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1.  Epoetin alfa decreases the number of red blood cell transfusions in patients with acute lymphoblastic leukemia, lymphoblastic lymphoma, and Burkitt’s leukemia/lymphoma—results of a randomized clinical trial 
Cancer  2011;118(3):848-855.
Purpose
Anemia is an expected consequence of intensive chemotherapy regimens administered to acute leukemia patients. This study was designed to determine if epoetin alfa would decrease the number of transfusion events and units of packed red blood cells (PRBCs) transfused, and secondarily, to study its effects on quality of life (QOL) and complete remission (CR) rates.
Patients and Methods
Patients with acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL), or Burkitt’s lymphoma (BL) receiving frontline myelosuppressive chemotherapy were randomized to receive epoetin alfa or no epoetin during the first 6 cycles of their planned chemotherapy. QOL was assessed by Edmonton Symptom Assessment Scale (ESAS) and FACT-Anemia questionnaires.
Results
Fifty five patients were randomized to epoetin alfa and 54 to no epoetin. Transfusion data was available in 79 of the 81 (98%) evaluable patients who completed the treatment/observation period. The trial was stopped early due to poor accrual before the target of 123 evaluable patients was met. A mean of 10.6 units of PRBCs over 5 months were administered to those receiving epoetin alfa compared to 13 units for those who did not (p=0.04). There was no significant difference in QOL as assessed by FACT-Anemia or ESAS. The CR rate and 3-year CR duration were not adversely affected by use of epoetin alfa.
Conclusion
Epoetin alfa decreases the number of PRBC transfusions and does not appear to negatively impact remission duration. No difference in QOL was observed.
doi:10.1002/cncr.26341
PMCID: PMC3919032  PMID: 21751205
Anemia; epoetin; leukemia
2.  The Tumor Suppressor Gene TUSC2 (FUS1) Sensitizes NSCLC to the AKT Inhibitor MK2206 in LKB1-dependent Manner 
PLoS ONE  2013;8(10):e77067.
TUSC2-defective gene expression is detected in the majority of lung cancers and is associated with worse overall survival. We analyzed the effects of TUSC2 re-expression on tumor cell sensitivity to the AKT inhibitor, MK2206, and explored their mutual signaling connections, in vitro and in vivo. TUSC2 transient expression in three LKB1-defective non-small cell lung cancer (NSCLC) cell lines combined with MK2206 treatment resulted in increased repression of cell viability and colony formation, and increased apoptotic activity. In contrast, TUSC2 did not affect the response to MK2206 treatment for two LKB1-wild type NSCLC cell lines. In vivo, TUSC2 systemic delivery, by nanoparticle gene transfer, combined with MK2206 treatment markedly inhibited growth of tumors in a human LKB1-defective H322 lung cancer xenograft mouse model. Biochemical analysis showed that TUSC2 transient expression in LKB1-defective NSCLC cells significantly stimulated AMP-activated protein kinase (AMPK) phosphorylation and enzymatic activity. More importantly, AMPK gene knockdown abrogated TUSC2-MK2206 cooperation, as evidenced by reduced sensitivity to the combined treatment. Together, TUSC2 re-expression and MK2206 treatment was more effective in inhibiting the phosphorylation and kinase activities of AKT and mTOR proteins than either single agent alone. In conclusion, these findings support the hypothesis that TUSC2 expression status is a biological variable that potentiates MK2206 sensitivity in LKB1-defective NSCLC cells, and identifies the AMPK/AKT/mTOR signaling axis as an important regulator of this activity.
doi:10.1371/journal.pone.0077067
PMCID: PMC3798310  PMID: 24146957
3.  Combined MEK and VEGFR Inhibition in orthotopic human lung cancer models results in enhanced inhibition of tumor angiogenesis, growth, and metastasis 
Clinical Cancer Research  2012;18(6):1641-1654.
Purpose
Ras/Raf/MEK/ERK signaling is critical for tumor cell proliferation and survival. Selumetinib is a potent, selective, and orally available MEK1/2 inhibitor. In the current study, we evaluated the therapeutic efficacy of selumetinib alone or with cediranib, an orally available potent inhibitor of all three VEGFR tyrosine kinases, in murine orthotopic NSCLC models.
Experimental Design
NCI-H441 or NCI-H460 KRAS-mutant human NSCLC cells were injected into the lungs of mice. Mice were randomly assigned to treatment with selumetinib, cediranib, paclitaxel, selumetinib plus cediranib, or control. When controls became moribund, all animals were sacrificed and assessed for lung tumor burden and locoregional metastasis. Lung tumors and adjacent normal tissues were subjected to immunohistochemical analyses.
Results
Selumetinib inhibited lung tumor growth and, particularly at higher dose, reduced locoregional metastasis, as did cediranib. Combining selumetinib and cediranib markedly enhanced their antitumor effects, with near complete suppression of metastasis. Immunohistochemistry of tumor tissues revealed that selumetinib alone or with cediranib reduced ERK phosphorylation, angiogenesis, and tumor cell proliferation and increased apoptosis. The antiangiogenic and apoptotic effects were substantially enhanced when the agents were combined. Selumetinib also inhibited lung tumor VEGF production and VEGFR signaling.
