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1.  Ethnic Differences in the Effects of Hepatic Fat Deposition on Insulin Resistance in Non-Obese Middle School Girls 
Obesity (Silver Spring, Md.)  2013;22(1):243-248.
Objective
In non-obese youth, to investigate whether hepatic fat deposition and its metabolic consequences vary between ethnic groups.
Design Methods
Thirty-two non-obese girls (12 Hispanic White [H] and 20 non-Hispanic White [NHW] girls), aged 11–14 years old were recruited. Outcome measures were MRI measured hepatic proton density fat fraction (hepatic PDFF), BMI Z-score, waist circumference, fasting insulin, glucose, adiponectin, sex hormone binding globulin [SHBG], ALT, AST, and triglycerides, and HOMA-IR.
Results
There were no significant differences in mean BMI Z-scores (p=0.546) or hepatic PDFF (p=0.275) between H and NHW girls; however, H girls showed significant correlations between hepatic PDFF and markers of IR (fasting insulin, HOMA-IR, adiponectin, SHBG, triglycerides; all p<0.05), while NHW girls showed no significant correlations. Matched by hepatic PDFF or BMI-Z score, H girls had more evidence of IR for a given hepatic PDFF (mean insulin, HOMA-IR, and SHBG; all p<0.05) or BMI-Z score (mean insulin and HOMA-IR; all p<0.01) than NHW girls.
Conclusions
In non-obese female youth, ethnicity-related differences in effects of hepatic fat on IR are evident, so that in H girls, a given amount of hepatic fat appears to result in a more predictable and greater degree of IR than in NHW girls.
doi:10.1002/oby.20521
PMCID: PMC3946962  PMID: 23804504
Ethnicity; Non-obese; Insulin Resistance; Hepatic Steatosis
2.  Changes in Large Pulmonary Arterial Viscoelasticity in Chronic Pulmonary Hypertension 
PLoS ONE  2013;8(11):e78569.
Conduit pulmonary artery (PA) stiffening is characteristic of pulmonary arterial hypertension (PAH) and is an excellent predictor of mortality due to right ventricular (RV) overload. To better understand the impact of conduit PA stiffening on RV afterload, it is critical to examine the arterial viscoelastic properties, which require measurements of elasticity (energy storage behavior) and viscosity (energy dissipation behavior). Here we hypothesize that PAH leads to frequency-dependent changes in arterial stiffness (related to elasticity) and damping ratio (related to viscosity) in large PAs. To test our hypothesis, PAH was induced by the combination of chronic hypoxia and an antiangiogenic compound (SU5416) treatment in mice. Static and sinusoidal pressure-inflation tests were performed on isolated conduit PAs at various frequencies (0.01–20 Hz) to obtain the mechanical properties in the absence of smooth muscle contraction. Static mechanical tests showed significant stiffening of large PAs with PAH, as expected. In dynamic mechanical tests, structural stiffness (κ) increased and damping ratio (D) decreased at a physiologically relevant frequency (10 Hz) in hypertensive PAs. The dynamic elastic modulus (E), a material stiffness, did not increase significantly with PAH. All dynamic mechanical properties were strong functions of frequency. In particular, κ, E and D increased with increasing frequency in control PAs. While this behavior remained for D in hypertensive PAs, it reversed for κ and E. Since these novel dynamic mechanical property changes were found in the absence of changes in smooth muscle cell content or contraction, changes in collagen and proteoglycans and their interactions are likely critical to arterial viscoelasticity in a way that has not been previously described. The impact of these changes in PA viscoelasticity on RV afterload in PAH awaits further investigation.
doi:10.1371/journal.pone.0078569
PMCID: PMC3819365  PMID: 24223157
3.  A Bayesian adaptive design with biomarkers for targeted therapies 
Background
Targeted therapies are becoming increasingly important for the treatment of various diseases. Biomarkers are a critical component of a targeted therapy as they can be used to identify patients who are more likely to benefit from a treatment. Targeted therapies, however, have created major challenges in the design, conduct, and analysis of clinical trials. In traditional clinical trials, treatment effects for various biomarkers are typically evaluated in an exploratory fashion and only limited information about the predictive values of biomarkers obtained.
