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author:("goshen, Susan")
1.  Impact of the 2010 Consensus Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee 
Oncology phase III trials have a high failure rate, leading to high development costs. The Clinical Trials Design Task Force of the Investigational Drug Steering Committee of the NCI Cancer Therapy and Evaluation Program developed Recommendations regarding the design of phase II trials. We report here on the results of a Concordance Group review charged with documenting whether concordance rates improved after the publication of the Recommendations. One hundred and fifty-five trials were reviewed. Letter of Intents (LOIs) from the post-Recommendation period were more likely to be randomized (44% vs 34%) and biomarker-selected (19% vs 10%). Single arm studies using time-to-event endpoints (benchmarked against historical data) were similar as was the type of tumor. There was a significant improvement in the rate of concordance, with 74% of LOIs scored as concordant compared to 58% prior to the Recommendations (p=0.042). This included a marked decrease in the use of single arm designs to evaluate the activity of drug combinations (19% vs. 5%, p=0.009). There were areas for which clarification was warranted, including the need for protocols to include further development plans, the use of realistic benchmarks, the careful evaluation of historical controls and the use of a standard treatment option as a control. Ongoing critical evaluation of current trial design methodology and the development of new Guidelines when appropriate will continue to improve drug development ensuring that safe and effective cancer therapeutics are made available to our patients as quickly and efficiently as possible.
PMCID: PMC4646725  PMID: 26567365
2.  A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance and healthspan 
Cell metabolism  2015;22(1):86-99.
Prolonged fasting (PF) promotes stress resistance but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, four days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems; an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.
PMCID: PMC4509734  PMID: 26094889
3.  Significance of lymphovascular invasion in organ-confined, node-negative urothelial cancer of the bladder: data from the prospective p53-MVAC trial 
BJU international  2015;116(1):44-49.
To investigate the association between lymphovascular invasion (LVI) and clinical outcome in organ-confined, node-negative urothelial cancer of the bladder (UCB) in a post hoc analysis of a prospective clinical trial. To explore the effect of adjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) on outcome in the subset of patients whose tumours exhibited LVI.
Patients and Methods
Surgical and tumour factors were extracted from the operative and pathology reports of 499 patients who had undergone radical cystectomy (RC) for pT1–T2 N0 UCB in the p53-MVAC trial (Southwest Oncology Group 4B951/NCT00005047). The presence or absence of LVI was determined by pathological examination of transurethral resection or RC specimens. Variables were examined in univariate and multivariate Cox proportional hazards models for associations with time to recurrence (TTR) and overall survival (OS).
Among 499 patients with a median follow-up of 4.9 years, a subset of 102 (20%) had LVI-positive tumours. Of these, 34 patients had pT1 and 68 had pT2 disease. LVI was significantly associated with TTR with a hazard ratio (HR) of 1.78 [95% confidence interval (CI) 1.15–2.77; number of events (EV) 95; P = 0.01) and with OS with a HR of 2.02 (95% CI 1.31–3.11; EV 98; P = 0.001) after adjustment for pathological stage. Among 27 patients with LVI-positive tumours who were randomised to receive adjuvant chemotherapy, receiving MVAC was not significantly associated with TTR (HR 0.70, 95% CI 0.16–3.17; EV 7; P = 0.65) or with OS (HR 0.45, 95% CI 0.11–1.83; EV 9; P = 0.26).
Our post hoc analysis of the p53-MVAC trial revealed an association between LVI and shorter TTR and OS in patients with pT1–T2N0 disease. The analysis did not show a statistically significant benefit of adjuvant MVAC chemotherapy in patients with LVI, although a possible benefit was not excluded.
PMCID: PMC4524781  PMID: 25413313
adjuvant chemotherapy; lymphovascular invasion; SWOG; urothelial cancer
4.  Phase 1 Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma 
131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase 1 study was to determine the maximum tolerated doses of vorinostat and MIBG in combination.
Experimental Design
Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily Days 1–14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on Day 3 and peripheral blood stem cells on Day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design.
27 patients enrolled to 6 dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m2 vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m2 vorinostat), two patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m2 vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on Days 3 and 12–14.
Vorinostat at 180 mg/m2/dose is tolerable with 18 mCi/kg MIBG. A phase 2 trial comparing this regimen to single-agent MIBG is ongoing.
PMCID: PMC4470833  PMID: 25695691
131I-MIBG; Vorinostat; Radiation Sensitizer; Neuroblastoma; Relapse; Refractory
5.  Safety and feasibility of fasting in combination with platinum-based chemotherapy 
BMC Cancer  2016;16:360.
Short-term starvation prior to chemotherapy administration protects mice against toxicity. We undertook dose-escalation of fasting prior to platinum-based chemotherapy to determine safety and feasibility in cancer patients.