Conclusions
In the current study, we evaluated therapy directed against MEK combined with antiangiogenic therapy in distinct orthotopic NSCLC models. MEK inhibition resulted in potent antiangiogenic effects with decreased VEGF expression and signaling. Combining selumetinib with cediranib enhanced their anti-tumor and antiangiogenic effects. We conclude that combining selumetinib and cediranib represents a promising strategy for the treatment of NSCLC.
doi:10.1158/1078-0432.CCR-11-2324
PMCID: PMC3306446  PMID: 22275507
angiogenesis; selumetinib; cediranib; lung cancer; VEGF; MEK
4.  AP2β nucleolar localization predicts poor survival after stage I non–small cell lung cancer resection 
The Annals of Thoracic Surgery  2011;92(3):1044-1050.
Background
Activating enhancer-binding protein-2β (AP2β) is a transcription factor involved in apoptosis. The purpose of the current study was to assess the cellular location and level of AP2β in Non-Small Cell Lung Cancer (NSCLC) and normal lung tissue and investigate whether the level and localization of AP2β expression is predictive of overall survival in patients with stage I NSCLC.
Methods
We performed immunohistochemical analysis of tissue microarrays (TMAs) prepared from stage I NSCLC specimens with adjacent normal lung tissue from two independent sets of patients who underwent lung resection with curative intent at our institution. AP2β intensity was assessed in TMAs, and AP2β staining patterns were classified as either diffuseor nucleolar in the TMAs. AP2β intensity and localization were analyzed for correlation with patients' survival.
Results
Immunohistochemical analysis of TMAs showed that the intensity of AP2β immunohistochemical staining did not correlate with overall survival. When location of AP2β was analyzed in TMAs, all of the normal lung tissue had diffuse pattern of AP2β. In the first set of NSCLC, patients with nucleolar pattern had a significantly lower 5-year survival rate than patients with diffuse pattern (67% vs. 100%; P = 0.004); this finding was confirmed in the second set (64% vs. 91%; P = 0.02). Multivariate analysis revealed that nucleolar pattern was an independent predictor of poor overall survival in both sets.
Conclusions
The AP2β which is located in the nucleoplasm in normal lung tissue is found in either nucleoplasm or nucleoli in NSCLC. The patients with AP2β in the nucleoli had poor survival compared to patients with AP2β in the cytoplasm.
doi:10.1016/j.athoracsur.2011.04.029
PMCID: PMC3272351  PMID: 21871297
Lung cancer biology; survival analysis
5.  Myeloid Biomarkers Associated with Glioblastoma Response to Anti-Vascular Endothelial Growth Factor Therapy with Aflibercept 
Purpose
Vascular endothelial growth factor (VEGF) and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma.
Experimental Design
In this single-arm phase II trial aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days post-treatment. Plasma cytokines and angiogenic factors were quantified using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients.
Results
Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours post-treatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1+ monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating MMP9.
Conclusions
These data suggest that decreases in VEGF post-treatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis.
doi:10.1158/1078-0432.CCR-11-0271
PMCID: PMC3139700  PMID: 21632852
6.  Phase II study of dasatinib in the treatment of head and neck squamous cell carcinoma (HNSCC) 
Cancer  2010;117(10):2112-2119.
Purpose
Treatment options for patients with advanced HNSCC are scarce. This phase II study was conducted to evaluate the safety, tolerability, PK, and efficacy of dasatinib in this setting.
Experimental Design
Patients with recurrent and/or metastatic HNSCC after platinum-based therapy were treated with dasatinib either orally or via percutaneous feeding gastrostomy (PFG). Primary endpoints were 12-week progression-free survival (PFS) and objective response rate (ORR) with a 2 stage design and early stopping if 12-week PFS was 20% or less and no patients had an objective response (OR). Forty-nine serum cytokines and angiogenic factors (CAFs) were analyzed from treated patients.
Results
Of fifteen patients enrolled, twelve were evaluable for response, and all were evaluable for toxicity. No OR was observed and two patients (16.7%) had stable disease (SD) at eight weeks. Median treatment duration was 59 days, median time to progression (TTP) 3.9 weeks, and survival 26 weeks. One patient required dose reduction, 3 required interruptions, and 4 were hospitalized for toxicity. Dasatinib inhibited c-Src both when ingested and via PFG. Greater mean drug exposure, decreased half-life, and greater maximum concentration was observed in patients receiving dasatinib via PFG. Eleven baseline CAFs were associated with treatment outcome and one, MIF, was differentially modulated in correlation with SD versus progression.
Conclusions
Single-agent dasatinib failed to demonstrate significant activity in advanced HNSCC, despite c-Src inhibition. The toxicity profile was consistent with that reported in other solid tumors, and the drug can be given via PFG tube.
doi:10.1002/cncr.25769
PMCID: PMC3117018  PMID: 21523723
head and neck squamous cell cancer; serum markers
7.  Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the CNS 
Purpose
To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain.
Methods and Materials
Fourteen patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system (CNS) radiation necrosis. All patients were required to have radiographic or biopsy proof of CNS radiation necrosis and progressive neurological symptoms or signs. Eligible patients received irradiation for head and neck carcinomas, meningioma, or low- to mid-grade gliomas. Patients were randomized to receive IV saline or bevacizumab at 3-week intervals. MRI 3-weeks after the second treatment and clinical signs and symptoms defined response or progression.
