPN(-/-) mice showed that OPN modulated the expression of a number of genes (Col1a2, Timp1, Tnc, Eln, and Col3a1) linked to fibrosis via initiation and cross talk between IL-1β and epidermal growth factor receptor-related signaling pathways. Novel targets of OPN identified include genes involved in cell signaling, immune system/defense, extracellular matrix remodeling, and cell cycle regulation. Although it is unclear whether the present findings are specific to chrysotile asbestos or would be observed after inhalation of other fibers in general, these results highlight new potential mechanisms and therapeutic targets for asbestosis and other diseases (asthma, smoking-related interstitial lung diseases) linked to OPN overexpression.
American Journal Of Pathology 05/2011; 178(5):1975-85. · 4.89 Impact Factor
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Small 11/2010; 6(23):2678-82. · 8.35 Impact Factor
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Jedd M Hillegass,
Arti Shukla,
Sherrill A Lathrop,
Maximilian B MacPherson,
Stacie L Beuschel, Kelly J Butnor,
Joseph R Testa,
Harvey I Pass,
Michele Carbone,
Chad Steele,
Brooke T Mossman
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ABSTRACT: Asbestos fibers cause chronic inflammation that may be critical to the development of malignant mesothelioma (MM). Two human MM cell lines (Hmeso, PPM Mill) were used in a SCID mouse xenograft model to assess time-dependent patterns of inflammation and tumor formation. After intraperitoneal (IP) injection of MM cells, mice were euthanized at 7, 14, and 30 days, and peritoneal lavage fluid (PLF) was examined for immune cell profiles and human and mouse cytokines. Increases in human MM-derived IL-6, IL-8, bFGF, and VEGF were observed in mice at 7 days postinjection of either MM line, and a striking neutrophilia was observed at all time points. Free-floating tumor spheroids developed in mice at 14 days, and both spheroids and adherent MM tumor masses occurred in all mice at 30 days. Results suggest that inflammation and cytokine production precede and may be critical to the development of MMs.
Annals of the New York Academy of Sciences 08/2010; 1203:7-14. · 3.15 Impact Factor
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ABSTRACT: Tracheobronchial amyloidosis is a rare disorder of unknown cause associated with the extracellular deposition of amyloid protein in a characteristic spatial structure of β-sheet fibrils assembled into bundles. We present a case that represents the nodular form of tracheobronchial amyloidosis, which is the least common form of pulmonary amyloidosis with less than 20 cases reported so far. Patients with tracheobronchial amyloidosis may present with symptoms of dyspnea, localized wheezing, cough, hemoptysis, or recurrent pneumonias. The mainstay of the therapy is debridement of the symptomatic luminal obstruction with neodymium-doped yttrium aluminium garnet laser therapy. Other treatment strategies include airway stenting, external beam radiation therapy, bypass tracheostomy, or open surgical resection.
Journal of bronchology & interventional pulmonology. 07/2010; 17(3):248-52.
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ABSTRACT: Little is known about the cellular mechanisms contributing to the development and chemoresistance of malignant mesothelioma (MM), an aggressive asbestos-associated tumor. A human mesothelial cell line (LP9/TERT-1) and isolated human pleural mesothelial cells showed rapid and protracted asbestos-induced cAMP response element binding protein (CREB1) phosphorylation, which was inhibited in LP9/TERT-1 cells by small molecule inhibitors of epidermal growth factor receptor phosphorylation and protein kinase A. Asbestos increased expression of several CREB target genes (c-FOS, EGR-1, MKP1, BCL2, and MMP13) and apoptosis, which was enhanced using small interfering CREB. Human MM tissue arrays showed elevated endogenous levels of phosphorylated nuclear CREB1 as compared with reactive mesothelial hyperplasias and normal lung tissue. Significantly increased phosphorylated CREB1 and mRNA levels of BCL2, c-FOS, MMP9, and MMP13 were also observed in MM cells in vitro, which were further augmented after addition of Doxorubicin (Dox). Small interfering CREB inhibited migration of MMs, increased apoptosis by Dox, and decreased BCL2 and BCL-xL expression, suggesting a role for these molecules in CREB-induced MM survival. These data indicate that CREB1 and its target genes are up-regulated in asbestos-exposed human mesothelial cells through an epidermal growth factor receptor/protein kinase A pathway. Since activated CREB1 also is increased endogenously in human MM and modifies migration and resistance to Dox-induced apoptosis, inhibition of CREB1 may be a new strategy for MM therapy.
