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1.  Aspiration pneumonia after chemo–intensity-modulated radiation therapy of oropharyngeal carcinoma and its clinical and dysphagia-related predictors 
Head & neck  2013;36(1):120-125.
The purpose of this study was to assess aspiration pneumonia (AsPn) rates and predictors after chemo-irradiation for head and neck cancer.
The was a prospective study of 72 patients with stage III to IV oropharyngeal cancer treated definitively with intensity-modulated radiotherapy (IMRT) concurrent with weekly carboplatin and paclitaxel. AsPn was recorded prospectively and dysphagia was evaluated longitudinally through 2 years posttherapy by observer-rated (Common Toxicity Criteria version [CTCAE]) scores, patient-reported scores, and videofluoroscopy.
Sixteen patients (20%) developed AsPn. Predictive factors included T classification (p = .01), aspiration detected on videofluoroscopy (videofluoroscopy-asp; p = .0007), and patient-reported dysphagia (p = .02–.0003), but not observer-rated dysphagia (p = .4). Combining T classification, patient reported dysphagia, and videofluoroscopy-asp, provided the best predictive model.
AsPn continues to be an under-reported consequence of chemo-irradiation for head and neck cancer. These data support using patient-reported dysphagia to identify high-risk patients requiring videofluoroscopy evaluation for preventive measures. Reducing videofluoroscopy-asp rates, by reducing swallowing structures radiation doses and by trials reducing treatment intensity in patients predicted to do well, are likely to reduce AsPn rates.
PMCID: PMC4144677  PMID: 23729173
oropharyngeal cancer; head and neck cancer; IMRT; aspiration pneumonia; dysphagia
2.  Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR 
Cancer Medicine  2014;3(4):1041-1051.
Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D2) caused more adenomas in ApcMin/+ mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D2 (PGD2) binds to the prostaglandin D2 receptor known as PTGDR (or DP1). PGD2 metabolites bind to peroxisome proliferator-activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD2. To assess, we produced ApcMin/+ mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced ApcMin/+ mice expressing transgenic lipocalin-type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30–40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in ApcMin/+ mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. ApcMin/+ mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v-myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor-suppressing effect of transgenic PTGDS. However, tumor suppression by PGD2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD2 signals acting through PTGDR in suppression of intestinal tumors.
PMCID: PMC4303173  PMID: 24729479
Adenomatous polyposis coli; gastrointestinal neoplasms; PPAR gamma; prostaglandin D2 receptor; prostaglandin D2 synthases
3.  Permutation Tests for Random Effects in Linear Mixed Models 
Biometrics  2011;68(2):10.1111/j.1541-0420.2011.01675.x.
Inference regarding the inclusion or exclusion of random effects in linear mixed models is challenging because the variance components are located on the boundary of their parameter space under the usual null hypothesis. As a result, the asymptotic null distribution of the Wald, score, and likelihood ratio tests will not have the typical χ2 distribution. Although it has been proved that the correct asymptotic distribution is a mixture of χ2 distributions, the appropriate mixture distribution is rather cumbersome and nonintuitive when the null and alternative hypotheses differ by more than one random effect. As alternatives, we present two permutation tests, one that is based on the best linear unbiased predictors and one that is based on the restricted likelihood ratio test statistic. Both methods involve weighted residuals, with the weights determined by the among- and within-subject variance components. The null permutation distributions of our statistics are computed by permuting the residuals both within and among subjects and are valid both asymptotically and in small samples. We examine the size and power of our tests via simulation under a variety of settings and apply our test to a published data set of chronic myelogenous leukemia patients.
PMCID: PMC3883440  PMID: 21950470
Hypothesis testing; Longitudinal data; Variance components
4.  Concurrent whole brain radiotherapy and bortezomib for brain metastasis 
Survival of patients with brain metastasis particularly from historically more radio-resistant malignancies remains dismal. A phase I study of concurrent bortezomib and whole brain radiotherapy was conducted to determine the tolerance and safety of this approach in patients with previously untreated brain metastasis.
A phase I dose escalation study evaluated the safety of bortezomib (0.9, 1.1, 1.3, 1.5, and 1.7 mg/m2) given on days 1, 4, 8 and 11 of whole brain radiotherapy. Patients with confirmed brain metastasis were recruited for participation. The primary endpoint was the dose-limiting toxicity, defined as any ≥ grade 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity from the start of treatment to one month post irradiation. Time-to-Event Continual Reassessment Method (TITE-CRM) was used to determine dose escalation. A companion study of brain diffusion tensor imaging MRI was conducted on a subset of patients to assess changes in the brain that might predict delayed cognitive effects.
Twenty-four patients were recruited and completed the planned therapy. Patients with melanoma accounted for 83% of all participants. The bortezomib dose was escalated as planned to the highest dose of 1.7 mg/m2/dose. No grade 4/5 toxicities related to treatment were observed. Two patients had grade 3 dose-limiting toxicities (hyponatremia and encephalopathy). A partial or minor response was observed in 38% of patients. Bortezomib showed greater demyelination in hippocampus-associated white matter structures on MRI one month after radiotherapy compared to patients not treated with bortezomib (increase in radial diffusivity +16.8% versus 4.8%; p = 0.0023).