Results
The volumes of necrosis estimated on T2FLAIR and T1-weighted gadolinium-enhanced MRI demonstrated that, while no patient receiving placebo responded (0/7), all bevacizumab-treated patients did (5/5 randomized and 7/7 cross-over) with decreases in T2FLAIR and T1-weighted gadolinium-enhanced volumes and decrease Ktrans. All bevacizumab-treated patients – and none of the placebo-treated patients - showed improvement in neurological symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all 4 study doses, only 2 patients had experienced a recurrence of MRI changes consistent with progressive radiation necrosis, and this was the only patient to receive only 2 treatments with bevacizumab.
Conclusions
This class I evidence of bevacizumab efficacy in the treatment of CNS radiation necrosis justifies consideration of this treatment option for people who suffer radiation necrosis secondary to the treatment of head and neck and brain cancers.
doi:10.1016/j.ijrobp.2009.12.061
PMCID: PMC2908725  PMID: 20399573
brain edema; magnetic resonance imaging; volumetric MRI changes; Ktrans; neurotoxicity
8.  EXTENSIVE DISEASE SMALL CELL LUNG CANCER DOSE-RESPONSE RELATIONSHIPS: IMPLICATIONS FOR RESISTANCE MECHANISMS 
Background
Some studies (but not others) suggested high doses are beneficial in small cell lung cancer (SCLC). We hypothesized dose-response curve (DRC) shape reflects resistance mechanisms.
Methods
We reviewed published SCLC clinical trialss and converted response rates into estimated mean tumor cell kill, assuming killing is proportional to reduction in tumor volume. Mean % cell survival was plotted vs planned dose-intensity. Nonlinear and linear meta-regression analyses (weighted according to the number of patients in each study) were used to assess DRC characteristics.
Results
Although associations between dose and cell survival were not statistically significant, DRCs sloped downward for 5 of 7 agents across all doses and for all 7 when lowest doses were excluded. Maximum mean cell kill across all drugs and doses was approximately 90%, suggesting there may be a maximum achievable tumor cell kill irrespective of number of agents or drug doses.
Conclusions
Downward DRC slopes suggest that maintaining relatively high doses may possibly maximize palliation, although the associations between dose and slope did not achieve statistical significance, and slopes for most drugs tended to be shallow. DRC flattening at higher doses would preclude cure, and would suggest that “saturable passive resistance” (deficiency of factors required for cell killing) limits maximum achievable cell kill. An example of factors that could flatten the dose-response curve at higher doses and lead to saturable passive resistance would be presence of quiescent, non-cycling cells.
doi:10.1097/JTO.0b013e3181f387c7
PMCID: PMC2966343  PMID: 20881640
small cell; dose-response; resistance; quiescence
9.  Phase II Study of Dasatinib in Patients With Advanced Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2010;28(30):4609-4615.
Purpose
Src family kinases (SFKs) promote cancer progression and are commonly expressed in non–small-cell lung cancer (NSCLC), but the clinical effects of SFK inhibition in NSCLC are unknown. We conducted a phase II trial of the SFK inhibitor dasatinib for advanced NSCLC. We tested the hypotheses that the activation of epidermal growth factor receptor (EGFR) or SFK or modulation of serum cytokines may predict a response to dasatinib.
Patients and Methods
Patients received dasatinib as first-line therapy. Response was measured by tumor size on computed tomography scans and by metabolic activity on positron emission tomography scans. Tissue samples taken before patients received dasatinib were tested for EGFR and Kras mutation and phosphorylated SFK expression.
Results
Thirty-four patients were enrolled. The overall disease control rate (partial responses plus stable disease) for dasatinib was 43%. One patient had a partial response to therapy. Eleven patients (32%) had a metabolic response to dasatinib. SFK activation and EGFR and Kras mutations in tumor tissue did not predict response to dasatinib. Significant toxicities included fatigue and dyspnea. The presence of a pleural effusion before dasatanib therapy predicted the development of a clinically significant effusion during therapy.
Conclusion
Dasatinib as a single agent had modest clinical activity that was lower than that generally observed in patients with NSCLC who receive chemotherapy. Pleural effusion was an expected and problematic toxicity that was successfully treated with steroids, diuretics, and dose interruptions. Marked activity in one patient and prolonged stable disease in four others suggested a potential subpopulation of patients with dasatinib-sensitive NSCLC.
doi:10.1200/JCO.2010.30.5474
PMCID: PMC2974341  PMID: 20855820
10.  Assessing Toxicities in a Clinical Trial: Bayesian Inference for Ordinal Data Nested within Categories 
Biometrics  2010;66(3):966-974.
