JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Therapy with bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma: final results of a phase II trial (CALGB 50501).
Leuk. Lymphoma
PUBLISHED: 07-06-2014
Show Abstract
Hide Abstract
Cancer and Leukemia Group B designed a phase II trial of lenalidomide + bortezomib for relapsed/refractory mantle cell lymphoma (MCL). Induction therapy was lenalidomide (days 1-14) plus bortezomib (days 1/4/8/11), every 21 days for eight cycles. Complete/partial responders (CR, PR) received maintenance lenalidomide (days 1-14) and bortezomib (days 1/8), every 21 days. Primary endpoint was overall response rate; secondary endpoints were CR rate, progression-free (PFS), event-free (EFS) and overall survival (OS). Fifty-three eligible patients, median age 67 years, were accrued. Median number of cycles received was 4 (range, 1-82). Median followup was 46 (range, 12-67) months. Best response was CR 15%, PR 25%. 5/8 CR, and 4/13 PR patients received maintenance. Six CR and one PR patient remain in remission (median, 3.2 years). Thirty-three (62%) patients have died. One-year PFS, EFS and OS are 40%, 25% and 68%, respectively. This combination will not be pursued further.
Related JoVE Video
CALGB 150905 (Alliance): rituximab broadens the antilymphoma response by activating unlicensed NK cells.
Cancer Immunol Res
PUBLISHED: 06-23-2014
Show Abstract
Hide Abstract
Natural killer (NK) cells contribute to clinical responses in patients treated with rituximab, but the rules determining NK-cell responsiveness to mAb therapies are poorly defined. A deeper understanding of the mechanisms responsible for antibody-dependent cellular cytotoxicity (ADCC) could yield useful biomarkers for predicting clinical responses in patients. Unlicensed NK cells, defined as NK cells lacking expression of an inhibitory KIR for self-HLA class I ligands, are hyporesponsive in steady state, but are potent effectors in inflammatory conditions. We hypothesized that antitumor antibodies such as rituximab can overcome NK-cell dependence on licensing, making unlicensed NK cells important for clinical responses. Here, we examined the influences of variations in KIR and HLA class I alleles on in vitro responses to rituximab. We tested the clinical significance in a cohort of patients with follicular lymphoma treated with rituximab-containing mAb combinations, and show that rituximab triggers responses from all NK-cell populations regardless of licensing. Neither IL2 nor accessory cells are required for activating unlicensed NK cells, but both can augment rituximab-mediated ADCC. Moreover, in 101 patients with follicular lymphoma treated with rituximab-containing mAb combinations, a "missing ligand" genotype (predictive of unlicensed NK cells) is associated with a higher rate of progression-free survival. Our data suggest that the clinical efficacy of rituximab may be driven, in part, by its ability to broaden the NK-cell repertoire to include previously hyporesponsive, unlicensed NK cells. A "missing ligand" KIR and HLA class I genotype may be predictive of this benefit and useful for personalizing treatment decisions in lymphomas and other tumors.
Related JoVE Video
Optimal Estimation for Regression Models on ?-Year Survival Probability.
J Biopharm Stat
PUBLISHED: 06-05-2014
Show Abstract
Hide Abstract
ABSTRACT A logistic regression method can be applied to regressing the [Formula: see text]-year survival probability to covariates, if there are no censored observations before time [Formula: see text]. But if some observations are incomplete due to censoring before time [Formula: see text], then the logistic regression cannot be applied. Jung (1996) proposed to modify the score function for logistic regression to accommodate the right censored observations. His modified score function, motivated for a consistent estimation of regression parameters, becomes a regular logistic score function if no observations are censored before time [Formula: see text]. In this paper, we propose a modification of Jung's estimating function for an optimal estimation for the regression parameters in addition to consistency. We prove that the optimal estimator is more efficient than Jung's estimator. This theoretical comparison is illustrated with a real example data analysis and simulations.
Related JoVE Video
Clinical relevance of procalcitonin and C-reactive protein as infection markers in renal impairment: a cross sectional study.
Crit Care
PUBLISHED: 05-11-2014
Show Abstract
Hide Abstract
IntroductionAlthough the clinical application of procalcitonin (PCT) as an infection marker in patients with impaired renal function (estimated glomerular filtration rate (eGFR) <60 ml/min) has been increasing recently, it is unclear whether PCT is more accurate than C-reactive protein (CRP). We investigated the clinical value of CRP and PCT based on renal function.MethodsFrom November 2008 to July 2011, a total of 493 patients who simultaneously underwent CRP and PCT tests were enrolled. The area under the receiver operating characteristic (ROC) curve and characteristics of both markers were analyzed according to infection severity and renal function.ResultsIn patients with impaired renal function, the area under the ROC curve was 0.876 for CRP and 0.876 for PCT. In patients with infection, CRP levels differed depending on whether the infection was localized, septic, or severely septic, whereas PCT levels were higher in patients with severe sepsis or septic shock. In patients without infection, CRP did not correlate with eGFR, while PCT was negatively correlated with eGFR.ConclusionThis study demonstrates that CRP is accurate for predicting infection in patients with impaired renal function. The study suggests that in spite of its higher cost, PCT is not superior to CRP as an infection marker in terms of diagnostic value.
Related JoVE Video
Randomized phase II clinical trials.
J Biopharm Stat
PUBLISHED: 04-05-2014
Show Abstract
Hide Abstract
Traditionally, Phase II trials have been conducted as single-arm trials to compare the response probabilities between an experimental therapy and a historical control. Historical control data, however, often have a small sample size, are collected from a different patient population, or use a different response assessment method, so that a direct comparison between a historical control and an experimental therapy may be severely biased. Randomized Phase II trials entering patients prospectively to both experimental and control arms have been proposed to avoid any bias in such cases. The small sample sizes for typical Phase II clinical trials imply that the use of exact statistical methods for their design and analysis is appropriate. In this article, we propose two-stage randomized Phase II trials based on Fisher's exact test, which does not require specification of the response probability of the control arm for testing. Through numerical studies, we observe that the proposed method controls the type I error accurately and maintains a high power. If we specify the response probabilities of the two arms under the alternative hypothesis, we can identify good randomized Phase II trial designs by adopting the Simon's minimax and optimal design concepts that were developed for single-arm Phase II trials.
Related JoVE Video
Multifunctional tumor pH-sensitive self-assembled nanoparticles for bimodal imaging and treatment of resistant heterogeneous tumors.
