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1.  Diffusion tensor imaging detects treatment effects of FTY720 in experimental autoimmune encephalomyelitis mice 
NMR in biomedicine  2013;26(12):10.1002/nbm.3012.
Fingolimod (FTY720) is an orally available sphingosine-1-phosphate (S1P) receptor modulator reducing relapse frequency in relapse-remitting multiple sclerosis (RRMS) patients. In addition to immunosuppression, neuronal protection of FTY720 has also been suggested but remains controversial. Axial and radial diffusivities derived from in vivo diffusion tensor imaging (DTI) were employed as non-invasive biomarkers of axonal injury and demyelination to assess axonal protection of FTY720 in experimental autoimmune encephalomyelitis (EAE) mice. EAE was induced through active immunization of C57BL/6 mice using myelin oligodendrocyte glycoprotein peptide 35 – 55 (MOG35–55). We evaluated both prophylactic and therapeutic treatment effect of FTY720 at doses of 3 and 10 mg/kg on these EAE mice by daily clinical scoring and end-point in vivo DTI. Prophylactic administration of FTY720 suppressed the disease onset and prevented axon and myelin damage as compared with EAE mice without treatment. Therapeutic treatment of FTY720 did not prevent EAE onset but reduced the disease severity improving axial and radial diffusivity toward the control values without a statistical significance. Consistent with previous findings, in vivo DTI-derived axial and radial diffusivity correlated with clinical scores in EAE mice. Results support the use of in vivo DTI as an effective outcome measure for preclinical drug development.
doi:10.1002/nbm.3012
PMCID: PMC3838438  PMID: 23939596
diffusion tensor imaging; axial diffusivity; radial diffusivity; axonal injury; demyelination; experimental autoimmune encephalomyelitis; multiple sclerosis; FTY720
2.  A prospective trial comparing FDG-PET/CT and CT to assess tumor response to cetuximab in patients with incurable squamous cell carcinoma of the head and neck 
Cancer Medicine  2014;3(6):1493-1501.
Computed tomography (CT), the standard method to assess tumor response to cetuximab in incurable squamous cell carcinoma of the head and neck (SCCHN), performs poorly as judged by the disparity between high disease control rate (46%) and short time to progression (TTP) (70 days). F-18 fluorodeoxyglucose positron emission tomography (FDG-PET)/CT is an alternative method to assess tumor response. The primary objective of this prospective trial was to evaluate the metabolic response of target lesions, assessed as the change in maximum standardized uptake value (SUVmax) on FDG-PET/CT before and after 8 weeks (cycle 1) of cetuximab. Secondary objectives were to compare tumor response by CT (RECIST 1.0) and FDG-PET/CT (EORTC criteria) following cycle 1, and determine TTP with continued cetuximab administration in patients with disease control by CT after cycle 1 but stratified for disease control or progression by FDG-PET/CT. Among 27 patients, the mean percent change of SUVmax of target lesions after cycle 1 was −21% (range: +72% to −81%); by FDG-PET/CT, partial response (PR)/stable disease (SD) occurred in 15 patients (56%) and progression in 12 (44%), whereas by CT, PR/SD occurred in 20 (74%) and progression in 7 (26%). FDG-PET/CT and CT assessments were discordant in 14 patients (P = 0.0029) and had low agreement (κ = 0.30; 95% confidence interval [CI]: 0.12, 0.48). With disease control by CT after cycle 1, median TTP was 166 days (CI: 86, 217) if the FDG-PET/CT showed disease control and 105 days (CI: 66, 159) if the FDG-PET/CT showed progression (P < 0.0001). Median TTP of the seven patients whose post cycle 1 CT showed progression compared to the 12 whose FDG-PET/CT showed progression were similar (53 [CI: 49, 56] vs. 61 [CI: 50, 105] days, respectively). FDG-PET/CT may be better than CT in assessing benefit of cetuximab in incurable SCCHN.
doi:10.1002/cam4.294
PMCID: PMC4298375  PMID: 25081631
Cetuximab; CT; FDG-PET/CT; head and neck; squamous cell carcinoma
3.  Cisplatin versus Cetuximab Given Concurrently with Definitive Radiation Therapy for Locally Advanced Head and Neck Squamous Cell Carcinoma 
Oncology  2013;85(5):290-296.
Objective
Whether or not cisplatin and cetuximab are similarly effective in improving outcomes when added to radiation therapy(RT) in HNSCC is unknown.
Methods
Retrospective analysis of patients treated with definitive RT and cisplatin(n=18) or cetuximab(n=29).
Results
T and N classifications, stage, HPV status, and smoking history were balanced in the two groups; however, patients in the cisplatin group were younger, and had better performance status. Delivery of RT was similar between the two groups. Median follow-up was 23(4–64) months. Disease-specific(DSS) survival at 3 years was 83% in the cisplatin group and 31% in the cetuximab group. Recurrent disease was more common in the cetuximab group compared with the cisplatin group(17 versus 4 patients). Propensity score analysis to adjust for differences in patient characteristics which influenced treatment selection showed that DSS was indeed longer with cisplatin than with cetuximab(DSS Hazard Ratio[HR] 0.15{Confidence Interval[CI]0.033,0.66},p=0.012).
