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1.  Multiplex Protein Signature for the Detection of Bladder Cancer in Voided Urine Samples 
The Journal of urology  2013;190(6):2257-2262.
Accurate urine assays for bladder cancer detection would benefit patients and health care systems. Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples. In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort.
Materials and Methods
We performed a case-control, phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders. The urine concentration of 8 biomarkers (IL-8, MMP and 10, PAI-1, VEGF, ANG, CA9 and APOE) was assessed by enzyme-linked immunosorbent assay. Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values, eg sensitivity and specificity.
Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer. The 7 biomarkers were assessed in a new model, which had an AUROC of 0.88 (95% CI 0.84–0.93), and 74% sensitivity and 90% specificity. In contrast, the sensitivity of voided urine cytology and the UroVysion® cytogenetic test in this cohort was 39% and 54%, respectively. Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls.
The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays.
PMCID: PMC4013793  PMID: 23764080
urinary bladder neoplasms; urine; biological markers; molecular biology; diagnosis
2.  Tandem Autologous Stem Cell Transplantation for Multiple Myeloma Patients Based on Response to Their First Transplant—A Prospective Phase II Study 
In this prospective phase II clinical trial, multiple myeloma (MM) patients were randomized to receive a second (tandem) autologous stem cell transplantation (ASCT) based on whether they achieved a partial response or worse (≤PR) following initial ASCT (ASCT1). Patients who achieved a very good partial response or better (≥VGPR) had salvage ASCT at relapse. Seventy-five patients received conditioning therapy and ASCT1. A total of 44 patients (59%) achieved ≥VGPR, whereas 31 patients entered ≤PR and were offered tandem ASCT. In all, 20 patients agreed to tandem ASCT. Demographic and clinical characteristics were similar between the two cohorts except for median lactate dehydrogenase (LDH) (P = 0.0141) and percentage of marrow plasma cells before ASCT1 (P = 0.0047), both lower in the ≥VGPR group. Intent to treat analysis showed that patients who achieved ≥VGPR to ASCT1 had a trend toward improved progression-free survival (PFS) (37 vs. 26 months, P = 0.078) and superior overall survival (OS) (not reached vs. 50 months, P = 0.0073). Patients with ≤PR who declined tandem transplantation had shortened PFS (20 vs. 28 months, P = 0.05) but similar OS (53 vs. 57.5 months, P = 0.29) compared to those who received it. Thus, a favorable clinical response to ASCT1 identifies a low-risk group with superior long-term prognosis despite similar PFS.
PMCID: PMC4159376  PMID: 25232286
multiple myeloma; autologous stem cell transplantation; tandem; survival
3.  Diagnostic Potential of Urinary α1-Antitrypsin and Apolipoprotein E in the Detection of Bladder Cancer 
The Journal of urology  2012;188(6):2377-2383.
The ability to reliably diagnose bladder cancer in voided urine samples would be a major advance. Using high throughput technologies, we identified a panel of bladder cancer associated biomarkers with potential clinical usefulness. In this study we tested 4 potential biomarkers for the noninvasive detection of bladder cancer.
Materials and Methods
We examined voided urine specimens from 124 patients, including 63 newly diagnosed with bladder cancer and 61 controls. Concentrations of proteins were assessed by enzyme-linked immunosorbent assay, including α1-antitrypsin, apolipoprotein E, osteopontin and pentraxin 3. Data were compared to the results of urinary cytology and the BTA Trak® enzyme-linked immunosorbent assay based bladder cancer detection assay. We used the AUC of ROC curves to compare the usefulness of each biomarker to detect bladder cancer.
Urinary levels of α1-antitrypsin, apolipoprotein E and bladder tumor antigen were significantly increased in subjects with bladder cancer. α1-Antitrypsin (AUC 0.9087, 95% CI 0.8555–0.9619) and apolipoprotein E (AUC 0.8987, 95% CI 0.8449–0.9525) were the most accurate biomarkers. The combination of α1-antitrypsin and apolipoprotein E (AUC 0.9399) achieved 91% sensitivity, 89% specificity, and a positive and negative predictive value of 89% and 90%, respectively. Multivariate regression analysis highlighted only apolipoprotein E as an independent predictor of bladder cancer (OR 24.9, 95% CI 4.22–146.7, p = 0.0004).
Alone or in combination, α1-antitrypsin and apolipoprotein E show promise for the noninvasive detection of bladder cancer (OR 24.9, 95% CI 4.22– 146.7, p = 0.0004). Larger, prospective studies including more low grade, low stage tumors are needed to confirm these results.
PMCID: PMC4013779  PMID: 23088986
urinary bladder; urinary bladder neoplasms; alpha 1-antitrypsin; apolipoproteins A; diagnosis
4.  Role of observation of live cases done by Japanese experts in the acquisition of ESD skills by a western endoscopist 
AIM: To evaluate the role of observation of experts performing endoscopic submucosal dissection (ESD) in the acquisition of ESD skills.
