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Puja Kachroo,
Peter S Pak,
Harpavan S Sandha,
Catherine Lee,
David Elashoff,
Scott D Nelson,
Bartosz Chmielowski,
Michael T Selch,
Robert B Cameron,
E Carmack Holmes,
Fritz C Eilber, Jay M Lee
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ABSTRACT: Primary chest wall sarcomas are rare mesenchymal tumors and their mainstay of therapy is wide surgical resection. We report our single-institution, multidisciplinary experience with full-thickness resection for primary chest wall sarcomas.
A retrospective review of our prospectively maintained databases revealed that 51 patients were referred for primary chest wall sarcomas from 1990 to 2009.
All patients required resections that included rib and/or sternum. Twenty-nine patients (57%) had extended resections beyond the chest wall. Forty-two patients (82%) required prosthetic reconstruction and 17 patients (33%) had muscle flap coverage. Overall, 51% (26/51) of patients received neoadjuvant therapy. Seventy-three percent (11/15) of high-grade soft tissue sarcomas, 77% (10/13) of high-risk bony sarcomas, and 67% (4/6) of desmoid tumors were treated with induction therapy. Negative margins were obtained in 46 patients (90%). There were no perioperative mortalities. Eight patients (16%) experienced complications. Local recurrence and metastasis was detected in 14 and 23%. Five-year overall and disease-free survivals were 66% and 47%, respectively. Favorable prognostic variables for survival included age ≤50 years, tumor volume ≤200 cm, desmoid tumor, bony tumor, chondrosarcoma, and low-grade soft tissue sarcoma.
We report our multidisciplinary experience with primary chest wall sarcomas that included induction therapy in the majority of high-risk soft tissue and bony sarcomas and desmoid tumors. Despite aggressive preoperative treatments, acceptable surgical results with low morbidity and mortality can be achieved. Neoadjuvant systemic therapy may reduce local and distant recurrence and improve overall survival.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2012; 7(3):552-8. · 4.55 Impact Factor
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ABSTRACT: Sarcomas are rare mesenchymal malignancies. Accurate preoperative diagnosis is a prerequisite in considering investigational or institutional management algorithms that include neoadjuvant treatment. We reviewed our experience using core needle biopsy for chest wall sarcomas.
A retrospective review of our sarcoma databases revealed that 40 core needle biopsies and 35 tumor resections were performed in 34 patients, with chest wall musculoskeletal tumors, referred to the University of California, Los Angeles from 1991 to 2010. Primary, metastatic, or recurrent sarcomas involving the sternum, ribs, and soft tissues of the chest wall were evaluated for (1) adequacy of tissue from image-guided core needle biopsies and (2) accuracy in determining malignancy, histological subtype, and sarcoma grade.
Twenty-eight of the 40 needle biopsy samples (70%) were adequate for histopathological analysis. Forty-two percent of nondiagnostic findings occurred due to insufficient tissue, whereas the remainder had sufficient tissue, but the pathologist was unable to determine specific histology. Excluding the nondiagnostic samples, the accuracy in determining malignancy, histological subtype, and grade in sarcomas was 100, 92, and 87%, respectively. The sensitivity and specificity of determining malignancy and high-grade sarcomas were 100, 100, 77, and 100%, respectively. There were no complications from the image-guided biopsies.
We demonstrated that image-guided core needle biopsy when performed and reviewed by experienced radiologists and musculoskeletal pathologists is a safe and accurate diagnostic technique for chest wall sarcomas. Core needle biopsy should be considered in the multidisciplinary approach to chest wall musculoskeletal tumors, especially when induction therapy is considered.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2011; 7(1):151-6. · 4.55 Impact Factor
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ABSTRACT: Despite advances in treatments, lung cancer has been the leading cause of cancer-related deaths in the United States for the past several decades. Recent findings from the National Lung Screening Trial reveal that low-dose helical computed tomography (CT) scan screening of high-risk individuals reduces lung cancer mortality. This suggests that early detection is of key importance to improving patient outcome. However, of those screened with CT scans, 25% had positive scans that require further follow-up studies which often involve more radiation exposure and invasive tests to reduce false positive results. The purpose of this study was to identify candidate plasma biomarkers to aid in diagnosis of lung cancer in at-risk individuals. We found increased expression of the CXC chemokine connective tissue-activating peptide (CTAP)-III from plasma specimens of lung cancer patients compared to at-risk control subjects. Identification of the peptide was confirmed by the addition of an anti-NAP-2 antibody that recognizes CTAP-III and NAP-2. We also quantified and verified the increased levels of plasma CTAP-III with ELISA in patients with lung cancer (mean ± SD, 1859 ± 1219 ng/mL) compared to controls (698 ± 434 ng/mL; P<0.001). Our findings demonstrate elevated plasma levels of CTAP-III occur in lung cancer patients. Further studies are required to determine if this chemokine could be utilized in a blood-based biomarker panel for the diagnosis of lung cancer.