Summary
This article addresses modeling and inference for ordinal outcomes nested within categorical responses. We propose a mixture of normal distributions for latent variables associated with the ordinal data. This mixture model allows us to fix without loss of generality the cutpoint parameters that link the latent variable with the observed ordinal outcome. Moreover, the mixture model is shown to be more flexible in estimating cell probabilities when compared to the traditional Bayesian ordinal probit regression model with random cutpoint parameters. We extend our model to take into account possible dependence among the outcomes in different categories. We apply the model to a randomized phase III study to compare treatments on the basis of toxicities recorded by type of toxicity and grade within type. The data include the different (categorical) toxicity types exhibited in each patient. Each type of toxicity has an (ordinal) grade associated to it. The dependence among the different types of toxicity exhibited by the same patient is modeled by introducing patient-specific random effects.
doi:10.1111/j.1541-0420.2009.01359.x
PMCID: PMC3062977  PMID: 19930188
Adverse events; Clinical trial; Gibbs sampling; Latent variable; Ordinal data nested within categories; Probit model
11.  Genome-wide DNA methylation profiling of chronic lymphocytic leukemia allows identification of epigenetically repressed molecular pathways with clinical impact 
Epigenetics  2010;5(6):499-508.
We performed a genome-wide analysis of aberrant DNA methylation in chronic lymphocytic leukemia (CLL) using methylated CpG island amplification (MCA) coupled with a promoter microarray. We identified 280 potential targets of aberrant DNA methylation in CLL. These genes were located more frequently in chromosomes 19 (16%, p = 0.001), 16 (11%, p = 0.001), 17 (10%, p = 0.02) and 11 (9%, p = 0.02) and could be grouped in several functional networks. Methylation status was confirmed for 22 of these genes (SOX11, DLX1, FAM62C, SOX14, RSPO1, ADCY5, HAND2, SPOCK, MLL, ING1, PRIMA1, BCL11B, LTBP2, BNC1, NR2F2, SALL1, GALGT2, LHX1, DLX4, KLK10, TFAP2 and APP) in 78 CLL patients by pyrosequencing. As a proof of principle, we analyzed the expression of 2 genes, PRIMA1 and APP, in primary cells and of GALGT2, TFAP2C and PRIMA1 in leukemia cells. There was an inverse association between methylation and gene expression. This could be reversed by treatment with 5-aza-2′-deoxycytidine in cell lines. Treatment in a clinical trial with 5-azacitidine resulted in decreased methylation of LINE, DLX4 and SALL1 in the peripheral blood B-cells of patients with CLL. IgVH mutational status or ZAP-70 expression were not associated with specific methylation profiles. By multivariate analysis, methylation of LINE and APP was associated with shorter overall survival (p = 0.045 and 0.0035, respectively). This study demonstrates that aberrant DNA methylation is common and has potential prognostic and therapeutic value in CLL.
doi:10.4161/epi.5.6.12179
PMCID: PMC3322493  PMID: 20484983
chronic lymphocytic leukemia; DNA methylation; MCA/promoter microarray; epigenetics
12.  Adult ependymal tumors: prognosis and the M. D. Anderson Cancer Center experience 
Neuro-Oncology  2010;12(8):862-870.
Ependymomas in adults are rare and often misdiagnosed. This study reports on a series of adult patients with confirmed ependymoma treated at The University of Texas M. D. Anderson Cancer Center (MDACC). Patients aged >17 and with ependymoma were identified, and clinical data were collected by retrospective chart review. Descriptive statistics were used to describe the clinical data, Kaplan–Meier methods were used to generate survival curves, and Cox proportional hazards models were used to evaluate the association of clinical characteristics with survival. This series included 123 adult patients [51% male; median age 39 years (18–72)]. Forty had tumors in the brain, 80 in the spine, and 3 had both. The majority were Grade I/II lesions (108) vs Grade III (anaplastic; 15). Eighteen patients had tumors that were reclassified as ependymal tumors at MDACC. The most common presenting symptom was pain, with an average of 4 symptoms reported prior to diagnosis. Sixty-three percent of patients had a gross total resection, and 49% received radiation therapy. Average follow-up was 5.5 years, and 13% had died. Median time to recurrence was 21 months (Grade II) brain and 18 months (Grade III). Worse outcome measured by overall and progression-free survival were associated with brain location (P = .01, P = .04) and tumor anaplasia (P = .0025, P = .001). An MIB-1 > 10 was associated with worse outcome (P = .03). Tumor grade and brain location are associated with a worse prognosis. Reclassification of ependymoma by neuropathologists is common. Results of this study have lead to a multicenter study to further define important diagnostic and prognostic variables for adults with ependymoma.
doi:10.1093/neuonc/noq009
PMCID: PMC2940672  PMID: 20511182
brain tumor; ependymoma; prognosis
13.  Mesenchymal Stem Cells Display Tumor-Specific Tropism in an RCAS/Ntv-a Glioma Model1 
Neoplasia (New York, N.Y.)  2011;13(8):716-725.
