bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in Tumor Density in Patients with Advanced Hepatocellular Carcinoma Treated with Sunitinib
Authors: Faivre Sandrine , Zappa Magaly , Vilgrain Valérie , Boucher Eveline , Douillard Jean-Yves , Lim Ho Y. , Kim Jun S. , Im Seock-Ah , Kang Yoon-Koo , Bouattour Mohamed , Dokmak Safi , Dreyer Chantal , Sablin Marie-Paule , Serrate Camille , Cheng Ann-Lii , Lanzalone Silvana , Lin Xun , Lechuga Maria J. , Raymond Eric 
Published: April 2011

Abstract
Purpose: Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the efficacy of targeted therapies. In hepatocellular carcinoma (HCC) studies with sunitinib, RECIST-defined response rates are low, although hypodensity on computed tomography (CT) scans occurs more frequently. This exploratory analysis investigated tumor density as a surrogate endpoint of sunitinib activity in a phase II HCC study.
Experimental Design: Patients received sunitinib 50 mg/d (4 weeks on/2 weeks off). Tumor size and density were assessed on CT scans by using RECIST and Choi criteria, the latter of which classify a partial response as a 15% or more reduction in tumor density or a 10% or more reduction in tumor size. The overall percentage volume of tumor necrosis was calculated with volumetric reconstruction. Tumor perfusion parameters were assessed by using perfusion CT scans with specific acquisition.
Results: Among the 26 evaluable patients, 1 achieved a partial response and 22 had tumor stabilization by RECIST. In analysis of tumor density, 17 of 26 patients (65.4%) were responders by Choi criteria. Volumetric assessment showed major tumor necrosis (≥30% of tumor volume) in 10 of 21 patients (47.6%). Among four patients evaluated, tumor blood flow was reduced by 58.8% and blood volume by 68.4% after 4 weeks of treatment. The median time to progression (TTP) was 6.4 months. Patients with responses by Choi criteria had a significantly longer TTP (7.5 months) compared with nonresponders (4.8 months; HR = 0.33, two-sided P = 0.0182).
Conclusions: Tumor density assessment suggested that radiologic endpoints in addition to RECIST may be considered to capture sunitinib activity in HCC. Clin Cancer Res; 17(13); 4504–12. ©2011 AACR.
Dopamine Blocks Stress-Mediated Ovarian Carcinoma Growth
Authors: Moreno-Smith Myrthala , Lu Chunhua , Shahzad Mian M.K. , Pena Guillermo N. Armaiz , Allen Julie K. , Stone Rebecca L. , Mangala Lingegowda S. , Han Hee Dong , Kim Hye Sun , Farley Donna , Berestein Gabriel Lopez , Cole Steve W. , Lutgendorf Susan K. , Sood Anil K. 
Published: April 2011

Abstract
Purpose: Increased adrenergic activity in response to chronic stress is known to promote tumor growth by stimulating the tumor microenvironment. The focus of the current study was to determine whether dopamine, an inhibitory catecholamine, could block the effects of chronic stress on tumor growth.
Experimental Design: Expression of dopamine receptors (DR1–DR5) was analyzed by reverse transcriptase-PCR and by Western blotting. In vitro effects of dopamine on cell viability, apoptosis, and migration were examined. For in vivo therapy, murine and human DR2-siRNAs were incorporated into chitosan nanoparticles (CH-NP).
Results: In this model of chronic stress, tumoral norepinephrine levels remained elevated whereas dopamine levels were significantly decreased compared with nonstressed animals. Daily restraint stress resulted in significantly increased tumor growth in both immunodeficient (SKOV3ip1 and HeyA8) and immunocompetent (ID8) ovarian cancer models. This increase was completely blocked with daily dopamine treatment. Dopamine treatment also blocked the stress-induced increase in angiogenesis. Endothelial and ovarian cancer cells expressed all dopamine receptors except for the lack of DR3 expression in ovarian cancer cells. DR2 was responsible for the inhibitory effects of dopamine on tumor growth and microvessel density as well as the stimulatory effect on apoptosis, as the DR2 antagonist eticlopride reversed these effects. Dopamine significantly inhibited cell viability and stimulated apoptosis in vitro. Moreover, dopamine reduced cyclic AMP levels and inhibited norepinephrine and vascular permeability factor/VEGF-induced Src kinase activation.
Conclusions: Dopamine depletion under chronic stress conditions creates a permissive microenvironment for tumor growth that can be reversed by dopamine replacement. Clin Cancer Res; 17(11); 3649–59. ©2011 AACR.
Prospective Gene Signature Study Using microRNA to Identify the Tissue of Origin in Patients with Carcinoma of Unknown Primary
Authors: Varadhachary Gauri R. , Spector Yael , Abbruzzese James L. , Rosenwald Shai , Wang Huamin , Aharonov Ranit , Carlson Heather R. , Cohen Dalia , Karanth Siddharth , Macinskas Joanna , Lenzi Renato , Chajut Ayelet , Edmonston Tina B. , Raber Martin N. 
Published: April 2011