Conclusions
DSS was superior in the patients given cisplatin with definitive RT compared to cetuximab with definitive RT due to a lower risk of recurrent disease in the cisplatin group. These observations could not be explained by differences between the two groups in the patient and tumor characteristics or in treatment delivery.
doi:10.1159/000355194
PMCID: PMC3889644  PMID: 24217231
Radiation; Cetuximab; Cisplatin; Head and Neck; Neoplasms
4.  Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs) 
Annals of surgery  2014;259(2):197-203.
Objective
To explore the prognostic importance and preoperative predictors of lymph node metastasis in an effort to guide surgical decision making in patients with pancreatic neuroendocrine tumors (PNETs).
Background
PNETs are uncommon, and the natural history of the disease is not well described. As a result, there remains controversy regarding the optimal management of regional lymph nodes during resection of the primary tumor.
Methods
A retrospective review of a prospectively maintained database of patients who underwent surgery for locoregional PNET between 1994 and 2012 was performed. Logistic regression was used to identify predictors of nodal metastasis. Overall survival (OS) and disease-free survival (DFS) were calculated using Kaplan Meier method. Results were expressed as p- values and odds ratio estimates with 95% confidence intervals.
Results
One-hundred thirty six patients were identified, of whom 50 (38%) patients had nodal metastasis. The frequency of lymph node metastasis was higher for: larger tumors (> 1.5 cm (OR= 4.7), tumors of the head as compared to body-tail of the pancreas (OR= 2.8), tumors with Ki-67 > 20% (OR= 6.7), and tumors with lymph vascular invasion (OR= 3.6), (p value <0.05). Median DFS was lower for patients with nodal metastases (4.5 v 14.6 years, p < 0.0001).
Conclusions
Lymph node metastasis is predictive of poor outcomes in patients with PNETs. Preoperative variables are not able to reliably predict patients where the probability of lymph node involvement was less than 12%. These data support inclusion of regional lymphadenectmy in patients undergoing pancreatic resections for PNET.
doi:10.1097/SLA.0000000000000348
PMCID: PMC4164305  PMID: 24253141
5.  Randomized Controlled Trial of Oxybutynin Extended Release Versus Placebo for Urinary Symptoms During Intravesical Bacillus Calmette-Guérin Treatment 
The Journal of urology  2012;189(4):1268-1274.
Purpose
Intravesical bacillus Calmette-Guérin is used to decrease recurrence rates of nonmuscle invasive urothelial carcinoma. Irritative urinary symptoms are a common side effect of treatment and frequently limit treatment tolerance. While anticholinergic medications may be used for symptom prophylaxis, to our knowledge they have not been evaluated in a randomized controlled trial.
Materials and Methods
A total of 50 bacillus Calmette-Guérin naïve patients were randomized to 10 mg extended release oxybutynin daily or placebo starting the day before 6 weekly bacillus Calmette-Guérin treatments. A questionnaire assessing urinary symptoms (frequency, burning on urination, urgency, bladder pain, hematuria), systemic symptoms (flu-like symptoms, fever, arthralgia) and medication side effects (constipation, blurred vision, dry mouth) was recorded daily throughout the therapeutic course. A linear mixed repeated measures model tested the differences between each point and baseline score.
Results
The treatment group had a greater increase in urinary frequency and burning on urination compared to placebo (p = 0.004 and p = 0.04, respectively). There were no significant differences between groups for other urinary symptoms, which increased in severity after bacillus Calmette-Guérin but concomitantly returned to baseline in both groups. The treatment group experienced increases in fever, flu-like symptoms, dry mouth and constipation compared to placebo (p <0.0001, p = 0.0008, p = 0.045 and p = 0.001, respectively). There were otherwise no significant differences in nonurinary symptoms or medication adverse reactions.
Conclusions
Oxybutynin increased urinary frequency and burning on urination compared to placebo in patients receiving intravesical bacillus Calmette-Guérin treatment. Our results do not support the routine use of oxybutynin as prophylaxis against urinary symptoms during bacillus Calmette-Guérin therapy.
doi:10.1016/j.juro.2012.10.070
PMCID: PMC4150693  PMID: 23123375
carcinoma; transitional cell; urinary bladder neoplasms; BCG vaccine; cholinergic antagonists; comparative effectiveness research
6.  Spinal cord tract diffusion tensor imaging reveals disability substrate in demyelinating disease 
Neurology  2013;80(24):2201-2209.
Objective:
This study assessed the tissue integrity of major cervical cord tracts by using diffusion tensor imaging (DTI) to determine the relationship with specific clinical functions carried by those tracts.
Methods:
This was a cross-sectional study of 37 patients with multiple sclerosis or neuromyelitis optica with remote cervical cord disease. Finger vibratory thresholds, 25-foot timed walk (25FTW), 9-hole peg test (9HPT), and Expanded Disability Status Scale were determined. DTI covered cervical regions C1 through C6 with 17 5-mm slices (0.9 × 0.9 mm in-plane resolution). Regions of interest included posterior columns (PCs) and lateral corticospinal tracts (CSTs). Hierarchical linear mixed-effect modeling included covariates of disease subtype (multiple sclerosis vs neuromyelitis optica), disease duration, and sex.
Results:
Vibration thresholds were associated with radial diffusivity (RD) and fractional anisotropy (FA) in the PCs (both p < 0.01), but not CSTs (RD, p = 0.29; FA, p = 0.14). RD and FA in PCs, and RD in CSTs were related to 9HPT (each p < 0.0001). 25FTW was associated with RD and FA in PCs (p < 0.0001) and RD in CSTs (p = 0.008). Expanded Disability Status Scale was related to RD and FA in PCs and CSTs (p < 0.0001). Moderate/severe impairments in 9HPT (p = 0.006) and 25FTW (p = 0.017) were more likely to show combined moderate/severe tissue injury within both PCs and CSTs by DTI.