Bone marrow-derived mesenchymal stem cells (MSCs) have been shown to localize to gliomas and deliver therapeutic agents. However, the clinical translation of MSCs remains poorly defined because previous studies relied on glioma models with uncertain relevance to human disease, typically xenograft models in immunocompromised mice. To address this shortcoming, we used the RCAS/Ntv-a system, in which endogenous gliomas that recapitulate the tumor and stromal features of human gliomas develop in immunocompetent mice. MSCs were harvested from bonemarrowof Ntv-a mice and injected into the carotid artery of Ntv-a mice previously inoculated with RCAS-PDGF-B and RCAS-IGFBP2 to induce malignant gliomas (n = 9). MSCs were labeled with luciferase for in vivo bioluminescence imaging (BLI). After intra-arterial injection, BLI revealed MSCs in the right frontal lobe in seven of nine mice. At necropsy, gliomas were detected within the right frontal lobe in all these mice, correlating with the location of the MSCs. In the twomice without MSCs based on BLI, no tumor was found, indicating thatMSC localization was tumor specific. In another cohort of mice (n = 9), MSCs were labeled with SP-DiI, a fluorescent vital dye. After intra-arterial injection, fluorescence microscopy revealed SP-DiI-labeled MSCs throughout tumors 1 to 7 days after injection but not in nontumoral areas of the brain. MSCs injected intravenously did not localize to tumors (n = 12). We conclude that syngeneic MSCs are capable of homing to endogenous gliomas in immunocompetent mice. These findings support the use of MSCs as tumor-specific delivery vehicles for treating gliomas.
PMCID: PMC3156662  PMID: 21847363
14.  Nrf2 and Keap1 Abnormalities in Non-Small Cell Lung Carcinoma and Association with Clinicopathologic Features 
Purpose
To understand the role of Nrf2 and Keap1 in NSCLC, we studied their expression in a large series of tumors with annotated clinicopathologic data, including response to platinum-based adjuvant chemotherapy.
Experimental design
We determined the immunohistochemical expression of nuclear Nrf2 and cytoplasmic Keap1 in 304 NSCLCs and its association with patients’ clinicopathologic characteristics, and in 89 tumors from patients who received neoadjuvant (n=26) or adjuvant platinum-based chemotherapy (n=63). We evaluated NFE2L2 and KEAP1 mutations in 31 tumor specimens.
Results
We detected nuclear Nrf2 expression in 26% of NSCLCs; it was significantly more common in squamous cell carcinomas (38%) than in adenocarcinomas (18%; P<0.0001). Low or absent Keap1 expression was detected in 56% of NSCLCs; it was significantly more common in adenocarcinomas (62%) than in squamous cell carcinomas (46%; P=0.0057). In NSCLC, mutations of NFE2L2 and KEAP1 were very uncommon (2 of 29 and 1 of 31 cases, respectively). In multivariate analysis, Nrf2 expression was associated with worse overall survival (P=0.0139; HR=1.75) in NSCLC patients, and low or absent Keap1 expression was associated with worse overall survival (P=0.0181; HR=2.09) in squamous cell carcinoma. In univariate analysis, nuclear Nrf2 expression was associated with worse recurrence-free survival in squamous cell carcinoma patients who received adjuvant treatment (P=0.0410; HR=3.37).
Conclusions
Increased expression of Nrf2 and decreased expression of Keap1 are common abnormalities in NSCLC and are associated with a poor outcome. Nuclear expression of Nrf2 in malignant lung cancer cells may play a role in resistance to platinum-based treatment in squamous cell carcinoma.
doi:10.1158/1078-0432.CCR-09-3352
PMCID: PMC2920733  PMID: 20534738
Nrf2; Keap1; NSCLC
15.  Phase I/II Study of Combination Therapy With Sorafenib, Idarubicin, and Cytarabine in Younger Patients With Acute Myeloid Leukemia 
Journal of Clinical Oncology  2010;28(11):1856-1862.
Purpose
To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years.
Patients and Methods
In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m2 IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days.
Results
Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity.
Conclusion
Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.
doi:10.1200/JCO.2009.25.4888
PMCID: PMC2930809  PMID: 20212254
16.  CREB Overexpression: A Feature Associated with Negative Prognosis in Never-Smokers with NSCLC 
Cancer research  2008;68(15):6065-6073.
Lung cancer is the leading cause of cancer deaths worldwide. Recent advances in targeted therapies hold promise for the development of new treatments for certain subsets of cancer patients by targeting specific signaling molecule. Based on the identification of the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB) as an important regulator of growth of several types of cancers and our recent findings of its importance in normal differentiation of bronchial epithelial cells, we hypothesized that CREB plays an important pathobiologic role in lung carcinogenesis. We conducted this initial study to determine whether the expression and activation status of CREB are altered in non-small cell lung cancer (NSCLC) and of any prognostic importance in NSCLC patients. We found that the expression levels of mRNA and protein of CREB and phosphorylated CREB (p-CREB) were significantly higher in most of the NSCLC cell lines and tumor specimens than in the normal human tracheobronchial epithelial (NHTBE) cells and adjacent normal lung tissue, respectively. Analysis of CREB mRNA expression and the CREB gene copy number showed that CREB overexpression occurred mainly at the transcriptional level. Immunohistochemical analysis of tissue microarray (TMA) slides containing sections of NSCLC specimens obtained from 310 patients showed that a decreased survival duration was significantly associated with overexpression of CREB or p-CREB in never-smokers but not in current or former smokers with NSCLC. These are the first reported results illustrating the potential of CREB as a molecular target for the prevention and treatment of NSCLC, especially in never-smokers.
doi:10.1158/0008-5472.CAN-07-5376
PMCID: PMC3058903  PMID: 18676828
CREB overexpression; prognosis; NSCLC; adenocarcinoma; squamous cell carcinoma
17.  MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma 
Neuro-Oncology  2009;12(2):116-121.
Hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene has been shown to be associated with improved outcome in glioblastoma (GBM) and may be a predictive marker of sensitivity to alkylating agents. However, the predictive utility of this marker has not been rigorously tested with regard to sensitivity to other therapies, namely radiation. To address this issue, we assessed MGMT methylation status in a cohort of patients with GBM who underwent radiation treatment but did not receive chemotherapy as a component of adjuvant treatment. Formalin-fixed, paraffin-embedded tumor samples from 225 patients with newly diagnosed GBM were analyzed via methylation-specific, quantitative real-time polymerase chain reaction following bisulfite treatment on isolated DNA to assess MGMT promoter methylation status. In patients who received radiotherapy alone following resection, methylation of the MGMT promoter correlated with an improved response to radiotherapy. Unmethylated tumors were twice as likely to progress during radiation treatment. The median time interval between resection and tumor progression of unmethylated tumors was also nearly half that of methylated tumors. Promoter methylation was also found to confer improved overall survival in patients who did not receive adjuvant alkylating chemotherapy. Multivariable analysis demonstrated that methylation status was independent of age, Karnofsky performance score, and extent of resection as a predictor of time to progression and overall survival. Our data suggest that MGMT promoter methylation appears to be a predictive biomarker of radiation response. Since this biomarker has also been shown to predict response to alkylating agents, perhaps MGMT promoter methylation represents a general, favorable prognostic factor in GBM.
doi:10.1093/neuonc/nop020
PMCID: PMC2940581  PMID: 20150378
glioblastoma; methylation; MGMT; prognostic marker; radiotherapy
18.  Combination Treatment with MEK and AKT Inhibitors Is More Effective than Each Drug Alone in Human Non-Small Cell Lung Cancer In Vitro and In Vivo 
PLoS ONE  2010;5(11):e14124.
AZD6244 and MK2206 are targeted small-molecule drugs that inhibit MEK and AKT respectively. The efficacy of this combination in lung cancer is unknown. Our previous work showed the importance of activated AKT in mediating resistance of non-small cell lung cancer (NSCLC) to AZD6244. Thus we hypothesized that dual inhibition of both downstream MEK and AKT pathways would induce synergistic antitumor activity. In this study, we evaluated the efficacy of AZD6244 and MK2206 individually on a large panel of lung cancer cell lines. Then, we treated 28 human lung cancer cell lines with a combination of AZD6244 and MK2206 at clinically applicable drug molar ratios. The AZD6244-MK2206 combination therapy resulted in a synergistic effect on inhibition of lung cancer cell growth compared to the results of single drug treatment alone. MK2206 enhanced AZD6244-induced Bim overexpression and apoptosis in A549 and H157 cells. When we tested the combination of AZD6244 and MK2206 at ratios of 8∶1, 4∶1, 2∶1, and 1∶8, we found that the synergistic effect of the combination therapy was ratio-dependent. At ratios of 8∶1, 4∶1, and 2∶1, the drug combination consistently demonstrated synergy, whereas decreasing the ratio to 1∶8 resulted in a loss of synergy and produced an additive or antagonistic effect in most cell lines. Furthermore, the AZD6244-MK2206 combination therapy showed synergy in the suppression of A549 and H157 xenograft tumor growth and increased mean animal survival time. The AZD6244-MK2206 combination therapy resulted in effective inhibition of both p-ERK and p-AKT expression in tumor tissue. In addition, a significant increase of apoptosis was detected in tumor tissue from mice treated with AZD6244-MK2206 compared with that from the single agent treated mice. Our study suggests that the combination of AZD6244 and MK2206 has a significant synergistic effect on tumor growth in vitro and in vivo and leads to increased survival rates in mice bearing highly aggressive human lung tumors.
doi:10.1371/journal.pone.0014124
PMCID: PMC2993951  PMID: 21124782
19.  Application of the revised lung cancer staging system (IASLC Staging Project) to a cancer center population 
Objective
The International Association for the Study of Lung Cancer (IASLC) proposed a revision to the Union Internationale Contre le Cancer (UICC-6) staging system for non–small cell lung cancer. The goal of our study was to compare these systems in patients undergoing surgery for non–small cell lung cancer to determine whether one system is superior in staging operable disease.
Methods
Pathologic stages in 1154 patients undergoing complete resection over a 9-year period were analyzed. Patients were assigned a stage based on both IASLC and UICC-6 systems. We tested for statistically meaningful differences between the two staging systems using the Wilcoxon signed rank test and the permutation test.
Results
The IASLC system is more effective than the UICC-6 system at ordering and differentiating patients (P = .009). Application of the IASLC system resulted in 202 (17.5%) patients being reassigned to a different stage (P = .012), with the most common shifts occurring from IB to IIA and IIIB to IIIA. The 5-year and median survivals of the IASLC IIIA patients including those shifted from the UICC-6 IIIB were 37% and 35 months, respectively. Reclassifying UICC-6 IIIB to IASLC IIIA did not reduce survival for the newly characterized IIIA cohort.