J. Am. Chem. Soc.
PUBLISHED: 04-01-2014
Show Abstract
Hide Abstract
Nanoparticle-based diagnosis-therapy integrative systems represent an emerging approach to cancer treatment. However, the diagnostic sensitivity, treatment efficacy, and bioavailability of nanoparticles as well as the heterogeneity and drug resistance of tumors pose tremendous challenges for clinical implementation. We herein report on the fabrication of tumor pH-sensitive magnetic nanogrenades (termed PMNs) composed of self-assembled iron oxide nanoparticles and pH-responsive ligands. These PMNs can readily target tumors via surface-charge switching triggered by the acidic tumor microenvironment, and are further disassembled into a highly active state in acidic subcellular compartments that "turns on" MR contrast, fluorescence and photodynamic therapeutic activity. We successfully visualized small tumors implanted in mice via unique pH-responsive T1MR contrast and fluorescence, demonstrating early stage diagnosis of tumors without using any targeting agents. Furthermore, pH-triggered generation of singlet oxygen enabled pH-dependent photodynamic therapy to selectively kill cancer cells. In particular, we demonstrated the superior therapeutic efficacy of PMNs in highly heterogeneous drug-resistant tumors, showing a great potential for clinical applications.
Related JoVE Video
A randomized trial of diet in men with early stage prostate cancer on active surveillance: rationale and design of the Men's Eating and Living (MEAL) Study (CALGB 70807 [Alliance]).
Contemp Clin Trials
PUBLISHED: 03-07-2014
Show Abstract
Hide Abstract
Diet may substantially alter prostate cancer initiation and progression. However, large-scale clinical trials of diet modification have yet to be performed for prostate cancer. The Men's Eating and Living (MEAL) Study (CALGB 70807 [Alliance]) is investigating the effect of increased vegetable consumption on clinical progression in men with localized prostate cancer.
Related JoVE Video
Stratified Fisher's exact test and its sample size calculation.
Biom J
PUBLISHED: 01-08-2014
Show Abstract
Hide Abstract
Chi-squared test has been a popular approach to the analysis of a 2 × 2 table when the sample sizes for the four cells are large. When the large sample assumption does not hold, however, we need an exact testing method such as Fisher's test. When the study population is heterogeneous, we often partition the subjects into multiple strata, so that each stratum consists of homogeneous subjects and hence the stratified analysis has an improved testing power. While Mantel-Haenszel test has been widely used as an extension of the chi-squared test to test on stratified 2 × 2 tables with a large-sample approximation, we have been lacking an extension of Fisher's test for stratified exact testing. In this paper, we discuss an exact testing method for stratified 2 × 2 tables that is simplified to the standard Fisher's test in single 2 × 2 table cases, and propose its sample size calculation method that can be useful for designing a study with rare cell frequencies.
Related JoVE Video
Nanostring-based multigene assay to predict recurrence for gastric cancer patients after surgery.
PLoS ONE
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
Despite the benefits from adjuvant chemotherapy or chemoradiotherapy, approximately one-third of stage II gastric cancer (GC) patients developed recurrences. The aim of this study was to develop and validate a prognostic algorithm for gastric cancer (GCPS) that can robustly identify high-risk group for recurrence among stage II patients. A multi-step gene expression profiling study was conducted. First, a microarray gene expression profiling of archived paraffin-embedded tumor blocks was used to identify candidate prognostic genes (N=432). Second, a focused gene expression assay including prognostic genes was used to develop a robust clinical assay (GCPS) in stage II patients from the same cohort (N=186). Third, a predefined cut off for the GCPS was validated using an independent stage II cohort (N=216). The GCPS was validated in another set with stage II GC who underwent surgery without adjuvant treatment (N=300). GCPS was developed by summing the product of Cox regression coefficients and normalized expression levels of 8 genes (LAMP5, CDC25B, CDK1, CLIP4, LTB4R2, MATN3, NOX4, TFDP1). A prospectively defined cut-point for GCPS classified 22.7% of validation cohort treated with chemoradiotherapy (N=216) as high-risk group with 5-year recurrence rate of 58.6% compared to 85.4% in the low risk group (hazard ratio for recurrence=3.16, p=0.00004). GCPS also identified high-risk group among stage II patients treated with surgery only (hazard ratio=1.77, p=0.0053).
Related JoVE Video
Journal Club: Shoulder MRI utilization: relationship of physician MRI equipment ownership to negative study frequency.
AJR Am J Roentgenol
PUBLISHED: 08-27-2013
Show Abstract
Hide Abstract
The purpose of this article is to determine whether ownership of MRI equipment by ordering physicians influences the frequency of negative shoulder MRI scans.
Related JoVE Video
Gene expression profiles for the prediction of progression-free survival in diffuse large B cell lymphoma: results of a DASL assay.
Ann. Hematol.
PUBLISHED: 08-14-2013
Show Abstract
Hide Abstract
We performed the whole genome cDNA-mediated annealing, selection and ligation assay with 164 formalin-fixed paraffin-embedded (FFPE) tumor samples to develop robust prognostic gene expression profiles in patients with diffuse large B cell lymphoma. The prognostic gene expression profiles were developed and validated by a gradient lasso and leave-one-out cross-validation process. We identified a set of genes whose expression provided prognostic indicators from whole data set (PRKCDBP, CASP10, FAM3C, KCNK12, MAN1A2, PRND, RAB1A, TMEM39B, SLC6A6, MMP12, FEM1B, C3orh37, RBP1, HK1, LOC400464, KIAA0746, and SLC25A23). This gene expression profile-based risk model could classify patients into two cross-validated risk groups with a significant difference in 5-year progression-free survival rates (71.1 vs. 45.5 %) and with a hazard ratio for recurrence of 2.45 (95 % CI, 1.44-4.16, P?=?0.001). This model provided prognostic information independent of the International Prognostic Index (IPI), and discriminated high-risk group from patients belong to high/high-intermediate risk of IPI and activated B cell-like type. Thus, gene expression profiling from FFPE could provide additional prognostic information for diffuse large B cell lymphoma and our data underscore the need for development of risk-adapted treatment strategies based on gene expression profiles.
Related JoVE Video
Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentr
Lancet Oncol.
PUBLISHED: 07-29-2013
Show Abstract
Hide Abstract
The optimum endocrine treatment for postmenopausal women with advanced hormone-receptor-positive breast cancer that has progressed on non-steroidal aromatase inhibitors (NSAIs) is unclear. The aim of the SoFEA trial was to assess a maximum double endocrine targeting approach with the steroidal anti-oestrogen fulvestrant in combination with continued oestrogen deprivation.
Related JoVE Video
Genetic profiling to predict recurrence of early cervical cancer.
Gynecol. Oncol.
PUBLISHED: 07-24-2013
Show Abstract
Hide Abstract
Recurrence is the major cause of death in early cervical cancer. We compared the prediction powers for disease recurrence between the gene set prognostic model and the clinical prognostic model.
Related JoVE Video
Photo-activatable ternary complex based on a multifunctional shielding material for targeted shRNA delivery in cancer treatment.