American Journal of Translational Research 05/2011; 3(3):226-33.
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ABSTRACT: Solitary fibrous tumors of the pleura are rare neoplasms with both benign and malignant behaviors that are not reliably predicted by histologic findings. We report the case of a 55-year-old woman with recurrent pneumonias whose left mainstem bronchus was occluded by a 2.1- x 1.4-cm endobronchial mass that extended extraluminally into the subcarina. The mass was tissue diagnosed to be a solitary fibrous tumor preoperatively, and was completely resected by sleeve resection of the left mainstem bronchus with lung preservation. This report describes the challenging surgical management of an infrequently encountered tumor in a unique location.
The Annals of thoracic surgery 08/2010; 90(2):659-61. · 3.74 Impact Factor
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ABSTRACT: While genetic changes are critical for the malignant transformation of epithelial cells, the microenvironment in which the
cells reside also governs carcinogenesis. Most tumors arise within a cellular microenvironment characterized by suppressed
host immunity, dysregulated inflammation, and increased production of cellular growth and survival factors that induce angiogenesis
and inhibit apoptosis. The studies highlighted in this chapter indicate that the lung tumor and its microenvironment interact,
together informing the process of carcinogenesis. Understanding the molecular mechanisms driving the contributions of the
tumor microenvironment to lung carcinogenesis may afford us the opportunity to develop new drugs that target these reversible
nonmutational events in the prevention and treatment of lung cancer. Findings from recent microenvironment-related clinical
studies have implications for understanding the immunopathobiology of lung cancer, for targeting surgery and adjuvant therapy,
and for designing future trials of adjuvant therapy. If the field is to progress and promising leads in the laboratory are
to translate into anticancer therapeutics, future trials targeting the tumor microenvironment must incorporate improved patient
risk assessment and selection, in addition to the continued evaluation of combination therapies using the optimal biological
dose of each compound being tested. Appropriately targeting the tumor microenvironment in a highly selected patient population
is a newly emerging strategy that holds unique potential for advancing the current state of lung cancer prevention and treatment.
KeywordsTumor microenvironment-NSCLC prognosis-Mast cells-Macrophage-Dendritic cells-Ectopic lymph nodes-T regulatory cells-MMP-COX-2-PGE2-PPARγ-15-PGDH-Inflammation-EMT-NF-κB-HGF-c-MET-Angiogenesis-Molecular signatures
03/2010: pages 27-69;
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Felicita Baratelli, Jay M Lee,
Saswati Hazra,
Ying Lin,
Tonya C Walser,
Dorthe Schaue,
Peter S Pak,
David Elashoff,
Karen Reckamp,
Ling Zhang,
Michael C Fishbein,
Sherven Sharma,
Steven M Dubinett
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ABSTRACT: CD4(+)CD25(bright) regulatory T cells (T(reg)) play an important role in cancer-mediated immunosuppression. We and others have previously shown that prostaglandin E2 (PGE(2)) and transforming growth factor beta (TGF-beta) induce CD4(+)CD25(bright)FOXP3(+)T(reg). Based on these studies, we investigated the requirement for PGE(2) in Treg induction by TGF-beta. TGF-beta stimulation of human CD4(+) T cells induced COX-2-dependent production of PGE(2). PGE(2)-neutralizing antibody treatment significantly reduced the suppressive function of TGF-beta-induced T(reg) (TGF-beta-T(reg)) in vitro. TGF-beta concentration measured in the plasma of non-small cell lung cancer (NSCLC) patients directly correlated with the frequency of circulating CD4(+)CD25(bright)FOXP3(+)T cells. Flow cytometry analysis showed increased FOXP3 expression in circulating CD4(+)CD25(+)HLA-DR- cells of lung cancer patients compared to control subjects. Immunohistochemical analysis revealed co-expression of TGF-beta, COX-2, and FOXP3 in serial sections from resected lung tumor tissues. All together these observations suggest interplay between TGF-beta and COX-2 in the induction of T(reg) activities. Interrupting TGF-beta and PGE(2) signaling may be important in therapeutic interventions that aim to limit T(reg)function in lung cancer.