METHODS: This prospective study is documenting the learning curve of one Western endoscopist. The study consisted of three periods. In the first period (pre-observation), the trainee performed ESDs in animal models in his home institution in the United States. The second period (observation) consisted of visit to Japan and observation of live ESD cases done by experts. The observation of cases occurred over a 5-wk period. During the third period (post-observation), the trainee performed ESD in animal models in a similar fashion as in the first period. Three animal models were used: live 40-50 kg Yorkshire pig, explanted pig stomach model, and explanted pig rectum model. The outcomes from the ESDs done in the animal models before and after observation of live human cases (main study intervention) were compared. Statistical analysis of the data included: Fisher’s exact test to compare distributions of a categorical variable, Wilcoxon rank sum test to compare distributions of a continuous variable between the two groups (pre-observation and post-observation), and Kruskal-Wallis test to evaluate the impact of lesion location and type of model (ex-vivo vs live pig) on lesion removal time.
RESULTS: The trainee performed 38 ESDs in animal model (29 pre-observation/9 post-observation). The removal times post-observation were significantly shorter than those pre-observation (32.7 ± 15.0 min vs 63.5 ± 9.8 min, P < 0.001). To minimize the impact of improving physician skill, the 9 lesions post-observation were compared to the last 9 lesions pre-observation and the removal times remained significantly shorter (32.7 ± 15.0 min vs 61.0 ± 7.4 min, P = 0.0011). Regression analysis showed that ESD observation significantly reduced removal time when controlling for the sequence of lesion removal (P = 0.025). Furthermore, it was also noted a trend towards decrease in failure to remove lesions and decrease in complications after the period of observation. This study did not find a significant difference in the time needed to remove lesions in different animal models. This finding could have important implications in designing training programs due to the substantial difference in cost between live animal and explanted organ models. The main limitation of this study is that it reflects the experience of a single endoscopist.
CONCLUSION: Observation of experts performing ESD over short period of time can significantly contribute to the acquisition of ESD skills.
PMCID: PMC4000503  PMID: 24782619
Endoscopic submucosal dissection; Training; Animal models; Early gastric cancer; Learning curve
5.  Improved Two-Stage Tests for Stratified Phase II Cancer Clinical Trials 
Statistics in medicine  2012;31(16):1688-1698.
In a single-arm, two-stage, phase II cancer clinical trial for efficacy screening of cytotoxic agents, a common primary endpoint is a binary (yes/no) patient response to treatment. Usually, fixed decision boundaries are used in binomial tests to determine whether the study treatment is promising enough to be studied in a large-scale, randomized phase III trial. We may know in advance that the patient response distribution for a phase II clinical trial will be heterogeneous, making it advisable to stratify patients into subgroups, each with a different prognosis. In this case, fixed decision boundaries may be inappropriate. In this article, we propose two-stage tests based on the Neyman-Pearson lemma. The proposed test statistic is a linear combination of the observed number of responders in each stratum. The test allows adjustment of the decision boundaries to the observed numbers of patients in each stratum and permits sample sizes to be increased adaptively after the originally planned number of patients is observed at each of the two stages. Our numerical results show that the proposed test is more powerful than an existing test in many cases. Finally, we present an application to a Children’s Oncology Group (COG) phase II clinical trial in patients who relapsed after initial treatment for neuroblastoma.
PMCID: PMC3972010  PMID: 22422466
Adaptive design; Decision boundaries; Neyman-Pearson lemma; Likelihood ratio; Type I and type II error probability spending functions
6.  Clinical implications in the shift of syndecan-1 expression from the cell membrane to the cytoplasm in bladder cancer 
BMC Cancer  2014;14:86.
To determine the diagnostic and prognostic capability of urinary and tumoral syndecan-1 (SDC-1) levels in patients with cancer of the urinary bladder.
SDC-1 levels were quantitated by enzyme-linked immunosorbent assay (ELISA) in 308 subjects (102 cancer subjects and 206 non-cancer subjects) to assess its diagnostic capabilities in voided urine. The performance of SDC-1 was evaluated using the area under the curve of a receiver operating characteristic curve. In addition, immunohistochemical (IHC) staining assessed SDC-1 protein expression in 193 bladder specimens (185 cancer subjects and 8 non-cancer subjects). Outcomes were correlated to SDC-1 levels.
Mean urinary levels of SDC-1 did not differ between the cancer subjects and the non-cancer subjects, however, the mean urinary levels of SDC-1 were reduced in high-grade compared to low-grade disease (p < 0.0001), and in muscle invasive bladder cancer (MIBC) compared to non-muscle invasive bladder cancer (NMIBC) (p = 0.005). Correspondingly, preliminary data note a shift from a membranous cellular localization of SDC-1 in normal tissue, low-grade tumors and NMIBC, to a distinctly cytoplasmic localization in high-grade tumors and MIBC was observed in tissue specimens.