3 cohorts fasted before chemotherapy for 24, 48 and 72 h (divided as 48 pre-chemo and 24 post-chemo) and recorded all calories consumed. Feasibility was defined as ≥ 3/6 subjects in each cohort consuming ≤ 200 kcal per 24 h during the fast period without excess toxicity. Oxidative stress was evaluated in leukocytes using the COMET assay. Insulin, glucose, ketones, insulin-like growth factor-1 (IGF-1) and IGF binding proteins (IGFBPs) were measured as biomarkers of the fasting state.
The median age of our 20 subjects was 61, and 85 % were women. Feasibility criteria were met. Fasting-related toxicities were limited to ≤ grade 2, most commonly fatigue, headache, and dizziness. The COMET assay indicated reduced DNA damage in leukocytes from subjects who fasted for ≥48 h (p = 0.08). There was a non-significant trend toward less grade 3 or 4 neutropenia in the 48 and 72 h cohorts compared to 24 h cohort (p = 0.17). IGF-1 levels decreased by 30, 33 and 8 % in the 24, 48 and 72 h fasting cohorts respectively after the first fasting period.
Fasting for 72 h around chemotherapy administration is safe and feasible for cancer patients. Biomarkers such as IGF-1 may facilitate assessment of differences in chemotherapy toxicity in subgroups achieving the physiologic fasting state. An onging randomized trial is studying the effect of 72 h of fasting.
Trial registration
NCT00936364, registered propectively on July 9, 2009.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2370-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4901417  PMID: 27282289
Fasting; Chemotherapy; Neutropenia; Oxidative stress; Insulin-like growth factor
6.  Variability in surgical quality in a phase III clinical trial of radical cystectomy in patients with organ-confined, node-negative urothelial carcinoma of the bladder 
Journal of surgical oncology  2015;111(7):923-928.
Background and Objectives
Previous studies have shown that variability in surgical technique can affect the outcomes of cooperative group trials. We analyzed measures of surgical quality and clinical outcomes in patients enrolled in the p53-MVAC trial.
We performed a post-hoc analysis of patients with pT1-T2N0M0 urothelial carcinoma of the bladder following radical cystectomy (RC) and bilateral pelvic and iliac lymphadenectomy (LND). Measures of surgical quality were examined for associations with time to recurrence (TTR) and overall survival (OS).
We reviewed operative and/or pathology reports for 440 patients from 35 sites. We found that only 31% of patients met all suggested trial eligibility criteria of having ≥15 lymph nodes identified in the pathologic specimen (LN#) and having undergone both extended and presacral LND. There was no association between extent of LND, LN#, or presacral LND and TTR or OS after adjustment for confounders and multiple testing.
We demonstrated that there was substantial variability in surgical technique within a cooperative group trial. Despite explicit entry criteria, many patients did not undergo per-protocol LNDs. While outcomes were not apparently affected, it is nonetheless evident that careful attention to study design and quality monitoring will be critical to successful future trials.
PMCID: PMC4602027  PMID: 25873574
Carcinoma; transitional cell; chemotherapy; adjuvant; cystectomy; genes; p53
7.  Monoamine oxidase A (MAO A) inhibitors decrease glioma progression 
Oncotarget  2016;7(12):13842-13853.
Glioblastoma (GBM) is an aggressive brain tumor which is currently treated with temozolomide (TMZ). Tumors usually become resistant to TMZ and recur; no effective therapy is then available. Monoamine Oxidase A (MAO A) oxidizes monoamine neurotransmitters resulting in reactive oxygen species which cause cancer. This study shows that MAO A expression is increased in human glioma tissues and cell lines. MAO A inhibitors, clorgyline or the near-infrared-dye MHI-148 conjugated to clorgyline (NMI), were cytotoxic for glioma and decreased invasion in vitro. Using the intracranial TMZ-resistant glioma model, clorgyline or NMI alone or in combination with low-dose TMZ reduced tumor growth and increased animal survival. NMI was localized specifically to the tumor. Immunocytochemistry studies showed that the MAO A inhibitor reduced proliferation, microvessel density and invasion, and increased macrophage infiltration. In conclusion, we have identified MAO A inhibitors as potential novel stand-alone drugs or as combination therapy with low dose TMZ for drug-resistant gliomas. NMI can also be used as a non-invasive imaging tool. Thus has a dual function for both therapy and diagnosis.
PMCID: PMC4924682  PMID: 26871599
MAO A; MAO A inhibitors; glioma; TMZ-resistant; near-infrared dye conjugate
8.  RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer 
Nature Communications  2016;7:10751.
