Bansal N.,Section on Molecular Medicine |
Mims J.,Section on Molecular Medicine |
Olex A.L.,Wake forest University |
Zhao W.,Section on Molecular Medicine |
And 9 more authors.
Antioxidants and Redox Signaling | Year: 2014
Aims: The central issue of resistance to radiation remains a significant challenge in the treatment of cancer despite improvements in treatment modality and emergence of new therapies. To facilitate the identification of molecular factors that elicit protection against ionizing radiation, we developed a matched model of radiation resistance for head and neck squamous cell cancer (HNSCC) and characterized its properties using quantitative mass spectrometry and complementary assays. Results: Functional network analysis of proteomics data identified DNA replication and base excision repair, extracellular matrix-receptor interaction, cell cycle, focal adhesion, and regulation of actin cytoskeleton as significantly up- or downregulated networks in resistant (rSCC-61) HNSCC cells. Upregulated proteins in rSCC-61 included a number of cytokeratins, fatty acid synthase, and antioxidant proteins. In addition, the rSCC-61 cells displayed two unexpected features compared with parental radiation-sensitive SCC-61 cells: (i) rSCC-61 had increased sensitivity to Erlotinib, a small-molecule inhibitor of epidermal growth factor receptor; and (ii) there was evidence of mesenchymal-to-epithelial transition in rSCC-61, confirmed by the expression of protein markers and functional assays (e.g., Vimentin, migration). Innovation: The matched model of radiation resistance presented here shows that multiple signaling and metabolic pathways converge to produce the rSCC-61 phenotype, and this points to the function of the antioxidant system as a major regulator of resistance to ionizing radiation in rSCC-61, a phenomenon further confirmed by analysis of HNSCC tumor samples. Conclusion: The rSCC-61/SCC-61 model provides the opportunity for future investigations of the redox-regulated mechanisms of response to combined radiation and Erlotinib in a preclinical setting. Antioxid. Redox Signal. 21, 221-236. © Mary Ann Liebert, Inc. 2014.
Chaudhary L.N.,Medical College of Wisconsin |
Swisher A.K.,West Virginia University |
Kurian S.,Section of Hematology and Oncology |
Abraham J.,Section of Hematology and Oncology |
Abraham J.,Cleveland Clinic
Journal of Community and Supportive Oncology | Year: 2014
Background Studies have shown that breast cancer treatment can cause an increase in weight. Weight gain during chemotherapy is usually significant and may be associated with poor survival. However, the role of third-generation chemotherapy regimens and weight gain is not well reviewed. Methods We retrospectively analyzed the mean percentage weight change during the first year after breast cancer diagnosis in 246 patients at West Virginia University during September 2007 and October 2010. KruskalWallis test and post hoc pair wise comparisons were used to assess the influence of age, histology, stage, ER/PR/HER2/neu status, menopausal status, and types of therapeutic modalities received on the percentage weight change. Kaplan-Meier method with log-rank test was used to evaluate recurrence-free survival (RFS). Local or distant recurrence and disease progression were events for RFS analysis and disease-free patients were censored at last follow-up. Results Mean weight gain was 0.39% (SD, 0.40) of baseline body weight, 1 year after diagnosis of breast cancer. Premenopausal status was the only factor associated with significant weight gain (+1.67% vs-0.10% for postmenopausal patients; P = .02). Stages ≥ III was associated with significant weight loss (-1.64% for stages III, IV vs +0.85% for stages 0, I, II; P = .02) and a lower RFS at 3 years and 5 years (P < .0001). Higher baseline weight (> 90th percentile) did not have any significant impact on RFS (0.84 vs 0.91; P = .19). There was no significant change in weight relative to other factors. Conclusion Our study in patients receiving third-generation adjuvant chemotherapy regimens did not show any significant change in percentage weight with chemotherapy. Premenopausal status was the only significant factor associated with weight gain. As expected, stage III or higher disease was associated with significant weight loss and lower RFS. ©2014 Frontline Medical Communications.
PubMed | Section of Hematology and Oncology, Wake Forest Baptist Medical Center and Comprehensive Cancer Center
Type: Journal Article | Journal: Clinical lymphoma, myeloma & leukemia | Year: 2016
Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) was developed in an effort to overcome inadequate drug concentrations and compensate for increased drug clearance. The goal of the present study was to examine the risk factors and outcomes of patients with aggressive non-Hodgkin lymphoma (aNHL) treated with DA-EPOCH.We report the data from 136 patients with previously untreated aNHL who received infusional DA-EPOCH chemotherapy with or without rituximab from 2005 to 2013. Overall survival was estimated using Kaplan-Meier methods. Univariate and multivariate logistic regression was used to determine the factors associated with death, progression, or relapse at 2 years.The overall response rate was 82%. The relapse-free survival rate at 1, 3, and 5 years was 68%, 63%, and 52% with 95% confidence intervals (CIs) of 0.59% to 0.85%, 0.54% to 0.70%, and 0.31% to 0.70%, respectively. Patients with T-cell aNHL had an increased risk of death, progression, or relapse (Odds Ratio, 3.5; 95% CI, 1.4-8.8) compared with those with B-cell aNHL. In multivariate analysis, current smoking, disease in the bone marrow, and the number of cycles completed were independent predictors of death and relapse.Our data suggest that EPOCH with or without rituximab is active in both B- and T-cell aNHL. Toxicity did not significantly affect timing of treatment delivery or treatment outcomes. Dose adjustment by hematopoietic nadir similarly had no effect. The effect of smoking during chemotherapy should be evaluated further.