Purpose
New study designs are required, which effectively evaluate both the diagnostic and the therapeutic implication of biomarkers.
Methods
The Bayesian approach provides a useful framework for optimizing the clinical trial design by directly integrating information about biomarkers and clinical outcomes as they become available. We propose a Bayesian covariate-adjusted response-adaptive randomization design, which utilizes individual biomarker profiles and patient's clinical outcomes as they become available during the course of the trial, to assign the most efficacious treatment to individual patients. Predictive biomarker subgroups are determined adaptively using a partial least squares regression approach.
Results
A series of simulation studies were conducted to examine the operating characteristics of the proposed study design. The simulation studies show that the proposed design efficiently identifies patients who benefit most from a targeted therapy and that there are substantial savings in the sample size requirements when compared to alternative designs.
Limitations
The design does not control for the type I error in the traditional sense and a positive result should be confirmed by conducting an independent phase III study focusing on the selected biomarker profile groups.
Conclusions
We conclude that the proposed design may serve a useful role in the early efficacy phase of targeted therapy development.
doi:10.1177/1740774510372657
PMCID: PMC3788617  PMID: 20571131
4.  Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer 
Cancer Immunology, Immunotherapy  2011;61(7):1137-1147.
CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles, 3 months apart, in which they received bicalutamide 150 mg daily days 1–28 and tremelimumab on day 29. The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression.
doi:10.1007/s00262-011-1193-1
PMCID: PMC3349783  PMID: 22210552
Tremelimumab; Anti-CTLA-4 monoclonal antibody; Bicalutamide; Prostate cancer; Clinical trial
5.  Inpatient Hospitalization of Oncology Patients: Are We Missing an Opportunity for End-of-Life Care? 
Journal of Oncology Practice  2012;9(1):51-54.
The authors conclude that the inpatient oncology service predominantly cares for a population nearing the end of life; therefore, goals should include symptom control and end-of-life planning.
Introduction:
Despite advances in the care of patients with cancer over the last 10 years, cancer remains the second leading cause of death in the United States. Many patients receive aggressive, in-hospital end-of-life care at high cost. There are few data on outcomes after unplanned hospitalization of patients with metastatic cancer.
Methods:
In 2000 and 2010, data were collected on admissions, interventions, and survival for patients admitted to an academic inpatient medical oncology service.
Results:
The 2000 survey included 191 admissions of 151 unique patients. The 2010 survey assessed 149 admissions of 119 patients. Lung, GI, and breast cancers were the most common cancer diagnoses. In the 2010 assessment, pain was the most common chief complaint, accounting for 28%. Although symptoms were the dominant reason for admission in 2010, procedures and imaging were common in both surveys. The median survival of patients after discharge was 4.7 months in 2000 and 3.4 months in 2010. Despite poor survival in this patient population, hospice was recommended in only 23% and 24% of patients in 2000 and 2010, respectively. Seventy percent of patients were discharged home without additional services.
Conclusion:
On the basis of our data, an unscheduled hospitalization for a patient with advanced cancer strongly predicts a median survival of fewer than 6 months. We believe that hospital admission represents an opportunity to commence and/or consolidate appropriate palliative care services and end-of-life care.
doi:10.1200/JOP.2012.000698
PMCID: PMC3545663  PMID: 23633971
6.  Maintenance rituximab following induction chemo-immunotherapy for mantle cell lymphoma: long-term follow-up of a pilot study from the Wisconsin Oncology Network 
Leukemia & lymphoma  2011;52(9):1675-1680.
