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Find video protocols related to scientific articles indexed in Pubmed.
Impact of prior cancer on eligibility for lung cancer clinical trials.
J. Natl. Cancer Inst.
PUBLISHED: 11-01-2014
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In oncology clinical trials, the assumption that a prior cancer diagnosis could interfere with study conduct or outcomes results in frequent exclusion of such patients. We determined the prevalence and characteristics of this practice in lung cancer clinical trials and estimated impact on trial accrual.
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Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic Non-Small-Cell Lung Cancer.
J. Clin. Oncol.
PUBLISHED: 10-29-2014
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Patients with stage IV non-small-cell lung cancer (NSCLC) who progress through first-line therapy have poor progression-free survival (PFS) and overall survival (OS), most commonly failing in original sites of gross disease. Cytoreduction with stereotactic body radiation therapy (SBRT) may help systemic agents delay relapse.
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Choroid plexus papilloma-A case highlighting the challenges of extrapolating pediatric chemotherapy regimens to adult populations.
J Oncol Pharm Pract
PUBLISHED: 07-27-2014
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The treatment of adults who present with rare pediatric tumors is not characterized well in the literature. We report an instance of a 40-year-old African American woman with a diagnosis of choroid plexus carcinoma admitted to the intensive care unit for severe sepsis seven days after receiving chemotherapy consisting of carboplatin (350?mg/m(2) on Days 1 and 2 plus etoposide 100?mg/m(2) on Days 1-5). Her laboratory results were significant for an absolute neutrophil count of 0/µL and blood cultures positive for Capnocytophagia species. She was supported with broad spectrum antibiotics and myeloid growth factors. She eventually recovered and was discharged in stable condition. The management of adults with malignancies most commonly seen in pediatric populations presents substantial challenges. There are multiple age-specific differences in renal and hepatic function that explain the need for higher dosing in pediatric patients without increasing the risk of toxicity. Furthermore, differences in pharmacokinetic parameters such as absorption, distribution, and clearance are present but are less likely to affect patients. It is expected that the pediatric population will have more bone marrow reserve and, therefore, less susceptible to myelosuppression. The extrapolation of pediatric dosing to an adult presents a problematic situation in treating adults with malignancies that primarily effect pediatric patients. We recommend extrapolating from adult treatment regimens with similar agents rather than extrapolating from pediatric treatment regimens to reduce the risk of toxicity. We also recommend the consideration of adding myeloid growth factors. If the treatment is tolerated without significant toxicity, dose escalation can be considered.
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Laparoscopic-assisted ablation of hepatic tumors: a review.
Semin Intervent Radiol
PUBLISHED: 07-24-2014
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Thermal ablation of hepatic tumors has been an evolving field over the last two decades. It is used in the treatment of both primary and metastatic neoplasms, and with evolutions in the technology, there has been an increasing interest in treating lesions where hepatic resection is not an option. Laparoscopic or minimally invasive surgical procedures have also advanced during this same time period, and the interface of these tools has been associated with the genesis of a new approach for treating hepatic lesions which are located in difficult to reach locations or found immediately adjacent to other intra-abdominal organs. This review summarizes the published literature focusing on the treatment of primary and metastatic neoplasms located in the liver, including a review of outcomes.
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Predictors and intensity of online access to electronic medical records among patients with cancer.
J Oncol Pract
PUBLISHED: 07-08-2014
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Electronic portals are secure Web-based servers that provide patients with real-time access to their personal health record (PHR). These applications are now widely used at cancer centers nationwide, but their impact has not been well studied. This study set out to determine predictors and patterns of use of a Web-based portal for accessing PHRs and communicating with health providers among patients with cancer.
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Direct excitation of parvalbumin-positive interneurons by M1 muscarinic acetylcholine receptors: roles in cellular excitability, inhibitory transmission and cognition.
J. Physiol. (Lond.)
PUBLISHED: 05-30-2014
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Parvalbumin-containing (PV) neurons, a major class of GABAergic interneurons, are essential circuit elements of learning networks. As levels of acetylcholine rise during active learning tasks, PV neurons become increasingly engaged in network dynamics. Conversely, impairment of either cholinergic or PV interneuron function induces learning deficits. Here, we examined PV interneurons in hippocampus (HC) and prefrontal cortex (PFC) and their modulation by muscarinic acetylcholine receptors (mAChRs). HC PV cells, visualized by crossing PV-CRE mice with Rosa26YFP mice, were anatomically identified as basket cells and PV bistratified cells in the stratum pyramidale; in stratum oriens, HC PV cells were electrophysiologically distinct from somatostatin-containing cells. With glutamatergic transmission pharmacologically blocked, mAChR activation enhanced PV cell excitability in both CA1 HC and PFC; however, CA1 HC PV cells exhibited a stronger postsynaptic depolarization than PFC PV cells. To delete M1 mAChRs genetically from PV interneurons, we created PV-M1 knockout mice by crossing PV-CRE and floxed M1 mice. The elimination of M1 mAChRs from PV cells diminished M1 mAChR immunoreactivity and muscarinic excitation of HC PV cells. Selective cholinergic activation of HC PV interneurons using Designer Receptors Exclusively Activated by Designer Drugs technology enhanced the frequency and amplitude of inhibitory synaptic currents in CA1 pyramidal cells. Finally, relative to wild-type controls, PV-M1 knockout mice exhibited impaired novel object recognition and, to a lesser extent, impaired spatial working memory, but reference memory remained intact. Therefore, the direct activation of M1 mAChRs on PV cells contributes to some forms of learning and memory.
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Management and future directions in non-small cell lung cancer with known activating mutations.
Am Soc Clin Oncol Educ Book
PUBLISHED: 05-27-2014
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Lung cancer accounts for a quarter of all cancer deaths. Non-small cell lung cancer (NSCLC) is currently segregated by the presence of actionable driver oncogenes. This review will provide an overview of molecular subsets of lung cancer, including descriptions of the defining oncogenes (EGFR, ALK, KRAS, ROS1, RET, BRAF, ERBB2, NTRK1, FGFR, among others) and how these predict for response to small molecule tyrosine kinase inhibitors (TKIs) that are either clinically available or in clinical trial development for advanced NSCLC. Particular focus will be placed on subsets with EGFR mutated and ALK rearranged NSCLC. Somatic TKI-sensitizing EGFR mutations (such as exon 19 deletions and L858R substitutions) are the most robust predictive biomarker for symptom improvement, radiographic response, and increment in progression-free survival (PFS) when EGFR TKIs (gefitinib, erlotinib, and afatinib) are used for patients with advanced NSCLC. However, the palliative benefits that EGFR TKIs afford are limited by multiple biologic mechanisms of tumor adaptation/resistance (such as the EGFR-T790M mutation and oncogene bypass tracks), and future efforts toward delaying, preventing, and treating resistance are underway. Similar to EGFR mutations, ALK rearrangements exemplify an oncogene-driven NSCLC that can be effectively palliated with a precision TKI therapy (the multitargeted ALK/MET/ROS1 TKI crizotinib). When resistance to first-line crizotinib therapy occurs, multiple second generation ALK TKIs have demonstrated impressive rates of disease control in clinical trials, and these may modify long-term outcomes for patients with ALK-positive NSCLC. The development of TKIs for other oncogene-driven NSCLCs may expand the portfolio of precision therapies for this recalcitrant cancer.
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Bavituximab plus paclitaxel and carboplatin for the treatment of advanced non-small-cell lung cancer.
Lung Cancer
PUBLISHED: 03-12-2014
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Bavituximab is a phosphatidylserine (PS)-targeting monoclonal antibody with immune-modulating and tumor-specific vascular targeting properties. Preclinical studies have shown activity against numerous solid tumors and at least an additive effect in combination with chemotherapy. This study evaluated bavituximab in combination with paclitaxel and carboplatin in patients with previously untreated, locally advanced or metastatic non-small-cell lung cancer (NSCLC).
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A reevaluation of CD22 expression in human lung cancer.
Cancer Res.
