Zhengjia Chen

Emory University, Atlanta, Georgia, United States

Are you Zhengjia Chen?

Claim your profile

Publications (117)553.25 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in the United States. DLBCL comprises biologically distinct subtypes including germinal center-like (GCB) and activated-B-cell-like DLBCL (ABC). The most aggressive type, ABC-DLBCL, displays dysregulation of both canonical and noncanonical NF-κB pathway as well as genomic instability. Although, much is known about the tumorigenic roles of the canonical NF-kB pathway, the precise role of the noncanonical NF-kB pathway remains unknown. Here we show that activation of the noncanonical NF-κB pathway regulates chromosome stability, DNA damage response and centrosome duplication in DLBCL. Analysis of 92 DLBCL samples revealed that activation of the noncanonical NF-κB pathway is associated with low levels of DNA damage and centrosome amplification. Inhibiting the noncanonical pathway in lymphoma cells uncovered baseline DNA damage and prevented doxorubicin-induced DNA damage repair. In addition, it triggered centrosome amplification and chromosome instability, indicated by anaphase bridges, multipolar spindles and chromosome missegregation. We determined that the noncanonical NF-κB pathway execute these functions through the regulation of GADD45α and REDD1 in a p53-independent manner, while it collaborates with p53 to regulate cyclin G2 expression. Furthermore, this pathway regulates GADD45α, REDD1 and cyclin G2 through direct binding of NF-κB sites to their promoter region. Overall, these results indicate that the noncanonical NF-κB pathway plays a central role in maintaining genome integrity in DLBCL. Our data suggests that inhibition of the noncanonical NF-kB pathway should be considered as an important component in DLBCL therapeutic approach. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 05/2015; 136(10). DOI:10.1002/ijc.29301 · 6.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives Categorization of response criteria for multiple myeloma (MM) is based on magnitude of change in serum and urine paraprotein values and normalization of free light chain ratio (rFLC). However, the association between improvements in these surrogate markers and patient outcomes is not validated in the phase I setting. Early measures of response would be beneficial for patients and agents to identify those likely to have prolonged disease-free intervals and to validate agent activity for rapid movement to subsequent development.Methods We identified 31 trials that met enrollment criteria of phase I, relapsed or refractory disease, and non-transplant study population. Clinical and demographic data collected included age, sex, race, ECOG performance status (PS) at entry, myeloma subtype and isotype, prior therapy, cytogenetics at study entry, date of progression, and date of expiration. Patients with t(4;14), del13, del17p, t(14;16), or t(14;20) were considered to have non-standard risk cytogenetics. Evaluation of the relationship between progression free survival (PFS) and change in plasma cell activity by the rFLC and magnitude of response in serum/urine paraprotein per IMWG criteria was performed. Landmark analyses occurred at cycle 2 and 4, 8, and 12 months. Progression free survival (PFS) at 12 months was the primary outcome of interest.Results Among 87 patients; 47 (54%) were female; 56 (64%) white, 29 (33%) black; 27 (31%) non-standard risk cytogenetics; ECOG PS 1 in 73 (84%); and median prior lines 5 (1-11). Eighty were evaluable for paraprotein changes, 71 for rFLC. Normalization of rFLC at 4 months conferred a PFS advantage (11.3 v 2.8 months, p = 0.038) (Table 1). Normalization of rFLC by 12 months was found to predict PFS (6.1 vs. 2.8 months, p = 0.015) and a longer OS (45 vs. 17.4 months, p = 0.002). Magnitude of response in paraprotein was found to predict and correlate linearly with PFS at all time landmarks (r2 = 0.769 to 0.952). Analysis of PFS by IMWG criteria and by quartiles of 50% changes were both linear (p < 0.001) (Figure 1).Normalization of rFLC, PFS, and OS.Figure 1Kaplan-Meier Analysis of PFS and Magnitude of Response by IMWG Criteria (A) and 50% Quartiles (B)Conclusion These findings suggest that normalization of the rFLC and magnitude of paraprotein response are viable surrogate disease endpoints in phase I clinical trials of novel agents and combinations. The use of current IMWG criteria in the phase I setting is valuable, but the addition of time of response and alterations of response boundaries should be further evaluated in the setting of improved treatments.Disclosures: Kaufman: Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Lonial: Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.