Biomaterials
PUBLISHED: 07-17-2013
Show Abstract
Hide Abstract
A photo-activatable ternary complex (PTC) consisting of multifunctional shielding material (MSM) with photosensitizer (PS)-conjugated chondroitin sulfate and polyethyleneimine based binary complexes containing epidermal growth factor receptor (EGFR)-shRNA delivery for CD44 targeted cancer therapy has been developed. The PTC has a negative surface charge of -37.9 mV, and a size of approximately 90 nm, and the ternary complexes were found to be stable against plasma proteins. The stable nanostructure of PTC especially could enable CD44-receptor mediated tumor-targeted delivery and PS-mediated endosomal disruption for efficient gene silencing, and an enhanced rate of cancer cell death was achieved both in vitro and in vivo. This suggests that PTC could represent a promising strategy for the delivery of other therapeutic genes for cancer therapy.
Related JoVE Video
Phase II trial of capecitabine and everolimus (RAD001) combination in refractory gastric cancer patients.
Invest New Drugs
PUBLISHED: 07-15-2013
Show Abstract
Hide Abstract
The aim of this study was to assess the efficacy and safety of combination regimen of capecitabine plus everolimus in patients with refractory gastric cancer who have failed to at least two cytotoxic regimens.
Related JoVE Video
Endolysosomal environment-responsive photodynamic nanocarrier to enhance cytosolic drug delivery via photosensitizer-mediated membrane disruption.
Biomaterials
PUBLISHED: 07-01-2013
Show Abstract
Hide Abstract
The endolysosome is a major barrier for the effective intracellular delivery by conventional nanocarriers. Herein, we demonstrate that endolysosome environment-responsive photodynamic nanocarriers (EPNs) are capable of encapsulation of the hydrophobic drug paclitaxel (PTX) and photosensitizer (PS)-mediated ELB disruption for effective cancer therapy. EPNs were self-assembled from PS (chlorin e6, Ce6) or Black Hole Quencher-3 (BHQ3) conjugated covalently to polypeptide-based amphiphilic copolymers [monomethoxy polyethylene glycol-block-poly(?-benzyl-L-aspartic acid), mPEG-pBLA]. EPNs have a spherical shape and a unimodal size distribution below 100 nm. Photoquenching of the EPNs was dependent on the molar ratio of mPEG-pBLA-BHQ3/mPEG-pBLA-Ce6. However, in the presence of the endolysosomal enzyme (e.g., esterase), the benzyl ester bond is cleaved which leads to the structural collapse of EPNs, thus triggering drug release and restoring photoactivity. Live cell imaging studies demonstrated that PS-mediated lipid peroxidation significantly increased the ability of model drug (i.e., Nile red) to overcome the ELB. In comparison with PTX treatment alone, the combined treatment of PTX encapsulated EPNs with laser irradiation synergistically induced the death of HeLa and drug-resistant HCT-8 cells in vitro, and suppressed CT-26 tumor growth in vivo. These results suggest that this approach is a promising platform for cancer treatment. Furthermore, this EPN system offers significant potential for effective cytosolic delivery of chemical and biological therapeutics.
Related JoVE Video
Prediction of disease-free survival in hepatocellular carcinoma by gene expression profiling.
Ann. Surg. Oncol.
PUBLISHED: 06-26-2013
Show Abstract
Hide Abstract
Progression of hepatocellular carcinoma (HCC) often leads to vascular invasion and intrahepatic metastasis, which correlate with recurrence after surgical treatment and poor prognosis. The molecular prognostic model that could be applied to the HCC patient population in general is needed for effectively predicting disease-free survival (DFS).
Related JoVE Video
Biodegradable cationic nanoparticles loaded with an anticancer drug for deep penetration of heterogeneous tumours.
Biomaterials
PUBLISHED: 05-31-2013
Show Abstract
Hide Abstract
To enhance limited drug penetration that mediated drug resistance and heterogeneity within the tumour microenvironment, we designed a paclitaxel (PTX) loaded degradable cationic nanogel (DpNG) consisted with acetylated pullulan and low molecular weight polyethyleneimine ((Low)bPEI, 1.8 kDa). The restoration of cationic charge on the DpNG was achieved via HA degradation by hyaluronidase which is secreted in tumour. The size and surface charge of HA-coated DpNG loaded with PTX (HA/DpNG-PTX) was 200-250 nm and 0 mV, respectively. The DpNG-PTX was showed significant cytotoxicity in heterogeneous cancer cells. The IC50 value of DpNG-PTX was 100 times less than that of free PTX. The growth of heterogeneous tumour in Balb/c mice was inhibited via intravenous injection of HA/DpNG-PTX. Furthermore, the invasive distance and amount of HA/DpNG-PTX localised within the deep tissue regions were increased two times than that of PA-PTX. Therefore, the DpNG based drug delivery system could be useful for treatment of heterogeneous tumour.
Related JoVE Video
SNP selection in genome-wide association studies via penalized support vector machine with MAX test.
Comput Math Methods Med
PUBLISHED: 05-22-2013
Show Abstract
Hide Abstract
One of main objectives of a genome-wide association study (GWAS) is to develop a prediction model for a binary clinical outcome using single-nucleotide polymorphisms (SNPs) which can be used for diagnostic and prognostic purposes and for better understanding of the relationship between the disease and SNPs. Penalized support vector machine (SVM) methods have been widely used toward this end. However, since investigators often ignore the genetic models of SNPs, a final model results in a loss of efficiency in prediction of the clinical outcome. In order to overcome this problem, we propose a two-stage method such that the the genetic models of each SNP are identified using the MAX test and then a prediction model is fitted using a penalized SVM method. We apply the proposed method to various penalized SVMs and compare the performance of SVMs using various penalty functions. The results from simulations and real GWAS data analysis show that the proposed method performs better than the prediction methods ignoring the genetic models in terms of prediction power and selectivity.
Related JoVE Video
Photo-mediated internalization of nanocomplex for effective gene delivery to adipose tissue-derived stem cells.
Colloids Surf B Biointerfaces
PUBLISHED: 04-30-2013
Show Abstract
Hide Abstract
To deliver efficiently osteogenic, chondrogenic or adipogenic induction genes, such as Runx2, SOX9 and C/EBP-?, to adipose tissue-derived stem cells (ADSCs), a photo-mediated nanocomplex internalization gene delivery system was designed using chlorin e6 as a photosensitizer (PS) and polyethyleneimine (PEI) as a gene delivery carrier. In this system, gene delivery efficacy was significantly increased in ADSCs by photo irradiation. The gene transfection efficiency of Runx2, SOX9 and C/EBP-? was increased by 8.6-, 6.7- and 9.3-fold, respectively, by applying 0.7J/cm(2) of irradiation. Osteogenic, chondrogenic and adipogenic differentiation was confirmed by differentiation-related markers and histological analysis. ADSCs transfected with Runx2, SOX9 and C/EBP-? genes via photo irradiation indicated enhanced differentiation in comparison to the non-irradiated cells. These findings demonstrate that photo-mediated internalization is a promising system for efficient gene delivery and differentiation in ADSCs.