PUBLISHED: 01-08-2014
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CD22 is a transmembrane glycoprotein expressed by mature B cells. It inhibits signal transduction by the B-cell receptor and its coreceptor CD19. Recent reports indicate that most human lung cancer cells and cell lines express CD22, making it an important new therapeutic target for lung cancer. The objective of our studies was to independently validate these results with the goal of testing the efficacy of our CD22 immunotoxins on lung cancer cell lines. As determined by quantitative real-time PCR analysis, we found that levels of CD22 mRNA in a panel of human lung cancer cell lines were 200 to 60,000-fold lower than those observed in the human CD22(+) Burkitt lymphoma cells, Daudi. Using flow cytometry with a panel of CD22 monoclonal antibodies and Western blot analyses, we could not detect surface or intracellular expression of CD22 protein in a panel of lung cancer cell lines. In addition, the in vitro proliferation of the lung tumor cell lines was not affected by either CD22 antibodies or our highly potent anti-CD22 immunotoxin. In contrast, CD22(+) Daudi cells expressed high levels of CD22 mRNA and protein, and were sensitive to our CD22 immunotoxin. Importantly, primary non-small cell lung cancers from more than 250 patient specimens did not express detectable levels of CD22 protein as assessed by immunohistochemistry. We conclude that CD22 is not expressed at measurable levels on the surface of lung cancer cells, and that these cells cannot be killed by anti-CD22 immunotoxins.
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Reducing liver transplant length of stay: a Lean Six Sigma approach.
Prog Transplant
PUBLISHED: 12-07-2013
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Context-Organ transplant centers are under increasing scrutiny to maintain outcomes while controlling cost in a challenging population of patients. Throughout health care and transplant specifically, length of stay is used as a benchmark for both quality and resource utilization.Objective-To decrease our length of stay for liver transplant by using Lean Six Sigma methods.Design-The Six Sigma DMAIC (Define, Measure, Analyze, Improve, Control) method was used to systematically analyze our process from transplant listing to hospital discharge after transplant, identifying many factors affecting length of stay.Patients or Other Participants-Adult, single-organ, primary liver transplant recipients between July 2008 and June 2012 were included in the study. Recipients with living donors or fulminant liver failure were excluded.Intervention(s)-Multiple interventions, including a clinical pathway and enhanced communication, were implemented.Main Outcome Measure(s)-Length of stay after liver transplant and readmission after liver transplant.Results-Median length of stay decreased significantly from 11 days before the intervention to 8 days after the intervention. Readmission rate did not change throughout the study. The improved length of stay was maintained for 24 months after the study.Conclusion-Using a Lean Six Sigma approach, we were able to significantly decrease the length of stay of liver transplant patients. These results brought our centers outcomes in accordance with our goal and industry benchmark of 8 days. Clear expectations, improved teamwork, and a multidisciplinary clinical pathway were key elements in achieving and maintaining these gains.
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Evaluation of a Minimally Invasive Image-Guided Surgery System for Hepatic Ablation Procedures.
Surg Innov
PUBLISHED: 11-06-2013
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Background. The Explorer Minimally Invasive Liver (MIL) system uses imaging to create a 3-dimensional model of the liver. Intraoperatively, the system displays the position of instruments relative to the virtual liver. A prospective clinical study compared it with intraoperative ultrasound (iUS) in laparoscopic liver ablations. Methods. Patients undergoing ablations were accrued from 2 clinical sites. During the procedures, probes were positioned in the standard fashion using iUS. The position was synchronously recorded using the Explorer system. The distances from the probe tip to the tumor boundary and center were measured on the ultrasound image and in the corresponding virtual image captured by the Explorer system. Results. Data were obtained on the placement of 47 ablation probes during 27 procedures. The absolute difference between iUS and the Explorer system for the probe tip to tumor boundary distance was 5.5 ± 5.6 mm, not a statistically significant difference. The absolute difference for probe tip to tumor center distance was 8.6 ± 7.0 mm, not statistically different from 5 mm. Discussion. The initial clinical experience with the Explorer MIL system shows a strong correlation with iUS for the positioning of ablation probes. The Explorer MIL system is a promising tool to provide supplemental guidance information during laparoscopic liver ablation procedures.
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Development of a High-Throughput AlphaScreen Assay for Modulators of Synapsin I Phosphorylation in Primary Neurons.
J Biomol Screen
PUBLISHED: 10-02-2013
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Alterations in synaptic transmission have been implicated in a number of psychiatric and neurological disorders. The discovery of small-molecule modulators of proteins that regulate neurotransmission represents a novel therapeutic strategy for these diseases. However, high-throughput screening (HTS) approaches in primary neurons have been limited by challenges in preparing and applying primary neuronal cultures under conditions required for generating sufficiently robust and sensitive HTS assays. Synapsin I is an abundant presynaptic protein that plays a critical role in neurotransmission through tethering synaptic vesicles to the actin cytoskeleton. It has several phosphorylation sites that regulate its modulation of synaptic vesicle trafficking and, therefore, the efficacy of synaptic transmission. Here, we describe the development of a rapid, sensitive, and homogeneous assay to detect phospho-synapsin I (pSYN1) in primary cortical neurons in 384-well plates using AlphaScreen technology. From results of a pilot screening campaign, we show that the assay can identify compounds that modulate synapsin I phosphorylation via multiple signaling pathways. The implementation of the AlphaScreen pSYN1 assay and future development of additional primary neuronal HTS assays provides an attractive approach for discovery of novel classes of therapeutic candidates for a variety of CNS disorders.
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Biliary tree stem cells, precursors to pancreatic committed progenitors: evidence for possible life-long pancreatic organogenesis.
Stem Cells
PUBLISHED: 09-19-2013
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Peribiliary glands (PBGs) in bile duct walls, and pancreatic duct glands (PDGs) associated with pancreatic ducts, in humans of all ages, contain a continuous, ramifying network of cells in overlapping maturational lineages. We show that proximal (PBGs)-to-distal (PDGs) maturational lineages start near the duodenum with cells expressing markers of pluripotency (NANOG, OCT4, and SOX2), proliferation (Ki67), self-replication (SALL4), and early hepato-pancreatic commitment (SOX9, SOX17, PDX1, and LGR5), transitioning to PDG cells with no expression of pluripotency or self-replication markers, maintenance of pancreatic genes (PDX1), and expression of markers of pancreatic endocrine maturation (NGN3, MUC6, and insulin). Radial-axis lineages start in PBGs near the ducts fibromuscular layers with stem cells and end at the ducts lumens with cells devoid of stem cell traits and positive for pancreatic endocrine genes. Biliary tree-derived cells behaved as stem cells in culture under expansion conditions, culture plastic and serum-free Kubotas Medium, proliferating for months as undifferentiated cells, whereas pancreas-derived cells underwent only approximately 8-10 divisions, then partially differentiated towards an islet fate. Biliary tree-derived cells proved precursors of pancreas committed progenitors. Both could be driven by three-dimensional conditions, islet-derived matrix components and a serum-free, hormonally defined medium for an islet fate (HDM-P), to form spheroids with ultrastructural, electrophysiological and functional characteristics of neoislets, including glucose regulatability. Implantation of these neoislets into epididymal fat pads of immunocompromised mice, chemically rendered diabetic, resulted in secretion of human C-peptide, regulatable by glucose, and able to alleviate hyperglycemia in hosts. The biliary tree-derived stem cells and their connections to pancreatic committed progenitors constitute a biological framework for life-long pancreatic organogenesis.
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Phase 2 Study of Pemetrexed Plus Carboplatin, or Pemetrexed Plus Cisplatin with Concurrent Radiation Therapy Followed by Pemetrexed Consolidation in Patients with Favorable-Prognosis Inoperable Stage IIIA/B Non-Small-Cell Lung Cancer.
J Thorac Oncol
PUBLISHED: 08-29-2013
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There is no consensus chemotherapy regimen with concurrent radiotherapy (RT) for inoperable stage IIIA/B non-small-cell lung cancer. This trial evaluated pemetrexed with carboplatin (PCb) or cisplatin (PC) with concurrent RT followed by consolidation pemetrexed.
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Donor-associated malignancy in kidney transplant patients.
J. Clin. Invest.
PUBLISHED: 08-27-2013
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Skin cancer cells with donor genotype have been identified in allogeneic transplant patients; however, the donor contribution to the recipients epithelial malignancy remains to be established. In this issue of the JCI, Verneuil et al. provide the first evidence for donor contribution to the malignant epithelium of skin squamous cell carcinoma in a kidney transplant recipient. This case report may have important implications for cancer research and clinical care of long-surviving kidney transplant patients.