American Journal of Translational Research 01/2010; 2(4):356-67.
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Jane Yanagawa,
Tonya C Walser,
Li X Zhu,
Longsheng Hong,
Michael C Fishbein,
Vei Mah,
David Chia,
Lee Goodglick,
David A Elashoff,
Jie Luo,
Clara E Magyar,
Mariam Dohadwala, Jay M Lee,
Maie A St John,
Robert M Strieter,
Sherven Sharma,
Steven M Dubinett
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ABSTRACT: As a transcriptional repressor of E-cadherin, Snail has predominantly been associated with epithelial-mesenchymal transition, invasion, and metastasis. However, other important Snail-dependent malignant phenotypes have not been fully explored. Here, we investigate the contributions of Snail to the progression of non-small cell lung cancer (NSCLC).
Immunohistochemistry was done to quantify and localize Snail in human lung cancer tissues, and tissue microarray analysis was used to correlate these findings with survival. NSCLC cell lines gene-modified to stably overexpress Snail were evaluated in vivo in two severe combined immunodeficiency murine tumor models. Differential gene expression between Snail-overexpressing and control cell lines was evaluated using gene expression microarray analysis.
Snail is upregulated in human NSCLC tissue, and high levels of Snail expression correlate with decreased survival (P < 0.026). In a heterotopic model, mice bearing Snail-overexpressing tumors developed increased primary tumor burden (P = 0.008). In an orthotopic model, mice bearing Snail-overexpressing tumors also showed a trend toward increased metastases. In addition, Snail overexpression led to increased angiogenesis in primary tumors as measured by MECA-32 (P < 0.05) positivity and CXCL8 (P = 0.002) and CXCL5 (P = 0.0003) concentrations in tumor homogenates. Demonstrating the importance of these proangiogenic chemokines, the Snail-mediated increase in tumor burden was abrogated with CXCR2 blockade. Gene expression analysis also revealed Snail-associated differential gene expression with the potential to affect angiogenesis and diverse aspects of lung cancer progression.
Snail upregulation plays a role in human NSCLC by promoting tumor progression mediated by CXCR2 ligands.
Clinical Cancer Research 11/2009; 15(22):6820-9. · 7.74 Impact Factor
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ABSTRACT: Progression and metastasis of cancer proceeds in the context of a host response that includes interactions with immune cells
that can both attenuate and paradoxically promote the process of metastasis. Growing evidence demonstrating the role of the
inflammatory response in carcinogenesis is shedding light on a functional relationship between the host immune system and
the malignant neoplasm. The interaction between neoplasm and the immune system can be described with the concepts of (1) cancer
immunosurveillance, (2) cancer immunoediting, (3) complicity of the host cellular networks in lung tumorigenesis, and (4)
tumor-mediated immunosuppression. Understanding the molecular mechanisms involved in inflammation and lung carcinogenesis
provides insight for new drug development that target reversible, non-mutational events in the chemoprevention and treatment
of lung cancer.