Related JoVE Video
Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202).
J. Clin. Oncol.
PUBLISHED: 04-08-2013
Show Abstract
Hide Abstract
Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS lymphoma (PCNSL). We performed a multicenter study of high-dose consolidation, without WBRT, in PCNSL. Objectives were to determine: one, rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R); two, feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA); three, progression-free survival (PFS); and four, correlation between clinical and molecular prognostic factors and outcome.
Related JoVE Video
Designs for randomized phase II clinical trials with two treatment arms.
Stat Med
PUBLISHED: 03-27-2013
Show Abstract
Hide Abstract
The most common primary statistical end point of a phase II clinical trial is the categorization of a patient as either a responder or nonresponder. The primary objective of typical randomized phase II anticancer clinical trials is to evaluate experimental treatments that potentially will increase response rate over a historical baseline and select one to consider for further study. We propose single-stage and two-stage designs for randomized phase II clinical trials, precisely defining various type I error rates and powers to achieve this objective. We develop a program to compute these error rates and powers exactly, and we provide many design examples to satisfy pre-fixed requirements on error rates and powers. Finally, we apply our method to a randomized phase II trial in patients with relapsed non-Hodgkins disease. Copyright ©?2013 John Wiley & Sons, Ltd.
Related JoVE Video
Prediction of a time-to-event trait using genome wide SNP data.
BMC Bioinformatics
PUBLISHED: 02-12-2013
Show Abstract
Hide Abstract
A popular objective of many high-throughput genome projects is to discover various genomic markers associated with traits and develop statistical models to predict traits of future patients based on marker values.
Related JoVE Video
A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701.
Cancer
PUBLISHED: 01-24-2013
Show Abstract
Hide Abstract
Rituximab combined with chemotherapy has improved the survival of previously untreated patients with follicular lymphoma (FL). Nevertheless, many patients neither want nor can tolerate chemotherapy, leading to interest in biological approaches. Epratuzumab is a humanized anti-CD22 monoclonal antibody with efficacy in relapsed FL. Because both rituximab and epratuzumab have single-agent activity in FL, the antibody combination was evaluated as initial treatment of patients with FL.
Related JoVE Video
Sample size considerations of prediction-validation methods in high-dimensional data for survival outcomes.
Genet. Epidemiol.
PUBLISHED: 01-21-2013
Show Abstract
Hide Abstract
A variety of prediction methods are used to relate high-dimensional genome data with a clinical outcome using a prediction model. Once a prediction model is developed from a data set, it should be validated using a resampling method or an independent data set. Although the existing prediction methods have been intensively evaluated by many investigators, there has not been a comprehensive study investigating the performance of the validation methods, especially with a survival clinical outcome. Understanding the properties of the various validation methods can allow researchers to perform more powerful validations while controlling for type I error. In addition, sample size calculation strategy based on these validation methods is lacking. We conduct extensive simulations to examine the statistical properties of these validation strategies. In both simulations and a real data example, we have found that 10-fold cross-validation with permutation gave the best power while controlling type I error close to the nominal level. Based on this, we have also developed a sample size calculation method that will be used to design a validation study with a user-chosen combination of prediction. Microarray and genome-wide association studies data are used as illustrations. The power calculation method in this presentation can be used for the design of any biomedical studies involving high-dimensional data and survival outcomes.
Related JoVE Video
Phase II clinical trials with time-to-event endpoints: Optimal two-stage designs with one-sample log-rank test.
Stat Med
PUBLISHED: 01-07-2013
Show Abstract
Hide Abstract
Phase II clinical trials are often conducted to determine whether a new treatment is sufficiently promising to warrant a major controlled clinical evaluation against a standard therapy. We consider single-arm phase II clinical trials with right censored survival time responses where the ordinary one-sample logrank test is commonly used for testing the treatment efficacy. For planning such clinical trials, this paper presents two-stage designs that are optimal in the sense that the expected sample size is minimized if the new regimen has low efficacy subject to constraints of the type I and type II errors. Two-stage designs, which minimize the maximal sample size, are also determined. Optimal and minimax designs for a range of design parameters are tabulated along with examples. Copyright © 2013 John Wiley & Sons, Ltd.
Related JoVE Video
The anti-CD80 primatized monoclonal antibody, galiximab, is well-tolerated but has limited activity in relapsed Hodgkin lymphoma: Cancer and Leukemia Group B 50602 (Alliance).
Leuk. Lymphoma
PUBLISHED: 01-04-2013
Show Abstract
Hide Abstract
Relapsed Hodgkin lymphoma remains a clinical challenge, with few non-cytotoxic treatment options. CD80 is a surface antigen that normally functions as a co-stimulatory molecule but is aberrantly and uniformly expressed on Reed-Sternberg cells. Galiximab is a primatized monoclonal antibody against CD80, with a favorable toxicity profile demonstrated in other lymphomas. Cancer and Leukemia Group B (CALGB) 50602 (Alliance) tested single-agent galiximab in a highly refractory group of patients with Hodgkin lymphoma (median 3 prior regimens, 83% failing after prior stem cell transplant) to determine the efficacy. The overall response rate was 10.3% and the median progression-free survival was 1.6 months. Galiximab was well-tolerated, with minimal grade 3 or 4 toxicities. Despite this preclinical rationale, single-agent galiximab had limited activity in heavily pretreated Hodgkin lymphoma.
Related JoVE Video
Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial.
J. Clin. Oncol.
PUBLISHED: 12-19-2011
Show Abstract
Hide Abstract
The ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial was the first study to our knowledge to investigate the role of postoperative chemoradiotherapy therapy in patients with curatively resected gastric cancer with D2 lymph node dissection. This trial was designed to compare postoperative treatment with capecitabine plus cisplatin (XP) versus XP plus radiotherapy with capecitabine (XP/XRT/XP).
Related JoVE Video
A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype.
Haematologica
PUBLISHED: 12-01-2011
Show Abstract
Hide Abstract
A phase II trial of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) from the National Cancer Institute showed promising activity in untreated diffuse large B-cell lymphoma. The Cancer and Leukemia Group B conducted a study to determine if these results could be reproduced in a multi-institutional setting.
Related JoVE Video
Statistical considerations for analysis of microarray experiments.