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Circulating Fibrocytes Stabilize Blood Vessels during Angiogenesis in a Paracrine Manner.
Am. J. Pathol.
PUBLISHED: 08-14-2013
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Accumulating evidence supports that circulating fibrocytes play important roles in angiogenesis. However, the specific role of fibrocytes in angiogenesis and the underlying mechanisms remain unclear. In this study, we found that fibrocytes stabilized newly formed blood vessels in a mouse wound-healing model by inhibiting angiogenesis during the proliferative phase and inhibiting blood vessel regression during the remodeling phase. Fibrocytes also inhibited angiogenesis in a Matrigel mouse model. In vitro study showed that fibrocytes inhibited both the apoptosis and proliferation of vascular endothelial cells (VECs) in a permeable support (Transwell) co-culture system. In a three-dimensional collagen gel, fibrocytes stabilized the VEC tubes by decreasing VEC tube density on stimulation with growth factors and preventing VEC tube regression on withdrawal of growth factors. Further mechanistic investigation revealed that fibrocytes expressed many prosurvival factors that are responsible for the prosurvival effect of fibrocytes on VECs and blood vessels. Fibrocytes also expressed angiogenesis inhibitors, including thrombospondin-1 (THBS1). THBS1 knockdown partially blocked the fibrocyte-induced inhibition of VEC proliferation in the Transwell co-culture system and recovered the fibrocyte-induced decrease of VEC tube density in collagen gel. Purified fibrocytes transfected with THBS1 siRNA partially recovered the fibrocyte-induced inhibition of angiogenesis in both the wound-healing and Matrigel models. In conclusion, our findings reveal that fibrocytes stabilize blood vessels via prosurvival factors and anti-angiogenic factors, including THBS1.
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Maintenance therapy for advanced lung cancer: who, what, and when?
J. Clin. Oncol.
PUBLISHED: 07-08-2013
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A 60-year-old woman with hypertension, dyslipidemia, and 35-pack-year smoking history is referred for treatment of advanced non-small-cell lung cancer (NSCLC). She initially presented after a transient ischemic attack, when a chest radiograph demonstrated a right lung mass. Computed tomography (CT) of the chest revealed a 5-cm right upper lobe mass, without mediastinal adenopathy, and a 6-cm cystic mass in the spleen. Additional imaging showed no brain metastasis. Endobronchial ulstrasound-guided core biopsies of the lung mass and ipsilateral mediastinal nodes confirmed a poorly differentiated non-small-cell carcinoma. Immunohistochemical stains were positive for napsin A and thyroid transcription factor 1, suggestive of adenocarcinoma (Fig 1). Molecular analysis identified a KRAS G12C mutation. A positron emission tomography (PET) -CT scan demonstrated [(18)F]fluorodeoxyglucose uptake in the right upper lobe mass and splenic lesion (Fig 2A). CT-guided fine-needle aspiration of the splenic lesion was performed and revealed metastatic carcinoma, consistent with the lung primary. Treatment with carboplatin plus pemetrexed was initiated, without bevacizumab because of the recent transient ischemic attack; carboplatin was selected over cisplatin because of similar concerns. The patient received two cycles of chemotherapy without complications, and repeat imaging showed decrease in size of the lung mass and splenic lesion (Figs 2B and 2C). After four cycles of chemotherapy, a chest CT showed ongoing response (Fig 2D). Her Eastern Cooperative Oncology Group performance status remained 0.
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Working memory impairment in calcineurin knock-out mice is associated with alterations in synaptic vesicle cycling and disruption of high-frequency synaptic and network activity in prefrontal cortex.
J. Neurosci.
PUBLISHED: 07-05-2013
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Working memory is an essential component of higher cognitive function, and its impairment is a core symptom of multiple CNS disorders, including schizophrenia. Neuronal mechanisms supporting working memory under normal conditions have been described and include persistent, high-frequency activity of prefrontal cortical neurons. However, little is known about the molecular and cellular basis of working memory dysfunction in the context of neuropsychiatric disorders. To elucidate synaptic and neuronal mechanisms of working memory dysfunction, we have performed a comprehensive analysis of a mouse model of schizophrenia, the forebrain-specific calcineurin knock-out mouse. Biochemical analyses of cortical tissue from these mice revealed a pronounced hyperphosphorylation of synaptic vesicle cycling proteins known to be necessary for high-frequency synaptic transmission. Examination of the synaptic vesicle cycle in calcineurin-deficient neurons demonstrated an impairment of vesicle release enhancement during periods of intense stimulation. Moreover, brain slice and in vivo electrophysiological analyses showed that loss of calcineurin leads to a gene dose-dependent disruption of high-frequency synaptic transmission and network activity in the PFC, correlating with selective working memory impairment. Finally, we showed that levels of dynamin I, a key presynaptic protein and calcineurin substrate, are significantly reduced in prefrontal cortical samples from schizophrenia patients, extending the disease relevance of our findings. Our data provide support for a model in which impaired synaptic vesicle cycling represents a critical node for disease pathologies underlying the cognitive deficits in schizophrenia.
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Secondary Intracranial Hypertension from Testosterone Therapy in a Transgender Patient.
Semin Ophthalmol
PUBLISHED: 06-12-2013
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Abstract We report an occurrence of intracranial hypertension secondary to testosterone therapy in a transgender patient. This is the first reported case to our knowledge demonstrating a direct association with raised levels of free testosterone and intracranial hypertension.
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BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer.
Mol. Cancer Ther.
PUBLISHED: 05-31-2013
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Signaling from other angiokinases may underlie resistance to VEGF-directed therapy. We evaluated the antitumor and biologic effects of BIBF 1120 (nintedanib), a tyrosine kinase inhibitor that targets VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor in preclinical models of lung and pancreatic cancer, including models resistant to VEGF-targeted treatments. In vitro, BIBF 1120 did not show antiproliferative effects, nor did it sensitize tumor cells to chemotherapy. However, in vivo BIBF 1120 inhibited primary tumor growth in all models as a single agent and in combination with standard chemotherapy. Analysis of tumor tissue posttreatment revealed that BIBF 1120 reduced proliferation (phospho-histone 3) and elevated apoptosis (cleaved caspase-3) to a greater extent than chemotherapy alone. Furthermore, BIBF 1120 showed potent antiangiogenic effects, including decreases in microvessel density (CD31), pericyte coverage (NG2), vessel permeability, and perfusion, while increasing hypoxia. Despite the induction of hypoxia, markers of epithelial-to-mesenchymal transition (EMT) were not elevated in BIBF 1120-treated tumors. In summary, BIBF 1120 showed potent antitumor and antiangiogenic activity in preclinical models of lung and pancreatic cancer where it induced hypoxia but not EMT. The absence of EMT induction, which has been implicated in resistance to antiangiogenic therapies, is noteworthy. Together, these results warrant further clinical studies of BIBF 1120.
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Locally advanced lung cancer: an optimal setting for vaccines and other immunotherapies.
Cancer J
PUBLISHED: 05-28-2013
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Lung cancer has traditionally been considered relatively resistant to immunotherapies. However, recent advances in the understanding of tumor-associated antigens, anti-tumor immune responses, and tumor immunosuppression mechanisms have resulted in a number of promising immunomodulatory therapies such as vaccines and checkpoint inhibitors. Locally advanced non-small cell lung cancer is an optimal setting for these treatments because standard therapies such as surgery, radiation, and chemotherapy may enhance anti-tumor immune effects by debulking the tumor, increasing tumor antigen presentation, and promoting T-cell response and trafficking. Clinical trials incorporating immunomodulatory agents into combined modality therapy of locally advanced non-small cell lung cancer have shown promising results. Future challenges include identifying biomarkers to predict those patients most likely to benefit from this approach, radiographic assessment of treatment effects, the timing and dosing of combined modality treatment including immunotherapies, and avoidance of potentially overlapping toxicities.
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Influence of medical comorbidities on the presentation and outcomes of stage I-III non-small-cell lung cancer.