American Journal Of Pathology 10/2009; 175(5):2197-206. · 4.89 Impact Factor
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Kelly J Butnor,
Mary Beth Beasley,
Philip T Cagle,
Steven M Grunberg,
Feng-Ming Kong,
Alberto Marchevsky,
Nader T Okby,
Victor L Roggli,
Saul Suster,
Henry D Tazelaar,
William D Travis
Archives of pathology & laboratory medicine 10/2009; 133(10):1552-9. · 2.58 Impact Factor
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Annals of Occupational Hygiene 02/2009; 53(2):191; author reply 192-3. · 1.95 Impact Factor
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ABSTRACT: Associations between air pollution and morbidity/mortality from cardiovascular disease are recognized in epidemiologic and clinical studies, but the mechanisms by which inhaled fibers or particles mediate the exacerbation of atherosclerosis are unclear.
To determine whether lung inflammation after inhalation of a well-characterized pathogenic particulate, chrysotile asbestos, is directly linked to exacerbation of atherosclerosis and the mechanisms involved, we exposed apolipoprotein E-deficient (ApoE(-/-)) mice and ApoE(-/-) mice crossed with CD4(-/-) mice to ambient air, NIEHS (National Institute of Environmental Health Sciences) reference sample of chrysotile asbestos, or fine titanium dioxide (TiO(2)), a nonpathogenic control particle, for 3, 9, or 30 days.
ApoE(-/-) mice exposed to inhaled asbestos fibers had approximately 3-fold larger atherosclerotic lesions than did TiO(2)-exposed ApoE(-/-) mice or asbestos-exposed ApoE(-/-)/CD4(-/-) double-knockout (DKO) mice. Lung inflammation and the magnitude of lung fibrosis assessed histologically were similar in asbestos-exposed ApoE(-/-) and DKO mice. Monocyte chemoattractant protein-1 (MCP-1) levels were increased in bronchoalveolar lavage fluid and plasma, and plasma concentrations correlated with lesion size (p < 0.04) in asbestos-exposed ApoE(-/-) mice. At 9 days, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), transcription factors linked to inflammation and found in the promoter region of the MCP-1 gene, were increased in aortas of asbestos-exposed ApoE(-/-) but not DKO mice.
Our findings show that the degree of lung inflammation and fibrosis does not correlate directly with cardiovascular effects of inhaled asbestos fibers and support a critical role of CD4(+) T cells in linking fiber-induced pulmonary signaling to consequent activation of AP-1- and NF-kappaB-regulated genes in atherogenesis.
Environmental Health Perspectives 10/2008; 116(9):1218-25. · 7.04 Impact Factor
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Kelly J Butnor
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ABSTRACT: Given the magnitude of the therapeutic and prognostic implications, it is critical that pathologists diagnose lung cancer accurately. This can sometimes be a formidable challenge, as a number of benign entities mimic lung carcinoma and vice versa.
To present strategies for recognizing benign entities likely to be confused with lung carcinoma, malignancies of the lung prone to misinterpretation as benign, and commonly misclassified pulmonary neoplasms.
The medical literature and experience from consultative and surgical practice.
In addition to understanding the clinical context in which a lung biopsy is procured and the radiographic findings, appreciating the histologic distribution of disease and what, if any, pathologic features are present in the background can go a long way toward averting a misdiagnosis of lung cancer. Recognizing the limitations posed by small samples and communicating clearly to clinicians the level of diagnostic uncertainty are equally as important for establishing an accurate diagnosis of lung cancer.
Archives of pathology & laboratory medicine 08/2008; 132(7):1118-32. · 2.58 Impact Factor
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ABSTRACT: To analyze the immunohistochemical expression of uroplakin (URO) in pleural malignant mesothelioma (PMM).
We analyzed URO expression in PMM using similar immunohistochemical techniques at 2 separate institutions. At an antibody dilution of 1:10, 0/5 PMMs were immunoreactive for URO. At 1:8, diffuse weak cytoplasmic staining was seen in all 38 PMMs tested, but no membrane staining was observed. Adjacent nontumor tissue and positive control tissue showed cytoplasmic staining of equivalent intensity. Similar staining results were observed in 27 PMMs at a 1:5 dilution.