    Blood 03/2015; 122(6-21):1958. DOI:10.1002/cncr.29136 · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Malignant bowel obstruction affects an estimated 3% to 15% of patients with cancer, with a mean survival of <4 weeks reported in patients with inoperable malignant bowel obstruction. In the current study, the authors assessed predictors of survival and the influence of treatment modality in US patients with cancer who were hospitalized for malignant bowel obstruction. All the US cancer patients hospitalized with malignant bowel obstruction in 2006 and 2010 were included. Data were obtained from the Nationwide Inpatient Sample provided by the Agency for Healthcare Research and Quality. Malignant bowel obstruction diagnoses and treatment variables were identified using Clinical Classifications Software codes based on International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes. Univariate and multivariate analyses were performed with a logistic model, weighted chi-square test, and a generalized linear model. The authors identified 942,014 and 1,103,528 hospitalizations for malignant bowel obstruction in 2006 and 2010, respectively. Medical management, upper gastrointestinal obstruction, health insurance coverage, and obesity were found to be significantly associated with better hospital survival. Multivariate analysis also demonstrated significantly increased odds of death with male sex, advanced age, AJCC stage IV disease, multiple comorbid conditions (except acquired immunodeficiency syndrome), and weight loss. There were no significant differences with stratification based on the location and etiology of the obstruction (primary tumor vs metastatic). Malignant bowel obstruction is a common cause of death in hospitalized patients with advanced cancer in the United States. The odds of death are especially high in older patients and those with concurrent medical illnesses. Lack of insurance coverage, significant weight loss, and surgical management also appear to be associated with higher mortality in this population. Cancer 2015. © 2015 American Cancer Society. © 2015 American Cancer Society.
    Cancer 03/2015; DOI:10.1002/cncr.29297 · 5.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: ALK-EML4 translocation is an established driver aberration in non-small cell lung cancer (NSCLC), with reported predilection for cases with signet ring histology. We assessed the presence of anaplastic lymphoma kinase (ALK) gene rearrangements in signet ring cancers arising in the stomach and colon. Histologically confirmed cases of signet ring adenocarcinoma of the stomach or the colon were identified. The presence of the classic ALK and EML4 fusion gene was initially determined by fluorescence in-situ hybridization (FISH) technique. Immunohistochemistry (IHC) was performed using two previously validated antibodies, ALK1 clone (1:100; DAKO) and 5A4 (Novocastra, Leica Biosystems) along with positive controls of ALK-translocated lung cancer. We employed 42 cases of signet ring carcinoma diagnosed between 2001 and 2011; 25 gastric and 17 colon cancer. Median age 63.3 years; male/female 17/25; race, black 47.5%, white 47.5%, others, 5%; stage I, 21.4%; stage II, 31%; stage III, 26.2%; stage IV, 21.4%. One of 42 cases (2.3%) was positive for ALK translocation by FISH using the standard criteria of at least 15% positive cells for the break-apart signal (50-70 cells enumerated per case). Using a less restrictive cut-off of 10% positive cells, 7 cases (16%) were considered possibly positive. None of the 'possibly positive' cases was found to harbor ALK translocation by another molecular testing approach (IHC). IHC with two previously validated monoclonal antibodies showed 0 of 42 (0%) cases positive. ALK gene rearrangement is very rare in gastrointestinal cancers and enrichment strategy focusing on signet ring cell histology did not significantly improve the detection rate.