Recent high-throughput studies revealed recurrent RUNX1 mutations in breast cancer, specifically in oestrogen receptor-positive (ER+) tumours. However, mechanisms underlying the implied RUNX1-mediated tumour suppression remain elusive. Here, by depleting mammary epithelial cells of RUNX1 in vivo and in vitro, we demonstrate combinatorial regulation of AXIN1 by RUNX1 and oestrogen. RUNX1 and ER occupy adjacent elements in AXIN1's second intron, and RUNX1 antagonizes oestrogen-mediated AXIN1 suppression. Accordingly, RNA-seq and immunohistochemical analyses demonstrate an ER-dependent correlation between RUNX1 and AXIN1 in tumour biopsies. RUNX1 loss in ER+ mammary epithelial cells increases β-catenin, deregulates mitosis and stimulates cell proliferation and expression of stem cell markers. However, it does not stimulate LEF/TCF, c-Myc or CCND1, and it does not accelerate G1/S cell cycle phase transition. Finally, RUNX1 loss-mediated deregulation of β-catenin and mitosis is ameliorated by AXIN1 stabilization in vitro, highlighting AXIN1 as a potential target for the management of ER+ breast cancer.
The tumour suppressor RUNX1 is often lost or mutated in oestrogen receptor-positive breast cancers. In this study, the authors demonstrate that the loss of RUNX1 unleashes oestrogen-mediated inhibition of AXIN1, a negative regulator of β-catenin, resulting in β-catenin signalling-mediated cancer cell proliferation and mitosis deregulation.
PMCID: PMC4773428  PMID: 26916619
9.  Novel Neoadjuvant Therapy Paradigms for Bladder Cancer: Results from the National Cancer Center Institute Forum 
Urologic oncology  2014;32(8):1108-1115.
Although bladder cancer (BC) is a significant health threat to the US population, integrated clinical and laboratory investigations of this disease lag behind those of other types of cancer. Advances in BC are especially challenged due in part to a general decreased level of funding over the past 5 years. It is ironic that despite the awareness that BC is the 5th most commonly diagnosed solid malignancy in the United States, and one of the most costly to treat, funding for this organ site lags far behind that of other less common malignancies. Moreover, BC offers several unique opportunities for translational research that make it an ideal candidate for investigation. One distinct advantage over other solid tumor sites is that urine and tissue are readily available for translational studies that can direct the development of novel therapy for this disease. The NCI sponsored “Novel Neoadjuvant Therapy for Bladder Cancer” forum held in brought leading clinical and laboratory-based scientists together with the advocacy community to lay the groundwork for collaborative discovery and translation. The goal of the meeting was to bridge the gaps in translational science and develop the concepts for two novel biomarker-driven clinical trials, one in the neoadjuvant presurgical setting and the other in the setting of bladder preservation with chemoradiation. The meeting provided a unique opportunity to launch a collective effort to establish molecular-based therapy for UC. Herein, we summarize the proceedings of this meeting, and the future plans resulting from this forum.
PMCID: PMC4262150  PMID: 25443274
10.  Design of Phase I Combination Trials: Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee 
Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistical and regulatory challenges. The phase 1 trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute (NCI) Investigational Drug Steering Committee developed a set of recommendations for the phase 1 development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biological or pharmacological rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase 1 clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamic (i.e., biomarker).
PMCID: PMC4135521  PMID: 25125258
11.  A Phase II Trial of a Combination Herbal Supplement for Men with Biochemically Recurrent Prostate Cancer 
Men with biochemical recurrence (BCR) of prostate cancer are typically observed or treated with androgen deprivation therapy. Non-hormonal, non-toxic treatments to slow the rise of PSA are desirable. We studied a combination herbal supplement, Prostate Health Cocktail (PHC), in prostate cancer cell lines and in a population of men with BCR.
PC3, LAPC3, and LNCaP cells were incubated with increasing concentrations of PHC suspension. Men previously treated for prostate cancer with surgery, radiation, or both with rising PSA but no radiographic metastases were treated with 3 capsules of PHC daily; the primary endpoint was 50% PSA decline. Circulating tumor cells (CTCs) were identified using parylene membrane filters.
PHC showed a strong dose-dependent anti-proliferative effect in androgen-sensitive and independent cell lines in vitro and suppression of androgen receptor expression. 40 eligible patients were enrolled in the clinical trial. Median baseline PSA was 2.8 ng/mL (1.1-84.1) and 15 men (38%) had a PSA decline on study (1%-55% reduction) ; 25 (62%) had rising PSA on study. The median duration of PSA stability was 6.4 months. Two patients had grade 2/3 transaminitis; the only other grade 2 toxicities were hyperglycemia, hypercalcemia and flatulence. There were no significant changes in testosterone or dihydrotestosterone. CTCs were identified in 19 men (47%).