Concurrent bortezomib and whole brain irradiation for brain metastasis is well tolerated at one month follow-up, but MRI changes that have been shown to predict delayed cognitive function can be detected within one month of treatment.
PMCID: PMC3765365  PMID: 23965287
Radiation; Brain; Melanoma; Bortezomib; Phase I; TITE-CRM; Diffusion tensor imaging; MRI
5.  Stereotactic Body Radiation Therapy for Primary and Metastatic Liver Tumors1 
Translational Oncology  2013;6(4):442-446.
OBJECTIVES: The full potential of stereotactic body radiation therapy (SBRT), in the treatment of unresectable intrahepatic malignancies, has yet to be realized as our experience is still limited. Thus, we evaluated SBRT outcomes for primary and metastatic liver tumors, with the goal of identifying factors that may aid in optimization of therapy. METHODS: From 2005 to 2010, 62 patients with 106 primary and metastatic liver tumors were treated with SBRT to a median biologic effective dose (BED) of 100 Gy (42.6–180). The majority of patients received either three (47%) or five fractions (48%). Median gross tumor volume (GTV) was 8.8 cm3 (0.2–222.4). RESULTS: With a median follow-up of 18 months (0.46–46.8), freedom from local progression (FFLP) was observed in 97 of 106 treated tumors, with 1- and 2-year FFLP rates of 93% and 82%. Median overall survival (OS) for all patients was 25.2 months, with 1- and 2-year OS of 81% and 52%. Neither BED nor GTV significantly predicted for FFLP. Local failure was associated with a higher risk of death [hazard ratio (HR) = 5.1, P = .0007]. One Child-Pugh Class B patient developed radiation-induced liver disease. There were no other significant toxicities. CONCLUSIONS: SBRT provides excellent local control for both primary and metastatic liver lesions with minimal toxicity. Future studies should focus on appropriate selection of patients and on careful assessment of liver function to maximize both the safety and efficacy of treatment.
PMCID: PMC3730019  PMID: 23908687
6.  Regional Variation in Brain White Matter Diffusion Index Changes following Chemoradiotherapy: A Prospective Study Using Tract-Based Spatial Statistics 
PLoS ONE  2013;8(3):e57768.
There is little known about how brain white matter structures differ in their response to radiation, which may have implications for radiation-induced neurocognitive impairment. We used diffusion tensor imaging (DTI) to examine regional variation in white matter changes following chemoradiotherapy.
Fourteen patients receiving two or three weeks of whole-brain radiation therapy (RT) ± chemotherapy underwent DTI pre-RT, at end-RT, and one month post-RT. Three diffusion indices were measured: fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). We determined significant individual voxel changes of diffusion indices using tract-based spatial statistics, and mean changes of the indices within fourteen white matter structures of interest.
Voxels of significant FA decreases and RD increases were seen in all structures (p<0.05), with the largest changes (20–50%) in the fornix, cingula, and corpus callosum. There were highly significant between-structure differences in pre-RT to end-RT mean FA changes (p<0.001). The inferior cingula had a mean FA decrease from pre-RT to end-RT significantly greater than 11 of the 13 other structures (p<0.00385).
Brain white matter structures varied greatly in their response to chemoradiotherapy as measured by DTI changes. Changes in FA and RD related to white matter demyelination were prominent in the cingula and fornix, structures relevant to radiation-induced neurocognitive impairment. Future research should evaluate DTI as a predictive biomarker of brain chemoradiotherapy adverse effects.
PMCID: PMC3587621  PMID: 23469234
7.  Development and Validation of a qRT-PCR Classifier for Lung Cancer Prognosis 
This prospective study aimed to develop a robust and clinically-applicable method to identify high-risk early stage lung cancer patients and then to validate this method for use in future translational studies.
Patients and Methods
Three published Affymetrix microarray data sets representing 680 primary tumors were used in the survival-related gene selection procedure using clustering, Cox model and random survival forest (RSF) analysis. A final set of 91 genes was selected and tested as a predictor of survival using a qRT-PCR-based assay utilizing an independent cohort of 101 lung adenocarcinomas.
The RSF model built from 91 genes in the training set predicted patient survival in an independent cohort of 101 lung adenocarcinomas, with a prediction error rate of 26.6%. The mortality risk index (MRI) was significantly related to survival (Cox model p < 0.00001) and separated all patients into low, medium, and high-risk groups (HR = 1.00, 2.82, 4.42). The MRI was also related to survival in stage 1 patients (Cox model p = 0.001), separating patients into low, medium, and high-risk groups (HR = 1.00, 3.29, 3.77).
The development and validation of this robust qRT-PCR platform allows prediction of patient survival with early stage lung cancer. Utilization will now allow investigators to evaluate it prospectively by incorporation into new clinical trials with the goal of personalized treatment of lung cancer patients and improving patient survival.
PMCID: PMC3167380  PMID: 21792073
Lung cancer; qRT-PCR; Prognosis

Results 1-7 (7)