  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine the effects of doxorubicin drug eluting bead transarterial chemoembolization (DEB-TACE) therapies on health-related quality of life (HRQOL) in patients with unresectable hepatocellular carcinoma (HCC). Single-center, prospective study assessing HRQOL of consecutive patients with unresectable HCC who underwent DEB-TACE. Longitudinal assessment of HRQOL scores via Short Form-36 (SF-36) was performed. Baseline HRQOL scores were evaluated for significant change (p<0.05) pre-therapy, post-therapy and at 6- and 12-month follow-up. Analysis of OS from HCC diagnosis and OS from first DEB-TACE was performed. Paired t-tests were used to compare HRQOL domain scores. 118 patients (83 male; median age 60 years) were enrolled. Patients had lower baseline scores within all 8 HRQOL domains of the SF-36 compared to US age-adjusted healthy norms. No significant changes in all 8 domains were observed post-therapy, at 6- or 12-month follow-up compared to baseline (p>0.05). No significant differences in all 8 domains were observed between patients receiving ≥4 vs. ≤3 DEB-TACE (p>0.05). Both groups were similar for age at HCC diagnosis, gender, ethnicity, HCC etiology, Child-Pugh class and ECOG PS (p>0.05). Patients receiving staged DEB-TACE demonstrated significantly greater median OS from HCC diagnosis (≥4 vs. ≤3 DEB-TACE procedures, 31.9 vs. 23.7 months, p=0.04), and from first DEB-TACE (≥4 vs. ≤3 DEB-TACE, 29.1 vs. 20.2 months, p=0.03). DEB-TACE therapy for HCC demonstrated long-term preservation of HRQOL. In addition, staged DEB-TACE with 4 or more therapies does not significantly impact long-term HRQOL compared to patients who received 3 or fewer therapies. This article is protected by copyright. All rights reserved.
    Journal of Gastroenterology and Hepatology 02/2015; DOI:10.1111/jgh.12920 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Altered PI3K/mTOR pathway is implicated in lung cancer but mTOR inhibitors have failed to demonstrate efficacy in advanced lung cancer. We studied the pharmacodynamic effects of everolimus in resectable non-small cell lung cancer (NSCLC) to inform further development of these agents in lung cancer. Experimental Design: We enrolled 33 patients and obtained baseline tumor biopsy and FDG-PET/CT imaging followed by everolimus treatment (5 or 10 mg daily, up to 28 days), or without intervening treatment for controls. Target modulation by everolimus was quantified in vivo and ex vivo by comparing metabolic activity on paired PET scans and expression of active phosphorylated forms of mTOR, Akt, S6, eIF4e, p70S6K, 4EBP1 and total Bim protein between pretreatment and post treatment tissue samples. Results: There were 23 patients on the treatment arm and 10 controls; median age 64 years; 22 (67%) were adenocarcinomas. There was a dose-dependent reduction in metabolic activity (SUVmax: 29.0%, -21%, -24%; p=0.014), tumor size (10.1%, 5.8%, -11.6%; p=0.047), and modulation of S6 (-36.1, -13.7, -77.0; p=0.071) and pS6 (-41.25, -61.57, -47.21; p=0.063) in patients treated in the control, 5mg and 10mg cohorts respectively. Targeted DNA sequencing in all patients along with exome and whole transcriptome RNA-seq in an index patient with hypersensitive tumor was employed to further elucidate the mechanism of everolimus activity. Conclusion: This "window-of-opportunity" study demonstrated measurable, dose-dependent, biologic, metabolic and antitumor activity of everolimus in early stage NSCLC. Copyright © 2015, American Association for Cancer Research.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with lung cancer are at high risk of developing venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism. We sought to characterize the clinical factors associated with development of VTE and the impact of VTE on outcomes for hospitalized lung cancer patients. We analyzed data captured in the Nationwide Inpatient Sample (NIS) database of the Agency of Healthcare Research and Quality (AHRQ). The study included all lung cancer patients hospitalized between 2006 and 2010 who had VTE captured as one of the top three discharge diagnoses. Demographics and outcomes of this population were compared to those of inpatient lung cancer patients without a VTE diagnosis. All analyses were performed using SAS version 9.3. Out of 570,304 lung cancer hospitalizations, 20,672 had a clinically relevant diagnosis