Conclusions:
DTI can serve as an imaging biomarker of spinal cord tissue injury at the tract level. RD and FA demonstrate strong and consistent relationships with clinical outcomes, specific to the clinical modality.
doi:10.1212/WNL.0b013e318296e8f1
PMCID: PMC3721096  PMID: 23667060
7.  Are We Overtreating Papillomas Diagnosed on Core Needle Biopsy? 
Annals of surgical oncology  2010;18(4):946-951.
Background
Breast papillomas often are diagnosed with core needle biopsy (CNB). Most studies support excision for atypical papillomas, because as many as one half will be upgraded to malignancy on final pathology. The literature is less clear on the management of papillomas without atypia on CNB. Our goal was to determine factors associated with pathology upgrade on excision.
Methods
Our pathology database was searched for breast papillomas diagnosed by CNB during the past 10 years. We identified 277 charts and excluded lesions associated with atypia or malignancy on CNB. Two groups were identified: papillomas that were surgically excised (group 1) and those that were not (group 2). Charts were reviewed for the subsequent diagnosis of cancer or high-risk lesions. Appropriate statistical tests were used to analyze the data.
Results
A total of 193 papillomas were identified. Eighty-two lesions were excised (42%). Caucasian women were more likely to undergo excision (p = 0.03). Twelve percent of excised lesions were upgraded to malignancy. Increasing age was a predictor of upgrading, but this was not significant. Clinical presentation, lesion location, biopsy technique, and breast cancer history were not associated with pathology upgrade. Two lesions in group 2 ultimately required excision due to enlargement, and both were upgraded to malignancy.
Conclusions
Twenty-four percent of papillomas diagnosed on CNB have upgraded pathology on excision—half to malignancy. All of the cancers diagnosed were stage 0 or I. For patients in whom excision was not performed, 2 of 111 papillomas were later excised and upgraded to malignancy.
doi:10.1245/s10434-010-1403-7
PMCID: PMC3980447  PMID: 21046266
8.  A gene expression signature that predicts the therapeutic response of the basal-like breast cancer to neoadjuvant chemotherapy 
Several gene expression profiles have been reported to predict breast cancer response to neoadjuvant chemotherapy. These studies often consider breast cancer as a homogeneous entity, although higher rates of pathologic complete response (pCR) are known to occur within the basal-like subclass. We postulated that profiles with higher predictive accuracy could be derived from a subset analysis of basal-like tumors in isolation. Using a previously described “intrinsic” signature to differentiate breast tumor subclasses, we identified 50 basal-like tumors from two independent clinical trials associated with gene expression profile data. 24 tumor data sets were derived from a 119-patient neoadjuvant trial at our institution and an additional 26 tumor data sets were identified from a published data set (Hess et al. J Clin Oncol 24:4236–4244, 2006). The combined 50 basal-like tumors were partitioned to form a 37 sample training set with 13 sequestered for validation. Clinical surveillance occurred for a mean of 26 months. We identified a 23-gene profile which predicted pCR in basal-like breast cancers with 92% predictive accuracy in the sequestered validation data set. Furthermore, distinct cluster of patients with high rates of cancer recurrence was observed based on cluster analysis with the 23-gene signature. Disease-free survival analysis of these three clusters revealed significantly reduced survival in the patients of this high recurrence cluster. We identified a 23-gene signature which predicts response of basal-like breast cancer to neoadjuvant chemotherapy as well as disease-free survival. This signature is independent of tissue collection method and chemotherapeutic regimen.
doi:10.1007/s10549-009-0664-y
PMCID: PMC3965252  PMID: 19967557
Breast cancer; Expression profiling; Therapeutic response
9.  The characteristics and outcomes of patients with multiple myeloma dual refractory or intolerant to bortezomib and lenalidomide in the era of carfilzomib and pomalidomide 
Leukemia & lymphoma  2013;55(2):337-341.
Patients with multiple myeloma who are refractory or intolerant to both bortezomib and lenalidomide have a poor prognosis. Next-generation therapies carfilzomib and pomalidomide have shown promising activity in this dual refractory population. Here we describe the clinical characteristics and ascertain the effects of carfilzomib and pomalidomide on survival in this patient cohort. We retrospectively reviewed the records of 65 dual refractory/intolerant myeloma patients diagnosed between January 2007 and May 2012 at a single institution. The median overall survival (OS) from the time patients became dual refractory/intolerant was 10.2 months. Patients who received carfilzomib or pomalidomide after they became dual refractory/intolerant had a better OS compared to those who did not (12.6 vs. 6.8 months, p=0.03 by Wilcoxon test). Prospective randomized control trials are needed for confirmation.
doi:10.3109/10428194.2013.803547
PMCID: PMC3951876  PMID: 23662990
multiple myeloma; lenalidomide; bortezomib; pomalidomide; carfilzomib
10.  Improved in vivo diffusion tensor imaging of human cervical spinal cord 
NeuroImage  2012;67:64-76.