Alone urinary SDC-1 may not be a diagnostic biomarker for bladder cancer, but its urinary levels and cellular localization were associated with the differentiation status of patients with bladder tumors. Further studies are warranted to define the potential role for SDC-1 in bladder cancer progression.
PMCID: PMC3930286  PMID: 24524203
Syndecan; Bladder; Cancer biomarker; Specificity
7.  Cardiomyopathy in Children With Down Syndrome Treated for Acute Myeloid Leukemia: A Report From the Children's Oncology Group Study POG 9421 
To determine the outcomes, with particular attention to toxicity, of children with Down syndrome (DS) and acute myeloid leukemia (AML) treated on Pediatric Oncology Group (POG) protocol 9421.
Patients and Methods
Children with DS and newly diagnosed AML (n = 57) were prospectively enrolled onto the standard-therapy arm of POG 9421 and were administered five cycles of chemotherapy, which included daunorubicin 135 mg/m2 and mitoxantrone 80 mg/m2. Outcomes and toxicity were evaluated prospectively and were compared with the non-DS–AML cohort (n = 565). A retrospective chart review was performed to identify adverse cardiac events.
In the DS-AML group, 54 patients (94.7%) entered remission. One experienced induction failure and two died. Of the 54 who entered remission, three relapsed and six died as a result of other causes. The remission induction rate was similar in the non-DS–French-American-British (FAB) M7 (91.7%) and non-DS–non-M7 (89.3%) groups. The 5-year overall survival was significantly better in the DS-AML group (78.6%) than in the non-DS–M7 (36.3%) or the non-DS-non-M7 (51.8%) groups (P < .001). No age-related difference in 5-year, event-free survival was seen between patients younger than 2 years (75.8%) and those aged 2 to 4 years (78.3%). Symptomatic cardiomyopathy developed in 10 patients (17.5%) with DS-AML during or soon after completion of treatment; three died as a result of congestive heart failure.
The POG 9421 treatment regimen was highly effective in both remission induction and disease-free survival for patients with DS-AML. However, there was a high incidence of cardiomyopathy, which supports current strategies for dose reduction of anthracyclines in this patient population.
PMCID: PMC3897300  PMID: 18202418
8.  Transition From Colitis to Cancer: High Wnt Activity Sustains The Tumor-Initiating Potential Of Colon Cancer Stem Cell Precursors 
Cancer research  2012;72(19):5091-5100.
Ulcerative colitis (UC) increases the risk of colorectal cancer (CRC), but the mechanisms involved in colitis-to-cancer transition (CCT) are not well understood. CCT may involve a inflammation-dysplasia-carcinoma progression sequence compared to the better characterized adenoma-carcinoma progression sequence associated with sporadic CRC. One common thread may be activating mutations in components of the Wnt/β-catenin signaling pathway, which occur commonly as early events in sporadic CRC. To examine this hypothesis, we evaluated possible associations between Wnt/β-catenin signaling and CCT based on the cancer stem cell (CSC) model. Wnt/β-catenin immunostaining indicated that UC patients have a level of Wnt-pathway-active cells that is intermediate between normal colon and CRC. These UC cells exhibiting activation of the Wnt pathway constituted a major subpopulation (52%+7.21) of the colonic epithelial cells positive for aldehyde dehydrogenase (ALDH), a putative marker of precursor colon CSC (pCCSC). We further fractionated this subpopulation of pCCSC using a Wnt pathway reporter assay. Over successive passages, pCCSCs with the highest Wnt activity exhibited higher clonogenic and tumorigenic potential than pCCSCs with the lowest Wnt activity, thereby establishing the key role of Wnt activity in driving CSC-like properties in these cells. Notably, 5/20 single cell injections of high-Wnt pCCSC resulted in tumor formation, suggesting a correlation with CCT. Attenuation of Wnt/β-catenin in high-Wnt pCCSC by shRNA-mediated downregulation or pharmacological inhibition significantly reduced tumor growth rates. Overall, the results of our study indicates (i) that early activation of Wnt/β-catenin signaling is critical for CCT, and (ii) that high levels of Wnt/β-catenin signaling can further demarcate ALDH+ tumor-initiating cells in the non-dysplastic epithelium of UC patients. As such, our findings offer plausible diagnostic markers and therapeutic target in the Wnt signaling pathway for early intervention in CCT.
PMCID: PMC3463774  PMID: 22902411
Colitis; Colorectal cancer; CSC; ALDH and Wnt/β-catenin
9.  Investigation of CCL18 and A1AT as potential urinary biomarkers for bladder cancer detection 
BMC Urology  2013;13:42.
In this study, we further investigated the association of two biomarkers, CCL18 and A1AT, with bladder cancer (BCa) and evaluated the influence of potentially confounding factors in an experimental model.
In a cohort of 308 subjects (102 with BCa), urinary concentrations of CCL18 and A1AT were assessed by enzyme-linked immunosorbent assay (ELISA). In an experimental model, benign or cancerous cells, in addition to blood, were added to urines from healthy controls and analyzed by ELISA. Lastly, immunohistochemical staining for CCL18 and A1AT in human bladder tumors was performed.