of VTE, accounting for 3.6% of all events. The median age of lung cancer patients with VTE was 68 years; 48% were females, 79% were Caucasians, and 43% had metastatic disease. When compared to a lung cancer cohort without VTE (n=502,153), patients with VTE had significantly longer length of stay (LOS) (7.15 days vs. 6.05 days, OR 1.12), higher inpatient mortality (10.03% vs. 8.69%, OR 1.06), higher total hospital charges ($43,800 vs. $37,800, OR 1.07), and greater likelihood of moderate to severe disability upon discharge (55% vs. 49%, OR 1.23). VTE in hospitalized lung cancer patients is associated with longer LOS, higher inpatient mortality rates, increased cost and greater disability upon discharge compared to other inpatient lung cancer patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Lung Cancer 02/2015; DOI:10.1016/j.lungcan.2015.01.022 · 3.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate nuclear hypoxia-inducible factor 1α (HIF-1α) expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) after pancreatic adenocarcinoma resection. Tissue specimens were collected from 98 patients with pancreatic adenocarcinoma who underwent resection without neoadjuvant therapy between January 2000 and December 2011. Local recurrence was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. Distant recurrence was defined as radiographically or pathologically confirmed recurrent disease in other sites. Immunohistochemical staining was performed and scored by an independent pathologist blinded to patient outcomes. High HIF-1α overall expression score was defined as high percentage and intensity staining and thus score >1.33. Univariate analysis was performed for HIF-1α score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR. Median follow-up time for all patients was 16.3 months. Eight patients (8%) demonstrated isolated LR, 26 patients (26.5%) had isolated DR, and 13 patients had both LR and DR. Fifty-three patients (54%) had high HIF-1α expression, and 45 patients (46%) had low HIF-1α expression. High HIF-1α expression was significantly associated with DR (P=.03), and low HIF-1α expression was significantly associated with isolated LR (P=.03). On multivariate logistic regression analysis, high HIF-1α was the only significant predictor of DR (odds ratio 2.46 [95% confidence interval 1.06-5.72]; P=.03). In patients with a known recurrence, an HIF-1α score ≥2.5 demonstrated a specificity of 100% for DR. High HIF-1α expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. Expression of HIF-1α may have utility in determining candidates for adjuvant local radiation therapy and systemic chemotherapy. Copyright © 2015 Elsevier Inc. All rights reserved.
    International Journal of Radiation OncologyBiologyPhysics 01/2015; DOI:10.1016/j.ijrobp.2014.11.004 · 4.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE. The purpose of this study was to investigate the overall survival, efficacy, and safety of small (100-300 µm) versus large (300-500 and 500-700 µm) doxorubicin drug-eluting beads transarterial chemoembolization (DEB TACE) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS. Ninety-four consecutive patients with unresectable HCC who underwent 269 DEB TACE procedures in 48 months were studied. DEB TACE procedures were performed using different DEB sizes: 100-300 µm (Group A, 59 patients) and with mixed 300-500 and 500-700 µm DEB (Group B, 35 patients). Survival rates were compared between the groups. RESULTS. The overall median survival in groups A and B were 15.1 and 11.1 months, respectively (p = 0.005). Both groups were similar in demographics, tumor burden, and differential staging (p > 0.5). Substratification of overall survival according to Child-Pugh class and Okuda, Cancer of the Liver Italian Program (CLIP), and Barcelona Clinic Liver Cancer (BCLC) staging were significantly higher in group A than in group B (p < 0.05). Common terminology criteria for adverse events (CTCAE) grade III adverse events and 30-day mortality were significantly lower in group A than in group B (6.8% vs 20%; p = 0.04, and 0% vs 14.3%; p = 0.001, respectively). The particle size, Child-Pugh class, and serum α-fetoprotein level were significant prognostic indicators of survival on multivariate analysis. CONCLUSION. TACE with 100-300 µm sized DEB is associated with significantly higher survival rate and lower complications than TACE with 300-500 and 500-700 µm sized DEB.