Mantle cell lymphoma (MCL) is challenging to manage, with a median survival of 3–5 years. While intensive strategies are often appropriate for younger patients, these approaches are often not appropriate for older patients. In 2006, we reported our initial results using modified R-hyperCVAD (rituximab with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with maintenance rituximab. The complete response rate was 64%, and median progression-free survival (PFS) 37 months. Herein, we update our results, now with a median follow-up of 62 months. The median PFS is unchanged and the median overall survival (OS) is 70 months. The proportion of patients surviving at 5 years is 62%, comparable to studies using intensive strategies in similar patient populations. No late toxicities were noted in our cohort. These long-term results suggest that the modified R-hyperCVAD regimen with maintenance rituximab is an excellent option for older patients with newly diagnosed mantle cell lymphoma.
doi:10.3109/10428194.2011.580404
PMCID: PMC3489168  PMID: 21864042
Mantle cell lymphoma; non-Hodgkin’s lymphoma; rituximab maintenance; modified R-hyperCVAD
7.  Enhancement of radiation response with bevacizumab 
Background
Vascular endothelial growth factor (VEGF) plays a critical role in tumor angiogenesis. Bevacizumab is a humanized monoclonal antibody that neutralizes VEGF. We examined the impact on radiation response by blocking VEGF signaling with bevacizumab.
Methods
Human umbilical vein endothelial cell (HUVEC) growth inhibition and apoptosis were examined by crystal violet assay and flow cytometry, respectively. In vitro HUVEC tube formation and in vivo Matrigel assays were performed to assess the anti-angiogenic effect. Finally, a series of experiments of growth inhibition on head and neck (H&N) SCC1 and lung H226 tumor xenograft models were conducted to evaluate the impact of bevacizumab on radiation response in concurrent as well as sequential therapy.
Results
The anti-angiogenic effect of bevacizumab appeared to derive not only from inhibition of endothelial cell growth (40%) but also by interfering with endothelial cell function including mobility, cell-to-cell interaction and the ability to form capillaries as reflected by tube formation. In cell culture, bevacizumab induced a 2 ~ 3 fold increase in endothelial cell apoptosis following radiation. In both SCC1 and H226 xenograft models, the concurrent administration of bevacizumab and radiation reduced tumor blood vessel formation and inhibited tumor growth compared to either modality alone. We observed a siginificant tumor reduction in mice receiving the combination of bevacizumab and radiation in comparison to mice treated with bevacizumab or radiation alone. We investigated the impact of bevacizumab and radiation treatment sequence on tumor response. In the SCC1 model, tumor response was strongest with radiation followed by bevacizumab with less sequence impact observed in the H226 model.
Conclusions
Overall, these data demonstrate enhanced tumor response when bevacizumab is combined with radiation, supporting the emerging clinical investigations that are combining anti-angiogenic therapies with radiation.
doi:10.1186/1756-9966-31-37
PMCID: PMC3537546  PMID: 22538017
Anti-angiogenesis; VEGF; Bevacizumab; Radiation
8.  Survival of gastrointestinal stromal tumor patients in the imatinib era: life raft group observational registry 
BMC Cancer  2012;12:90.
Background
Gastrointestinal stromal tumors (GIST), one of the most common mesenchymal tumors of the gastrointestinal tract, prior to routine immunohistochemical staining and the introduction of tyrosine kinase inhibitors, were often mistaken for neoplasms of smooth muscle origin such as leiomyomas, leiomyosarcomas or leiomyoblastomas. Since the advent of imatinib, GIST has been further delineated into adult- (KIT or PDGFRα mutations) and pediatric- (typified by wild-type GIST/succinate dehydrogenase deficiencies) types. Using varying gender ratios at age of diagnosis we sought to elucidate prognostic factors for each sub-type and their impact on overall survival.
Methods
This is a long-term retrospective analysis of a large observational study of an international open cohort of patients from a GIST research and patient advocacy's lifetime registry. Demographic and disease-specific data were voluntarily supplied by its members from May 2000-October 2010; the primary outcome was overall survival. Associations between survival and prognostic factors were evaluated by univariate Cox proportional hazard analyses, with backward selection at P < 0.05 used to identify independent factors.
Results
Inflections in gender ratios by age at diagnosis in years delineated two distinct groups: above and below age 35 at diagnosis. Closer analysis confirmed the above 35 age group as previously reported for adult-type GIST, typified by mixed primary tumor sites and gender, KIT or PDGFRα mutations, and shorter survival times. The pediatric group (< age 18 at diagnosis) was also as previously reported with predominantly stomach tumors, females, wild-type GIST or SDH mutations, and extended survival. "Young adults" however formed a third group aged 18-35 at diagnosis, and were a clear mix of these two previously reported distinct sub-types.