Median urinary protein concentrations of CCL18 (52.84 pg/ml vs. 11.13 pg/ml, p < 0.0001) and A1AT (606.4 ng/ml vs. 120.0 ng/ml, p < 0.0001) were significantly elevated in BCa subjects compared to controls. Furthermore, the addition of whole blood to pooled normal urine resulted in a significant increase in both CCL18 and A1AT. IHC staining of bladder tumors revealed CCL18 immunoreactivity in inflammatory cells only, and there was no significant increase in these immunoreactive cells within benign and cancerous tissue and no association with BCa grade nor stage was noted. A1AT immunoreactivity was observed in the cytoplasm of epithelia cells and intensity of immunostaining increased with tumor grade, but not tumor stage.
Further development of A1AT as a diagnostic biomarker for BCa is warranted.
PMCID: PMC3846766  PMID: 24011266
Biomarkers; Bladder cancer; Specificity; Urine
10.  Enhanced Responses to Angiogenic Cues Underlie the Pathogenesis of Hereditary Hemorrhagic Telangiectasia 2 
PLoS ONE  2013;8(5):e63138.
Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic vascular disease in which arteriovenous malformations (AVMs) manifest in skin and multiple visceral organs. HHT is caused by heterozygous mutations in endoglin (ENG), activin receptor-like kinase 1 (ALK1), or SMAD4. ALK1 regulates angiogenesis, but the precise function of ALK1 in endothelial cells (ECs) remains elusive. Since most blood vessels of HHT patients do not produce pathological vascular lesions, ALK1 heterozygous ECs may be normal unless additional genetic or environmental stresses are imposed. To investigate the cellular and biochemical phenotypes of Alk1-null versus Alk1-heterozygous ECs, we have generated pulmonary EC lines in which a genotype switch from the Alk1-conditional allele (Alk12f) to the Alk1-null allele (Alk11f) can be induced by tamoxifen treatment. Alk1-null (1 f/1 f) ECs displayed increased migratory properties in vitro in response to bFGF compared with Alk1-het (2 f/1 f) ECs. The 1 f/1 f-ECs formed a denser and more persistent tubular network as compared with their parental 2 f/1 f-ECs. Interestingly, the response to BMP-9 on SMAD1/5 phosphorylation was impaired in both 2 f/1 f- and 1 f/1 f-ECs at a comparable manner, suggesting that other factors in addition to SMADs may play a crucial role for enhanced angiogenic activity in 1 f/1 f-ECs. We also demonstrated in vivo that Alk1-deficient ECs exhibited high migratory and invasive properties. Taken together, these data suggest that enhanced responses to angiogenic cues in ALK1-deficient ECs underlie the pathogenesis of HHT2.
PMCID: PMC3651154  PMID: 23675457
11.  VEGF, CA9 and Angiogenin as a Urinary Biomarker for Bladder Cancer Detection 
Urology  2012;79(5):1185.e1-1185.e6.
To investigate whether elevated urinary levels of vascular endothelial growth factor (VEGF), carbonic anhydrase 9 (CA9) and angiogenin are associated with BCa.
This is a case-control study in which voided urines from 127 patients: control subjects (n = 63) and tumor bearing subjects (n = 64) were analyzed. The urinary concentrations of VEGF, CA9, angiogenin and BTA were assessed by enzyme-linked immunosorbent assay (ELISA). We used the area under the curve (AUC) of receiver operating characteristic curves to determine the ability of VEGF, CA9, and angiogenin to detect BCa in voided urine samples. Data were also compared to a commercial ELISA-based BCa detection assay (BTA-Trak©). Sensitivity, specificity, positive and negative predictive values were calculated.
Urinary concentrations of VEGF, CA9, angiogenin and BTA were significantly elevated in BCa. VEGF was the most accurate urinary biomarker (AUC: 0.886; 95% confidence interval [CI]: 0.8301–0.9418). Furthermore, multivariate regression analysis highlighted VEGF (OR: 5.90; 95% CI: 2.60–13.40, p < 0.0001) as an independent variable. The sensitivities and specificities for VEGF (sensitivity, 83% and specificity, 87%) outperformed BTA (sensitivity, 80% and specificity, 84%).
VEGF may be a valuable addition to voided urine sample analysis for the detection of BCa. Larger, prospective studies are needed to determine the clinical utility of urinary VEGF and angiogenin as biomarkers in the non-invasive evaluation of BCa patients.
PMCID: PMC3341520  PMID: 22386755
angiogenin; bladder cancer; biomarkers; diagnosis; VEGF
12.  Phase II Cancer Clinical Trials with Heterogeneous Patient Populations 
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 Simon’s optimal or minimax design to test on 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 problem 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.
PMCID: PMC3324125  PMID: 22251176
Conditional power; Conditional type I error; Minimax design; Optimal design; Prevalence
13.  A Multi-Analyte Assay for the Non-Invasive Detection of Bladder Cancer 
PLoS ONE  2012;7(10):e47469.
