[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.
AJR. American journal of roentgenology. 12/2014; 203(6):W706-14.
[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; · 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; · 2.47 Impact Factor
[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; · 0.71 Impact Factor
[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).
[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.
[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.
[Show abstract][Hide abstract] ABSTRACT: The EGFR monoclonal antibody cetuximab is the only approved targeted agent for treating head and neck squamous cell carcinoma (HNSCC). Yet resistance to cetuximab has hindered its activity in this disease. Intrinsic or compensatory HER3 signaling may contribute to cetuximab resistance. To investigate the therapeutic benefit of combining MM-121/SAR256212, an anti-HER3 monoclonal antibody, with cetuximab in HNSCC, we initially screened twelve HNSCC cell lines for total and phosphorylated levels of the four HER receptors. We also investigated the combination of MM-121 with cetuximab in preclinical models of HNSCC. Our results revealed that HER3 is widely expressed and activated in HNSCC cell lines. MM-121 strongly inhibited phosphorylation of HER3 and AKT. When combined with cetuximab, MM-121 exerted a more potent anti-tumor activity through simultaneously inhibiting the activation of HER3 and EGFR and consequently the downstream PI3K/AKT and ERK pathways in vitro. Both high and low doses of MM-121 in combination with cetuximab significantly suppressed tumor growth in xenograft models and inhibited activations of HER3, EGFR, AKT and ERK in vivo. Our current work is the first report on this new combination in HNSCC and supports the concept that HER3 inhibition may play an important role in future therapy of HNSCC. Our results open the door for further mechanistic studies to better understand the role of HER3 in resistance to EGFR inhibitors in HNSCC.
Molecular Cancer Therapeutics 04/2014; · 5.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer has a distinct clinicopathologic presentation in younger patients. The aim of this paper was to evaluate the outcome of younger (age below 50 y) and older patients with stage IV (advanced) colorectal cancer in the modern era of combination chemotherapy.
Cases of metastatic colorectal cancer reported in Surveillance, Epidemiology, and End Results registry (1973 to 2008) were reviewed. Demographics, tumor characteristics, and overall and cancer-specific survivals in patients below 50 and above 50 years of age were compared by Cox proportional hazard analyses. Joinpoint regression analysis was used to evaluate secular trends in 2-year survival.
Younger patients had a greater proportion of negative clinicopathologic features (male sex, African American ethnicity, and signet ring or mucinous histology). In multivariate analysis, older age, male sex, African American ethnicity, right-sided tumors, and signet ring histology were associated with higher mortality risk. Younger patients had improved survival (hazard ratio 0.72; 95% confidence interval: 0.70-0.75) compared with older patients, whereas all patients experienced increased 2-year survival by joinpoint analysis beginning in 1999-2000.
The results confirm decreased mortality from advanced colorectal cancer in the era of modern combination chemotherapy in younger and older patients. Younger age, non-right-sided tumors, and absence of signet ring histology significantly associate with better survival.
American journal of clinical oncology 03/2014; · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human papillomavirus (HPV) is the etiologic risk factor for cervical cancer. Some studies have suggested an association with a subset of lung tumors, but the etiologic link has not been firmly established. We performed an international pooled analysis of cross-sectional studies (27 datasets, n = 3,249 patients) to evaluate HPV DNA prevalence in lung cancer and to investigate viral presence according to clinical and demographic characteristics. HPV16/18 were the most commonly detected, but with substantial variation in viral prevalence between geographic regions. The highest prevalence of HPV16/18 was observed in South & Central America, followed by Asia, North America and Europe (Adjusted prevalence rates = 22%, 5%, 4% and 3% respectively). Higher HPV16 prevalence was noted in each geographic region compared to HPV18, except in North America. HPV16/18-positive lung cancer was less likely observed among White race (Adjusted OR = 0.33, 95% CI = 0.12-0.90), while no associations were observed with gender, smoking history, age, histology or stage. Comparisons between tumor and normal lung tissue show that HPV was more likely to be present in lung cancer rather than normal lung tissues (OR = 3.86, 95% CI = 2.87-5.19). Among a subset of patients with HPV16-positive tumors, integration was primarily among female patients (93%, 13/14), while the physical status in male cases (N = 14) was inconsistent. Our findings confirm that HPV DNA is present in a small fraction of lung tumors, with large geographic variations. Further comprehensive analysis is needed to assess whether this association reflects a causal relationship.
[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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: The primary purposes of Phase I cancer clinical trials are to determine the maximum tolerated dose (MTD) and the treatment schedule of a new drug. Phase I trials usually involve a small number of patients so that fully utilizing all toxicity information including time to event toxicity data is key to improving the trial efficiency and the accuracy of MTD estimation. Chen et al.  proposed a novel normalized equivalent toxicity score (NETS) system to fully utilize multiple toxicities per patient instead of a binary indicator of dose limiting toxicity (DLT). Cheung and Chappell  developed the time to toxicity event (TITE) approach to incorporate time to toxicity event data. Escalation with Overdose Control (EWOC) is an adaptive Bayesian Phase I design which can allow rapid dose escalation while controlling the probability of overdosing patients . In this manuscript, we use EWOC as a framework and integrate it with the NETS system and the TITE approach to develop an advanced Phase I design entitled EWOC-NETS-TITE. We have conducted simulation studies to compare its operating characteristics using selected derived versions of EWOC because EWOC itself has already been extensively compared with common Phase I designs . Simulation results demonstrate that EWOC-NETS-TITE can substantially improve the trial efficiency and accuracy of MTD determination as well as allow patients to be entered in a staggered fashion to significantly shorten trial duration. Moreover, user-friendly software for EWOC-NETS-TITE is under development.
[Show abstract][Hide abstract] ABSTRACT: Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies.
We conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease.
The annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/beta-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/beta-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or beta-catenin (functional read out of Wnt/beta-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from beta-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/beta-catenin classifier had a greater risk of lung and brain, but not bone metastases.
These data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways.
BMC Cancer 11/2013; 13(1):537. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, and irinotecan) as compared with gemcitabine in pancreatic cancer (PC) has superior activity and increased toxicity. The bolus 5-FU contributes to the toxicity. We hypothesized that the elimination of bolus 5-FU and use of hematopoietic growth factor will improve the safety profile without compromising the activity of FOLFIRINOX.
Sixty patients with PC treated with modified FOLFIRINOX (no bolus 5-FU) were reviewed. Patients were divided into metastatic or nonmetastatic (locally advanced or borderline resectable) disease. Toxicity, response rate, progression-free survival, and overall survival were evaluated.
Nonmetastatic and metastatic disease were present in 24 (40%) and 36 (60%) patients, respectively. The incidence of grade 4 neutropenia, grade 3/4 diarrhea, and fatigue were 3%, 13%, and 13%, respectively. Response rate was 30%. The median progression-free survival for nonmetastatic disease was 13.7 months (95% confidence interval [CI], 9.6-24.6 months), and that for metastatic disease was 8.5 months (95% CI, 3.7-11.0 months), respectively. The median overall survival for nonmetastatic disease was 17.8 months (95% CI, 9.9 months to not estimable), and that for metastatic disease was and 9.0 months (95% CI, 7.1 months to not estimable), respectively.
Modified FOLFIRINOX has an improved safety profile with maintained efficacy in metastatic PC. Modified FOLFIRINOX has promising activity in nonmetastatic disease.