Conclusions
Pediatric- and adult-type GIST have been previously characterized in clinical settings and these observations confirm significant prognostic factors for each from a diverse real-world cohort. Additionally, these findings suggest that extra diligence be taken with "young adults" (aged 18-35 at diagnosis) as pediatric-type GIST may present well beyond adolescence, particularly as these distinct sub-types have different causes, and consequently respond differently to treatments.
doi:10.1186/1471-2407-12-90
PMCID: PMC3364851  PMID: 22429770
9.  Gender and race influence metabolic benefits of fitness in children: a cross-sectional study 
Background
Increasing obesity and poor cardiovascular fitness (CVF) contribute to higher rates of type 2 diabetes mellitus (T2DM) in children. While the relative contributions of fitness and body fat on development of insulin resistance (IR) in children and adolescents remains unresolved, gender- and race-specific differences likely exist in the degree to which CVF influences IR and risk for T2DM. Better understanding of how gender and race affect interactions between body fat, CVF, and metabolic health would be helpful in designing effective and targeted strategies to reduce obesity-associated disease risk. We evaluated whether metabolic benefits of fitness on reducing inflammation and insulin resistance (IR) are affected by gender and race.
Methods
This cross-sectional study included 203 healthy children (mean age 12.2 y, 50% male, 46% non-Hispanic white (NHW), 54% racially diverse (RD)). Fasting insulin, glucose, hsCRP, and adiponectin were measured; race was self-reported; cardiovascular fitness (CVF) was evaluated by the Progressive Aerobic Cardiovascular Endurance Run. Associations between inflammation and gender, race, and CVF were evaluated using analysis of covariance. Multivariate regression analysis identified independent predictors of IR.
Results
Fitness and inflammation were inversely related in both males and females (p < 0.01); this effect was marginally stronger in RD children (p = 0.06) and non-overweight males (p = 0.07). High BMI (p < 0.001), low fitness (p = 0.006), and (female) gender (p = 0.003) were independently associated with higher HOMA-IR. In males, BMI and fitness, but not race independently predicted HOMA-IR. In females, BMI and race, but not fitness independently predicted HOMA-IR.
Conclusions
In middle school children, the beneficial effects of fitness vary based on gender and race. High CVF has an enhanced anti-inflammatory effect in male and RD children. While BMI is the strongest predictor of IR in the study group as a whole, fitness is a significant predictor of IR only in males, and race is a significant predictor of IR only in females.
doi:10.1186/1687-9856-2012-4
PMCID: PMC3353855  PMID: 22420715
Gender; Race; Cardiovascular Fitness; Insulin Resistance
10.  Antibody Responses to Prostate-Associated Antigens in Patients with Prostatitis and Prostate Cancer 
The Prostate  2011;71(2):134-146.
Background
An important focus of tumor immunotherapy has been the identification of appropriate antigenic targets. Serum-based screening approaches have led to the discovery of hundreds of tumor-associated antigens recognized by IgG. Our efforts to identify immunologically recognized proteins in prostate cancer have yielded a multitude of antigens, however prioritizing these antigens as targets for evaluation in immunotherapies has been challenging. In this report, we set out to determine whether the evaluation of multiple antigenic targets would allow the identification of a subset of antigens that are common immunologic targets in patients with prostate cancer.
Methods
Using a phage immunoblot approach, we evaluated IgG responses in patients with prostate cancer (n=126), patients with chronic prostatitis (n=45), and men without prostate disease (n=53).
Results
We found that patients with prostate cancer or prostatitis have IgG specific for multiple common antigens. A subset of 23 proteins was identified to which IgG were detected in 38% of patients with prostate cancer and 33% patients with prostatitis versus 6% of controls (p<0.001 and p=0.003, respectively). Responses to multiple members were not higher in patients with advanced disease, suggesting antibody immune responses occur early in the natural history of cancer progression.