We describe a cardiac gated high in-plane resolution axial human cervical spinal cord diffusion tensor imaging (DTI) protocol. Multiple steps were taken to optimize both image acquisition and image processing. The former includes slice-by-slice cardiac triggering and individually tiltable slices. The latter includes (i) iterative 2D retrospective motion correction, (ii) image intensity outlier detection to minimize the influence of physiological noise, (iii) a non-linear DTI estimation procedure incorporating non-negative eigenvalue priors, and (iv) tract-specific region-of-interest (ROI) identification based on an objective geometry reference. Using these strategies in combination, radial diffusivity (λ⊥) was reproducibly measured in white matter (WM) tracts (adjusted mean [95% confidence interval]=0.25 [0.22, 0.29]µm2/ms), lower than previously reported λ⊥ values in the in vivo human spinal cord DTI literature. Radial diffusivity and fractional anisotropy (FA) measured in WM varied from rostral to caudal as did mean translational motion, likely reflecting respiratory motion effect. Given the considerable sensitivity of DTI measurements to motion artifact, we believe outlier detection is indispensable in spinal cord diffusion imaging. We also recommend using a mixed-effects model to account for systematic measurement bias depending on cord segment.
doi:10.1016/j.neuroimage.2012.11.014
PMCID: PMC3604900  PMID: 23178538
Directional diffusivity; Outlier rejection; Non-negative eigenvalue priors; Reduced FOV; Cardiac gating; Cervical spinal cord; Lateral corticospinal tract; Posterior column; Diffusion tensor imaging; Reproducibility
11.  PET-Based Estradiol Challenge as a Predictive Biomarker of Response to Endocrine Therapy in Women with Estrogen-Receptor-Positive Breast Cancer 
Breast cancer research and treatment  2008;113(3):10.1007/s10549-008-9953-0.
Purpose
To determine if response to endocrine therapy of breast cancer can be predicted by either a metabolic “flare reaction” detected by positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxyglucose (FDG), induced by an estradiol challenge, or by estrogen-receptor (ER) status, determined by PET with the estrogen analog 16α-[18F]fluoroestradiol-17β (FES).
Methods
Fifty-one post-menopausal women with advanced estrogen-receptor positive breast cancer were studied. Patients underwent FES-PET and FDG-PET at baseline and repeat FDG-PET after 30 mg estradiol. Tracer uptakes was measured as the standardized uptake value (SUV). Patients were subsequently treated with either an aromatase inhibitor or fulvestrant. A prospectively defined cut-off SUV ≥2 for FES was considered positive for ER expression. A cutoff of ≥12% increase in SUV for FDG, determined by ROC analysis, represented metabolic flare. PET results were correlated with responsiveness to endocrine therapy.
Results
Seventeen patients responded and 34 patients did not respond to endocrine therapy. Four responders and 1 non-responder had a clinical flare reaction, while only the responders demonstrated metabolic flare. After estradiol challenge, a significantly higher mean (±SD) percent change in SUV for FDG was noted in responders (20.9±24.2) compared with non-responders (−4.3±11.0, p<0.0001). On FES-PET, a higher tumor SUV was noted in responders (3.5±2.5) compared with non-responders (2.1±1.8, p=0.0049). There was significantly longer overall survival in patients with metabolic flare than in those without flare regardless of type of endocrine therapy (p=0.0062).
Conclusion
Baseline tumor FES uptake and metabolic flare after an estradiol challenge are both predictive of responsiveness to endocrine therapy in ER+ breast cancer.
doi:10.1007/s10549-008-9953-0
PMCID: PMC3883567  PMID: 18327670
breast cancer; FDG; FES; flare reaction; hormone therapy; metabolic flare; PET; positron emission tomography
12.  A Phase II Trial of Induction nab-Paclitaxel and Cetuximab Given With Cisplatin and 5-Fluorouracil Followed by Concurrent Cisplatin and Radiation for Locally Advanced Squamous Cell Carcinoma of the Head and Neck 
Cancer  2012;119(4):10.1002/cncr.27741.
Background
Complete Response (CR) at the primary tumor site as assessed by clinical examination following induction chemotherapy with cisPlatin and 5-Fluorouracil (5-FU)[PF] is a favorable predictive factor for overall survival and disease-control in patients with locally advanced squamous cell carcinoma of the head and neck. In most series, the rate of CR at the primary site after induction PF was 20–30%. We evaluated the efficacy and feasibility of induction nAb-paclitaxel and Cetuximab given with PF (ACPF) followed by definitive chemoradiation (CRT) in a phase II trial.
Methods
Patients with HNSCC were treated with ACPF (nab-paclitaxel 100 mg/m2/week; cetuximab 250 mg/m2/week; cisplatin 75 mg/m2 Day 1; 5-fluorouracil 750 mg/m2/day Days 1–3) every 21 days for 3 cycles followed by CRT (cisplatin 100 mg/m2 on days 1,22 and 43 of RT). CR at the primary tumor site after 2 cycles of ACPF was the primary endpoint.
Results
Thirty patients were enrolled, of which 22 (73%) had large (T3/T4) primary tumors. The CR rate at the primary tumor site after 2 cycles of ACPF was 53% and the overall response rate was 100%. Twenty-nine (96%) patients completed 3 cycles of ACPF, 26 (90%) completed definitive radiation therapy (RT) per protocol and 22 of the 27 evaluable patients (81%) received > 2 of the 3 planned doses of cisplatin with RT. The estimated 2-year overall and progression-free survivals were 84% and 65%, respectively.