Clin Lung Cancer
PUBLISHED: 04-25-2013
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Non-small-cell lung cancer presentation, treatment, and outcomes vary widely according to socioeconomic factors and other patient characteristics. To determine whether medical comorbidities account for these observations, we incorporated a validated medical comorbidity index into an analysis of patients diagnosed with stage I to III NSCLC.
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Concise review: clinical programs of stem cell therapies for liver and pancreas.
Stem Cells
PUBLISHED: 03-22-2013
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Regenerative medicine is transitioning into clinical programs using stem/progenitor cell therapies for repair of damaged organs. We summarize those for liver and pancreas, organs that share endodermal stem cell populations, biliary tree stem cells (hBTSCs), located in peribiliary glands. They are precursors to hepatic stem/progenitors in canals of Hering and to committed progenitors in pancreatic duct glands. They give rise to maturational lineages along a radial axis within bile duct walls and a proximal-to-distal axis starting at the duodenum and ending with mature cells in the liver or pancreas. Clinical trials have been ongoing for years assessing effects of determined stem cells (fetal-liver-derived hepatic stem/progenitors) transplanted into the hepatic artery of patients with various liver diseases. Immunosuppression was not required. Control subjects, those given standard of care for a given condition, all died within a year or deteriorated in their liver functions. Subjects transplanted with 100-150 million hepatic stem/progenitor cells had improved liver functions and survival extending for several years. Full evaluations of safety and efficacy of transplants are still in progress. Determined stem cell therapies for diabetes using hBTSCs remain to be explored but are likely to occur following ongoing preclinical studies. In addition, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are being used for patients with chronic liver conditions or with diabetes. MSCs have demonstrated significant effects through paracrine signaling of trophic and immunomodulatory factors, and there is limited evidence for inefficient lineage restriction into mature parenchymal or islet cells. HSCs effects are primarily via modulation of immune mechanisms.
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Local access to subspecialty care influences the chance of receiving a liver transplant.
Liver Transpl.
PUBLISHED: 03-17-2013
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Prior studies have examined the impact of demographic factors on liver transplant outcomes. These factors may be surrogate markers for access to medical care. We investigated physician density in referred patients hospital service areas (HSAs) as a factor in patients probability of receiving a liver transplant. We performed a retrospective review of patients referred for liver transplantation from 2002 through 2010. Data on physician density were obtained from the Dartmouth Atlas of Health Care. The primary outcome was the receipt of a liver transplant. A Cox hazard analysis was used to control for various demographic and medical covariates. Over the time period, 1485 adult patients were considered for liver transplantation. Factors that influenced the hazard of receiving a liver transplant were the Model for End-Stage Disease (MELD) score at referral {Hazard ratios (HR) per point = 1.11 [95% confidence interval (CI) = 1.09-1.14]}, a secondary diagnosis of hepatocellular carcinoma [HR = 2.72 (95% CI = 1.76-4.20)], blood group AB [HR = 2.98 (95% CI = 1.52-5.87) with blood group A as the referent], the type of insurance [HR for Medicare = 0.36 (95% CI = 0.14-0.89) with commercial insurance as the referent], and the number of gastroenterologists in an HSA [odds ratio with each additional gastroenterologist per 100,000 population = 1.12 (95% CI = 1.01-1.25)]. Age, race, sex, distance to the transplant center, and residence in a rural community did not influence the chance of receiving a liver transplant. In conclusion, the hazard of receiving a liver transplant are influenced by the diagnosis, MELD score, and insurance status; in addition, patients were 12% more likely to receive a transplant with each additional gastroenterologist per 100,000 population in their local HSA. Local access to gastroenterology subspecialty care is an important factor in receiving a liver transplant.
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Stigma among patients with lung cancer: a patient-reported measurement model.
Psychooncology
PUBLISHED: 03-07-2013
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Although stigma may have negative psychosocial and behavioral outcomes for patients with lung cancer, its measurement has been limited. A conceptual model of lung cancer stigma and a patient-reported outcome measure are needed to mitigate these sequelae. This study identified key stigma-related themes to provide a blueprint for item development through a thematic analysis of semi-structured interviews and focus groups with lung cancer patients.
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Prevalence and impact of anemia in hospitalized patients.
South. Med. J.
PUBLISHED: 03-07-2013
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The prevalence of anemia is increasing in the general population similarly to other comorbidities and is associated with high mortality in a variety of settings. Most studies, however, have analyzed older adults or specific comorbidities, and the independent impact of anemia on outcomes in a general population of hospitalized patients has not been clearly defined.
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Maintenance chemotherapy for advanced non-small-cell lung cancer: new life for an old idea.
J. Clin. Oncol.
PUBLISHED: 02-11-2013
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Although well established for the treatment of certain hematologic malignancies, maintenance therapy has only recently become a treatment paradigm for advanced non-small-cell lung cancer. Maintenance therapy, which is designed to prolong a clinically favorable state after completion of a predefined number of induction chemotherapy cycles, has two principal paradigms. Continuation maintenance therapy entails the ongoing administration of a component of the initial chemotherapy regimen, generally the nonplatinum cytotoxic drug or a molecular targeted agent. With switch maintenance (also known as sequential therapy), a new and potentially non-cross-resistant agent is introduced immediately on completion of first-line chemotherapy. Potential rationales for maintenance therapy include increased exposure to effective therapies, decreasing chemotherapy resistance, optimizing efficacy of chemotherapeutic agents, antiangiogenic effects, and altering antitumor immunity. To date, switch maintenance therapy strategies with pemetrexed and erlotinib have demonstrated improved overall survival, resulting in US Food and Drug Administration approval for this indication. Recently, continuation maintenance with pemetrexed was found to prolong overall survival as well. Factors predicting benefit from maintenance chemotherapy include the degree of response to first-line therapy, performance status, the likelihood of receiving further therapy at the time of progression, and tumor histology and molecular characteristics. Several aspects of maintenance therapy have raised considerable debate in the thoracic oncology community, including clinical trial end points, the prevalence of second-line chemotherapy administration, the role of treatment-free intervals, quality of life, economic considerations, and whether progression-free survival is a worthy therapeutic goal in this disease setting.
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Impact of renal function on treatment options and outcomes in advanced non-small cell lung cancer.
Lung Cancer
PUBLISHED: 01-18-2013
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Certain chemotherapeutic agents commonly used for advanced non-small cell lung cancer (NSCLC) require minimum threshold renal function for administration. To determine how such requirements affect treatment options, we evaluated renal function patterns in this population.
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Successful transplantation of human hepatic stem cells with restricted localization to liver using hyaluronan grafts.
Hepatology
PUBLISHED: 01-10-2013
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Cell therapies are potential alternatives to organ transplantation for liver failure or dysfunction but are compromised by inefficient engraftment, cell dispersal to ectopic sites, and emboli formation. Grafting strategies have been devised for transplantation of human hepatic stem cells (hHpSCs) embedded into a mix of soluble signals and extracellular matrix biomaterials (hyaluronans, type III collagen, laminin) found in stem cell niches. The hHpSCs maintain a stable stem cell phenotype under the graft conditions. The grafts were transplanted into the livers of immunocompromised murine hosts with and without carbon tetrachloride treatment to assess the effects of quiescent versus injured liver conditions. Grafted cells remained localized to the livers, resulting in a larger bolus of engrafted cells in the host livers under quiescent conditions and with potential for more rapid expansion under injured liver conditions. By contrast, transplantation by direct injection or via a vascular route resulted in inefficient engraftment and cell dispersal to ectopic sites. Transplantation by grafting is proposed as a preferred strategy for cell therapies for solid organs such as the liver.
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Targeted therapies for lung cancer: clinical experience and novel agents.