Conclusions
These findings suggest an association between inflammatory conditions of the prostate and prostate cancer, and suggest that IgG responses to a panel of commonly recognized prostate antigens could be potentially used in the identification of patients at risk for prostate cancer or as a tool to identify immune responses elicited to prostate tissue.
doi:10.1002/pros.21229
PMCID: PMC2978272  PMID: 20632317
IgG; autoantibody; prostate cancer; prostatitis; high-throughput immunoblot
11.  PILOT STUDY OF GEFITINIB AND FULVESTRANT IN THE TREATMENT OF POST-MENOPAUSAL WOMEN WITH ADVANCED NON-SMALL CELL LUNG CANCER 
SUMMARY
Introduction
Estrogen receptor beta (ERβ) has been detected in NSCLC cell lines and tumor specimens. The ER down-regulator, fulvestrant, blocked estradiol-stimulation of tumor growth and gene transcription in NSCLC preclinical models and showed additive effects with the EGFR inhibitor gefitinib. The safety and tolerability of combination therapy with the EGFR inhibitor, gefitinib, and fulvestrant was explored.
Methods
Post-menopausal women with advanced NSCLC received gefitinib 250 mg po daily and fulvestrant 250 mg IM monthly.
Results
Twenty-two patients were enrolled. Eight patients had adenocarcinoma, 6 NSCLC-NOS, 4 squamous cell, and 4 BAC. Seven patients were never smokers. Eight patients received ≥ 2 lines of prior chemotherapy, 6 received one prior chemotherapy, and 8 were treatment naive. One patient experienced grade 4 dyspnea possibly related to treatment; all other grade 3/4 toxicities were unrelated to treatment. Twenty patients were evaluable for response: 3 PRs were confirmed (response rate of 15%, 95% CI: 5% – 36%). The median PFS, OS, and estimated 1 yr OS were 12 wks (3–112 wks), 38.5 weeks (7–135 wks), and 41% (95% CI 20–62%), respectively. Survival outcomes did not differ by prior lines of therapy. A subset analysis revealed that OS in the 8 patients whose tumors exhibited at least 60% ERβ nuclear IHC staining measured 65.5 weeks, while that of the 5 patients with ERβ staining of less than 60% was 21 weeks. One patient with BAC and a PR had an EGFR L858R mutation in exon 21. There was no correlation between ERβ IHC expression and histology or smoking history.
Conclusions
Combination therapy with gefitinib and fulvestrant in this population was well-tolerated and demonstrated disease activity.
doi:10.1016/j.lungcan.2008.07.002
PMCID: PMC3164240  PMID: 18701186
epidermal growth factor receptor; hormonal treatment; non-small cell lung cancer; sex; age; estrogen receptor
12.  PROPOFOL-FENTANYL VERSUS PROPOFOL ALONE FOR LUMBAR PUNCTURE SEDATION IN CHILDREN WITH ACUTE HEMATOLOGIC MALIGNANCIES: PROPOFOL DOSING AND ADVERSE EVENTS 
Objective
We sought to determine whether the combination of propofol and fentanyl results in lower propofol doses and fewer adverse cardiopulmonary events than propofol and placebo for lumbar puncture (LP) in children with acute hematologic malignancies.
Design
Randomized, controlled, double blind, crossover study.
Setting
Pediatric Sedation Program
Patients
Children with acute leukemia or lymphoma receiving sedation for LP.
Interventions
Each patient received two sedations in random order, one with propofol/placebo and one with propofol/fentanyl. The study investigator and patient/parent were blinded to placebo or fentanyl. Data collected included patient age and diagnosis, propofol dose and adverse events. Adverse events included oxygen saturation < 94%, airway obstruction, apnea, hypotension and bradycardia (< 5% mean for age). Logistic regression analysis was utilized to assess probability of adverse events and the Wilcoxon Signed Rank and McNemar’s tests were used for paired comparisons.