Accurate urinary assays for bladder cancer (BCa) detection would benefit both patients and healthcare systems. Through genomic and proteomic profiling of urine components, we have previously identified a panel of biomarkers that can outperform current urine-based biomarkers for the non-invasive detection of BCa. Herein, we report the diagnostic utility of various multivariate combinations of these biomarkers. We performed a case-controlled validation study in which voided urines from 127 patients (64 tumor bearing subjects) were analyzed. The urinary concentrations of 14 biomarkers (IL-8, MMP-9, MMP-10, SDC1, CCL18, PAI-1, CD44, VEGF, ANG, CA9, A1AT, OPN, PTX3, and APOE) were assessed by enzyme-linked immunosorbent assay (ELISA). Diagnostic performance of each biomarker and multivariate models were compared using receiver operating characteristic curves and the chi-square test. An 8-biomarker model achieved the most accurate BCa diagnosis (sensitivity 92%, specificity 97%), but a combination of 3 of the 8 biomarkers (IL-8, VEGF, and APOE) was also highly accurate (sensitivity 90%, specificity 97%). For comparison, the commercial BTA-Trak ELISA test achieved a sensitivity of 79% and a specificity of 83%, and voided urine cytology detected only 33% of BCa cases in the same cohort. These datashow that a multivariate urine-based assay can markedly improve the accuracy of non-invasive BCa detection. Further validation studies are under way to investigate the clinical utility of this panel of biomarkers for BCa diagnosis and disease monitoring.
PMCID: PMC3477150  PMID: 23094052
14.  CCL18 in a Multiplex Urine-Based Assay for the Detection of Bladder Cancer 
PLoS ONE  2012;7(5):e37797.
The early detection of bladder cancer (BCa) is pivotal for successful patient treatment and management. Through genomic and proteomic studies, we have identified a number of bladder cancer-associated biomarkers that have potential clinical utility. In a case-control study, we examined voided urines from 127 subjects: 64 tumor-bearing subjects and 63 controls. The urine concentrations of the following proteins were assessed by enzyme-linked immunosorbent assay (ELISA); C-C motif chemokine 18 (CCL18), Plasminogen Activator Inhibitor 1 (PAI-1) and CD44. Data were compared to a commercial ELISA-based BCa detection assay (BTA-Trak©) and voided urinary cytology. We used analysis of the area under the curve of receiver operating characteristic curves to compare the ability of CCL18, PAI-1, CD44, and BTA to detect BCa in voided urine samples. Urinary concentrations of CCL18, PAI-1, and BTA were significantly elevated in subjects with BCa. CCL18 was the most accurate biomarker (AUC; 0.919; 95% confidence interval [CI], 0.8704-0.9674). Multivariate regression analysis highlighted CCL18 (OR; 18.31; 95% CI, 4.95-67.70, p<0.0001) and BTA (OR; 6.43; 95% CI, 1.86-22.21, p = 0.0033) as independent predictors of BCa in voided urine samples. The combination of CCL18, PAI-1 and CD44 improved the area under the curve to0.938. Preliminary results indicate that CCL18 was a highly accurate biomarker for BCa detection in this cohort. Monitoring CCL18 in voided urine samples has the potential to improve non-invasive tests for BCa diagnosis. Furthermore using the combination of CCL18, PAI-1 and CD44 may make the model more robust to errors to detect BCa over the individual biomarkers or BTA.
PMCID: PMC3357344  PMID: 22629457
15.  IL-8 as a urinary biomarker for the detection of bladder cancer 
BMC Urology  2012;12:12.
Current urine-based assays for bladder cancer (BCa) diagnosis lack accuracy, so the search for improved biomarkers continues. Through genomic and proteomic profiling of urine, we have identified a panel of biomarkers associated with the presence of BCa. In this study, we evaluated the utility of three of these biomarkers, interleukin 8 (IL-8), Matrix metallopeptidase 9 (MMP-9) and Syndecan in the diagnosis of BCa through urinalysis.
Voided urines from 127 subjects, cancer subjects (n = 64), non-cancer subjects (n = 63) were analyzed. The protein concentrations of IL-8, MMP-9, and Syndecan were assessed by enzyme-linked immunosorbent assay (ELISA). Data were also compared to a commercial ELISA-based BCa detection assay (BTA-Trak©) and urinary cytology. We used the area under the curve of a receiver operating characteristic (AUROC) to compare the performance of each biomarker.
Urinary protein concentrations of IL-8, MMP-9 and BTA were significantly elevated in BCa subjects. Of the experimental markers compared to BTA-Trak©, IL-8 was the most prominent marker (AUC; 0.79; 95% confidence interval [CI], 0.72-0.86). Multivariate regression analysis revealed that only IL-8 (OR; 1.51; 95% CI, 1.16-1.97, p = 0.002) was an independent factor for the detection of BCa.