Clin Transl Sci
PUBLISHED: 11-07-2011
Show Abstract
Hide Abstract
Microarray technologies enable the simultaneous interrogation of expressions from thousands of genes from a biospecimen sample taken from a patient. This large set of expressions generates a genetic profile of the patient that may be used to identify potential prognostic or predictive genes or genetic models for clinical outcomes. The aim of this article is to provide a broad overview of some of the major statistical considerations for the design and analysis of microarrays experiments conducted as correlative science studies to clinical trials. An emphasis will be placed on how the lack of understanding and improper use of statistical concepts and methods will lead to noise discovery and misinterpretation of experimental results.
Related JoVE Video
Multiple testing for gene sets from microarray experiments.
BMC Bioinformatics
PUBLISHED: 05-26-2011
Show Abstract
Hide Abstract
A key objective in many microarray association studies is the identification of individual genes associated with clinical outcome. It is often of additional interest to identify sets of genes, known a priori to have similar biologic function, associated with the outcome.
Related JoVE Video
The controlled photoactivity of nanoparticles derived from ionic interactions between a water soluble polymeric photosensitizer and polysaccharide quencher.
Biomaterials
PUBLISHED: 05-10-2011
Show Abstract
Hide Abstract
In order to design a water soluble polymeric photosensitizer (WPS) with controllable photoactivity, a nano-photosensitizer (NPS) was prepared from a polyelectrolyte complex between polyethylene glycol-polyethylenimine-chlorine e6 conjugate (PEG-PEI-Ce6) and Black Hole Quencher-3 chondroitin sulfate conjugate (BHQ-3-CS). NPSs have a unimodal size distribution below 100 nm. Photoquenching of the NPS was dependent on the weight ratio of BHQ-3-CS/WPS. This phenomenon was maintained in a salt condition up to 300 mm, indicating that the photoactivity of the NPS disappears in the normal blood stream of the body. The quenched photoactivity was restored by the enzyme degradation of BHQ-3-CS after esterase treatment. In a HCT-116 (human colon cancer) cell test, the rapid cellular internalization of the NPS without any other ligands was observed by confocal imaging. Upon light irradiation after internalization, phototoxicity was detected via MTT colorimetric assay. Also, when the NPS was subcutaneously injected in both tumoral and normal regions of HCT-116 tumor-bearing mice, the fluorescence signal in the tumors rapidly increased compared to the normal region due to the enzymatic-triggered dissociation of the NPS in vivo. These results suggest that the NPS can provide both tumor diagnosis and therapy simultaneously, and has great potential for biological studies and clinical treatments of various tumors.
Related JoVE Video
Doxorubicin, vinblastine, and gemcitabine (CALGB 50203) for stage I/II nonbulky Hodgkin lymphoma: pretreatment prognostic factors and interim PET.
Blood
PUBLISHED: 02-25-2011
Show Abstract
Hide Abstract
To reduce doxorubicin, bleomycin, vinblastine and dacarbazine toxicity, the Cancer and Leukemia Group B conducted a phase 2 trial of doxorubicin, vinblastine, and gemcitabine for newly diagnosed, nonbulky stages I and II Hodgkin lymphoma. Ninety-nine assessable patients received 6 cycles of doxorubicin 25 mg/m(2), vinblastine 6 mg/m(2), and gemcitabine 800 mg/m(2) (1000 mg/m(2) in first 6) on days 1 and 15 every 28 days. Computed tomography (CT) and positron emission tomography (PET) were performed before and after 2 and 6 cycles. Complete remission (CR)/CR unconfirmed was achieved in 72 of 99 patients (72.7%) and partial remission in 24 of 99 patients (24.2%). The CR rate was 81% when using PET criteria. Two patients have died of Hodgkin lymphoma progression. Median follow-up for nonprogressing patients is 3.3 years. The progression-free survival (PFS) at 3 years was 77% (95% confidence interval, 68%-84%). The relapse rate was less than 10% for patients with favorable prognostic factors. The 2-year PFS for cycle 2 PET-negative and -positive patients was 88% and 54%, respectively (P = .0009), compared with 89% and 27% for cycle 6 PET-negative and -positive patients (P = .0001). Although the CR rate and PFS were lower than anticipated, patients with favorable prognostic features had a low rate of relapse. Cycle 2 PET and cycle 6 PET were predictive of PFS.
Related JoVE Video
Mutational hotspots in the mitochondrial genome of lung cancer.
Biochem. Biophys. Res. Commun.
PUBLISHED: 02-10-2011
Show Abstract
Hide Abstract
We determined the somatic mutations in the mitochondrial genomes of 70 lung cancer patients by pair-wise comparative analyses of the normal- and tumor-genome sequences acquired using Affymetrix Mitochondrial Resequencing Array 2.0. The overall mutation rates in lung cancers were Approximately 100 fold higher than those in normal cells, with significant statistical correlation with smoking (p=0.00088). Total of 532 somatic mutations were evenly distributed in 499 positions with very low overall frequency (1.07/bp), but the non-synonymous mutations causing amino acid substitution occurred more frequently (1.83/bp), particularly at two positions, 8701 and 10398 (10.5/bp) that code for ATPase6 and NADH dehydrogenase 3, respectively. Despite the randomness or even distribution of the mutations, these two mutations occurred together in 86% of the cases. The linkage between the two most frequent mutations suggests that they were selected together, possibly due to their cooperative role during cancer development. Indeed, the mutation at 10398 was shown by Canter, Pezzotti, and their colleagues in 2009, as a risk factor for breast cancer. In this study, we identified two potential biomarkers that might be functionally linked together during the development of cancer.
Related JoVE Video
A SAS macro for a clustered logrank test.
Comput Methods Programs Biomed
PUBLISHED: 02-03-2011
Show Abstract
Hide Abstract
The clustered logrank test is a nonparametric method of significance testing for correlated survival data. Examples of its application include cluster randomized trials where groups of patients rather than individuals are randomized to either a treatment or a control intervention. We describe a SAS macro that implements the 2-sample clustered logrank test for data where the entire cluster is randomized to the same treatment group. We discuss the theory and applications behind this test as well as details of the SAS code.
Related JoVE Video
A phase III study of anti-B4-blocked ricin as adjuvant therapy post-autologous bone marrow transplant: CALGB 9254.