Measurements and Main Results
Twenty-two patients were enrolled. Fourteen patients were male and 8 were female. Each patient was studied twice for a total of 44 sedations. The median age was 5.0 years (range 2.2–17.2 years). All procedures were successfully completed. The median total dose of propofol was 5.05 mg/kg (range 2.4–10.2 mg/kg) for propofol/placebo versus 3.00 mg/kg (range 1.4–10.5 mg/kg) for propofol/fentanyl (p < 0.001). Twelve adverse events occurred in 11 of 22 patients (50.0%) propofol/placebo compared to 6 of 22 (18.2%) propofol/fentanyl (p= 0.02). The most common adverse event was hypotension.
Conclusions
The combination of propofol and fentanyl versus propofol alone for LP sedation in children with acute hematologic malignancies resulted in lower propofol doses and fewer adverse events.
doi:10.1097/PCC.0b013e31818e3ad3
PMCID: PMC3076743  PMID: 18838923
propofol; fentanyl; pediatric oncology; procedural sedation
13.  A Phase II Study of Oxaliplatin, 5-Fluorouracil, Leucovorin, and High-Dose Capecitabine in Patients With Metastatic Colorectal Cancer 
Clinical colorectal cancer  2010;9(3):157-161.
Purpose
Capecitabine has shown similar efficacy to 5-fluorouracil (5-FU); a regimen containing 2 weeks of capecitabine/oxaliplatin (CapOx) has demonstrated noninferiority to infusional 5-FU/oxaliplatin/leucovorin (FOLFOX) for the treatment of metastatic colorectal cancer (mCRC). This phase II study explores the efficacy and safety of a 2-day course of oxaliplatin/capecitabine (2DOC), with oxaliplatin given on day 1 and capecitabine given orally every 8 hours in high doses over 6 doses, mimicking FOLFOX6.
Patients and Methods
This phase II study was conducted by the University of Wisconsin Carbone Cancer Center. Eligible patients with mCRC received oxaliplatin 100 mg/m2 intravenously (I.V.) over 2 hours followed by leucovorin 20 mg/m2 I.V. bolus and 5-FU 400 mg/m2 I.V. bolus on day 1 and day 15. Capecitabine was administered at 1500 mg/m2 orally every 8 hours over 6 doses starting on day 1 and day 15.
Results
A total of 45 patients were enrolled; 44 were evaluated for response. Seventeen patients (39%) had objective responses. Median time to progression was 6.8 months, and median overall survival (OS) was 17.5 months. The most common side effects were grade 1/2 neuropathy, fatigue, and nausea. Severe hand-foot syndrome (HFS) was rare.
Conclusion
The overall response rate with the 2DOC regimen is similar to published CapOx regimens, and time to progression and OS are similar. The incidence of HFS, diarrhea, and mucositis were lower compared with published results of 2-week schedules of capecitabine. The 2DOC regimen merits further study as a more convenient regimen than infusional 5-FU with less HFS when compared with a 2-week administration of capecitabine.
doi:10.3816/CCC.2010.n.021
PMCID: PMC3058720  PMID: 20643620
2DOC; FOLFOX6; Irinotecan; Neutropenia; Thrombocytopenia
15.  The maximum tolerated dose and biologic effects of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) in combination with irinotecan for patients with refractory solid tumors 
Purpose
3-AP is a ribonucleotide reductase inhibitor and has been postulated to act synergistically with other chemotherapeutic agents. This study was conducted to determine the toxicity and antitumor activity of 3-AP with irinotecan. Correlative studies included pharmacokinetics and the effects of ABCB1 and UGT1A1 polymorphisms.
Methods
The treatment plan consisted of irinotecan on day 1 with 3-AP on days 1-3 of a 21-day cycle. Starting dose was irinotecan 150 mg/m2 and 3-AP 85 mg/m2/d. Polymorphisms of ABCB1 were evaluated by pyrosequencing. Drug concentrations were determined by HPLC.