Cancer J
PUBLISHED: 12-14-2011
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Although lung cancer remains the leading cancer killer in the United States, recently a number of developments indicate future clinical benefit. These include evidence that computed tomography-based screening decreases lung cancer mortality, the use of stereotactic radiation for early-stage tumors, the development of molecular methods to predict chemotherapy sensitivity, and genome-wide expression and mutation analysis data that have uncovered oncogene "addictions" as important therapeutic targets. Perhaps the most significant advance in the treatment of this challenging disease is the introduction of molecularly targeted therapies, a term that currently includes monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The development of effective targeted therapeutics requires knowledge of the genes and pathways involved and how they relate to the biologic behavior of lung cancer. Drugs targeting the epidermal growth factor receptor, anaplastic lymphoma kinase, and vascular endothelial growth factor are now U.S. Food and Drug Administration approved for the treatment of advanced non-small cell lung cancer. These agents are generally better tolerated than conventional chemotherapy and show dramatic efficacy when their use is coupled with a clear understanding of clinical data, mechanism, patient selection, drug interactions, and toxicities. Integrating genome-wide tumor analysis with drug- and targeted agent-responsive phenotypes will provide a wealth of new possibilities for lung cancer-targeted therapeutics. Ongoing research efforts in these areas as well as a discussion of emerging targeted agents being evaluated in clinical trials are the subjects of this review.
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Phase I safety and pharmacokinetic study of bavituximab, a chimeric phosphatidylserine-targeting monoclonal antibody, in patients with advanced solid tumors.
Clin. Cancer Res.
PUBLISHED: 10-11-2011
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Bavituximab is a chimeric immunoglobulin G1 phosphatidylserine-targeting monoclonal antibody that triggers vascular disruption and enhances antitumor immune response. This phase I study assessed the safety and pharmacokinetics of bavituximab in patients with advanced solid tumors.
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Development of bavituximab, a vascular targeting agent with immune-modulating properties, for lung cancer treatment.
Immunotherapy
PUBLISHED: 08-17-2011
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Bavituximab is a chimeric monoclonal antibody directed against the membrane phospholipid phosphatidylserine. Phosphatidylserine exposure is increased on endothelial cells and apoptotic cancer cells in solid tumors, allowing tumor-specific targeting of bavituximab. Bavituximab binding results in tumor vessel occlusion and enhanced antitumor immunity. Preclinical investigations have demonstrated efficacy as monotherapy and in combination with other modalities against multiple cancer types. Phase I clinical trials of bavituximab monotherapy and in combination with chemotherapy in adults with refractory solid tumors have been completed. Phase II trials of bavituximab in combination with chemotherapy for the first- and second-line treatment of advanced non-small-cell lung cancer are currently ongoing. This article summarizes the preclinical development and clinical experience with bavituximab in non-small-cell lung cancer.
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Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets.
Hepatology
PUBLISHED: 08-03-2011
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Multipotent stem/progenitors are present in peribiliary glands of extrahepatic biliary trees from humans of all ages and in high numbers in hepato-pancreatic common duct, cystic duct, and hilum. They express endodermal transcription factors (e.g., Sox9, SOX17, FOXA2, PDX1, HES1, NGN3, PROX1) intranuclearly, stem/progenitor surface markers (EpCAM, NCAM, CD133, CXCR4), and sometimes weakly adult liver, bile duct, and pancreatic genes (albumin, cystic fibrosis transmembrane conductance regulator [CFTR], and insulin). They clonogenically expand on plastic and in serum-free medium, tailored for endodermal progenitors, remaining phenotypically stable as undifferentiated cells for months with a cell division initially every ?36 hours and slowing to one every 2-3 days. Transfer into distinct culture conditions, each comprised of a specific mix of hormones and matrix components, yields either cords of hepatocytes (express albumin, CYP3A4, and transferrin), branching ducts of cholangiocytes (expressing anion exchanger-2-AE2 and CFTR), or regulatable C-peptide secreting neoislet-like clusters (expressing glucagon, insulin) and accompanied by changes in gene expression correlating with the adult fate. Transplantation into quiescent livers of immunocompromised mice results in functional human hepatocytes and cholangiocytes, whereas if into fat pads of streptozocin-induced diabetic mice, results in functional islets secreting glucose-regulatable human C-peptide. Conclusion: The phenotypes and availability from all age donors suggest that these stem/progenitors have considerable potential for regenerative therapies of liver, bile duct, and pancreatic diseases including diabetes.
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Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer.
J. Clin. Oncol.
PUBLISHED: 07-18-2011
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c-MET (MET) receptor activation is associated with poor prognosis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small-cell lung cancer (NSCLC). This global, randomized phase II trial examined erlotinib plus tivantinib (ARQ 197; ArQule, Woburn, MA), a novel MET inhibitor.
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A system for performing high throughput assays of synaptic function.
PLoS ONE
PUBLISHED: 06-16-2011
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Unbiased, high-throughput screening has proven invaluable for dissecting complex biological processes. Application of this general approach to synaptic function would have a major impact on neuroscience research and drug discovery. However, existing techniques for studying synaptic physiology are labor intensive and low-throughput. Here, we describe a new high-throughput technology for performing assays of synaptic function in primary neurons cultured in microtiter plates. We show that this system can perform 96 synaptic vesicle cycling assays in parallel with high sensitivity, precision, uniformity, and reproducibility and can detect modulators of presynaptic function. By screening libraries of pharmacologically defined compounds on rat forebrain cultures, we have used this system to identify novel effects of compounds on specific aspects of presynaptic function. As a system for unbiased compound as well as genomic screening, this technology has significant applications for basic neuroscience research and for the discovery of novel, mechanism-based treatments for central nervous system disorders.
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Consent timing and experience: modifiable factors that may influence interest in clinical research.
J Oncol Pract
PUBLISHED: 06-06-2011
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Low rates of participation in cancer clinical trials have been attributed to patient, institutional, and study characteristics. However, few studies have examined factors related to the consent process. We therefore evaluated the impact of consent timing and experience on markers of patient interest in research.
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MRI findings of recurrent hepatocellular carcinoma after liver transplantation: preliminary results.
J Magn Reson Imaging
PUBLISHED: 05-19-2011
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To describe the patterns of recurrence and serial magnetic resonance imaging (MRI) features of hepatocellular carcinoma (HCC) after liver transplantation.
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Premature ejaculation and other sexual dysfunctions in opiate dependent men receiving methadone substitution treatment.
Addict Behav
PUBLISHED: 05-10-2011
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A significant number of men with opiate misuse have sexual problems. Premature ejaculation (PE) occurs predominantly on discontinuation of the opiate but seems to persist in some cases. The aims of this study were to determine the rates of PE and other sexual dysfunctions in patients maintained on methadone; to determine the time of onset of PE in relation to onset of opiate misuse; and to look at the patients perception of the effect of heroin and methadone on PE.
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MAPK/ERK and Wnt/?-Catenin pathways are synergistically involved in proliferation of Sca-1 positive hepatic progenitor cells.
Biochem. Biophys. Res. Commun.
PUBLISHED: 05-10-2011
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Hepatic progenitor cells (HPCs) persist in adulthood and have the potential to play a major role in regenerating diseased liver. However, the signaling pathways that both directly and indirectly regulate HPCs self-renewal and differentiation remain elusive. Previously, we identified a bipotent, stem cell antigen-1 (Sca-1) positive HPC population from naïve adult liver tissue. In the present study, we aimed to investigate the involvement of various signaling pathways in Sca-1(+) HPC proliferation. Epidermal growth factor (EGF) supplementation shows a significant increase in Sca-1(+) HPC proliferation and colony formation while stimulating phosphorylation of ERK1/2 and activating the induction of Cyclin D1. There were no demonstrable effects of EGF on Akt. The MEK inhibitor, PD0325901, inhibits proliferation and ERK1/2 phosphorylation while also suppressing the expression of Cyclin D1. In addition, activation of either IL-6/STAT3 or Wnt/?-Catenin pathway did not independently support cell proliferation and colony formation of HPCs. The Wnt/?-Catenin pathway can cooperate with EGF to significantly promote HPC colony formation ratio and maintain long-term HPC in vitro. The data indicates that the MAPK/ERK pathway is both essential and critical for HPC proliferation, and the Wnt signaling pathway is not sufficient, while it works synergistically with the MAPK/ERK signaling pathway to promote HPC proliferation.
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Predictors and impact of second-line chemotherapy for advanced non-small cell lung cancer in the United States: real-world considerations for maintenance therapy.
J Thorac Oncol
PUBLISHED: 05-06-2011
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: Recent clinical trials incorporating maintenance chemotherapy into the initial treatment of advanced non-small cell lung cancer (NSCLC) have highlighted the benefits of exposing patients to second-line therapies. We, therefore, determined the predictors and impact of second-line chemotherapy administration in a contemporary, diverse NSCLC population.