Leuk. Lymphoma
PUBLISHED: 01-28-2011
Show Abstract
Hide Abstract
Anti-B4-blocked ricin (anti-B4-bR) is a potent immunotoxin directed against the CD19 antigen. Previous phase I and II studies suggested a possible role for anti-B4-bR as consolidation after high-dose chemotherapy and autologous stem cell transplant. Cancer and Leukemia Group B (CALGB) 9254 is a phase III study which randomized 157 patients with B-cell lymphoma in complete remission following autologous transplant to treatment with anti-B4-bR or observation. With a median follow-up time for patients of 5.8 years, the median event-free survival for protocol treatment and observation are 2.1 and 2.9 years, respectively (p = 0.275). The median overall survival for treatment and observation are 6.1 years and not reached, respectively (p = 0.063). Therefore, no differences were found in event-free survival and overall survival between protocol treatment and observation, although there was a trend toward improved survival with observation. These data fail to support a role for anti-B4-bR as consolidative therapy after bone marrow transplant in patients with B-cell lymphoma.
Related JoVE Video
Sample size and power calculation for molecular biology studies.
Methods Mol. Biol.
PUBLISHED: 07-24-2010
Show Abstract
Hide Abstract
Sample size calculation is a critical procedure when designing a new biological study. In this chapter, we consider molecular biology studies generating huge dimensional data. Microarray studies are typical examples, so that we state this chapter in terms of gene microarray data, but the discussed methods can be used for design and analysis of any molecular biology studies involving high-dimensional data. In this chapter, we discuss sample size calculation methods for molecular biology studies when the discovery of prognostic molecular markers is performed by accurately controlling false discovery rate (FDR) or family-wise error rate (FWER) in the final data analysis. We limit our discussion to the two-sample case.
Related JoVE Video
Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy.
Mol. Cancer Ther.
PUBLISHED: 06-22-2010
Show Abstract
Hide Abstract
Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 micromol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.
Related JoVE Video
Potential of self-organizing nanogel with acetylated chondroitin sulfate as an anti-cancer drug carrier.
Colloids Surf B Biointerfaces
PUBLISHED: 05-14-2010
Show Abstract
Hide Abstract
In order to obtain feasibility data regarding the possibility of using chondroitin sulfate (CS) in an anti-cancer drug delivery system, CS was chemically modified by a one-step process with acetic anhydride. Although 3 samples with different degrees of acetylation were synthesized, only the sample with the highest degree of acetylation (AC-CS3) was tested as a nanogel because the others (AC-CS1 and 2) dissolved in distilled water (DW) in the test range (1-10 mg/ml). The AC-CS3 nanogel was characterized by fluorescence probe and dynamic light scattering (DLS) techniques. Its critical aggregation concentration (CAC) was <2.0 x 10(-2) mg/ml at 25 degrees C. The partition equilibrium constant, K(v), of the nanogel (7.88 x 10(5)) was similar to that of polymeric micelles, which means that the acetyl group may act as a hydrophobic core controlling pharmacokinetic behavior. The higher surface charge value in the nanogel, above - 40 due to carboxyl and sulfate groups in CS, explains its good stability. The anticancer drug doxorubicin (DOX) loading efficiency of the AC-CS3 nanogel was also superior, at above 90%. Changes in the size of the polydispersion index (PDI) of nanogels loaded with DOX over a 3-week period were negligible. The nanogels interacted with HeLa cells and were internalized together with the entrapped drug within the cytoplasm, probably via an endocytic mechanism exploited by sugar receptors. Based on these results, the AC-CS3 nanogel is expected to prove useful as an anti-cancer drug carrier for chemotherapy.
Related JoVE Video
Gene expression signatures as a guide to treatment strategies for in-transit metastatic melanoma.
Mol. Cancer Ther.
PUBLISHED: 04-06-2010
Show Abstract
Hide Abstract
In-transit metastatic melanoma, which typically presents as multifocal lesions, provides a unique setting to evaluate the utility of gene signatures for defining optimal regional therapeutic strategies and assessing the efficacy of treatment. The goal of this study was to determine whether a single multifocal lesion is representative of residual tumor burden in terms of gene expression signatures predictive of response to therapy. Using microarray-based gene expression profiling, we examined 55 in-transit melanoma lesions across 29 patients with multifocal disease. Principal component analysis, unsupervised hierarchical clustering, one-way ANOVA, binary regression analysis, and gene signatures predictive of oncogenic pathway activation were used to compare patterns of gene expression across all multifocal lesions from a patient. Patterns of gene expression were highly similar (P < 0.006; average r = 0.979) across pretreatment lesions from a single patient compared with the significantly different patterns observed across patients (P < 0.05). The findings presented in this study show that individual melanoma tumor nodules in patients with multifocal disease harbor similar patterns of gene expression and a single lesion can be used to predict response to chemotherapy, evaluate the activation status of oncogenic signaling pathways, and characterize other aspects of the biology of an individual patients disease. These results will facilitate the use of gene expression profiling in melanoma regional therapy clinical trials to not only select optimal regional chemotherapeutic agents but to also allow for a more rational identification of candidates for specific targeted therapies and evaluation of their therapeutic efficacy. Mol Cancer Ther; 9(4); 779-90. (c)2010 AACR.
Related JoVE Video
permGPU: Using graphics processing units in RNA microarray association studies.
BMC Bioinformatics
PUBLISHED: 03-22-2010
Show Abstract
Hide Abstract
Many analyses of microarray association studies involve permutation, bootstrap resampling and cross-validation, that are ideally formulated as embarrassingly parallel computing problems. Given that these analyses are computationally intensive, scalable approaches that can take advantage of multi-core processor systems need to be developed.
Related JoVE Video
Robust test method for time-course microarray experiments.
BMC Bioinformatics
PUBLISHED: 03-08-2010
Show Abstract
Hide Abstract
In a time-course microarray experiment, the expression level for each gene is observed across a number of time-points in order to characterize the temporal trajectories of the gene-expression profiles. For many of these experiments, the scientific aim is the identification of genes for which the trajectories depend on an experimental or phenotypic factor. There is an extensive recent body of literature on statistical methodology for addressing this analytical problem. Most of the existing methods are based on estimating the time-course trajectories using parametric or non-parametric mean regression methods. The sensitivity of these regression methods to outliers, an issue that is well documented in the statistical literature, should be of concern when analyzing microarray data.
Related JoVE Video
Sample size calculation for microarray experiments with blocked one-way design.
BMC Bioinformatics
PUBLISHED: 05-28-2009
Show Abstract
Hide Abstract
One of the main objectives of microarray analysis is to identify differentially expressed genes for different types of cells or treatments. Many statistical methods have been proposed to assess the treatment effects in microarray experiments.
Related JoVE Video
Gradient lasso for Cox proportional hazards model.