Results
Twenty-three patients were enrolled, 10 men and 13 women. Tumor types included 7 patients with pancreatic cancer, 4 with lung cancer, 2 with cholangiocarcinoma, 2 with mesothelioma, 2 with ovarian cancer, and 6 with other malignancies. Two patients experienced dose-limiting toxicity (DLT) at dose level 1, requiring amendment of the dose escalation scheme. Maximal tolerated dose (MTD) was determined to be 3-AP 60 mg/m2/d and irinotecan 200 mg/m2. DLTs consisted of hypoxia, leukopenia, fatigue, infection, thrombocytopenia, dehydration and ALT elevation. One partial response in a patient with refractory non-small cell lung cancer was seen. Genotyping suggests that patients with wild-type ABCB1 have a higher rate of grade 3 or 4 toxicity than those with ABCB1 mutations.
Conclusions
The MTD for this combination was 3-AP 60 mg/m2/d on days 1-3 and irinotecan 200 mg/m2 on day 1 every 21 days. Antitumor activity in a patient with refractory non-small cell lung cancer was noted at level 1.
doi:10.1007/s00280-010-1250-z
PMCID: PMC2921466  PMID: 20127092
Triapine®; 3-AP; irinotecan; ABCB1; UGT1A1
16.  Safety and Immunological Efficacy of a DNA Vaccine Encoding Prostatic Acid Phosphatase in Patients With Stage D0 Prostate Cancer 
Journal of Clinical Oncology  2009;27(25):4047-4054.
Purpose
Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer.
Patients and Methods
Twenty-two patients were treated in a dose-escalation trial with 100 μg, 500 μg, or 1,500 μg plasmid DNA, coadministered intradermally with 200 μg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment.
Results
No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFNγ-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054).
Conclusion
The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.
doi:10.1200/JCO.2008.19.9968
PMCID: PMC2734418  PMID: 19636017
17.  Dose-escalation study of fixed-dose rate gemcitabine combined with capecitabine in advanced solid malignancies 
PURPOSE
To define dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of capecitabine with fixed-dose rate (FDR) gemcitabine.
PATIENTS AND METHODS
Eligible adults (advanced solid tumor; performance status ≤ 2) received capecitabine 500mg/m2 PO BID days 1-14 and FDR gemcitabine (400-1000mg/m2 escalated by 200mg/m2 increments) at 10 mg/m2/min days 1 and 8 on a 21-day cycle. A traditional 3+3 cohort design was used to determine the MTD.
RESULTS
Thirty patients (median age 59 years) were enrolled. The predominant grade ≥ 3 toxicity was myelosuppression, particularly neutropenia. At dose level 4 (1000 mg/m2 gemcitabine), two out of five evaluable patients had a DLT (grade 4 neutropenia ≥ 7 days). At dose level 3 (800 mg/m2 gemcitabine), one patient had a DLT (grade 3 neutropenia ≥ 7 days) among six evaluable patients. Therefore, the MTD and recommended phase II dose was designated as capecitabine 500 mg/m2 PO BID days 1-14 with 800 mg/m2 FDR gemcitabine days 1 and 8 infused at 10 mg/m2/min on a 21-day cycle. Partial responses occurred in pretreated patients with esophageal, renal cell and bladder carcinomas.
CONCLUSIONS
This regimen was well tolerated and may deserve evaluation in advanced gastrointestinal and genitourinary carcinomas.
doi:10.1007/s00280-008-0844-1
PMCID: PMC2676212  PMID: 18841362
capecitabine; gemcitabine; phase I; fixed-dose rate
18.  Respiratory Depression in Young Prader Willi Syndrome Patients following Clonidine Provocation for Growth Hormone Secretion Testing 
Objectives. To determine the sedative and respiratory effects of clonidine when used to evaluate growth hormone (GH) secretion in children with Prader Willi Syndrome (PWS). Methods. The study prospectively evaluated children with PWS who received clonidine (0.15 mg/m2) to assess GH responsiveness. Patients were studied up to four times over three years. Vital signs, oxygen saturation, and sedation level were recorded at baseline and every five minutes following clonidine. Changes between baseline and post-clonidine were evaluated using a repeated measurement analysis. Results. Sixty studies were performed on 17 patients, mean age 30.4 ± 15.0 months. The mean ± SD dose of clonidine was 0.074 ± 0.027 mg (5.3 ± 1.72 mcg/kg). All patients achieved a sedation score of 4 to 5 (drowsy to asleep). Mean declines in respiratory rate (7.5 ± 6.1 breaths/min; P < .001), and oxygen saturation (2.2 ± 2.0%; P < .001) occurred following clonidine. Five patients (29%) experienced oxygen saturations ≤94% on nine occasions. Three oxygen desaturations were accompanied by partial airway obstruction. Conclusions. Clonidine doses to assess GH secretion often exceed doses used for sedation and result in significant respiratory depression in some children with PWS. There was no association between oxygen desaturation and BMI.