09/2009: pages 111-134;
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ABSTRACT: The role of surgical resection in patients with metastatic thyroid cancer is not clearly defined. Reported is a case of concurrent thyroid metastases to the lungs and sternum treated with total sternectomy followed by radioiodine therapy. A comprehensive review of the literature was also performed to evaluate the characteristics of reported cases of sternal thyroid cancer metastases treated with surgical resection. Overall, we demonstrate that radical resection of sternal metastases can be performed safely even in patients with poor prognosis to achieve palliation and potentiation of radioiodine therapy for concurrent metastases.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2009; 4(8):1022-5. · 4.55 Impact Factor
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ABSTRACT: Worldwide over 1 million people die due to lung cancer each year. It is estimated that cigarette smoking explains almost 90% of lung cancer risk in men and 70 to 80% in women. Clinically evident lung cancers have multiple genetic and epigenetic abnormalities. These abnormalities may result in activation of oncogenes and inactivation of tumor-suppressor genes. Chronic inflammation, which is known to promote cancer, may result both from smoking and from genetic abnormalities. These mediators in turn may be responsible for increased macrophage recruitment, delayed neutrophil clearance, and increase in reactive oxygen species (ROS). Thus, the pulmonary environment presents a unique milieu in which lung carcinogenesis proceeds in complicity with the host cellular network. The pulmonary diseases that are associated with the greatest risk for lung cancer are characterized by abundant and deregulated inflammation. Pulmonary disorders such as chronic obstructive pulmonary disease (COPD)/emphysema are characterized by profound abnormalities in inflammatory and fibrotic pathways. The cytokines and growth factors aberrantly produced in COPD and the developing tumor microenvironment have been found to have deleterious properties that simultaneously pave the way for both epithelial-mesenchymal transition (EMT) and destruction of specific host cell-mediated immune responses. Full definition of these pathways will afford the opportunity to intervene in specific inflammatory events mediating lung tumorigenesis and resistance to therapy.
Proceedings of the American Thoracic Society 01/2009; 5(8):811-5.
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ABSTRACT: Lung carcinogenesis is a complex process involving the acquisition of genetic mutations that confer cancer development and the malignant phenotype, and is critically linked to apoptosis resistance, unregulated proliferation, invasion, metastasis, and angiogenesis. Epithelial mesenchymal transition (EMT) in cancer is an unregulated process in a host environment with deregulated inflammatory response that impairs cell-mediated immunity and permits cancer progression. Given the immunosuppressive tumor environment, strategies to reverse these events by stimulating host immune responses are an important area of investigation. Cyclooxygenase 2 (COX-2) and its downstream signaling pathways are potential targets for lung cancer chemoprevention and therapy. Clinical trials are underway to evaluate COX-2 inhibitors as adjuvants to chemotherapy in patients with lung cancer and to determine efficacy in prevention of bronchogenic carcinoma. The understanding of molecular mechanisms involved in inflammation and lung carcinogenesis provide insight for new drug development that target reversible, non-mutational events in the chemoprevention and treatment of lung cancer.
Critical Reviews in Oncology/Hematology 07/2008; 66(3):208-17. · 4.41 Impact Factor
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04/2008: pages 334 - 351; , ISBN: 9780470696330
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ABSTRACT: Inflammation is an important contributor to lung tumor development and progression. In addition, inflammatory signaling may promote epithelial to mesenchymal transition, development of aggressive metastatic tumor phenotypes, and play a role in resistance to targeted therapies. New insights in inflammatory signaling have led to the evaluation of combination therapies that target these specific pathways. In addition to developing the optimal combination of targeted agents, biomarker-based selection of patients who will likely benefit will be critical to the success of this strategy. Here we focus on the potential contribution of inflammatory mediator-induced resistance to epidermal growth factor receptor tyrosine kinase inhibitors.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2008; 3(2):107-10. · 4.55 Impact Factor
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Felicita Baratelli,
Hiroko Takedatsu,
Saswati Hazra,
Katherine Peebles,
Jie Luo,
Pam S Kurimoto,
Gang Zeng,
Raj K Batra,
Sherven Sharma,
Steven M Dubinett, Jay M Lee
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ABSTRACT: Our previous studies have demonstrated that transduction of human dendritic cells (DC) with adenovirus encoding secondary lymphoid chemokine, CCL21, led to secretion of biologically active CCL21 without altering DC phenotype or viability. In addition, intratumoral injections of CCL21-transduced DC into established murine lung tumors resulted in complete regression and protective anti-tumor immunity. These results have provided the rationale to generate a clinical grade adenoviral vector encoding CCL-21 for ex vivo transduction of human DC in order to assess intratumoral administration in late stage human lung cancer.
In the current study, human monocyte-derived DC were differentiated by exposure to GM-CSF and IL-4 from cryopreserved mononuclear cells obtained from healthy volunteers. Transduction with clinical grade adenoviral vector encoding CCL21 (1167 viral particles per cell) resulted in secretion of CCL21 protein.