Conclusion
Induction ACPF resulted in a high CR rate (53%) at the primary tumor site even in large tumors and did not adversely affect delivery of definitive CRT. Further investigation of ACPF is warranted.
doi:10.1002/cncr.27741
PMCID: PMC3832987  PMID: 22991252
head and neck cancer; phase 2; nab-paclitaxel; cetuximab; cisplatin; 5-fluorouracil
13.  Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial 
The lancet oncology  2010;11(5):421-428.
Summary
Background
Treatment with bisphosphonates decreases bone loss and can increase disease-free survival in patients with breast cancer. The aim of our study was to assess the effect of zoledronic acid on clearance of disseminated tumour cells (DTCs) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer.
Methods
Patients were recruited for this open-label, phase 2 randomised trial between March 17, 2003, and May 19, 2006, at a single centre. Eligible patients had clinical stage II–III (≥T2 and/or ≥N1) newly diagnosed breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, and normal cardiac, renal, and liver function. 120 women were randomly assigned, using allocation concealment, to receive 4 mg zoledronic acid intravenously every 3 weeks (n=60), or no zoledronic acid (n=60), for 1 year concomitant with four cycles of neoadjuvant epirubicin (75 mg/m²) plus docetaxel (75 mg/m²) and two cycles of adjuvant epirubicin plus docetaxel. The primary endpoint was the number of patients with detectable DTCs at 3 months. Final analysis was done 1 year after the last patient was enrolled. Analyses were done for all patients with available data at 3 months. This study is registered with ClinicalTrials.gov, number NCT00242203.
Findings
Of the 120 patients initially enrolled, one withdrew after signing consent and one patient’s baseline bone marrow was not available. Both of these patients were in the control group. At 3 months, 109 bone-marrow samples were available for analysis. In the zoledronic acid group, bone marrow was not collected from one patient because of disease progression, one patient was taken off study because of severe diarrhoea, and two patients had not consented at the time of surgery. In the control group, bone marrow was not collected from two patients because of disease progression, one patient withdrew consent, and three patients were not consented at the time of surgery. At baseline, DTCs were detected in 26 of 60 patients in the zoledronic acid group and 28 of 58 patients in the control group. At 3 months, 17 of 56 patients receiving zoledronic acid versus 25 of 53 patients who did not receive zoledronic acid had detectable DTCs (p=0·054). The most common grade 3–4 toxicities were infection (five of 60 patients in the zoledronic acid group and six of 59 in the control group) and thrombosis (five of 60 in the zoledronic acid and two of 59 in the control group). There was one documented case of osteonecrosis in the zoledronic acid group.
Interpretation
Zoledronic acid administered with chemotherapy resulted in a decreased proportion of patients with DTCs detected in the bone marrow at the time of surgery. Our study supports the hypothesis that the antimetastatic effects of zoledronic acid may be through effects on DTCs.
Funding
Novartis Pharmaceuticals and Pfi zer Inc.
doi:10.1016/S1470-2045(10)70054-1
PMCID: PMC3792651  PMID: 20362507
14.  Increased Radial Diffusivity in Spinal Cord Lesions in Neuromyelitis Optica Compared to Multiple Sclerosis 
Background
Multiple sclerosis (MS) and neuromyelitis optica (NMO) both affect spinal cord with notable differences in pathology.
Objective
Determine the utility of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions of NMO from MS within and outside T2 lesions.
Methods
Subjects ≥12 months from a clinical episode of transverse myelitis underwent a novel transaxial cervical spinal cord DTI sequence. Ten subjects with NMO, 10 with MS, and 10 healthy controls were included.
Results
Within T2 affected white matter regions, radial diffusivity was increased in both NMO and MS compared to healthy controls (p<0.001, respectively), and to a greater extent in NMO than MS (p<0.001). Axial diffusivity was decreased in T2 lesions in both NMO and MS compared to controls (p<0.001, p=0.001), but did not differ between the two diseases. Radial diffusivity and FA within white matter regions upstream and downstream of T2 lesions were different from controls in each disease.
Conclusions
Higher radial diffusivity, within spinal cord white matter tracts derived from diffusion tensor imaging were appreciated in NMO compared to MS, consistent with the known greater tissue destruction seen in NMO. DTI also detected tissue alterations outside T2 lesions, and may be a surrogate of anterograde and retrograde degeneration.
doi:10.1177/1352458512436593
PMCID: PMC3360125  PMID: 22354742
diffusion tensor imaging; neuromyelitis optica (NMO); multiple sclerosis (MS); spinal cord; MRI
15.  Factors associated with attaining coaching goals during an intervention to improve child asthma care 
Contemporary clinical trials  2012;33(5):912-919.
Purpose
To examine parent and child characteristics associated with engagement in a coaching intervention to improve pediatric asthma care and factors associated with readiness to adopt and maintain targeted asthma management behaviors.
Methods
Using methods based on the Transtheoretical Model, trained lay coaches worked with 120 parents of children with asthma promoting adoption and maintenance of asthma management strategies (behaviors). Coaches assigned stage-of-change (on continuum: pre-contemplation, contemplation, preparation, action, maintenance) for each behavior every time it was discussed. Improvement in stage-of-change was analyzed for association with characteristics of the participants (parents and children) and coaching processes.
Results
Having more coach contacts was associated with earlier first contact (p<0.001), fewer attempts per successful contact (p<0.001), prior asthma hospitalization (p=0.021), more intruding events (p<0.001), and less social support (p=0.048). In univariable models, three factors were associated with forward movement at least one stage for all three behaviors: more coach contacts overall, fewer attempts per successful contact, and more discussion/staging episodes for the particular behavior. In multivariable models adjusting for characteristics of participants and coaching process, the strongest predictor of any forward stage movement for each behavior was having more contacts (p<0.05).