These results suggest that the measurement of IL-8 in voided urinary samples may have utility for urine-based detection of BCa. These findings need to be confirmed in a larger, prospective cohort.
PMCID: PMC3404900  PMID: 22559832
IL-8; Biomarkers; Diagnosis; Bladder cancer
16.  Selecting a comparison group for 5-year oral and pharyngeal cancer survivors: Two methods 
To assess potential long-term consequences of cancer treatment, studies that include comparison groups are needed. These comparison groups should be selected in a way that allows the subtle long-range effects of cancer therapy to be detected and distinguishes them from the effects of aging and other risk factors. The purpose of this investigation was to test two methods of recruiting a comparison group for 5-year oral and pharyngeal cancer survivors (peer-nominated and listed sample) with emphasis on feasibility and the quality of the match.
Participants were drawn from a pool of 5-year survivors treated at a large Southeastern hospital. A peer-nominated sample was solicited from the survivors. A listed sample matched on sex, age, and zip code was purchased. Telephone interviews were conducted by a professional call center.
The following represent our key findings: The quality of matching between survivors and listed sample was better than that between survivors and peer-nominated group in age and sex. The quality of matching between the two methods on other key variables did not differ except for education, with the peer method providing a better match for the survivors than the listed sample. The yield for the listed sample method was greater than for the peer-nominated method. The cost per completed interview was greater for the peer-nominated method than the listed sample.
This study not only documents the methodological challenges in selecting a comparison group for studies examining the late effects of cancer treatment among older individuals but also documents challenges in matching groups that potentially have disproportionate levels of comorbidities and at-risk health behaviors.
PMCID: PMC3466141  PMID: 22551236
17.  Detection of antibodies directed at M. hyorhinis p37 in the serum of men with newly diagnosed prostate cancer 
BMC Cancer  2011;11:233.
Recent epidemiologic, genetic, and molecular studies suggest infection and inflammation initiate certain cancers, including cancers of the prostate. Over the past several years, our group has been studying how mycoplasmas could possibly initiate and propagate cancers of the prostate. Specifically, Mycoplasma hyorhinis encoded protein p37 was found to promote invasion of prostate cancer cells and cause changes in growth, morphology and gene expression of these cells to a more aggressive phenotype. Moreover, we found that chronic exposure of benign human prostate cells to M. hyorhinis resulted in significant phenotypic and karyotypic changes that ultimately resulted in the malignant transformation of the benign cells. In this study, we set out to investigate another potential link between mycoplasma and human prostate cancer.
We report the incidence of men with prostate cancer and benign prostatic hyperplasia (BPH) being seropositive for M. hyorhinis. Antibodies to M. hyorhinis were surveyed by a novel indirect enzyme-linked immunosorbent assay (ELISA) in serum samples collected from men presenting to an outpatient Urology clinic for BPH (N = 105) or prostate cancer (N = 114) from 2006-2009.
A seropositive rate of 36% in men with BPH and 52% in men with prostate cancer was reported, thus leading us to speculate a possible connection between M. hyorhinis exposure with prostate cancer.
These results further support a potential exacerbating role for mycoplasma in the development of prostate cancer.
PMCID: PMC3129326  PMID: 21663671
Mycoplasma hyorhinis; ELISA; cancer; prostate
18.  Phase I Study of Valspodar (PSC-833) with Mitoxantrone and Etoposide in Refractory and Relapsed Pediatric Acute Leukemia: A Report from the Children’s Oncology Group 
Pediatric blood & cancer  2010;54(5):694-702.
Valspodar, a non-immunosuppressive analog of cylosporine, is a potent P-glycoprotein (MDR1) inhibitor. As MDR1-mediated efflux of chemotherapeutic agents from leukemic blasts may contribute to drug resistance, a phase 1 study of valspodar combined with mitoxantrone and etoposide in pediatric patients with relapsed or refractory leukemias was performed.
Patients received a valspodar loading dose (2 mg/kg) followed by a five-day continuous valspodar infusion (8, 10, 12.5 or 15 mg/kg/day) combined with lower than standard doses of mitoxantrone and etoposide. The valspodar dose was escalated using a standard 3 + 3 phase I design.
21 patients were evaluable for toxicity and 20 for response. The maximum tolerated dose (MTD) of valspodar was 12.5 mg/kg/day, combined with 50% dose-reduced mitoxantrone and etoposide. The clearance of mitoxantrone and etoposide was decreased by 64% and 60%, respectively, when combined with valspodar. Dose-limiting toxicities included stomatitis, ataxia, and bone marrow aplasia. Three of 11 patients with acute lymphoblastic leukemia (ALL) had complete responses while no patient with acute myeloid leukemia (AML) had an objective response. In vitro studies demonstrated P-glycoprotein expression on the blasts of five of 14 patients, although only one had inhibition of rhodamine efflux by valspodar.
While this regimen was tolerable, responses in this heavily pretreated population were limited to a subset of patients with ALL.