    American Journal of Roentgenology 12/2014; 203(6):W706-14. DOI:10.2214/AJR.13.12308 · 2.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Poly (ADP) ribose polymerase (PARP) plays a key role in DNA repair and is highly expressed in small cell lung cancer (SCLC). We investigated the therapeutic impact of PARP inhibition in SCLC. In vitro cytotoxicity of veliparib, cisplatin, carboplatin, and etoposide singly and combined was determined by MTS in 9 SCLC cell lines (H69, H128, H146, H526, H187, H209, DMS53, DMS153, and DMS114). Subcutaneous xenografts in athymic nu/nu mice of H146 and H128 cells with relatively high and low platinum sensitivity, respectively, were employed for in vivo testing. Mechanisms of differential sensitivity of SCLC cell lines to PARP inhibition were investigated by comparing protein and gene expression profiles of the platinum sensitive and the less sensitive cell lines. Veliparib showed limited single-agent cytotoxicity but selectively potentiated (≥50% reduction in IC50) cisplatin, carboplatin, and etoposide in vitro in five of nine SCLC cell lines. Veliparib with cisplatin or etoposide or with both cisplatin and etoposide showed greater delay in tumor growth than chemotherapy alone in H146 but not H128 xenografts. The potentiating effect of veliparib was associated with in vitro cell line sensitivity to cisplatin (CC = 0.672; P = 0.048) and DNA-PKcs protein modulation. Gene expression profiling identified differential expression of a 5-gene panel (GLS, UBEC2, HACL1, MSI2, and LOC100129585) in cell lines with relatively greater sensitivity to platinum and veliparib combination. Veliparib potentiates standard cytotoxic agents against SCLC in a cell-specific manner. This potentiation correlates with platinum sensitivity, DNA-PKcs expression and a 5-gene expression profile.
    Cancer Medicine 12/2014; 3(6). DOI:10.1002/cam4.317
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Atypical carcinoid (AC) of the lung is a rare form of thoracic malignancy. The limited knowledge of its biology and outcome stems largely from small, single institution experiences. We analyzed the Surveillance, Epidemiology, and End Results database (SEER) to better understand the clinical characteristics of this disease.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2014; DOI:10.1097/JTO.0000000000000419 · 4.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study is to examine the reproducibility of anti-1-amino-3-[(18)F]fluorocyclobutane-1-carboxylic acid (anti-3-[(18)F]FACBC) quantitative measurements in key background structures and untreated malignant lesions.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 10/2014; DOI:10.1007/s11307-014-0797-1 · 2.47 Impact Factor
  • Zhengjia Chen, Xinjia Chen
    [Show abstract] [Hide abstract]
    ABSTRACT: In this article, we propose rigorous sample size methods for estimating the means of random variables, which require no information of the underlying distributions except that the random variables are known to be bounded in a certain interval. Our sample size methods can be applied without assuming that the samples are identical and independent. Moreover, our sample size methods involve no approximation. We demonstrate that the sample complexity can be significantly reduced by using a mixed error criterion. We derive explicit sample size formulae to ensure the statistical accuracy of estimation.
    Journal of Statistical Planning and Inference 09/2014; DOI:10.1016/j.jspi.2014.08.007 · 0.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND To understand the mechanism of frequent and early lymph node metastasis in high-risk human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC), this study investigated whether β-catenin is regulated by the HPV oncoprotein and contributes to OPSCC metastasis.METHODS Expression levels of p16, β-catenin, and epidermal growth factor receptor (EGFR) were examined in OPSCC samples (n = 208) by immunohistochemistry. The expression and subcellular localization of β-catenin and EGFR activation were also studied in HPV-positive and HPV-negative head and neck squamous cell carcinoma cell lines with western blot analysis. HPV16 E6 small interfering RNA was used to elucidate the effect of the HPV oncoprotein on β-catenin translocation. The involvement of EGFR in β-catenin translocation was confirmed by treatment with erlotinib. Moreover, the invasive capacity was evaluated after HPV16 E6/E7 repression.RESULTSThe results showed that the membrane weighted index of β-catenin was inversely correlated with p16 positivity (P < .001) and lymph node metastasis (P = .026), whereas nuclear staining of β-catenin was associated with p16-positive OPSCC (P < .001). A low level of membrane β-catenin expression was significantly associated with disease-free and overall survival (P < .0001 in both cases). Furthermore, the membrane weighted index of EGFR was inversely correlated with p16 positivity (P < .001) and positively correlated with membrane β-catenin (P < .001). The in vitro study showed that HPV16 E6 repression led to reductions of phospho-EGFR and nuclear β-catenin, which were also observed after erlotinib treatment, and inhibition of invasion.CONCLUSIONS The findings suggest that HPV16 E6 mediates the translocation of β-catenin to the nucleus, which may be regulated by activated EGFR. Cancer 2014. © 2014 American Cancer Society.