Bioinformatics
PUBLISHED: 05-15-2009
Show Abstract
Hide Abstract
There has been an increasing interest in expressing a survival phenotype (e.g. time to cancer recurrence or death) or its distribution in terms of a subset of the expression data of a subset of genes. Due to high dimensionality of gene expression data, however, there is a serious problem of collinearity in fitting a prediction model, e.g. Coxs proportional hazards model. To avoid the collinearity problem, several methods based on penalized Cox proportional hazards models have been proposed. However, those methods suffer from severe computational problems, such as slow or even failed convergence, because of high-dimensional matrix inversions required for model fitting. We propose to implement the penalized Cox regression with a lasso penalty via the gradient lasso algorithm that yields faster convergence to the global optimum than do other algorithms. Moreover the gradient lasso algorithm is guaranteed to converge to the optimum under mild regularity conditions. Hence, our gradient lasso algorithm can be a useful tool in developing a prediction model based on high-dimensional covariates including gene expression data.
Related JoVE Video
Regression on quantile residual life.
Biometrics
PUBLISHED: 05-07-2009
Show Abstract
Hide Abstract
A time-specific log-linear regression method on quantile residual lifetime is proposed. Under the proposed regression model, any quantile of a time-to-event distribution among survivors beyond a certain time point is associated with selected covariates under right censoring. Consistency and asymptotic normality of the regression estimator are established. An asymptotic test statistic is proposed to evaluate the covariate effects on the quantile residual lifetimes at a specific time point. Evaluation of the test statistic does not require estimation of the variance-covariance matrix of the regression estimators, which involves the probability density function of the survival distribution with censoring. Simulation studies are performed to assess finite sample properties of the regression parameter estimator and test statistic. The new regression method is applied to a breast cancer data set with long-term follow-up to estimate the patients median residual lifetimes, adjusting for important prognostic factors.
Related JoVE Video
Between-arm comparisons in randomized Phase II trials.
J Biopharm Stat
PUBLISHED: 04-23-2009
Show Abstract
Hide Abstract
In a Phase II trial, we may randomize patients to multiple arms of experimental therapies and evaluate their efficacy to determine if any of them is worthy of a large scale Phase III trial. Usually the primary objective of such a study is to identify experimental therapies that are efficacious compared to a historical control. Each arm is independently evaluated using a standard design a for single-arm Phase II trial, e.g., Simons optimal or minimax design. When more than one arm is accepted through such a randomized trial, we may want to select the winner(s) among them. There are methods for between-arm comparisons in the literature, but most of them have drawbacks. They have a large false selection (type I error) probability when the competing arms have a small difference in efficacy, or the statistical tests used in the selection procedure do not properly reflect the small sample sizes and multi-stage design of the trials. In this paper, we propose between-arm comparison methods for selection in randomized Phase II trials addressing these issues.
Related JoVE Video
A permutation-based multiple testing method for time-course microarray experiments.
BMC Bioinformatics
PUBLISHED: 03-18-2009
Show Abstract
Hide Abstract
Time-course microarray experiments are widely used to study the temporal profiles of gene expression. Storey et al. (2005) developed a method for analyzing time-course microarray studies that can be applied to discovering genes whose expression trajectories change over time within a single biological group, or those that follow different time trajectories among multiple groups. They estimated the expression trajectories of each gene using natural cubic splines under the null (no time-course) and alternative (time-course) hypotheses, and used a goodness of fit test statistic to quantify the discrepancy. The null distribution of the statistic was approximated through a bootstrap method. Gene expression levels in microarray data are often complicatedly correlated. An accurate type I error control adjusting for multiple testing requires the joint null distribution of test statistics for a large number of genes. For this purpose, permutation methods have been widely used because of computational ease and their intuitive interpretation.
Related JoVE Video
Photoreceptor layer thinning over drusen in eyes with age-related macular degeneration imaged in vivo with spectral-domain optical coherence tomography.
Ophthalmology
PUBLISHED: 01-22-2009
Show Abstract
Hide Abstract
Detect changes in the neurosensory retina using spectral-domain optical coherence tomography (SD OCT) imaging over drusen in age-related macular degeneration (AMD). Quantitative imaging biomarkers may aid in defining risk of disease progression.
Related JoVE Video
Humanoid Path Planning From HRI Perspective: A Scalable Approach via Waypoints With a Time Index.
IEEE Trans Syst Man Cybern B Cybern
Show Abstract
Hide Abstract
This paper proposes a path planner for a humanoid robot to enhance its performance in terms of the human-robot interaction perspective. From the human point of view, the proposed method uses the time index that can generate a path that humans feel to be natural. In terms of the robot, the proposed method yields a waypoint-based path, the simplicity of which enables accurate tracking even for humanoid robots with complex dynamics. From an environmental perspective through which interactions occur, the proposed method can be easily expanded to a wide area. Overall, the proposed method can be described as a scalable path planner via waypoints with a time index for humanoid robots. Experiments have been conducted in test beds where the robot encounters unexpected exceptional situations. Throughout these trials, the robot successfully reached the goal location while iteratively replanning the path.
Related JoVE Video
Alveolar macrophages from overweight/obese subjects with asthma demonstrate a proinflammatory phenotype.
Am. J. Respir. Crit. Care Med.
Show Abstract
Hide Abstract
Obesity is associated with increased prevalence and severity of asthma. Adipose tissue macrophages can contribute to the systemic proinflammatory state associated with obesity. However, it remains unknown whether alveolar macrophages have a unique phenotype in overweight/obese patients with asthma.
Related JoVE Video
Genetic variability of prostaglandin E2 receptor subtype EP4 gene in aspirin-intolerant chronic urticaria.
J. Hum. Genet.
Show Abstract
Hide Abstract
Prostaglandin E2 receptor subtype EP4 (PTGER4) is one of the four subtypes of receptors for prostaglandin E2 (PGE2). Overproduction of cysteinyl leukotriene in mast cells may be related with suppression of PGE2 in patients with aspirin hypersensitivity. Considering the association of PTGER4 in mast cells, urticaria- and aspirin-related disease, we hypothesized the genetic variability of PTGER4 may be associated with aspirin-intolerant chronic urticaria (AICU). The case-control study was performed in 141 with AICU, 153 with aspirin-tolerant chronic urticaria (ATCU) and 174 with normal controls (NCs). PTGER4 promoter single-nucleotide polymorphism was genotyped using a primer extension method with the SNAPshot ddNTP primer extension kit. The functional variability of PTGER4 promoter polymorphism was carried out by dual-luciferase system and electrophoretic mobility shift assay (EMSA) in human mast cells (HMC-1). Furthermore, the effect of aspirin was performed for PTGER4 mRNA expression using real-time PCR, and PGE2 production was checked in HMC-1 cells using ELISA. AICU patients carrying GG genotype at -1254?G>A showed significantly higher frequency compared with NC (P=0.032). Similarly, the minor allele frequency, G allele was significantly higher in AICU compared with NC (P=0.031). In vitro functional study demonstrated that the -1254?G allele had lower luciferase activity (P<0.001) in HMC-1 cells. EMSA finding showed that PTGER4 -1254?G produced a specific band. Significantly decreased PTGER4 expression (P=0.008) and PGE2 production by aspirin exposure was confirmed in in vitro HMC cell line model (P=0.001). The PTGER4 -1254?G allele demonstrated a higher frequency in AICU patients and lower promoter activity with decreased expression of PTGER4 and contributes to the development of AICU.