CCL21 protein production from transduced DC was detected in supernatants (24-72 hours, 3.5-6.7 ng/4-5 x 10(6) cells). DC transduced with the clinical grade adenoviral vector were > 88% viable (n = 16), conserved their phenotype and maintained integral biological activities including dextran uptake, production of immunostimulatory cytokines/chemokines and antigen presentation. Furthermore, supernatant from CCL21-DC induced the chemotaxis of T2 cells in vitro.
Viable and biologically active clinical grade CCL21 gene-modified DC can be generated from cryopreserved PBMC.
Journal of Translational Medicine 01/2008; 6:38. · 3.41 Impact Factor
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Katherine A Peebles, Jay M Lee,
Jenny T Mao,
Saswati Hazra,
Karen L Reckamp,
Kostyantyn Krysan,
Mariam Dohadwala,
Eileen L Heinrich,
Tonya C Walser,
Xiaoyan Cui,
Felicita E Baratelli,
Edward Garon,
Sherven Sharma,
Steven M Dubinett
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ABSTRACT: Lung carcinogenesis is a complex process requiring the acquisition of genetic mutations that confer the malignant phenotype as well as epigenetic alterations that may be manipulated in the course of therapy. Inflammatory signals in the lung cancer microenvironment can promote apoptosis resistance, proliferation, invasion, metastasis, and secretion of proangiogenic and immunosuppressive factors. Here, we discuss several prototypical inflammatory mediators controlling the malignant phenotype in lung cancer. Investigation into the detailed molecular mechanisms underlying the tumor-promoting effects of inflammation in lung cancer has revealed novel potential drug targets. Cytokines, growth factors and small-molecule inflammatory mediators released in the developing tumor microenvironment pave the way for epithelial-mesenchymal transition, the shift from a polarized, epithelial phenotype to a highly motile mesenchymal phenotype that becomes dysregulated during tumor invasion. Inflammatory mediators within the tumor microenvironment are derived from neoplastic cells as well as stromal and inflammatory cells; thus, lung cancer develops in a host environment in which the deregulated inflammatory response promotes tumor progression. Inflammation-related metabolic and catabolic enzymes (prostaglandin E(2) synthase, prostaglandin I(2) synthase and 15-hydroxyprostaglandin dehydrogenase), cell-surface receptors (E-type prostaglandin receptors) and transcription factors (ZEB1, SNAIL, PPARs, STATs and NF-kappaB) are differentially expressed in lung cancer cells compared with normal lung epithelial cells and, thus, may contribute to tumor initiation and progression. These newly discovered molecular mechanisms in the pathogenesis of lung cancer provide novel opportunities for targeted therapy and prevention in lung cancer.
Expert Review of Anti-infective Therapy 11/2007; 7(10):1405-21. · 2.65 Impact Factor
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ABSTRACT: The report by Tsubochi and colleagues adds to the growing evidence indicating that tumor cyclo-oxygenase (Cox)-2 has a multifaceted role in conferring the malignant phenotype of non-small-cell lung cancer (NSCLC), and provides insight into the use of markers to provide prognostic information. Cox-2 has been implicated in apoptosis resistance, angiogenesis, decreased host immunity and enhanced invasion and metastasis, and, thus, has a critical involvement in carcinogenesis. This study, as well as others, has contributed to providing an insight into opportunities for targeted therapies in NSCLC. Cox-2 is one of the novel targets being studied for lung cancer therapy and chemoprevention.
Future Oncology 05/2007; 3(2):149-53. · 3.16 Impact Factor
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ABSTRACT: Chemokines (ie, chemoattractant cytokines) are a family of small secreted molecules that mediate leukocyte migration. It is becoming increasingly more evident that chemokines play an integral role in the initiation of a specific immune response. With respect to cancer, chemokines are being studied for both their role in tumor biology and as promising immunotherapy candidates. We review several areas of chemokine importance in tumor immunity and discuss the experimental evidence that is leading to the clinical use of this cytokine family in new treatment approaches for patients with cancer.
The Cancer Journal 16(4):325-35. · 3.26 Impact Factor