PubMed | Section of Ophthalmology., Section of Hematology and Oncology. and University of Chicago
Type: Journal Article | Journal: Neuro-ophthalmology (Aeolus Press) | Year: 2016
A 56-year-old female with early-stage breast cancer, stage IA grade 1 endometrial cancer, and stage IC grade 1 ovarian cancer developed sudden-onset visual changes and right inferior visual field defect following anastrozole therapy. Examination revealed severe bilateral optic disc swelling and impaired visual acuity. Laboratory work-up was otherwise unremarkable. Anastrozole was discontinued and over the next month, patient had near-complete resolution of swelling in the right eye and improvement in the left eye. This is the only reported case of optic disc swelling following anastrozole therapy.
Ruiz M.,Section of Geriatric Medicine |
Ruiz M.,Louisiana State University Health Sciences Center |
Reske T.,Section of Hematology and Oncology |
Cefalu C.,Section of Geriatric Medicine |
Estrada J.,Louisiana State University Health Sciences Center
American Journal of the Medical Sciences | Year: 2013
OBJECTIVES:: Management of elderly and frail patients with cancer is complex and requires a multidisciplinary approach. This article reviews and discusses the current literature that evaluates the relevance of comprehensive geriatrics assessment (CGA) and other evaluation tools in the detection of this vulnerable patient population. METHODS:: A literature search of articles in English, Spanish and Portuguese was conducted in PubMed through September 2011. RESULTS:: There is lack of detailed information concerning the efficacy, tolerability and toxicity of cancer therapies in senior adults, although the literature indicates that there is a trend toward including elderly patients and their outcome. Recent guidelines advocate a careful patient selection through a CGA. For vulnerable (pre-frail) and frail elderly cancer patients, there is no consensus in relation to selection and type of treatments. CGA has been advocated as the gold standard for evaluation of elderly patients, but thorough evaluation of vulnerable and frail patients has not been undertaken. A tool to evaluate vulnerable elderly patients to predict treatment outcomes is also needed. DISCUSSION:: The adoption of the CGA in oncology practice has been slow because of the difficulties with practicality and objectivity. A shorter reliable tool for rapid and complete assessment is needed. Inclusion of frail elderly patients in treatment trials is recommended. New treatment approaches for frail elderly cancer patients need to be further investigated. Some studies that used serum markers of frailty found that even in the absence of clinical signs, some elderly patients might be already vulnerable. A potential cancer frailty index also needs further investigation. © 2012 Lippincott Williams & Wilkins.
Ma S.-F.,University of Chicago |
Xie L.,University of Illinois at Chicago |
Pino-Yanes M.,Institute Salud Carlos III |
Pino-Yanes M.,Hospital Universitario Nuestra Senora Of Candelaria |
And 18 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2011
The role of thyroid hormone metabolism in clinical outcomes of the critically ill remains unclear. Using preclinical models of acute lung injury (ALI), we assessed the gene and protein expression of type 2 deiodinase (DIO2), a key driver for synthesis of biologically active triiodothyronine, and addressed potential association of DIO2 genetic variants with ALI in a multiethnic cohort.DIO2geneandprotein expression levels in murine lung were validated by microarrays and immunoblotting. Lung injury was assessed by levels of bronchoalveolar lavage protein and leukocytes. Single-nucleotide polymorphisms were genotyped and ALI susceptibility association assessed. Significant increases in both DIO2 gene and D2 protein expression were observed in lung tissues from murine ALI models (LPS- and ventilator-induced lung injury), with expression directly increasing with the extent of lung injury. Mice with reduced levels of DIO2 expression (by silencing RNA) demonstrated reduced thyroxine levels in plasma and increased lung injury (increased bronchoalveolar lavage proteinandleukocytes), suggesting a protective role for DIO2 in ALI. The G (Ala) allele of the Thr92Ala coding single-nucleotide polymorphism (rs225014) was protective in severe sepsis and severe sepsis-associated ALI after adjustments for age, sex, and genetic ancestry in a logistic regression model in European Americans. Our studies indicate that DIO2 is a novel ALI candidate gene, the non-synonymous Thr92Ala coding variant of which confers ALI protection. Increased DIO2 expression may dampen the ALI inflammatory response, thereby strengthening the premise that thyroid hormone metabolismis intimately linked to the integrated response to inflammatory injury in critically ill patients.