Related JoVE Video
The transfection efficiency of photosensitizer-induced gene delivery to human MSCs and internalization rates of EGFP and Runx2 genes.
Biomaterials
Show Abstract
Hide Abstract
To improve the transfection efficiency of non-viral gene vectors to human mesenchymal stem cells (hMSCs), a photosensitizer (PS)-induced gene delivery system was designed by using pheophorbide-a (pheo-a) as a PS. In FACS results, this system showed excellent gene transfection efficiency depending on irradiation power. The result was strongly supported by western blot and real-time quantitative PCR (RT-qPCR) assays. The protein and mRNA expression of enhanced green fluorescent protein (EGFP) in hMSCs treated with 0.9 J/cm(2) irradiation increased 9.8- and 8.7-fold compared with non-irradiated hMSCs, respectively. Furthermore, the internalization of PEI/pDNA complexes in hMSCs was enhanced by light irradiation even under conditions that inhibited endocytosis. The hemolytic activity of PS with irradiation (0.9 J/cm(2)) significantly increased to 55%. Thus, PS with light irradiation facilitated both the internalization and endosomal escape of gene complexes. For osteogenic induction, the Runt-related transcription factor 2 (Runx2) gene was transferred to hMSCs via PS-induced transfection. Von Kossa staining indicated that Runx2 overexpression significantly enhanced the osteogenesis of hMSCs. Therefore, this PS-induced gene delivery method has potential value for stem cell therapy via gene delivery.
Related JoVE Video
Power and sample size calculations for SNP association studies with censored time-to-event outcomes.
Genet. Epidemiol.
Show Abstract
Hide Abstract
For many clinical studies in cancer, germline DNA is prospectively collected for the purpose of discovering or validating single-nucleotide polymorphisms (SNPs) associated with clinical outcomes. The primary clinical endpoint for many of these studies are time-to-event outcomes such as time of death or disease progression which are subject to censoring mechanisms. The Cox score test can be readily employed to test the association between a SNP and the outcome of interest. In addition to the effect and sample size, and censoring distribution, the power of the test will depend on the underlying genetic risk model and the distribution of the risk allele. We propose a rigorous account for power and sample size calculations under a variety of genetic risk models without resorting to the commonly used contiguous alternative assumption. Practical advice along with an open-source software package to design SNP association studies with survival outcomes are provided.
Related JoVE Video
Physician self-referral of lumbar spine MRI with comparative analysis of negative study rates as a marker of utilization appropriateness.
AJR Am J Roentgenol
Show Abstract
Hide Abstract
Financial interest in imaging equipment may affect the imaging referral patterns of ordering physicians. The purpose of this article is to determine whether ownership of MRI equipment by ordering physicians predicts the likelihood and prevalence of positive findings on lumbar spine MRI as a metric for comparison of utilization.
Related JoVE Video
Interim [(18)F]fluorodeoxyglucose positron emission tomography imaging in stage I-II non-bulky Hodgkin lymphoma: would using combined positron emission tomography and computed tomography criteria better predict response than each test alone?
Leuk. Lymphoma
Show Abstract
Hide Abstract
Our objective was to validate the International Harmonization Project (IHP) positron emission tomography (PET) response criteria and correlate with the Deauville criteria and diagnostic computed tomography-based (dCT) lesion size changes. All patients were recruited prospectively to the Cancer and Leukemia Group B (CALGB) 50203 trial for the treatment of stage I-II, non-bulky Hodgkin lymphoma (HL). [(18)F]Fluorodeoxyglucose (FDG) PET and dCT were performed at baseline and after two doxorubicin, vinblastine and gemcitabine (AVG) cycles (PET-2, dCT-2) in 88 patients. IHP and Deauville criteria and percent decrease in the sum of the products of the perpendicular diameters (%SPPD) after two cycles were correlated with progression-free survival (PFS). After a median follow-up of 3.3 years, 23.9% of patients relapsed/progressed (3-year PFS 77%). By IHP, the 2-year PFS was 88% and 54% for PET-2 negative and positive groups, respectively (p = 0.0009). Similar results were obtained for Deauville criteria. In a univariate analysis, PET-2 predicted PFS better than %SPPD, and in a combinatorial analysis, in the PET-2 positive group, a negative dCT-2 increased PFS by 27-35%. However, some confidence intervals were large due to small sample sizes. In conclusion, IHP and Deauville criteria-based interpretation of PET-2 was strongly associated with 2-year PFS. The combined analysis of PET-2 with dCT-2 suggested a better predictive value for PFS compared to either test alone. Further studies are under way to confirm these findings.
Related JoVE Video
On sample size calculation for comparing survival curves under general hypothesis testing.
J Biopharm Stat
Show Abstract
Hide Abstract
The log-rank test is commonly used to test the equivalence of two survival distributions under right censoring. Jung et al. (2005) proposed a modified log-rank test for noninferiority trials and its corresponding sample size calculation. In this article, we extend the use of the modified log-rank test for clinical trials with various types of nonconventional study objectives and propose its sample size calculation under general null and alternative hypotheses. The proposed formula is so flexible that we can specify any survival distributions and accrual pattern. The proposed methods are illustrated with designing real clinical trials. Through simulations, the modified log-rank test and the derived formula for sample size calculation are shown to have satisfactory small sample performance.
Related JoVE Video
Phase II cancer clinical trials with heterogeneous patient populations.
J Biopharm Stat
Show Abstract
Hide Abstract
The patient population for a Phase II trial often consists of multiple subgroups in terms of risk level. In this case, a popular design approach is to specify the response rate and the prevalence of each subgroup, to calculate the response rate of the whole population by the weighted average of the response rates across subgroups, and to choose a standard Phase II design such as Simons optimal or minimax design to test the response rate for the whole population. In this case, although the prevalence of each subgroup is accurately specified, the observed prevalence among the accrued patients to the study may be quite different from the expected one because of the small sample size, which is typical in most Phase II trials. The fixed rejection value for a chosen standard Phase II design may be either too conservative (i.e., increasing the false rejection probability of the experimental therapy) if the trial accrues more high-risk patients than expected, or too anti-conservative (i.e., increasing the false acceptance probability of the experimental therapy) if the trial accrues more low-risk patients than expected. We can avoid such problems by adjusting the rejection values, depending on the observed prevalence from the trial. In this paper, we investigate the performance of the flexible designs compared with the standard design with fixed rejection values under various settings.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.