Conclusions
Improvement in readiness to adopt and maintain asthma management behaviors was mostly associated with factors reflecting more engagement of participants in the program. Similar coaching interventions should focus on early and frequent contacts to achieve intervention goals, recognizing that parents of children with less severe disease and who have more social support may be more difficult to engage.
doi:10.1016/j.cct.2012.05.012
PMCID: PMC3408563  PMID: 22664649
asthma; child; parent; coach; stage-of-change; engagement
16.  A randomized controlled trial of parental asthma coaching to improve outcomes in urban minority children 
Objectives
Investigate if asthma coaching reduces emergency department (ED) visits and hospitalizations and increases outpatient asthma monitoring (AM) visits.
Design
Randomized controlled trial
Setting
Urban tertiary-care children’s hospital
Participants
Primary caregivers (“parents”) of children age 2–10 years with asthma, Medicaid-insurance, and urban residence who were attending the ED for acute asthma care.
Intervention
18 months of coaching focused on asthma home management, completing periodic outpatient AM visits, and developing collaborative relationship with primary care provider (PCP); or usual care (control group).
Outcome Measures
Primary = ED visits. Secondary = hospitalizations and AM visits (non-acute visits focused on asthma care). Outcomes were measured during year before and 2 years after enrollment.
Results
We included 120 intervention and 121 control parents. More children of coached parents had ≥ 1 AM visit after enrollment (relative risk [RR], 1.21; 95% confidence interval [CI], 1.04–1.41), but proportions with ≥ 4 AM visits over 2 years were low (intervention=20%; control=10%). Similar proportions of children per study group had ≥ 1 ED visit (71/120 versus 76/121; RR, 0.94; 95% CI, 0.77–1.15) and ≥ 1 hospitalization (29/120 versus 32/121; RR, 0.91; 95% CI 0.59–1.41) after enrollment. An ED visit after enrollment was more likely if one occurred before enrollment (RR, 1.46; 95% CI 1.16–1.86; adjusted for study group), but risk was similar per study group when adjusted for previous ED visits (RR, 1.02; 95% CI, 0.82–1.27).
Conclusions
This parental asthma coaching intervention increased outpatient asthma monitoring visits, although these visits were infrequent, but did not reduce ED visits.
doi:10.1001/archpediatrics.2011.57
PMCID: PMC3733385  PMID: 21646584
17.  Glycogen Synthase Kinase 3β Inhibition as a Therapeutic Approach in the Treatment of Endometrial Cancer 
Alternative strategies beyond current chemotherapy and radiation therapy regimens are needed in the treatment of advanced stage and recurrent endometrial cancers. There is considerable promise for biologic agents targeting the extracellular signal-regulated kinase (ERK) pathway for treatment of these cancers. Many downstream substrates of the ERK signaling pathway, such as glycogen synthase kinase 3β (GSK3β), and their roles in endometrial carcinogenesis have not yet been investigated. In this study, we tested the importance of GSK3β inhibition in endometrial cancer cell lines and in vivo models. Inhibition of GSK3β by either lithium chloride (LiCl) or specific GSK3β inhibitor VIII showed cytostatic and cytotoxic effects on multiple endometrial cancer cell lines, with little effect on the immortalized normal endometrial cell line. Flow cytometry and immunofluorescence revealed a G2/M cell cycle arrest in both type I (AN3CA, KLE, and RL952) and type II (ARK1) endometrial cancer cell lines. In addition, LiCl pre-treatment sensitized AN3CA cells to the chemotherapy agent paclitaxel. Administration of LiCl to AN3CA tumor-bearing mice resulted in partial or complete regression of some tumors. Thus, GSK3β activity is associated with endometrial cancer tumorigenesis and its pharmacologic inhibition reduces cell proliferation and tumor growth.
doi:10.3390/ijms140816617
PMCID: PMC3759928  PMID: 23941783
lithium chloride; GSK3β; endometrial cancer
18.  IL-12p70–producing patient DC vaccine elicits Tc1-polarized immunity 
The Journal of Clinical Investigation  2013;123(8):3383-3394.
Background. Systemic administration of IL-12p70 has demonstrated clinical activity in cancer patients, but dose-limiting toxicities have hindered its incorporation in vaccine formulations. Here, we report on the immunological and clinical outcomes upon vaccination with CD40L/IFN-γ–matured, IL-12p70–producing DCs.
Methods. 7 HLA-A*0201+ newly diagnosed stage IV melanoma patients were immunized against the gp100 melanoma antigen using autologous peptide-pulsed, CD40L/IFN-γ–matured DCs. PBMCs were taken weekly for immune monitoring by tetramer analysis and functional assays. CT imaging was performed at baseline, week 9, and week 18 for clinical assessment using RECIST.