PMCID: PMC2838930  PMID: 20209646
leukemia; MDR1; multidrug resistance; P-glycoprotein; PSC-833; valspodar
19.  A Statistical Design for Testing Transgenerational Genomic Imprinting in Natural Human Populations 
PLoS ONE  2011;6(2):e16858.
Genomic imprinting is a phenomenon in which the same allele is expressed differently, depending on its parental origin. Such a phenomenon, also called the parent-of-origin effect, has been recognized to play a pivotal role in embryological development and pathogenesis in many species. Here we propose a statistical design for detecting imprinted loci that control quantitative traits based on a random set of three-generation families from a natural population in humans. This design provides a pathway for characterizing the effects of imprinted genes on a complex trait or disease at different generations and testing transgenerational changes of imprinted effects. The design is integrated with population and cytogenetic principles of gene segregation and transmission from a previous generation to next. The implementation of the EM algorithm within the design framework leads to the estimation of genetic parameters that define imprinted effects. A simulation study is used to investigate the statistical properties of the model and validate its utilization. This new design, coupled with increasingly used genome-wide association studies, should have an immediate implication for studying the genetic architecture of complex traits in humans.
PMCID: PMC3045439  PMID: 21364891
20.  Combination of IFN-α/Gm-CSF as a Maintenance Therapy for Multiple Myeloma Patients After Autologous Stem Cell Transplantation (ASCT): A Prospective Phase II Study 
Interferon alpha (IFN-α) has been used as a maintenance therapy after autologous stem cell transplantation (ASCT) for multiple myeloma (MM) patients. In this study, we combined GM-CSF with IFN-α in order to improve IFN tolerance in post-ASCT myeloma patients. Primary aims were to evaluate myelotoxicity and effectiveness of this maintenance therapy. The treatment included 4 × 106 units of IFN-α and 125 μg/m2 of GM-CSF given three times a week for twelve months. Twenty seven patients were enrolled within 120 days after ASCT. One patient discontinued treatment due to thrombocytopenia and seven others were taken off study due to flu-like symptoms and/or increase in liver enzymes. With a median follow-up of 45.5 months, the median overall survival was not reached while the median progression-free survival was 28 months. Eleven patients (42%) have remained in very good partial remission or complete remission since ASCT. In conclusion, our results demonstrate that maintenance with GM-CSF and IFN-α is safe and effective.
PMCID: PMC2999958  PMID: 21151584
autologous stem cell transplant; interferon alpha; GM-CSF; multiple myeloma; maintenance therapy; toxicity
21.  A Statistical Model for Genetic Mapping of Viral Infection by Integrating Epidemiological Behavior 
Large-scale studies of genetic variation may be helpful for understanding the genetic control mechanisms of viral infection and, ultimately, predicting and eliminating infectious disease outbreaks. We propose a new statistical model for detecting specific DNA sequence variants that are responsible for viral infection. This model considers additive, dominance and epistatic effects of haplotypes from three different genomes, recipient, transmitter and virus, through an epidemiological process. The model is constructed within the maximum likelihood framework and implemented with the EM algorithm. A number of hypothesis tests about population genetic structure and diversity and the pattern of genetic control are formulated. A series of closed forms for the EM algorithm to estimate haplotype frequencies and haplotype effects in a network of genetic interactions among three genomes are derived. Simulation studies were performed to test the statistical properties of the model, recommending necessary sample sizes for obtaining reasonably good accuracy and precision of parameter estimation. By integrating, for the first time, the epidemiological principle of viral infection into genetic mapping, the new model shall find an immediate application to studying the genetic architecture of viral infection.
PMCID: PMC2861318  PMID: 19799557
22.  Minimal Disseminated Disease in Childhood T-Cell Lymphoblastic Lymphoma: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2009;27(21):3533-3539.
Disease dissemination to the bone marrow is detected at diagnosis in approximately 15% of children with T-cell lymphoblastic lymphoma (T-LL). It is unclear whether the remaining patients have submicroscopic systemic disease and, if so, what is the clinical significance of this finding.
Patients and Methods
Using a flow cytometric method that can detect one T-LL cell among 10,000 normal cells, we examined bone marrow and peripheral-blood samples collected from 99 children with T-LL at diagnosis, as well as blood samples collected from 42 patients during treatment.
In 71 (71.7%) of the 99 marrow samples obtained at diagnosis, T-LL cells represented 0.01% to 31.6% (median, 0.22%) of mononuclear cells; 57 of the 71 T-LL–positive samples were from patients with stage II/III disease. Results of studies in bilateral marrow aspirates were highly concordant. Two-year event-free survival (EFS) was 68.1% ± 11.1% (SE) for patients with ≥ 1% T-LL cells in bone marrow versus 90.7% ± 4.4% for those with lower levels of marrow involvement (P = .031); EFS for patients with ≥ 5% lymphoblasts was 51.9% ± 18.0% (P = .009). T-LL cells were as prevalent in blood as in marrow; monitoring residual T-LL cells in blood during remission induction therapy identified patients with slower disease clearance.