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Improvement of gastrointestinal symptoms after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in liver transplant patients.
Clin Transplant
PUBLISHED: 04-07-2011
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As many as 50% of liver transplant patients suffer gastrointestinal (GI) disturbances post-transplant. Conversion from mycophenolate mofetil (MMF) to mycophenolate sodium (EC-MPS) alleviates GI symptom burden in renal transplant recipients. We employed a validated patient and physician-reported assessment to evaluate the impact of conversion to EC-MPS in liver transplant patients. This is a prospective, longitudinal, single-center, open-label pilot study. Thirty-one MMF-treated liver transplant patients with GI symptoms were converted to equimolar EC-MPS. Gastrointestinal Symptom Rating Scale (GSRS), GI Quality of Life, SF-12v2 and physician-reported assessments were used to evaluate GI symptom burden and severity. A significant improvement in overall GSRS score was noted from baseline (2.57; 95% CI 2.12-3.10) to one month (1.90; 1.68-2.12; p = 0.0007) and three months (1.82; 1.60-2.04; p = 0.0002) post-conversion with significant reductions in all subgroups except Reflux. The overall Gastrointestinal Quality of Life Index (GIQLI) score also showed significant increase in health-related quality of life between one month (90.89; 84.04-97.75) and three months (100.04; 94.57-105.51; p = 0.0009), with all subgroups except social functioning (p = 0.0861) and medical treatment (p = 0.3156) demonstrating significant improvements. This pilot study demonstrates improvement in GI symptom burden when converting from equimolar doses of MMF to EC-MPS. This benefit persisted for three months without evidence of rejection.
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Laparoscopic-assisted microwave ablation for hepatocellular carcinoma: safety and efficacy in comparison with radiofrequency ablation.
J Surg Oncol
PUBLISHED: 03-11-2011
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Thermal ablation techniques are increasingly important in the search for improved locoregional therapy of hepatocellular carcinoma (HCC) in patients with cirrhosis. This study reports the largest US series using laparoscopic-assisted microwave ablation (Lap-MWA) with a 915-MHz generator for HCC and compares it with a contemporary laparoscopic-assisted radiofrequency ablation (Lap-RFA) experience.
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Association between out-of-hospital emergency department transfer and poor hospital outcome in critically ill stroke patients.
J Crit Care
PUBLISHED: 02-16-2011
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Transfer of critically ill patients from outside emergency department has the potential for delaying the admission to the intensive care unit. We sought to determine the effect of outside emergency department transfer on hospital outcomes in critically ill patients with stroke.
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A novel polymer gel for the delivery of local therapies to intracranial tumors: In vivo safety evaluation.
J Biomed Mater Res A
PUBLISHED: 01-18-2011
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The treatment of intracranial malignancies is limited by the ability of systemically administered therapies to cross the blood-brain barrier. Royer resorbable matrix, or R-Gel, is a dextran polymer administered in liquid form via needle injection. Within minutes of preparation, the polymer forms a gel and subsequently solidifies, thereby conforming to the dimensions of the injection cavity. R-Gel can accommodate a wide variety of therapeutic agents that may provide new options for local treatment delivery. This preclinical study evaluates the neurotoxicity of R-Gel implanted in the rat brain. Fifteen rats underwent intracranial administration of R-Gel (N = 9) or saline (N = 6) were monitored for systemic and neurotoxicity, and sacrificed at pre-determined time points. Animals that received the R-Gel injection demonstrated no behavioral changes or weight loss. Histopathologic analysis revealed an inflammatory response in both groups on day 3 and day 7 after implantation, which resolved by day 42. These results suggest that intracranial R-Gel is well tolerated. Therapeutic studies of chemotherapy-complexed R-Gel are underway.
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ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time.
Cancer Cell
PUBLISHED: 12-16-2010
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It was only 3 years ago that an acquired translocation of EML4 with ALK leading to the expression of an EML4-ALK oncoprotein in non-small cell lung cancer (NSCLC) was reported. Tumor cells expressing EML4-ALK are "addicted" to its continued function. Now, crizotinib, an oral ALK inhibitor, is demonstrated to provide dramatic clinical benefit with little toxicity in patients having such advanced NSCLC, and a mechanism of clinical resistance to crizotinib is identified. Such therapy "targeted" at oncogenic proteins provides "personalized" medicine and prompts genome-wide mutation analysis of human tumors to find other therapeutic targets.
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Efficacy and tolerability of laparoscopic-assisted radiofrequency ablation of hepatocellular carcinoma in patients above 60 years of age.
Surg Laparosc Endosc Percutan Tech
PUBLISHED: 12-15-2010
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The purpose of this study was to evaluate the safety and efficacy of laparoscopic-assisted radiofrequency ablation (RFA) in patients with hepatocellular carcinoma above the age of 60 years. A single-center, retrospective study of a prospective dataset evaluated efficacy and morbidity of RFA in patients above 60 years of age. About 37% of patients had an intrahepatic recurrence 1 year after ablation. By multivariate analysis, only the number of lesions ablated was a predictor of recurrence (P=0.007). Overall mortality was 19% at 1 year and factors associated with mortality include elevated ?-fetoprotein, number of lesions ablated, and platelet count. Complications occurred in 10% of our population with 1 death. RFA is well tolerated in patients of 60 years of age and above. The outcomes in this study validate a local ablative strategy for the treatment of hepatocellular carcinoma in the elderly and it is superior to no treatment alone.
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Long-term survival after 67 hours of anhepatic state due to primary liver allograft nonfunction.
Liver Transpl.
PUBLISHED: 12-01-2010
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Primary liver allograft nonfunction immediately after transplantation poses a life-threatening situation for the recipient. Emergency retransplantation may not be immediately possible due to organ unavailability. Total hepatectomy with temporary portacaval shunt has been described as a bridge to retransplantation when the presence of the graft appears to be harming the recipient. Case reports of retransplantation after total hepatectomy with anhepatic times greater than 48 hours routinely describe poor outcomes. We present a case with excellent patient outcome after 95 hours of clinical anhepatic state, including 67 hours of anatomical anhepatic time, because of primary liver allograft nonfunction. This case report documents the longest anhepatic time with subsequent successful transplant to date.
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Paraneoplastic syndromes: an approach to diagnosis and treatment.
Mayo Clin. Proc.
PUBLISHED: 09-03-2010
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Recent medical advances have improved the understanding, diagnosis, and treatment of paraneoplastic syndromes. These disorders arise from tumor secretion of hormones, peptides, or cytokines or from immune cross-reactivity between malignant and normal tissues. Paraneoplastic syndromes may affect diverse organ systems, most notably the endocrine, neurologic, dermatologic, rheumatologic, and hematologic systems. The most commonly associated malignancies include small cell lung cancer, breast cancer, gynecologic tumors, and hematologic malignancies. In some instances, the timely diagnosis of these conditions may lead to detection of an otherwise clinically occult tumor at an early and highly treatable stage. Because paraneoplastic syndromes often cause considerable morbidity, effective treatment can improve patient quality of life, enhance the delivery of cancer therapy, and prolong survival. Treatments include addressing the underlying malignancy, immunosuppression (for neurologic, dermatologic, and rheumatologic paraneoplastic syndromes), and correction of electrolyte and hormonal derangements (for endocrine paraneoplastic syndromes). This review focuses on the diagnosis and treatment of paraneoplastic syndromes, with emphasis on those most frequently encountered clinically. Initial literature searches for this review were conducted using PubMed and the keyword paraneoplastic in conjunction with keywords such as malignancy, SIADH, and limbic encephalitis, depending on the particular topic. Date limitations typically were not used, but preference was given to recent articles when possible.
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The impact of packed red blood cell transfusion on clinical outcomes in patients with septic shock treated with early goal directed therapy.
Indian J Crit Care Med
PUBLISHED: 08-27-2010
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The optimal hemoglobin level and transfusion threshold in patients with septic shock treated with an early, goal oriented approach to resuscitation remains unknown.
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Towards the creation of decellularized organ constructs using irreversible electroporation and active mechanical perfusion.