Conclusion
Our data confirm that the proposed IASLC staging system is more effective at differentiating stage than the UICC-6 system. Reclassifying patients from UICC-6 IIIB to IASLC IIIA will shift some patients from a stage previously considered unresectable to a stage frequently offered surgical resection. Further study and validation of the IASLC system are warranted.
doi:10.1016/j.jtcvs.2009.01.033
PMCID: PMC2731793  PMID: 19619787
20.  A Bayesian hierarchical mixture model for platelet derived growth factor receptor phosphorylation to improve estimation of progression-free survival in prostate cancer 
SUMMARY
Advances in understanding the biological underpinnings of many cancers have led increasingly to the use of molecularly targeted anti-cancer therapies. Because the platelet-derived growth factor receptor (PDGFR) has been implicated in the progression of prostate cancer bone metastases, it is of great interest to examine possible relationships between PDGFR inhibition and therapeutic outcomes. Here, we analyze the association between change in activated PDGFR (p-PDGFR) and progression free survival (PFS) time based on large within-patient samples of cell-specific p-PDGFR values taken before and after treatment from each of 88 prostate cancer patients. To utilize these paired samples as covariate data in a regression model for PFS time, and because the p-PDGFR distributions are bimodal, we first employ a Bayesian hierarchical mixture model to obtain a deconvolution of the pre-treatment and post-treatment within-patient p-PDGFR distributions. We evaluate fits of the mixture model and a non-mixture model that ignores the bimodality by using a supnorm metric to compare the empirical distribution of each p-PDGFR data set with the corresponding fitted distribution under each model. Our results show that first using the mixture model to account for the bimodality of the within-patient p-PDGFR distributions, and then using the posterior within-patient component mean changes in p-PDGFR so obtained as covariates in the regression model for PFS time provides an improved estimation.
doi:10.1111/j.1467-9876.2009.00680.x
PMCID: PMC2853262  PMID: 20390057
Bayesian analysis; Survival analysis; Markov chain Monte Carlo; Platelet derived growth factor receptor; Prostate cancer
21.  Loss and Reduction of Fus1 Protein Expression is a Frequent Phenomenon in the Pathogenesis of Lung Cancer 
Purpose
FUS1, a novel tumor-suppressor gene located in the chromosome 3p21.3 region, may play an important role in lung cancer development. Currently, FUS1-expressing nanoparticles have been developed for treating patients with lung cancer. However, the expression of Fus1 protein has not been examined in a large series of lung cancers and their sequential preneoplastic lesions.
Experimental Design
Using tissue microarrays, we examined Fus1 immunohistochemical expression in 281 non – small cell lung carcinoma (NSCLC) and 22 small cell lung carcinoma tissue specimens and correlated the findings with patients’ clinicopathologic features. To investigate the expression of Fus1 in the early sequential pathogenesis of NSCLC, we studied Fus1 expression in 211 histologically normal and mildly abnormal bronchial epithelia, and 118 bronchial and alveolar preneoplastic lesions obtained from patients with lung cancer.
Results
Loss and reduction of expression was detected in 82% of NSCLCs and 100% of small cell lung carcinomas. In NSCLCs, loss of Fus1 immunohistochemical expression was associated with significantly worse overall survival. Bronchial squamous metaplastic and dysplastic lesions expressed significantly lower levels of Fus1 compared with normal (P = 0.014 and 0.047, respectively) and hyperplastic (P = 0.013 and 0.028, respectively) epithelia.
Conclusions
Our findings show a high frequency of Fus1 protein loss and reduction of expression in lung cancer, and suggests that this reduction may play an important role in the early pathogenesis of lung squamous cell carcinoma. These findings support the concept that FUS1 gene and Fus1 protein abnormalities could be used to develop new strategies for molecular cancer therapy for a significant subset of lung tumors.
doi:10.1158/1078-0432.CCR-07-1252
PMCID: PMC2833352  PMID: 18172250
22.  Elevated phospho-S6 expression is associated with metastasis in adenocarcinoma of the lung 
Purpose
The primary objective of this study was to determine whether markers of differentiation and activation of the Akt pathway are associated with metastasis in adenocarcinoma of the lung.
Experimental Design
Paired primary and metastatic tumor samples were obtained from 41 patients who had undergone resection of both primary lung adenocarcinoma and brain metastatic lesions. Paired samples were compared for relative expression of TTF-1 and E-cadherin as potential markers of differentiation. Activation of the Akt pathway was assessed by expression of p-Akt and p-S6. Biomarkers which showed relative discordance in expression between the matched pairs were then assessed in a cohort of 77 primary lung adenocarcinomas. Validation was performed in an independent cohort of 82 primary lung adenocarcinomas.
Results
Among the 41 matched pairs, E-cadherin (23 discordant pairs) and TTF-1 (18 discordant pairs) were overexpressed in primary tumors (20/23 and 15/18, respectively). In contrast, p-S6 overexpression was significantly associated with metastatic tumors (20 of 21 discordant pairs). The expression of E-cadherin, p-S6 and TTF-1 was evaluated in 77 primary lung adenocarcinomas, where high p-S6 expression was associated with shorter time to metastasis. The association of p-S6 with metastasis was then validated in an independent set of 82 tumors. In multivariable analysis, p-S6 expression was a negative independent predictor of metastasis-free survival after adjustment for tumor stage.