At an antibody dilution for which positive and negative control tissues stain appropriately, PMM does not stain for URO. At higher antibody concentrations, PMM exhibits nonspecific cytoplasmic staining. We assert that URO is not a useful immunohistochemical marker for the detection of PMM. Further studies addressing whether URO is overexpressed at the mRNA level in PMM are warranted.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 08/2008; 16(4):326-8. · 1.63 Impact Factor
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ABSTRACT: The effect of lung irradiation on subsequent inflammatory or fibrotic lung injuries remains poorly understood. We postulated that irradiation and bone marrow transplantation might impact the development and progression of lung remodeling resulting from asbestos inhalation. Our objective was to determine whether irradiation and bone marrow transplantation affected inflammation and fibrosis associated with inhaled asbestos exposure. Inflammation, cytokine production, and fibrosis were assessed in lungs of naïve and sex-mismatched chimeric mice exposed to asbestos for 3, 9, or 40 days. Potential engraftment of donor-derived cells in recipient lungs was examined by fluorescence in situ hybridization and immunohistochemistry. Compared with asbestos-exposed naïve (nonchimeric) mice, chimeric mice exposed to asbestos for 3, 9, or 40 days demonstrated significant abrogation of acute increases in asbestos-associated inflammatory mediators and fibrosis. Donor-derived cells trafficked to lung but did not significantly engraft as phenotypic lung cells. Irradiation and bone marrow transplantation alters inflammatory and fibrotic responses to asbestos, likely through modulation of soluble inflammatory mediators.
American Journal of Respiratory Cell and Molecular Biology 02/2008; 38(1):16-25. · 5.13 Impact Factor
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ABSTRACT: Visceral pleural invasion (VPI) increases the T category of non-small cell lung carcinomas (NSCLCs) that otherwise only meet T1 criteria to T2. The American Joint Committee on Cancer provides no guidelines on what constitutes VPI. Penetration beyond the visceral pleural elastic layer (VPEL) has been proposed as the minimum criterion but is not internationally accepted. The purposes of this study were to elucidate current international practices regarding assessment of VPI and identify histologic features pathologists consider necessary for VPI. We examined responses to an online quiz consisting of 15 NSCLCs adjacent to or involving the visceral pleura. Of 103 participants from 22 countries, 84.5% were in academic practice; 42.7% had a subspecialty interest in pulmonary pathology. Interobserver percentage agreement about whether VPI was present, absent, or indeterminate ranged from 36.9% to 93.2% (mean, 73.0%). The K for participants for all quiz cases was 0.35. There was considerable diagnostic variability in cases with extensive pleural elastosis and when tumor cells were intermingled with the VPEL. It seems that the majority of participants consider penetration of the VPEL necessary and also sufficient to categorize VPI as present. However, the formation of internationally recognized guidelines for assessing VPI by NSCLC is likely to improve diagnostic consensus.
American Journal of Clinical Pathology 11/2007; 128(4):638-47. · 2.60 Impact Factor
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ABSTRACT: As the number of long-term cancer survivors increases, secondary malignancies are becoming a greater clinical issue. Although some of these malignancies may be related to common environmental exposures, a significant number are considered to be therapy-related. Pleural malignant mesothelioma is a neoplasm that may be related to asbestos exposure or radiation exposure. Previous reports of pleural mesothelioma as a second malignancy have tended to follow radiotherapy for extra-thoracic malignancies such as Hodgkin's disease, breast cancer and Wilms' tumor. We report the case of a 66-year-old woman with no prior asbestos exposure who developed pleural mesothelioma 17 years after pneumonectomy and adjuvant radiation therapy for non-small cell lung cancer. Opacification of the lung field from prior therapy made determination of the diagnosis more challenging. Secondary malignancies such as mesothelioma should be considered in patients who develop unexplained symptoms even long after treatment of a primary tumor.
Lung Cancer 10/2007; 57(3):410-3. · 3.43 Impact Factor
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ABSTRACT: The mechanical dysfunction accompanying parenchymal diseases such as pulmonary fibrosis and emphysema may follow a different course from the progression of the underlying microscopic pathophysiology itself, particularly in the early stages. It is tempting to speculate that this may reflect the geographical nature of lung pathology. However, merely ascribing mechanical dysfunction of the parenchyma to the vagaries of lesional organization is unhelpful without some understanding of how the two are linked.
We attempt to forge such a link through a concept known as percolation, which has been invoked to account for numerous natural processes involving transmission of events across complex networks.
We numerically determined the bulk stiffness (corresponding to the inverse of lung compliance) of a network of springs representing the lung parenchyma. We simulated the development of fibrosis by randomly stiffening individual springs in the network, and the development of emphysema by preferentially cutting springs under the greatest tension.
When the number of stiff springs was increased to the point that they suddenly became connected across the network, the model developed a sharp increase in its bulk modulus. Conversely, when the cut springs became sufficiently numerous, the elasticity of the network fell to zero. These two conditions represent percolation thresholds that we show are mirrored structurally in both tissue pathology and macroscopic computed tomography images of human idiopathic fibrosis and emphysema.
The concept of percolation may explain why the development of symptoms related to lung function and the development of parenchymal pathology often do not progress together.
American Journal of Respiratory and Critical Care Medicine 10/2007; 176(6):617-23. · 11.08 Impact Factor