Nabhan C.,Section of Hematology and Oncology |
Ollberding N.J.,Cincinnati Childrens Hospital Medical Center |
Villines D.,University of Illinois at Chicago |
Chiu B.C.-H.,University of Chicago |
And 5 more authors.
Leukemia and Lymphoma | Year: 2014
We conducted a systematic review of grade 3/4 adverse events (AEs) reported in prospective trials enrolling patients with follicular lymphoma (FL) and mantle cell lymphoma (MCL) receiving maintenance rituximab (MR). Random-effects models were used to calculate summary estimates and 95% confidence intervals for the proportion of AEs occurring during MR. Differences by induction program, histology, setting and MR schedule were examined by stratified analyses and univariate random-effects meta-regression. Eleven trials met the search criteria, with nine sufficiently reporting AEs during the MR phase. Of 1009 patients receiving MR, the proportion experiencing cumulative grade 3/4 toxicity was 24% (95% confidence interval [CI]: 14-36%). Patients receiving MR every 6 months as four weekly infusions for 2 years had significantly less toxicity compared with those receiving MR every 2 months (10% vs. 28%; p = 0.035). Patients treated with rituximab alone during induction had fewer toxicities compared to those treated with rituximab plus chemotherapy induction (12% vs. 35%; p = 0.031). Myelosuppression and infections were the most common toxicities. Our literature analysis suggests that MR given every 6 months and rituximab alone as induction may be associated with fewer grade 3/4 AEs for patients with FL and MCL; however, assessing the true independent impact of induction regimens and schedule on toxicity will require prospective trials. © 2014 Informa UK, Ltd.
Freeman B.,Section of Hematology and Oncology |
Sloan J.M.,Section of Hematology and Oncology |
Sloan J.M.,Boston University |
Seldin D.C.,Section of Hematology and Oncology |
And 7 more authors.
Amyloid | Year: 2012
A 41-year-old woman with immunoglobulin light chain (AL) systemic amyloidosis with cardiac and gastrointestinal involvement developed multiple arterial and venous thromboembolic complications. Treatment with unfractionated heparin was complicated by life-threatening gastrointestinal bleeding. Work up for hereditary thrombophilia was unrevealing. Treatment with cyclophosphamide, bortezomib and dexamethasone combination regimen led to hematologic response without further thromboembolic complications. While thromboembolic complications have been reported in AL amyloidosis and cardiac involvement, this unique case highlights the complexity of the disease, the various pathogenic mechanisms at play and the difficult management decisions necessary in caring for these complex patients. A literature review of thrombembolic complications in patients with amyloidosis is presented. © 2012 Informa UK, Ltd.
Zapata-Mesina F.,University of Santo Tomas of Philippines |
Caguioa P.,Section of Hematology and Oncology
Phillippine Journal of Internal Medicine | Year: 2011
Objective: To describe a rare case of factor X deficiency associated with plasma cell disorder. Methods: We present the clinical and laboratory data in our patient and reviewed the related published literature regarding acquired factor X deficiency and its possible etiology. Discussion: A 52 year old male who presented with hematochezia, was admitted at our institution. He also has a history of atraumatic surgical abdomen, where hemoperitoneum was seen and post-surgical difficulty of hemostasis. Upon work up he has prolonged PT and APTT. Extended investigations of coagulation factors revealed low factor X level at 2% (N.V.70-120%) hence the diagnosis of Factor X or Stuart factor deficiency.Its etiology was determined by its common association with plasma cell disorders such as AL-amyloidosis, multiple myeloma, light chain deposition disease, others are due to malignancy and infection. Conclusion: The complexity of the hemostatic process should be meticulously reviewed in any patient with bleeding diathesis because Factor X deficiency, a rare disorder, can cause prolongation of both PT and APTT. It may present as recurrent gastrointestinal bleeding on top of a structural abnormality such as gastric ulcer. Treatment is factor replacement during acute bleeding and address the related primary cause of the disease.
Sentman C.L.,One Medical Center Drive |
Meehan K.R.,Section of Hematology and Oncology
Cancer Journal (United States) | Year: 2014
The NKG2D cell receptor and its ligands have attracted considerable interest as a potential strategy to attack tumor cells. NKG2D ligands are expressed on most types of tumors, and they demonstrate relative selectivity of ligand expression on tumor cells compared to healthy cells. Several different variants of NKG2D-based chimeric antigen receptors (CARs) have been developed, and extensive in vivo mechanistic studies performed demonstrated that cytotoxicity and cytokines are important for the efficacy NKG2D CAR adoptive T-cell therapy. NKG2D CARs target tumor cells, and they also target immunosuppressive cells within the tumor microenvironment. Under certain conditions, NKG2D ligand expression can be found on nontumor tissue, so potential off-tumor toxicity remains. In this article, we review the use of NKG2D as a basis for CAR targeting of tumors. Copyright © 2014 Lippincott Williams & Wilkins.