    Cancer 09/2014; 121(2). DOI:10.1002/cncr.29039 · 5.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Platinum compounds remain the most widely utilized systemic agents in combination with radiation for treating SCCHN in the concurrent setting. Despite recent interest in using taxanes in this setting, there is a lack of randomized clinical trials to support this approach. We conducted a systematic review of published clinical trials of taxane-containing versus standard non-taxane-based regimens used in definitive treatment of SCCHN. Methods Trials published between 1994 and 2012 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). All prospective studies were independently identified by two authors for inclusion. Studies were excluded if induction therapy was part of the regimen or if targeted agents were used. Trials using cisplatin- or carboplatin-based regimens and paclitaxel or docetaxel were included. Demographic data, treatment response, locoregional failure free rate (LFFR), progression-free and overall survival (PFS, OS) and toxicities were extracted and analyzed using Comprehensive Meta Analysis software (Version 2.0). Outcome data were pooled and reported as weighted response rate (RR), PFS and OS. Results A total of 790 studies were retrieved and 42 studies with 3120 patients were included: 804 patients were treated with taxanes (80% males, median age 57 years) and 2316 with non-taxanes (86% males, median age 56 years). Progression free survival was not different between the two groups. Weighted median survival was compared from those studies that reported these data; taxanes = 36.7 months (N = 197) versus non-taxanes = 25 months (N = 503), P < 0.001. Toxicity (grade 3 and above) was higher in non-taxane containing trials. Conclusions The improved overall survival observed supports the choice of taxane-based regimens in the concurrent setting but may also reflect the predominance of single arm multi-agent phase II trials in the taxane arm. Our findings urge the need for better standardization of taxane-based regimens.
    Oral Oncology 09/2014; DOI:10.1016/j.oraloncology.2014.06.014 · 3.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the diagnostic accuracy of ultrasound histogram features in the quantitative assessment of radiation-induced parotid gland injury and to identify potential imaging biomarkers for radiation-induced xerostomia (dry mouth)-the most common and debilitating side effect after head-and-neck radiotherapy (RT).
    Academic Radiology 08/2014; 21(10):1304–1313. DOI:10.1016/j.acra.2014.05.017 · 2.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND Platinum-based therapy combined with cetuximab is standard first-line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN.METHODS Patients received carboplatin (area under the curve = 2 mg/ml/min; 3 weeks on, 1 week off), cetuximab (with a loading dose of 400 mg/m2 and then 250 mg/m2 weekly), and dose-escalating everolimus (2.5, 5.0, 7.5, and 10 mg/day) with a 3+3 design. After 4 cycles, patients without progression continued cetuximab/everolimus until progression or intolerable toxicity. Patients (age ≥ 18 years) had previously untreated, unresectable RMSCCHN not amenable to radiotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2.RESULTSThe study enrolled 20 patients (male/female = 18/2) with RMSCCHN; the median age was 65 years (44-75 years). Thirteen patients received everolimus (male/female = 92%). Two of 6 patients receiving 2.5 mg/day experienced dose-limiting toxicity (DLT) with grade 3 hyponatremia and nausea. In 7 patients receiving de-escalated everolimus (2.5 mg every other day), grade 3 hyperglycemia produced DLT in 1 of 6 patients. The objective response rate (RR) was 61.5% (all partial responses). Progression-free survival (PFS) was 8.15 months. The pharmacokinetics of everolimus was described with a 2-compartment mixed-effects model. There was a significant correlation between tumor p-p44/42 staining and response (P = .044) and a marginally significant correlation between phosphorylated mammalian target of rapamycin and overall survival.CONCLUSIONS The maximum tolerated dose of everolimus with cetuximab and carboplatin was 2.5 mg every other day. The regimen was associated with an encouraging RR and PFS, and this suggested possible clinical efficacy in a select group of patients with squamous cell carcinoma of the head and neck. Cancer 2014. © 2014 American Cancer Society.