Biomed Eng Online
PUBLISHED: 08-21-2010
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Despite advances in transplant surgery and general medicine, the number of patients awaiting transplant organs continues to grow, while the supply of organs does not. This work outlines a method of organ decellularization using non-thermal irreversible electroporation (N-TIRE) which, in combination with reseeding, may help supplement the supply of organs for transplant.
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Paracrine signals from mesenchymal cell populations govern the expansion and differentiation of human hepatic stem cells to adult liver fates.
Hepatology
PUBLISHED: 08-20-2010
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The differentiation of embryonic or determined stem cell populations into adult liver fates under known conditions yields cells with some adult-specific genes but not others, aberrant regulation of one or more genes, and variations in the results from experiment to experiment. We tested the hypothesis that sets of signals produced by freshly isolated, lineage-dependent mesenchymal cell populations would yield greater efficiency and reproducibility in driving the differentiation of human hepatic stem cells (hHpSCs) into adult liver fates. The subpopulations of liver-derived mesenchymal cells, purified by immunoselection technologies, included (1) angioblasts, (2) mature endothelia, (3) hepatic stellate cell precursors, (4) mature stellate cells (pericytes), and (5) myofibroblasts. Freshly immunoselected cells of each of these subpopulations were established in primary cultures under wholly defined (serum-free) conditions that we developed for short-term cultures and were used as feeders with hHpSCs. Feeders of angioblasts yielded self-replication, stellate cell precursors caused lineage restriction to hepatoblasts, mature endothelia produced differentiation into hepatocytes, and mature stellate cells and/or myofibroblasts resulted in differentiation into cholangiocytes. Paracrine signals produced by the different feeders were identified by biochemical, immunohistochemical, and quantitative reverse-transcription polymerase chain reaction analyses, and then those signals were used to replace the feeders in monolayer and three-dimensional cultures to elicit the desired biological responses from hHpSCs. The defined paracrine signals were proved to be able to yield reproducible responses from hHpSCs and to permit differentiation into fully mature and functional parenchymal cells.
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The future of cell transplant therapies: a need for tissue grafting.
Transplantation
PUBLISHED: 08-14-2010
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Current methodologies of solid organ-derived cell transplant therapies introduce donor cells into hosts through a vascular route, a strategy modeled after hematopoietic therapies. These strategies fail because of inefficient engraftment, poor survival of the cells, and propensity for formation of life-threatening emboli. Transplant success necessitates grafting methods, requiring a mixture of appropriate cell sources embedded into or onto precise mixes of extracellular matrix components and then localized to the diseased or dysfunctional tissue, promoting necessary proliferation, engraftment, and vascularization. Grafting technologies are rapidly translatable to therapeutic uses in patients and provide alternative treatments for regenerative medicine.
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Looking beyond surveillance, epidemiology, and end results: patterns of chemotherapy administration for advanced non-small cell lung cancer in a contemporary, diverse population.
J Thorac Oncol
PUBLISHED: 07-16-2010
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Chemotherapy prolongs survival without substantially impairing quality of life for medically fit patients with advanced non-small cell lung cancer (NSCLC), but population-based studies have shown that only 20 to 30% of these patients receive chemotherapy. These earlier studies have relied on Medicare-linked Surveillance, Epidemiology, and End Results (SEER) data, thus excluding the 30 to 35% of lung cancer patients younger than 65 years. Therefore, we determined the use of chemotherapy in a contemporary, diverse NSCLC population encompassing all patient ages.
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Medical epidemiology of patients surviving ten years after liver transplantation.
Clin Transplant
PUBLISHED: 07-14-2010
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The transition into extended long-term follow-up after liver transplantation raises a new series of issues with respect to continuing care of this population. A retrospective study was performed, analyzing patients who underwent orthotopic liver transplant (OLT) and survived ?10 yr at a single institution. Long-term comorbidities such as diabetes mellitus (DM), hypertension (HTN), chronic kidney disease (CKD), coronary artery disease (CAD), and obesity were identified and standardized prevalence ratios ([SPR]) utilized to compare with the general US population. There was an increased prevalence of HTN ([SPR]?= 2.25 ± 0.61), DM ([SPR]?= 2.67 ± 0.72), and CKD ([SPR]?=?15.3 ± 4.04) but not CAD or obesity. In multivariate analysis, non-viral etiology of end-stage liver disease was associated with CKD (OR 3.42 CI 1.11-10.53), and an initial glomerular filtration rate (GFR) <60 mL/min per 1.73 m(2) (CKD stages III-V) was associated with HTN (OR 4.62 CI 1.14-18.73) after OLT. Creatinine ? 1.5 mg/dL at 10 yr was associated with an initial GFR <60 mL/min per 1.73 m(2) (p = 0.000) and CAD after OLT (p = 0.012). Patients, 10 yr after OLT, have a significantly higher prevalence of HTN, DM, and CKD than the general population, which is not confounded by obesity. Increased vigilance and proactive management are required to further improve long-term outcomes.
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Lineage restriction of human hepatic stem cells to mature fates is made efficient by tissue-specific biomatrix scaffolds.
Hepatology
PUBLISHED: 06-28-2010
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Current protocols for differentiation of stem cells make use of multiple treatments of soluble signals and/or matrix factors and result typically in partial differentiation to mature cells with under- or overexpression of adult tissue-specific genes. We developed a strategy for rapid and efficient differentiation of stem cells using substrata of biomatrix scaffolds, tissue-specific extracts enriched in extracellular matrix, and associated growth factors and cytokines, in combination with a serum-free, hormonally defined medium (HDM) tailored for the adult cell type of interest. Biomatrix scaffolds were prepared by a novel, four-step perfusion decellularization protocol using conditions designed to keep all collagen types insoluble. The scaffolds maintained native histology, patent vasculatures, and ?1% of the tissues proteins but >95% of its collagens, most of the tissues collagen-associated matrix components, and physiological levels of matrix-bound growth factors and cytokines. Collagens increased from almost undetectable levels to >15% of the scaffolds proteins with the remainder including laminins, fibronectins, elastin, nidogen/entactin, proteoglycans, and matrix-bound cytokines and growth factors in patterns that correlate with histology. Human hepatic stem cells (hHpSCs), seeded onto liver biomatrix scaffolds and in an HDM tailored for adult liver cells, lost stem cell markers and differentiated to mature, functional parenchymal cells in ?1 week, remaining viable and with stable mature cell phenotypes for more than 8 weeks.
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Risk of cardiac arrhythmias and conduction abnormalities in patients with acute myocardial infarction receiving packed red blood cell transfusions.
J Crit Care
PUBLISHED: 03-15-2010
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Although transfusion has been linked to the development of atrial fibrillation (AF) in cardiac surgical patients, this association has not been investigated in patients with acute myocardial infarction (AMI). Evidence supports an inflammatory mechanism in the development of AF, and red cell transfusions also elicit an inflammatory response. We therefore sought to evaluate whether packed red blood cell transfusion increases the risk of AF, ventricular tachycardia (VT), and other arrhythmias and conduction abnormalities in patients with AMI.
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Cetuximab in combination therapy: from bench to clinic.
Cancer Metastasis Rev.
PUBLISHED: 02-09-2010
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Cetuximab, a chimeric IgG(1) monoclonal antibody directed against the ligand-binding domain of the epidermal growth factor receptor, offers a paradigm for the combination of molecularly targeted therapies with cytotoxic agents. In preclinical models, the addition of cetuximab to chemotherapy or radiation therapy enhances antitumor activity. Proposed mechanisms include reducing tumor cell proliferation, angiogenesis, and DNA repair capacity; increasing apoptosis; and inducing cell cycle arrest at treatment-sensitive points. These effects may enhance and restore tumor sensitivity to cytotoxic therapies. In clinical trials, the addition of cetuximab to chemotherapy improves outcomes of patients who had previously failed such agents, as illustrated in irinotecan-resistant and oxaliplatin-refractory metastatic colorectal cancer. As initial therapy, the addition of cetuximab to chemotherapy extends survival in colorectal cancer, lung cancer, and head and neck cancer. Combining cetuximab with radiation therapy extends survival in locally advanced head and neck cancer. As predictive biomarkers are identified, it may become possible to select patients most likely to benefit from such combinations.