More than two thirds of children with T-LL have disseminated disease at diagnosis, a proportion much higher than previously demonstrated. Measurements of disease dissemination at diagnosis might provide useful prognostic information, which can be further refined by monitoring response to therapy through blood testing.
PMCID: PMC2717759  PMID: 19546402
23.  A Study of Rituximab and Ifosfamide, Carboplatin, and Etoposide Chemotherapy in Children with Recurrent/Refractory B-cell (CD20+) Non-Hodgkin Lymphoma and Mature B-Cell Acute Lymphoblastic Leukemia: A Report from the Children's Oncology Group 
Pediatric blood & cancer  2009;52(2):177-181.
To estimate the response rate and therapy related toxicities of the anti-CD20 monoclonal antibody rituximab when combined with chemotherapy including ifosfamide, carboplatin, and etoposide (ICE) in patients with relapsed and refractory B-cell non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia (B-ALL).
Patients received rituximab and ICE for 1 to 3 cycles, depending upon response. Rituximab (375 mg/m2) was given on day 1 and 3 of each cycle (day 1 only for cycle 3), with ifosfamide (3000 mg/m2) and etoposide (100 mg/m2) given on days 3, 4, and 5 and carboplatin (635 mg/m2) given on day 3 only.
Twenty-one patients were enrolled, of whom 20 were eligible and evaluable. Although hematologic toxicities were common, only one patient was removed from study due to prolonged myelosuppression. Toxicities related to infusions of rituximab were frequent but manageable. Of the 6 eligible patients with diffuse large B-cell lymphoma, 3 achieved complete remission (CR), 1 had stable disease (SD), and 2 had progressive disease (PD). Of the 14 eligible patients with Burkitt lymphoma and B-ALL, there were 4 complete responses (CR), 5 partial responses (PR), 1 SD and 4 with PD. Thus the CR/PR rate for the entire group was 12/20 (60%). Following completion of protocol therapy 6 patients were able to proceed to consolidation with high-dose therapy and stem cell rescue.
The combination of rituximab and ICE chemotherapy was associated with an encouraging objective response rate and an acceptable toxicity profile.
PMCID: PMC2728935  PMID: 18816698
Non-Hodgkin's Lymphoma; Large Cell Lymphoma; Burkitt's Lymphoma; Chemotherapy
24.  Utility of serial urinary cytology in the initial evaluation of the patient with microscopic hematuria 
BMC Urology  2009;9:12.
We determine the utility of serial urinary cytologies in patients presenting with microscopic hematuria who were evaluated with upper and lower urinary tract studies to rule out a malignancy.
Two hundred and thirty-seven patients with the diagnosis of microscopic hematuria were evaluated at an inner-city tertiary care hospital. Of these 239 patients, 182 patients had 405 cytologies obtained as part of their evaluation for hematuria. In addition, all patients had their lower urinary tract and upper tract thoroughly evaluated.
Two hundred and seventy four cytology samples were read as normal, 104 (26%) as atypia, 7 (2%) as suspicious/malignant, and 20 (5%) as unsatisfactory. Seventeen patients (9.3%) had biopsy confirmed bladder cancer. Of these 17 patients, 2 had normal cytology, 11 had atypia, and 5 had suspicious/malignant. No patient had a positive cytology and a negative biopsy. Overall the number of hematuric patients harboring bladder cancer was small (7%). Cytology #1 detected 4 cases of cancer, cytology #2 detected an additional case and cytology #3 did not detect any additional cancers.
Because of this low prevalence of bladder cancer in patients presenting with microscopic hematuria and the low sensitivity of detecting bladder cancers, the utility of urinary cytology in the initial evaluation of patients with hematuria may be minimal. The exact role of urinary cytology in the evaluation of hematuria is unknown.
PMCID: PMC2751768  PMID: 19744317
25.  Modeling genetic imprinting effects of DNA sequences with multilocus polymorphism data 
Single nucleotide polymorphisms (SNPs) represent the most widespread type of DNA sequence variation in the human genome and they have recently emerged as valuable genetic markers for revealing the genetic architecture of complex traits in terms of nucleotide combination and sequence. Here, we extend an algorithmic model for the haplotype analysis of SNPs to estimate the effects of genetic imprinting expressed at the DNA sequence level. The model provides a general procedure for identifying the number and types of optimal DNA sequence variants that are expressed differently due to their parental origin. The model is used to analyze a genetic data set collected from a pain genetics project. We find that DNA haplotype GAC from three SNPs, OPRKG36T (with two alleles G and T), OPRKA843G (with alleles A and G), and OPRKC846T (with alleles C and T), at the kappa-opioid receptor, triggers a significant effect on pain sensitivity, but with expression significantly depending on the parent from which it is inherited (p = 0.008). With a tremendous advance in SNP identification and automated screening, the model founded on haplotype discovery and statistical inference may provide a useful tool for genetic analysis of any quantitative trait with complex inheritance.
PMCID: PMC2739217  PMID: 19671182

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