Although the primary endpoint was not met, Prostate Health Cocktail was well tolerated and was associated with PSA declines and stabilization in a significant number of patients. This is the first report of detecting CTCs in men with BCR prostate cancer. Randomized studies are needed to better define the effect of PHC in men with BCR.
PMCID: PMC4234307  PMID: 25245366
12.  Differential effects of RUNX2 on the androgen receptor in prostate cancer: synergistic stimulation of a gene set exemplified by SNAI2 and subsequent invasiveness 
Cancer research  2014;74(10):2857-2868.
Changes in androgen signaling during prostate carcinogenesis are associated with both inhibition of cellular differentiation and promotion of malignant phenotypes. The androgen receptor (AR)-binding transcription factor (TF) RUNX2 has been linked to prostate cancer (PCa) progression but the underlying mechanisms have not been fully defined. In this study, we investigated the genome-wide influence of RUNX2 on androgen-induced gene expression and AR DNA binding in PCa cells. RUNX2 inhibited the androgen response partly by promoting the dissociation of AR from its target genes such as the tumor suppressor NKX3-1. However, AR activity persists in the presence of RUNX2 at other AR target genes, some of which are co-operatively stimulated by androgen and RUNX2 signaling. These genes are associated with putative enhancers co-occupied by AR and RUNX2. One such gene, the invasion-promoting Snail family TF SNAI2, was co-activated by AR and RUNX2. Indeed, these two TFs together, but neither alone stimulated PCa cell invasiveness, which could be abolished by SNAI2 silencing. In support of our results, an immunohistochemical analysis of SNAI2 in archived primary PCa specimens revealed a correlation with the RUNX2 histoscore; and, simultaneous strong staining for SNAI2, RUNX2 and AR (but not any pair alone) was associated with disease recurrence. Overall, our findings suggest that AR and RUNX2 cooperate to stimulate certain invasion-promoting genes like SNAI2, which might be targeted for individualized PCa therapy.
PMCID: PMC4051204  PMID: 24648349
combinatorial transcriptional control; mRNA profiling; ChIP-seq; metastasis; invasion; recurrence
13.  Expression and Functional Role of Orphan Receptor GPR158 in Prostate Cancer Growth and Progression 
PLoS ONE  2015;10(2):e0117758.
Prostate cancer (PCa) is the second-leading cause of cancer-related mortality, after lung cancer, in men from developed countries. In its early stages, primary tumor growth is dependent on androgens, thus generally can be controlled by androgen deprivation therapy (ADT). Eventually however, the disease progresses to castration-resistant prostate cancer (CRPC), a lethal form in need of more effective treatments. G-protein coupled receptors (GPCRs) comprise a large clan of cell surface proteins that have been implicated as therapeutic targets in PCa growth and progression. The findings reported here provide intriguing evidence of a role for the newly characterized glutamate family member GPR158 in PCa growth and progression. We found that GPR158 promotes PCa cell proliferation independent of androgen receptor (AR) functionality and that this requires its localization in the nucleus of the cell. This suggests that GPR158 acts by mechanisms different from other GPCRs. GPR158 expression is stimulated by androgens and GPR158 stimulates AR expression, implying a potential to sensitize tumors to low androgen conditions during ADT via a positive feedback loop. Further, we found GPR158 expression correlates with a neuroendocrine (NE) differentiation phenotype and promotes anchorage-independent colony formation implying a role for GPR158 in therapeutic progression and tumor formation. GPR158 expression was increased at the invading front of prostate tumors that formed in the genetically defined conditional Pten knockout mouse model, and co-localized with elevated AR expression in the cell nucleus. Kaplan-Meier analysis on a dataset from the Memorial Sloan Kettering cancer genome portal showed that increased GPR158 expression in tumors is associated with lower disease-free survival. Our findings strongly suggest that pharmaceuticals targeting GPR158 activities could represent a novel and innovative approach to the prevention and management of CRPC.
PMCID: PMC4333349  PMID: 25693195
14.  Bayesian hierarchical modeling of patient subpopulations: Efficient designs of Phase II oncology clinical trials 
Clinical trials (London, England)  2013;10(5):720-734.
In oncology, the treatment paradigm is shifting toward personalized medicine, where the goal is to match patients to the treatments most likely to deliver benefit. Treatment effects in various subpopulations may provide some information about treatment effects in other subpopulations.
We compare different approaches to Phase II trial design where a new treatment is being investigated in several groups of patients. We compare considering each group in an independent trial to a single trial with hierarchical modeling of the patient groups.
We assume four patient groups with different background response rates and simulate operating characteristics of three trial designs, Simon’s Optimal Two-Stage design, a Bayesian adaptive design with frequent interim analyses, and a Bayesian adaptive design with frequent interim analyses and hierarchical modeling across patient groups.