    Cancer 08/2014; 120(24). DOI:10.1002/cncr.28965 · 5.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Photodynamic therapy (PDT) is a highly specific anti-cancer treatment modality for various cancers, particularly for recurrent cancers which no longer respond to conventional anti-cancer therapies. PDT has been under development for decades, but light-associated toxicity limits its clinical applications. To reduce the toxicity of PDT, we recently developed a targeted nanoparticle (NP) platform that combines a second-generation PDT drug, Pc 4, with a cancer targeting ligand, and iron oxide (IO) NPs. Carboxyl functionalized IO NPs were first conjugated with a fibronectin-mimetic peptide (Fmp) which binds integrin 1. Then the PDT drug Pc 4 was successfully encapsulated into the ligand-conjugated IO NPs to generate Fmp-IO-Pc 4. Our study indicated that both non-targeted IO-Pc 4 and targeted Fmp-IO-Pc 4 NPs accumulated in xenograft tumors with higher concentrations than non-formulated Pc 4. As expected, both IO-Pc 4 and Fmp-IO-Pc 4 reduced the size of HNSCC xenograft tumors more effectively than free Pc 4. Using a 10-fold lower dose of Pc 4 than that reported in the literature, the targeted Fmp-IO-Pc 4 NPs demonstrated significantly greater inhibition of tumor growth than non-targeted IO-Pc 4 NPs. These results suggest that the delivery of a PDT agent Pc 4 by IO NPs can enhance treatment efficacy and reduce PDT drug dose. The targeted IO-Pc 4 NPs have great potential to serve as both a magnetic resonance imaging (MRI) agent and PDT drug in the clinic.
    ACS Nano 06/2014; DOI:10.1021/nn501652j · 12.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ampullary (AMP-A) and duodenal adenocarcinomas (DA) are rare tumors. The literature regarding treatment and outcome is very limited. The objective of this project is to compare the outcomes of AMP-A and DA. The records for AMP-A and DA patients between July 1995 and July 2012 at Emory University were reviewed for demographics, pathology, treatment, and survival. Survival rates were estimated by Kaplan-Meier method and compared with log-rank test. A Cox proportional hazard model was fitted to estimate the adjusted effect of AMP-A versus DA on overall survival (OS). Ninety-five AMP-A and 66 DA patients were identified. No significant difference between patients with DA and AMP-A was observed for age, gender, or grade. DA presented with larger tumors and higher stages. Treatment included surgery, surgery followed by adjuvant therapy or chemotherapy alone. No OS difference was observed when controlled for stage. AMP-A was sub-classified into intestinal (IAMP), pancreaticobiliary (PBAMP), and unspecified types. IAMP tended to present at a higher grade (P = 0.045) than PBAMP. No OS difference between the IAMP and PBAMP was observed. After accounting for stage, OS was not significantly different for AMP-A and DA patients. There was no OS difference comparing PBAMP with IAMP. J. Surg. Oncol. © 2013 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 05/2014; 109(6). DOI:10.1002/jso.23529 · 2.84 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-566-S-567. DOI:10.1016/S0016-5085(14)62051-5 · 13.93 Impact Factor

Publication Stats

1k Citations
553.25 Total Impact Points

Institutions

  • 2010–2015
    • Emory University
      • • Winship Cancer Institute
      • • Department of Biostatistics and Bioinformatics
      Atlanta, Georgia, United States
  • 2014
    • Georgia Department of Public Health
      Marietta, Georgia, United States
  • 2011
    • Moffitt Cancer Center
      • Department of Cancer Epidemiology
      Tampa, Florida, United States
  • 2005–2010
    • Children's Oncology Group
      Monrovia, California, United States
  • 2007–2009
    • University of Southern California
      • • Keck School of Medicine
      • • Department of Preventive Medicine
      Los Angeles, California, United States