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Thermoablative treatments for malignant liver lesions: 10-year experience of MRI appearances of treatment response.
AJR Am J Roentgenol
PUBLISHED: 01-23-2010
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The objective of our study was to describe our 10-year experience using MRI to evaluate response to local thermoablative interventions in the treatment of malignant liver lesions.
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Presynaptic m1 muscarinic receptors are necessary for mGluR long-term depression in the hippocampus.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 01-08-2010
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To investigate the role of M1 muscarininc acetylcholine receptors (m1 receptors) in metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD), we produced mouse lines in which deletion of the m1 gene is restricted to the forebrain (FB-m1KO) or hippocampal CA3 pyramidal neurons (CA3-m1KO). Stimulation in FB-m1KO hippocampal slices resulted in excitatory postsynaptic potentials and long-term synaptic plasticity (long-term potentiation and LTD) similar to controls. The mice were deficient in (S)-3,5-dihydroxyphenylglycine hydrate (DHPG)-induced mGluR LTD, which correlated with a presynaptic increase in the release of neurotransmitters. Protein kinase C (PKC) activity, which is downstream from both mGluRs and m1 receptors, was reduced in CA3 but not in CA1. The presynaptic requirement of m1 receptors was confirmed by the lack of DHPG-induced mGluR LTD in the CA1 of slices from CA3-m1KO mice. mGluR LTD was rescued by stimulating PKC activity pharmacologically in CA3-m1KO mice. These data confirm a role for PKC activation in presynaptic induction of mGluR LTD and distinguish between the roles of mGluRs and m1 receptors.
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Can outcomes of intensive care unit patients undergoing tracheostomy be predicted?
Respir Care
PUBLISHED: 12-08-2009
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To determine whether outcomes (mortality and need for intensive care unit [ICU] readmission) of patients undergoing tracheostomy in the ICU can be predicted by common clinical or historical criteria.
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Lung cancer diagnostic and treatment intervals in the United States: a health care disparity?
J Thorac Oncol
PUBLISHED: 09-16-2009
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Lung cancer diagnostic and treatment delays have been described for several patient populations. However, few studies have analyzed these intervals among patients treated in contemporary health care systems in the United States. We therefore studied the timing of lung cancer diagnosis and treatment at a U.S. medical center providing care to a diverse patient population within two different hospital systems.
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The impact of consenter characteristics and experience on patient interest in clinical research.
Oncologist
PUBLISHED: 04-28-2009
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To explain the historically low rates of participation in cancer clinical trials, several factors have been studied. These include subject characteristics and attitudes, clinical trial availability and eligibility criteria, and physician attitudes and communication skills. However, the impact of nonphysician research personnel, who often consent patients for studies, is unclear. We therefore evaluated the association between consenter characteristics and subject interest in clinical research.
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Location of patients before transfer to a tertiary care intensive care unit: impact on outcome.
J Crit Care
PUBLISHED: 03-11-2009
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To evaluate the impact of the source of patients transferred to a tertiary care intensive care unit (ICU) (referring hospital ICU vs referring hospital emergency department [ED]) on outcomes of transferred patients.
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Tissue-derived stem and progenitor cells.
Stem Cells Int
PUBLISHED: 03-06-2009
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The characterization and isolation of various stem cell populations, from embryonic through tissue-derived stem cells, have led a rapid growth in the field of stem cell research. These research efforts have often been interrelated as to the markers that identify a select cell population are frequently analyzed to determine their expression in cells of distinct organs/tissues. In this review, we will expand the current state of research involving select tissue-derived stem cell populations including the liver, central nervous system, and cardiac tissues as examples of the success and challenges in this field of research. Lastly, the challenges of clinical therapies will be discussed as it applies to these unique cell populations.
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How have we diagnosed early-stage lung cancer without radiographic screening? A contemporary single-center experience.
PLoS ONE
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The National Lung Screening Trial (NLST), which demonstrated a reduction in lung cancer mortality, may result in widespread computed tomography (CT)-based screening of select populations. How early-stage lung cancer has been diagnosed without screening, and what proportion of these cases would be captured by a screening program modeled on the NLST, is not currently known. We therefore evaluated current patterns of early-stage lung cancer presentation.
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Miscellaneous agents--cytotoxics and hormonal agents.
J Thorac Oncol
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Among the 19 presentations of miscellaneous new agents at this years meeting, several described novel cytotoxics and hormonal agents. The cytotoxic agents included microtubule inhibitors (eribulin, nanoparticle albumin-bound paclitaxel, peptide-bound paclitaxel), a topoisomerase inhibitor (nanoirinotecan), and an alkylating agent (palifosfamide). Hormonal agents included an aromatase inhibitor (anastrazole), an estrogen receptor antagonist (fulvestrant), and a selective androgen receptor modulator (GTx-024).
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Stromal platelet-derived growth factor receptor ? (PDGFR?) provides a therapeutic target independent of tumor cell PDGFR? expression in lung cancer xenografts.
Mol. Cancer Ther.
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In lung cancer, platelet-derived growth factor receptor ? (PDGFR?) is expressed frequently by tumor-associated stromal cells and by cancer cells in a subset of tumors. We sought to determine the effect of targeting stromal PDGFR? in preclinical lung tumor xenograft models (human tumor, mouse stroma). Effects of anti-human (IMC-3G3) and anti-mouse (1E10) PDGFR? monoclonal antibodies (mAb) on proliferation and PDGFR? signaling were evaluated in lung cancer cell lines and mouse fibroblasts. Therapy studies were conducted using established PDGFR?-positive H1703 cells and PDGFR?-negative Calu-6, H1993, and A549 subcutaneous tumors in immunocompromised mice treated with vehicle, anti-PDGFR? mAbs, chemotherapy, or combination therapy. Tumors were analyzed for growth and levels of growth factors. IMC-3G3 inhibited PDGFR? activation and the growth of H1703 cells in vitro and tumor growth in vivo, but had no effect on PDGFR?-negative cell lines or mouse fibroblasts. 1E10 inhibited growth and PDGFR? activation of mouse fibroblasts, but had no effect on human cancer cell lines in vitro. In vivo, 1E10-targeted inhibition of murine PDGFR? reduced tumor growth as single-agent therapy in Calu-6 cells and enhanced the effect of chemotherapy in xenografts derived from A549 cells. We also identified that low expression cancer cell expression of VEGF-A and elevated expression of PDGF-AA were associated with response to stromal PDGFR? targeting. We conclude that stromal PDGFR? inhibition represents a means for enhancing control of lung cancer growth in some cases, independent of tumor cell PDGFR? expression.
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A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma.
Lung Cancer
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Malignant mesothelioma (MM) cells express the vascular endothelial growth factor (VEGF) receptor, and VEGF protein expression is detected in a majority of human mesothelioma biopsy specimens. Bevacizumab is a recombinant humanized monoclonal antibody that blocks the binding of VEGF to its receptor. We evaluated the addition of bevacizumab to cisplatin and pemetrexed as first-line treatment in patients with advanced, unresectable MM.
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Risks of packed red blood cell transfusion in patients undergoing cardiac surgery.
J Crit Care
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Packed red blood cell (PRBC) transfusion is common in patients undergoing cardiac surgery. Evidence has accumulated demonstrating that such patients can tolerate relatively low hemoglobins, and an extensive body of literature has developed demonstrating that patients undergoing such surgery who receive PRBC are at risk for several adverse outcomes including increased mortality, atrial fibrillation, and more postoperative infections, as well as numerous other complications. The PubMed database was searched for the English language literature on the topic of PRBC transfusion and outcomes in patients undergoing cardiac surgery, as well as alternatives to this intervention. Data were reviewed to assess the impact of transfusion in patients undergoing cardiac surgery on mortality, cardiac, infectious, and pulmonary, as well as a variety of miscellaneous complications. Patients receiving PRBC were consistently identified as being at higher risk for complications in all categories. The limited prospective data were consistent with the retrospective data, which comprised most of the literature. The preponderance of the literature suggests that patients undergoing cardiac surgery can tolerate lower hemoglobin/hematocrit values than traditionally appreciated. Most published data also indicate that PRBC transfusion should be reserved for patients with an identifiable clinical/physiologic indication fir this intervention, consistent with recent specialty society guidelines.
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