Simon’s designs are based on 10% Type I and Type II error rates. The independent Bayesian designs are tuned to have similar error rates, but may have a slightly smaller mean sample size due to more frequent interim analyses. Under the null, the mean sample size is 2–4 patients smaller. A hierarchical model across patient groups can provide additional power and a further reduction in mean sample size. Under the null, the addition of the hierarchical model decreases the mean sample size an additional 4–7 patients in each group. Under the alternative hypothesis, power is increased to at least 98% in all groups.
Hierarchical borrowing can make finding a single group in which the treatment is promising, if there is only one, more difficult. In a scenario where the treatment is uninteresting in all but one group, power for that one group is reduced to 65%. When the drug appears promising in some groups and not in others, there is potential for borrowing to inflate the Type I error rate.
The Bayesian hierarchical design is more likely to correctly conclude efficacy or futility than the other two designs in many scenarios. The Bayesian hierarchical design is a strong design for addressing possibly differential effects in different groups.
PMCID: PMC4319656  PMID: 23983156
15.  Refining Patient Selection for Neoadjuvant Chemotherapy before Radical Cystectomy 
The Journal of urology  2013;191(1):40-47.
We evaluated the survival of patients with muscle invasive bladder cancer undergoing radical cystectomy without neoadjuvant chemotherapy to confirm the utility of existing clinical tools to identify low risk patients who could be treated with radical cystectomy alone and a high risk group most likely to benefit from neoadjuvant chemotherapy.
Materials and Methods
We identified patients with muscle invasive bladder cancer who underwent radical cystectomy without neoadjuvant chemotherapy at our institution between 2000 and 2010. Patients were considered high risk based on the clinical presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection. We evaluated survival (disease specific, progression-free and overall) and rate of pathological up staging. An independent cohort of patients from another institution was used to confirm our findings.
We identified 98 high risk and 199 low risk patients eligible for analysis. High risk patients exhibited decreased 5-year overall survival (47.0% vs 64.8%) and decreased disease specific (64.3% vs 83.5%) and progression-free (62.0% vs 84.1%) survival probabilities compared to low risk patients (p <0.001). Survival outcomes were confirmed in the validation subset. On final pathology 49.2% of low risk patients had disease up staged.
The 5-year disease specific survival of low risk patients was greater than 80%, supporting the distinction of high risk and low risk muscle invasive bladder cancer. The presence of high risk features identifies patients with a poor prognosis who are most likely to benefit from neoadjuvant chemotherapy, while many of those with low risk disease can undergo surgery up front with good expectations and avoid chemotherapy associated toxicity.
PMCID: PMC4158919  PMID: 23911605
urinary bladder neoplasms; cystectomy; neoadjuvant therapy; risk; outcomes assessment
16.  Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study 
Cancer chemotherapy and pharmacology  2011;68(4):1057-1065.
TrkB acts as an oncogenic kinase in a subset of human neuroblastomas. Lestaurtinib, a multi-kinase inhibitor with potent activity against Trk kinases, has demonstrated activity in preclinical models of neuroblastoma.
Patients with refractory high-risk neuroblastoma received lestaurtinib twice daily for 5 days out of seven in 28-day cycles, starting at 70% of the adult recommended Phase 2 dose. Lestaurtinib dose was escalated using a 3 + 3 design. Pharmacokinetics and plasma phospho-TrkB inhibitory activity were evaluated in the first cycle.
Forty-seven subjects were enrolled, and 10 dose levels explored starting at 25 mg/M2/dose BID. Forty-six subjects were evaluable for response, and 42 subjects were fully evaluable for determination of dose escalation. Asymptomatic and reversible grade 3–4 transaminase elevation was dose limiting in 4 subjects. Reversible pancreatitis (grade 2) was observed in 3 subjects after prolonged treatment at higher dose levels. Other toxicities were mild and reversible. Pharmacokinetic analyses revealed rapid drug absorption, however inter-patient variability was large. Plasma inhibition of phospho-TrkB activity was observed 1 h post-dosing at 85 mg/M2 with uniform inhibition at 120 mg/M2. There were two partial responses and nine subjects had prolonged stable disease at dose levels ≥ 5, (median: 6 cycles). A biologically effective and recommended phase 2 dose of 120 mg/M2/dose BID was established.
Lestaurtinib was well tolerated in patients with refractory neuroblastoma, and a dose level sufficient to inhibit TrkB activity was established. Safety and signs of activity at the higher dose levels warrant further evaluation in neuroblastoma.