Results. 6 of 7 treated patients developed sustained T cell immunity to all 3 melanoma gp100 antigen–derived peptides. 3 of the 6 immunological responders developed confirmed clinical responses (1 complete remission >4 years, 2 partial response). Importantly, DC vaccine–derived IL-12p70 levels positively correlated with time to progression (P = 0.019, log-rank), as did T-cytotoxic 1 (Tc1) immunity, as assessed by IFN-γ/IL-13 and IFN-γ/IL-5 ratios (P = 0.035 and P = 0.030, respectively, log-rank). In contrast, a pathway-specific defect in IL-12p35 transcription was identified upon CD40L/IFN-γ activation in clinical nonresponder patient DCs, and gp100-specific T cells from these patients displayed a Tc2 phenotype. Incorporation of TLR3 and TLR8 agonists into the CD40L/IFN-γ activation protocol corrected the IL-12p70 production defect in DCs derived from clinical nonresponder patients.
Conclusion. These findings underscore the essential role of IL-12p70 in the development of therapeutic type 1 antigen–specific CD8+ T cell immunity in humans with cancer.
Trial registration. Clinicaltrials.gov NCT00683670.
Funding. Barnes-Jewish Hospital Foundation, Siteman Cancer Frontier Fund, Washington University/JNJ Translational Medicine Award, and NCI (P30 CA91842).
doi:10.1172/JCI68395
PMCID: PMC3726168  PMID: 23867552
19.  Quantification of increased cellularity during inflammatory demyelination 
Brain  2011;134(12):3587-3598.
Multiple sclerosis is characterized by inflammatory demyelination and irreversible axonal injury leading to permanent neurological disabilities. Diffusion tensor imaging demonstrates an improved capability over standard magnetic resonance imaging to differentiate axon from myelin pathologies. However, the increased cellularity and vasogenic oedema associated with inflammation cannot be detected or separated from axon/myelin injury by diffusion tensor imaging, limiting its clinical applications. A novel diffusion basis spectrum imaging, capable of characterizing water diffusion properties associated with axon/myelin injury and inflammation, was developed to quantitatively reveal white matter pathologies in central nervous system disorders. Tissue phantoms made of normal fixed mouse trigeminal nerves juxtaposed with and without gel were employed to demonstrate the feasibility of diffusion basis spectrum imaging to quantify baseline cellularity in the absence and presence of vasogenic oedema. Following the phantom studies, in vivo diffusion basis spectrum imaging and diffusion tensor imaging with immunohistochemistry validation were performed on the corpus callosum of cuprizone treated mice. Results demonstrate that in vivo diffusion basis spectrum imaging can effectively separate the confounding effects of increased cellularity and/or grey matter contamination, allowing successful detection of immunohistochemistry confirmed axonal injury and/or demyelination in middle and rostral corpus callosum that were missed by diffusion tensor imaging. In addition, diffusion basis spectrum imaging-derived cellularity strongly correlated with numbers of cell nuclei determined using immunohistochemistry. Our findings suggest that diffusion basis spectrum imaging has great potential to provide non-invasive biomarkers for neuroinflammation, axonal injury and demyelination coexisting in multiple sclerosis.
doi:10.1093/brain/awr307
PMCID: PMC3235568  PMID: 22171354
magnetic resonance imaging; diffusion tensor imaging; multiple tensor model; white matter injury; inflammation
20.  Diffusion Tensor Imaging in Acute Optic Neuropathies 
Archives of neurology  2011;69(1):65-71.
Objective
To evaluate directional diffusivities within the optic nerve in a first event of acute optic neuritis to determine whether decreased axial diffusivity (AD) would predict 6-month visual outcome and optic nerve integrity measures.
Design
Cohort study.
Setting
Academic multiple sclerosis center.
Patients
Referred sample of 25 individuals who presented within 31 days after acute visual symptoms consistent with optic neuritis. Visits were scheduled at baseline, 2 weeks, and 1, 3, 6, and 12 months.
Main Outcome Measures
Visual acuity, contrast sensitivity, visual evoked potentials (VEPs), and thickness of the retinal nerve fiber layer (RNFL).
Results
An incomplete 6-month visual recovery was associated with a lower baseline AD (1.50 μm2/ms [95% confidence interval {CI}, 1.36–1.64 μm2/ms for incomplete recovery vs 1.75 μm2/ms [95% CI, 1.67–1.83 μm2/ms] for complete recovery). Odds of complete recovery decreased by 53% (95% CI, 27%–70%) for every 0.1-unit decrease in baseline AD. A lower baseline AD correlated with worse 6-month visual outcomes in visual acuity (r=0.40, P=.03), contrast sensitivity (r=0.41, P=.02), VEP amplitude (r=0.55, P<.01), VEP latency (r=−0.38, P=.04), and RNFL thickness (r=0.53, P=.02). Radial diffusivity increased between months 1 and 3 to become higher in those with incomplete recovery at 12 months than in those with complete recovery (1.45 μm2/ms [95% CI, 1.31–1.59 μm2/ms] vs 1.19 μm2/ms [95% CI, 1.10–1.28 μm2/ms]).
Conclusions
Decreased AD in acute optic neuritis was associated with a worse 6-month visual outcome and correlated with VEP and RNFL measures of axon and myelin injury. Axial diffusivity may serve as a marker of axon injury in acute white matter injury.
doi:10.1001/archneurol.2011.243
PMCID: PMC3489058  PMID: 21911658
21.  Radial Diffusivity Predicts Demyelination in ex-vivo Multiple Sclerosis Spinal Cords 
NeuroImage  2011;55(4):1454-1460.
Objective
Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords.
Background
In MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans.
Methods
DTI was performed at 4.7 Tesla on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate-severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. Results: Within ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate-severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p=0.091).