Conclusions
p-S6 is overexpressed in metastatic tumors. In primary tumors, higher p-S6 expression is associated with shorter metastatic-free survival. This biomarker has the potential for risk stratification in future clinical trials.
doi:10.1158/1078-0432.CCR-08-0565
PMCID: PMC2614348  PMID: 19047111
23.  VEGF Trap induces antiglioma effect at different stages of disease 
Neuro-Oncology  2008;10(6):940-945.
Pathological angiogenesis is a hallmark of cancer, specifically of glioblastomas, the most malignant and common primary brain tumor. Vascular endothelial growth factor (VEGF) is the key protein in the regulation of the hypervascular phenotype of primary malignant brain tumors. In this study, we tested VEGF Trap, a soluble decoy receptor for VEGF, in an intracranial glioma model. VEGF Trap was administered in short or prolonged schedules to animals bearing human gliomas at different stages of disease. Of importance, VEGF Trap treatment was efficacious in both initial and advanced phases of tumor development by significantly increasing overall survival. Furthermore, this effect was enhanced in animals treated with more prolonged regimens. In addition, we observed the emergence of a VEGF Trap-resistant phenotype characterized by tumor growth and increased invasiveness. Our results suggest that VEGF Trap will be effective in treating both patients with recurrent or progressive resectable glioblastoma and patients that have undergone extensive initial surgery. Finally, our results indicate that the clinical success of VEGF Trap may depend on a prolonged treatment in combined therapy aiming to simultaneously inhibit angiogenesis and tumor invasion.
doi:10.1215/15228517-2008-061
PMCID: PMC2719008  PMID: 18708344
glioblastoma; therapy; VEGF; VEGF Trap
24.  Epithelial-to-Mesenchymal Transition in the Development and Progression of Adenocarcinoma and Squamous Cell Carcinoma of the Lung 
Epithelial-to-mesenchymal transition is a process in which cells undergo a developmental switch from an epithelial to a mesenchymal phenotype. We investigated the role of this phenomenon in the pathogenesis and progression of adenocarcinoma and squamous cell carcinoma of the lung. Archived tissue from primary tumors (n=325) and brain metastases (n=48) and adjacent bronchial epithelial specimens (n=192) were analyzed for immunohistochemical expression by image analysis of E-cadherin, N-cadherin, integrin-αvβ6, vimentin, and matrix metalloproteinase-9. The findings were compared with patients’ clinicopathologic features. High expression of the epithelial-to-mesenchymal transition phenotype (low E-cadherin and high N-cadherin, integrin-αvβ6, vimentin, and matrix metalloproteinase-9) was found in most lung tumors examined, and the expression pattern varied according to the tumor histologic type. Low E-cadherin membrane and high N-cadherin cytoplasmic expression were significantly more common in squamous cell carcinoma than in adenocarcinoma (P=0.002 and 0.005, respectively). Dysplastic lesions had significantly lower expression of the epithelial-to-mesenchymal transition phenotype than did squamous cell carcinomas, and integrin-αvβ6 membrane expression increased stepwise according to the histopathologic severity. Brain metastases had decreased epithelial-to-mesenchymal transition expression compared with primary tumors. Brain metastases had significantly lower integrin-αvβ6 membrane (P=0.04) and N-cadherin membrane and cytoplasm (P<0.0002) expression than did primary tumors. The epithelial-to-mesenchymal transition phenotype is commonly expressed in primary squamous cell carcinoma and adenocarcinoma of the lung; this expression occurs early in the pathogenesis of squamous cell carcinoma. Brain metastases showed characteristics of reversed mesenchymal-to-epithelial transition. Our findings suggest that epithelial-to-mesenchymal transition is a potential target for lung cancer chemoprevention and therapy.
doi:10.1038/modpathol.2009.19
PMCID: PMC2675657  PMID: 19270647
epithelial-to-mesenchymal transition; tissue microarray; immunohistochemical analysis; lung cancer; preneoplasia; brain metastases
25.  Monitoring late-onset toxicities in phase I trials using predicted risks 
Biostatistics (Oxford, England)  2007;9(3):442-457.
Late-onset (LO) toxicities are a serious concern in many phase I trials. Since most dose-limiting toxicities occur soon after therapy begins, most dose-finding methods use a binary indicator of toxicity occurring within a short initial time period. If an agent causes LO toxicities, however, an undesirably large number of patients may be treated at toxic doses before any toxicities are observed. A method addressing this problem is the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell, 2000). We propose a Bayesian dose-finding method similar to the TITE-CRM in which doses are chosen using time-to-toxicity data. The new aspect of our method is a set of rules, based on predictive probabilities, that temporarily suspend accrual if the risk of toxicity at prospective doses for future patients is unacceptably high. If additional follow-up data reduce the predicted risk of toxicity to an acceptable level, then accrual is restarted, and this process may be repeated several times during the trial. A simulation study shows that the proposed method provides a greater degree of safety than the TITE-CRM, while still reliably choosing the preferred dose. This advantage increases with accrual rate, but the price of this additional safety is that the trial takes longer to complete on average.
doi:10.1093/biostatistics/kxm044
PMCID: PMC3294317  PMID: 18084008
Adaptive design; Bayesian inference; Dose finding; Isotonic regression; Latent variables; Markov chain Monte Carlo; Ordinal modeling; Predictive probability

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