PMCID: PMC4238911  PMID: 21340605
Neuroblastoma; Receptor tyrosine kinase; Targeted therapy; Lestaurtinib; Signal transduction
17.  Phase I Trial of Fenretinide Delivered Orally in a Novel Organized Lipid Complex in Patients with Relapsed/Refractory Neuroblastoma: A Report from the New Approaches to Neuroblastoma Therapy (NANT) Consortium 
Pediatric blood & cancer  2013;60(11):1801-1808.
A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma.
4-HPR/LXS powder (352 - 2210 mg/m2/day) was administered on Days 0 – 6, in 21-day courses, by standard 3+3 design.
Thirty-two patients (median age = 8 years, range 3 – 27 years) enrolled with thirty evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), 125/131I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m2/day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m2/day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1700 mg/m2/day. Of twenty-nine response-evaluable patients, six had stable disease (SD)(4 – 26 courses); four with marrow- or bone disease-only had complete responses (CR)(10 - 46 courses). 4-HPR plasma levels were several fold higher (P<0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1700 mg/m2/day was 21 μM. An MTD was not reached.
4-HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1500 mg/m2/day, TID, on Days 0 – 6, of a 21-day course.
PMCID: PMC4066886  PMID: 23813912
fenretinide; neuroblastoma; pediatric; powder; Lym-X-Sorb™
18.  Comparative performance of PET tracers in biochemical recurrence of prostate cancer: a critical analysis of literature 
Positron emission tomography (PET) with a number of tracers targeted to particular biological features of cancer has been explored for the imaging evaluation of patients with biochemical recurrence of prostate cancer after curative primary treatment. However, these reports are often heterogeneous in study design, patient cohorts, standards of reference for the imaging findings, data analysis, and data reporting. The aim of our study was to address these limitations by extracting and re-analyzing the PET detection data only from studies that satisfied pre-defined sets of patient selection criteria and verification standards. Our investigation analyzed the effects of 5 tracers (18F-fluorodeoxyglucose (FDG), 11C-acetate (ACET), 11C- or 18F-choline (CHOL), anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid (FACBC), and radiolabeled ligand targeted to prostate-specific membrane antigen (PSMA)), 2 treatment types (radical prostatectomy and radiation therapy), and whether the detected disease was local or metastatic, including lesion type (bone, lymph node, soft tissue). FDG exhibited the lowest detection rate for any suspected disease. ACET tended to be advantageous over CHOL in detecting local recurrence and lymph node lesions, even though the difference was not statistically significant. FACBC had greater likelihood of detecting local recurrence, when compared to CHOL, though this difference was not statistically significant. PSMA tended to show a higher proportion of patients with suspected disease compared to the other four tracers. Patients treated with radiation therapy had greater odds of displaying local recurrence on PET than those treated with radical prostatectomy. We also provide suggestions for future investigations that facilitate communication and the impact of the findings.
PMCID: PMC4171844  PMID: 25250207
PET; prostate; cancer; biochemical; recurrence
Cancer research  2013;73(13):3852-3864.
Drug resistance is a major cause of treatment failure in cancer. Here we have evaluated the role of STAT3 in environment-mediated drug resistance (EMDR) in human neuroblastoma. We determined that STAT3 was not constitutively active in most neuroblastoma cell lines but was rapidly activated upon treatment with interleukin-6 (IL-6) alone and in combination with the soluble IL-6 receptor (sIL-6R). Treatment of neuroblastoma cells with IL-6 protected them from drug-induced apoptosis in a STAT3-dependent manner because the protective effect of IL-6 was abrogated in the presence of a STAT3 inhibitor and upon STAT3 knockdown. STAT3 was necessary for the upregulation of several survival factors such as survivin (BIRC5) and Bcl-xL (BCL2L1) when cells were exposed to IL-6. Importantly, IL-6-mediated STAT3 activation was enhanced by sIL-6R produced by human monocytes, pointing to an important function of monocytes in promoting IL-6-mediated EMDR. Our data also point to the presence of reciprocal activation of STAT3 between tumor cells and bone marrow stromal cells including not only monocytes but also Treg cells and non-myeloid stromal cells. Thus, the data identify an IL-6/sIL-6R/STAT3 interactive pathway between neuroblastoma cells and their microenvironment that contributes to drug resistance.
PMCID: PMC3740971  PMID: 23633489
Interleukin-6; STAT3; drug resistance; neuroblastoma; tumor microenvironment
20.  A phase I trial of oxaliplatin in combination with docetaxel in patients with advanced solid tumors 
The primary objective of this trial was to establish the maximum tolerated dose (MTD) of oxaliplatin 130 mg/m2 preceded by escalating doses of docetaxel 60 mg/m2 (75, 90, 100 mg/m2) administered every 3 weeks. A total of 11 patients were entered; 10 evaluable for response: 4 stable disease (liver, ovary and esophagus) and 1 partial remission (esophagus). At dose level 1, there was 1 dose-limiting toxicity (DLT) (grade 3 allergic reaction). At dose level 2, there were 3 DLTs (3 grade 4 neutropenia, grade 3 gastritis, diarrhea, hypophosphatemia, neuro-mood). The MTD is docetaxel 60 mg/m2 with oxaliplatin 130 mg/m2.