doi:10.1155/2010/103742
PMCID: PMC2846681  PMID: 20368793
19.  Reliable Prediction of Insulin Resistance by a School-Based Fitness Test in Middle-School Children 
Objectives. (1) Determine the predictive value of a school-based test of cardiovascular fitness (CVF) for insulin resistance (IR); (2) compare a “school-based” prediction of IR to a “laboratory-based” prediction, using various measures of fitness and body composition. Methods. Middle school children (n = 82) performed the Progressive Aerobic Cardiovascular Endurance Run (PACER), a school-based CVF test, and underwent evaluation of maximal oxygen consumption treadmill testing (VO2 max), body composition (percent body fat and BMI z score), and IR (derived homeostasis model assessment index [HOMAIR]). Results. PACER showed a strong correlation with VO2 max/kg (rs = 0.83, P < .001) and with HOMAIR (rs = −0.60, P < .001). Multivariate regression analysis revealed that a school-based model (using PACER and BMI z score) predicted IR similar to a laboratory-based model (using VO2 max/kg of lean body mass and percent body fat). Conclusions. The PACER is a valid school-based test of CVF, is predictive of IR, and has a similar relationship to IR when compared to complex laboratory-based testing. Simple school-based measures of childhood fitness (PACER) and fatness (BMI z score) could be used to identify childhood risk for IR and evaluate interventions.
doi:10.1155/2009/487804
PMCID: PMC2777020  PMID: 19956706
20.  Pilot trial of interleukin-2 and zoledronic acid to augment γδ T cells as treatment for patients with refractory renal cell carcinoma 
Cancer immunology, immunotherapy : CII  2011;60(10):1447-1460.
Prior to the advent of VEGF-targeted therapies, renal cell carcinoma (RCC) was among the few solid tumors shown to respond to cytokine-based therapies such as interleukin-2 (IL-2) and interferon alpha. Previous work has shown that aminobisphosphonates, including zoledronic acid (ZA), are capable of activating human Vγ9 Vδ2 T cells in vitro, and these cells can be further expanded with IL-2. Moreover, these Vγ9 Vδ2 T cells have cytolytic activity in vitro to multiple human tumor cell lines. In the current report, we have conducted a pilot trial in patients with metastatic RCC, evaluating different doses of ZA in combination with low-dose IL-2 to determine whether combining these agents can promote in vivo proliferation of Vγ9 Vδ2 T cells and elicit an antitumor response. In 12 patients evaluated, no objective clinical responses were observed by RECIST criteria; however, two patients experienced prolonged stable disease. A modest increase in Vγ9 Vδ2 T-cell frequency could be detected by Day 8 of therapy in four of the nine patients who received at least one cycle of therapy, but not to the magnitude anticipated from preclinical models. Repeated administration of IL-2 and ZA resulted in both a diminished in vivo percentage of Vγ9 Vδ2 T cells as well as impaired expansion in vitro after the first cycle of therapy. These results suggest that repeated administration of IL-2 and ZA, at the doses and schedules used in this trial, may actually inhibit the proliferative capacity of Vγ9 Vδ2 T cell in patients with metastatic RCC.
doi:10.1007/s00262-011-1049-8
PMCID: PMC3177972  PMID: 21647691
Vγ9 Vδ2 lymphocyte; Interleukin-2; Zoledronic acid; Renal cell carcinoma

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