Conclusions
Increased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity can serve as a marker of overall tissue integrity within chronic MS lesions. This study provides pathologic foundation for on-going in vivo DTI studies in MS.
doi:10.1016/j.neuroimage.2011.01.007
PMCID: PMC3062747  PMID: 21238597
Multiple Sclerosis; Diffusion Tensor Imaging; Post mortum; Spinal cord
22.  PSYCHOLOGICAL FACTORS RELATED TO DELAY IN CONSULTATION FOR CANCER SYMPTOMS 
Psycho-Oncology  2005;14(5):339-350.
SUMMARY
This research investigated psychological characteristics associated with delay in seeking help for symptoms of rectal cancer. Sixty nine subjects reconstructed pivotal events beginning with symptom onset and ending with medical consultation, and completed the Temperament and Character Inventory (TCI) and the State-Trait Anxiety Inventory (STAI). The mean delay time was around 6 months, with about 1 out of 6 subjects waiting one year or more. Subjects estimated the lengths of two sequential segments of total time to consultation: (1) Symptom Appraisal time (from symptom onset to recognition of possible seriousness), and (2) Action Appraisal time (from recognition of seriousness to medical consultation). Symptom Appraisal time accounted for over two-thirds of total time and was associated with low scores on the TCI Harm Avoidance scale (TCI-HA), indicating dispositional insensitivity to threat, and marginally associated with less education and younger age. Action Appraisal time was not associated with any demographic or psychological variables. Low TCI-HA scores were also associated with lower likelihood of previous cancer screening, and with better judgments of premorbid health. Low STAI Trait scores were associated with better judgments of premorbid health and fewer doctor visits. Results are discussed regarding the importance of understanding dispositional characteristics related to health behavior.
doi:10.1002/pon.850
PMCID: PMC3320717  PMID: 15386764
23.  Thymidylate Synthase Genotype-Directed Neoadjuvant Chemoradiation for Patients With Rectal Adenocarcinoma 
Journal of Clinical Oncology  2011;29(7):875-883.
Purpose
Downstaging (DS) of rectal cancers is achieved in approximately 45% of patients with neoadjuvant fluorouracil (FU) -based chemoradiotherapy (CRT). Polymorphisms in the thymidylate synthase gene (TYMS) had previously defined two risk groups associated with disparate tumor DS rates (60% v 22%). We conducted a prospective single-institution phase II study using TYMS genotyping to direct neoadjuvant CRT for patients with rectal cancer.
Patients and Methods
Patients with T3/T4, N0-2, M0-1 rectal adenocarcinoma were evaluated for germline TYMS genotyping. Patients with TYMS *2/*2, *2/*3, or *2/*4 (good risk) were treated with standard chemoradiotherapy using infusional FU at 225 mg/m2/d. Patients with TYMS *3/*3 or *3/*4 (poor risk) were treated with FU/RT plus weekly intravenous irinotecan at 50 mg/m2. The primary end point was pathologic DS. Secondary end points included complete tumor response (ypT0), toxicity, recurrence rates, and overall survival.
Results
Overall, 135 patients were enrolled, of whom 27.4% (37 of 135) were considered poor risk. The prespecified statistical goals were achieved, with DS and ypT0 rates reaching 64.4% and 20% for good-risk and 64.5% and 42% for poor-risk patients, respectively.
Conclusion
To our knowledge, this is the first study to prospectively use TYMS genotyping to direct neoadjuvant CRT in patients with rectal cancer. High rates of DS and ypT0 were achieved among both risk groups when personalized treatment was based on TYMS genotype. These results are encouraging, and further evaluation of this genotype-based strategy using a randomized study design for locally advanced rectal cancer is warranted.
doi:10.1200/JCO.2010.32.3212
PMCID: PMC3068061  PMID: 21205745
25.  Rostro-Caudal Analysis of Corpus Callosum Demyelination and Axon Damage Across Disease Stages Refines Diffusion Tensor Imaging Correlations with Pathological Features 
Non-invasive assessment of the progression of axon damage is important for evaluating disease progression and developing neuroprotective interventions in multiple sclerosis (MS) patients. We examined the cellular responses correlated with diffusion tensor imaging (DTI)-derived axial (λ||) and radial (λ⊥) diffusivity values throughout acute (4 weeks) and chronic (12 weeks) stages of demyelination and after 6 weeks of recovery using the cuprizone demyelination of the corpus callosum model in C57BL/6 and Thy1-YFP-16 mice. The rostro-caudal progression of pathologic alterations in the corpus callosum enabled spatially and temporally defined correlations of pathological features with DTI measurements. During acute demyelination, microglial/macrophage activation was most extensive and axons exhibited swellings, neurofilament dephosphorylation, and reduced diameters. Axial diffusivity values decreased in the acute phase but did not correlate with axonal atrophy during chronic demyelination. In contrast, radial diffusivity increased with the progression of demyelination but did not correlate with myelin loss or astrogliosis. Unlike other animals models with progressive neurodegeneration and axon loss, the acute axon damage did not progress to discontinuity or loss of axons even after a period of chronic demyelination. Correlations of reversible axon pathology, demyelination, microglia/macrophage activation, and astrogliosis with regional axial and radial diffusivity measurements will facilitate the clinical application of DTI in MS patients.
doi:10.1097/NEN.0b013e3181e3de90
PMCID: PMC2901930  PMID: 20535036
Astrogliosis; Axon damage; Corpus callosum; Cuprizone; Demyelination; Diffusion tensor imaging; Microglia activation

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