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Islam K.M.M.,984395 Nebraska Medical Center | Jiang X.,984395 Nebraska Medical Center | Anggondowati T.,984395 Nebraska Medical Center | Lin G.,University of Nevada, Reno | And 3 more authors.
Cancer Epidemiology Biomarkers and Prevention

Background: As the population of the United States ages, there will be increasing numbers of lung cancer patients with comorbidities at diagnosis. Comorbid conditions are important factors in both the choice of the lung cancer treatment and outcomes. However, the impact of individual comorbid conditions on patient survival remains unclear. Methods: A population-based cohort study of 5,683 first-time diagnosed lung cancer patients was captured using the Nebraska Cancer Registry (NCR) linked with the Nebraska Hospital Discharge Data (NHDD) between 2005 and 2009. A Cox proportional hazards model was used to analyze the effect of comorbidities on the overall survival of patients stratified by stage and adjusting for age, race, sex, and histologic type. Results: Of these patients, 36.8% of them survived their first year after lung cancer diagnosis, with a median survival of 9.3 months for all stages combined. In this cohort, 26.7% of the patients did not have any comorbidity at diagnosis. The most common comorbid conditions were chronic pulmonary disease (52.5%), diabetes (15.7%), and congestive heart failure (12.9%). The adjusted overall survival of lung cancer patients was negatively associated with the existence of different comorbid conditions such as congestive heart failure, diabetes with complications, moderate or severe liver disease, dementia, renal disease, and cerebrovascular disease, depending on the stage. Conclusions: The presence of comorbid conditions was associated with worse survival. Different comorbid conditions were associated with worse outcomes at different stages. Impact: Future models for predicting lung cancer survival should take individual comorbid conditions into consideration. © 2015 American Association for Cancer Research. Source

Barber N.A.,University of Nebraska Medical Center | Ganti A.K.,VA Nebraska Western Iowa Health Care System
Targeted Oncology

Pulmonary toxicity is rarely seen with most commonly used targeted therapies. The endothelial growth factor receptor (EGFR) small-molecule tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib can cause interstitial lung disease (ILD). BCR-ABL tyrosine kinase inhibitors imatinib and dasatinib can cause pleural effusions. Infusion-related bronchospasm is common with the monoclonal antibodies to EGFR cetuximab and panitumumab, and case reports of bronchiolitis and pulmonary fibrosis have been described. Up to one-sixth of patients taking mammalian target of rapamycin (mTOR) inhibitors get a reversible interstitial pneumonitis. Bevacizumab, the monoclonal antibody to vascular endothelial growth factor (VEGF), has been associated with hemoptysis and pulmonary embolism particularly in patients with squamous cell lung cancer. Infusion-related bronchospasms, acute respiratory distress syndrome (ARDS), and interstitial pneumonitis can be seen with the anti-lymphocyte monoclonal antibodies rituximab, ofatumumab, and alemtuzumab. While most pulmonary toxicities from these therapies are mild and resolve promptly with dose reduction or discontinuation, it is important for the clinician to recognize these potential toxicities when faced with treatment-related complications. Discerning these pulmonary adverse effects may help in making decisions on diagnostic testing and therapy, particularly for those with pulmonary and cardiovascular co-morbidities. © Springer-Verlag (outside the USA) 2011. Source

Shivaswamy V.,VA Nebraska Western Iowa Health Care System | Shivaswamy V.,University of Nebraska Medical Center | Bennett R.G.,VA Nebraska Western Iowa Health Care System | Clure C.C.,VA Nebraska Western Iowa Health Care System | And 2 more authors.

Background Immunosuppressants are an important cause of posttransplantation diabetes mellitus. We have shown that tacrolimus and sirolimus induce hyperglycemia and hyperinsulinemia in normal rats. We hypothesized that metformin, given concurrently with tacrolimus and/or sirolimus, prevents disturbances in glucose and insulin metabolism. METHODS: Eight groups (n=6) of normal Sprague-Dawley rats were studied: four groups received tacrolimus, sirolimus, tacrolimus/sirolimus, or control for 14 days, and four more groups received similar treatments along with metformin. Daily glucoses were measured. All rats were administered an oral glucose challenge before sacrifice. Pancreata were analyzed by terminal deoxynucleotide tranferase-mediated dUTP nick-end labeling staining and immunohistochemistry. RESULTS: Tacrolimus, sirolimus, and tacrolimus/sirolimus impaired glucose tolerance compared to control. Sirolimus and tacrolimus/sirolimus also increased random blood glucose levels. Sirolimus alone resulted in hyperinsulinemia after oral glucose challenge compared to control. In the sirolimus/metformin and tacrolimus/sirolimus/metformin groups, mean daily random glucose was no longer increased, although the response to glucose challenge was still impaired. Metformin decreased pancreatic exocrine and trended to decrease endocrine apoptosis in tacrolimus/sirolimus group and reduced islet insulin content in sirolimus group. CONCLUSIONS: This is the first study to show that metformin can improve immunosuppressant-induced hyperglycemia, when administered concurrently, and reduces exocrine apoptosis (reducing the impact on potential islet progenitor cells). Copyright © 2013 Lippincott Williams & Wilkins. Source

Seshacharyulu P.,University of Nebraska Medical Center | Ponnusamy M.P.,University of Nebraska Medical Center | Haridas D.,University of Nebraska Medical Center | Jain M.,University of Nebraska Medical Center | And 3 more authors.
Expert Opinion on Therapeutic Targets

Introduction: Cancer is a devastating disease; however, several therapeutic advances have recently been made, wherein EGFR and its family members have emerged as useful biomarkers and therapeutic targets. EGFR, a transmembrane glycoprotein is a member of the ERBB receptor tyrosine kinase superfamily. EGFR binds to its cognate ligand EGF, which further induces tyrosine phosphorylation and receptor dimerization with other family members leading to enhanced uncontrolled proliferation. Several anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors have been developed, which has enabled clinicians to identify and treat specific patient cohorts. Areas covered: This review covers the basic mechanism of EGFR activation and the role of EGFR signaling in cancer progression. Furthermore, current developments made toward targeting the EGFR signaling pathway for the treatment of epithelial cancers and a summary of the various anti-EGFR therapeutic agents that are currently in use are also presented in this review. Expert opinion: EGFR signaling is a part of a complex network that has been the target of effective cancer therapies. However, a further understanding of the system is required to develop an effective anticancer regimen. A combination therapy that comprises an anti-EGFR and a chemotherapeutic/chemopreventive agent will exhibit a multi-pronged approach that can be developed into a highly attractive and specific molecular oriented remedy. © 2012 Informa UK, Ltd. Source

Macha M.A.,University of Nebraska Medical Center | Batra S.K.,University of Nebraska Medical Center | Ganti A.K.,VA Nebraska Western Iowa Health Care System | Ganti A.K.,University of Nebraska Medical Center
Cancer Management and Research

Basal cell carcinoma (BCC) is the most common human malignancy. Recent advances in our understanding of the critical biologic pathways implicated in the development and progression of BCC have led to the development of the first molecular targeted therapy for this disease. The hedgehog pathway is mutated in virtually all patients with BCC and recent trials with vismodegib, an inhibitor of this pathway, have shown significant responses. This review will discuss the importance of the hedgehog pathway in the pathogenesis of BCC and describe in detail the pharmacology of vismodegib in relation to its activity in advanced BCC. © 2013 Macha et al, publisher and licensee Dove Medical Press Ltd. Source

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