PMCID: PMC3779138  PMID: 23712328
Phase I; Oxaliplatin; Docetaxel; Oxaliplatin and Docetaxel
21.  Membrane-Bound TRAIL Supplements Natural Killer Cell Cytotoxicity Against Neuroblastoma Cells 
Neuroblastoma cells have been reported to be resistant to death induced by soluble, recombinant forms of TRAIL (CD253/TNFSF10) due to low or absent expression of caspase-8 and/or TRAIL-receptor 2 (TRAIL-R2/DR5/CD262/TNFRSF10b). However, their sensitivity to membrane-bound TRAIL on natural killer (NK) cells is not known. Comparing microarray gene expression and response to NK cell-mediated cytotoxicity, we observed a correlation between TRAIL-R2 expression and the sensitivity of fourteen neuroblastoma cell lines to the cytotoxicity of NK cells activated with IL-2 plus IL-15. Even though most NK cytotoxicity was dependent upon perforin, the cytotoxicity was supplemented by TRAIL in fourteen of seventeen (82%) neuroblastoma cell lines as demonstrated using an anti-TRAIL neutralizing antibody. Similarly, a recently developed NK cell expansion system employing IL-2 plus lethally irradiated K562 feeder cells constitutively expressing membrane-bound IL-21 (K562 clone 9.mbIL21) resulted in activated NK cells derived from normal healthy donors and neuroblastoma patients that also utilized TRAIL to supplement cytotoxicity. Exogenous IFNγ up-regulated expression of caspase-8 in three of four neuroblastoma cell lines and increased the contribution of TRAIL to NK cytotoxicity against two of the three lines; however, relatively little inhibition of cytotoxicity was observed when activated NK cells were treated with an anti-IFNγ neutralizing antibody. Constraining the binding of anti-TRAIL neutralizing antibody to membrane-bound TRAIL but not soluble TRAIL indicated that membrane-bound TRAIL alone was responsible for essentially all of the supplemental cytotoxicity. Together, these findings support a role for membrane-bound TRAIL in the cytotoxicity of NK cells against neuroblastoma cells.
PMCID: PMC4064791  PMID: 23719242
Neuroblastoma; TRAIL; Natural killer cells; Cytotoxicity
22.  Non-specific filtering of beta-distributed data 
BMC Bioinformatics  2014;15:199.
Non-specific feature selection is a dimension reduction procedure performed prior to cluster analysis of high dimensional molecular data. Not all measured features are expected to show biological variation, so only the most varying are selected for analysis. In DNA methylation studies, DNA methylation is measured as a proportion, bounded between 0 and 1, with variance a function of the mean. Filtering on standard deviation biases the selection of probes to those with mean values near 0.5. We explore the effect this has on clustering, and develop alternate filter methods that utilize a variance stabilizing transformation for Beta distributed data and do not share this bias.
We compared results for 11 different non-specific filters on eight Infinium HumanMethylation data sets, selected to span a variety of biological conditions. We found that for data sets having a small fraction of samples showing abnormal methylation of a subset of normally unmethylated CpGs, a characteristic of the CpG island methylator phenotype in cancer, a novel filter statistic that utilized a variance-stabilizing transformation for Beta distributed data outperformed the common filter of using standard deviation of the DNA methylation proportion, or its log-transformed M-value, in its ability to detect the cancer subtype in a cluster analysis. However, the standard deviation filter always performed among the best for distinguishing subgroups of normal tissue. The novel filter and standard deviation filter tended to favour features in different genome contexts; for the same data set, the novel filter always selected more features from CpG island promoters and the standard deviation filter always selected more features from non-CpG island intergenic regions. Interestingly, despite selecting largely non-overlapping sets of features, the two filters did find sample subsets that overlapped for some real data sets.
We found two different filter statistics that tended to prioritize features with different characteristics, each performed well for identifying clusters of cancer and non-cancer tissue, and identifying a cancer CpG island hypermethylation phenotype. Since cluster analysis is for discovery, we would suggest trying both filters on any new data sets, evaluating the overlap of features selected and clusters discovered.
PMCID: PMC4230495  PMID: 24943962
23.  Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study 
BMC Research Notes  2014;7:256.
Patients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study.
Case presentation
On Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 μM. Over the next three days, although blood cultures remained negative, the patient’s condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity.
After extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.
PMCID: PMC4006848  PMID: 24755475
Ceftriaxone; Fenretinide; Acetaminophen; Drug interaction; Biliary sludge; Fulminant hepatic failure
24.  Combination of Molecular Alterations and Smoking Intensity Predicts Bladder Cancer Outcome: A Report from the Los Angeles Cancer Surveillance Program 
Cancer  2013;119(4):756-765.
Traditional single-marker and multimarker molecular profiling approaches in bladder cancer do not account for major risk factors and their influence on clinical outcome. This study examined the prognostic value of molecular alterations across all disease stages after accounting for clinicopathological factors and smoking, the most common risk factor for bladder cancer in the developed world, in a population-based cohort.
Primary bladder tumors from 212 cancer registry patients (median follow-up, 13.2 years) were immunohistochemically profiled for Bax, caspase-3, Apaf-1, Bcl-2, p53, p21, cyclooxygenase-2, vascular endothelial growth factor, and E-cadherin alterations. “Smoking intensity” quantified the impact of duration and daily frequency of smoking.
Age, pathological stage, surgical modality, and adjuvant therapy administration were significantly associated with survival. Increasing smoking intensity was independently associated with worse outcome (P<0.001). Apaf-1, E-cadherin and p53 were prognostic for outcome (P=0.005, 0.014 and 0.032, respectively); E-cadherin remained prognostic following multivariable analysis (P=0.040). Combined alterations in all nine biomarkers were prognostic by univariable (P<0.001) and multivariable (P=0.006) analysis. A multivariable model that included all nine biomarkers and smoking intensity had greater accuracy in predicting prognosis than models comprising of standard clinicopathological covariates without or with smoking intensity (P<0.001 and P=0.018, respectively).
Apaf-1, E-cadherin and p53 alterations individually predicted survival in bladder cancer patients. Increasing number of biomarker alterations was significantly associated with worsening survival, although markers comprising the panel were not necessarily prognostic individually. Predictive value of the nine-biomarker panel with smoking intensity was significantly higher than that of routine clinicopathological parameters alone.
PMCID: PMC3565093  PMID: 23319010
25.  Baseline 18F-FDG PET/CT Parameters as Imaging Biomarkers of Overall Survival in Castrate-Resistant Metastatic Prostate Cancer 
The aim of this prospective investigation was to assess the association of parameters derived from baseline 18F-FDG PET/CT with overall survival (OS) in men with castrate-resistant metastatic prostate cancer.
Eighty-seven men with castrate-resistant metastatic prostate cancer underwent 18F-FDG PET/CT and were followed prospectively for OS. Median follow-up in patients who were alive was 22.2 mo (range, 1.6–62.5 mo). OS was defined as the time between the PET/CT imaging or the start of chemotherapy, whichever was later, and death, with patients who were alive censored at the last follow-up date. PET parameters included maximum standardized uptake value (SUVmax) of the most active lesion, sum of SUVmax, and average SUVmax of all metabolically active lesions, after subtraction of patient-specific background-liver average SUV. Comparison of OS was based on univariate and multivariable Cox regression analyses of continuous PET parameters adjusted for standard clinical parameters (age, serum prostate-specific antigen level, alkaline phosphatase, use of pain medication, prior chemotherapy, and Gleason score at initial diagnosis). Survival curves based on Kaplan–Meier estimates are presented.
Among the 87 patients, 61 were dead at the time of last follow-up. Median OS was 16.5 mo (95% confidence interval [CI], 12.1–23.4 mo), and the OS probability at 24 mo was 39% ± 6%. For the univariate analysis, the hazard ratios associated with each unit increase were 1.01 (95% CI, 1.006–1.02) for sum of SUVmax (P = 0.002), 1.11 (95% CI, 1.03–1.18) for maximum SUVmax (P = 0.010), and 1.13 (95% CI, 0.99–1.30) for average SUVmax (P = 0.095). For the multivariable analysis adjusting for relevant clinical parameters, the continuous parameter sum of SUVmax remained significant (P = 0.053), with a hazard ratio of 1.01 (95% CI, 1.001–1.02). When sum of SUVmax was grouped into quartile ranges, there was poorer survival probability for the patients in the fourth-quartile range than for those in the first-quartile range, with a univariate hazard ratio of 3.8 (95% CI, 1.8–7.9).
Sum of SUVmax derived from 18F-FDG PET/CT contributes independent prognostic information on OS in men with castrate-resistant metastatic prostate cancer, and this information may be useful in assessing the comparative effectiveness of various conventional and emerging treatment strategies.
PMCID: PMC3783857  PMID: 23785174
18F-FDG; prostate; cancer; castrate-resistant; survival

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