Abstract
Purpose: Accurate identification of tissue of origin (ToO) for patients with carcinoma of unknown primary (CUP) may help customize therapy to the putative primary and thereby improve the clinical outcome. We prospectively studied the performance of a microRNA-based assay to identify the ToO in CUP patients.
Experimental Design: Formalin-fixed paraffin-embedded (FFPE) metastatic tissue from 104 patients was reviewed and 87 of these contained sufficient tumor for testing. The assay quantitates 48 microRNAs and assigns one of 25 tumor diagnoses by using a biologically motivated binary decision tree and a K-nearest neighbors (KNN). The assay predictions were compared with clinicopathologic features and, where suitable, to therapeutic response.
Results: Seventy-four of the 87 cases were processed successfully. The assay result was consistent or compatible with the clinicopathologic features in 84% of cases processed successfully (71% of all samples attempted). In 65 patients, pathology and immunohistochemistry (IHC) suggested a diagnosis or (more often) a differential diagnosis. Out of those, the assay was consistent or compatible with the clinicopathologic presentation in 55 (85%) cases. Of the 9 patients with noncontributory IHC, the assay provided a ToO prediction that was compatible with the clinical presentation in 7 cases.
Conclusions: In this prospective study, the microRNA diagnosis was compatible with the clinicopathologic picture in the majority of cases. Comparative effectiveness research trials evaluating the added benefit of molecular profiling in appropriate CUP subsets are warranted. MicroRNA profiling may be particularly helpful in patients in whom the IHC profile of the metastasis is nondiagnostic or leaves a large differential diagnosis. Clin Cancer Res; 17(12); 4063–70. ©2011 AACR.
A Low-Toxicity IL-2–Based Immunocytokine Retains Antitumor Activity Despite Its High Degree of IL-2 Receptor Selectivity
Authors: Gillies Stephen D. , Lan Yan , Hettmann Thore , Brunkhorst Beatrice , Sun Yaping , Mueller Stefan O. , Lo Kin-Ming 
Published: April 2011

AbstractPurpose: The goal of the study was to engineer a form of interleukin 2 (IL-2) that, when delivered as a tumor-specific antibody fusion protein, retains the ability to stimulate an antitumor immune response via interaction with the high-affinity IL-2 receptor but has lower toxicity because of the reduced activation of the intermediate-affinity IL-2 receptor.Experimental Design: We investigated changes in the proposed toxin motif of IL-2 by introducing a D20T mutation that has little effect on the activity of free IL-2. We expressed this IL-2 variant as a fusion protein with an antibody (NHS76) that targets the necrotic core of tumors and characterized this molecule (NHS-IL2LT) in vitro and in vivo.Results: NHS-IL2LT was shown to have near normal biological activity in vitro by using T-cell lines expressing the high-affinity IL-2 receptor, but little or no activity by using cell lines expressing only the intermediate IL-2 receptor. Relative to the control antibody fusion protein containing wild-type IL-2, NHS-IL2LT retained antitumor activity against established neuroblastoma and non–small cell lung cancer metastases in syngeneic mouse tumor models but was much better tolerated in immune-competent mice and in cynomolgus monkeys.Conclusions: The qualities of low toxicity and single-agent efficacy shown suggest that NHS-IL2LT is a good candidate for therapeutic approaches combining standard cytotoxic and immune therapies. In fact, this molecule (also known as Selectikine or EMD 521873) is currently in phase I clinical trial. Clin Cancer Res; 17(11); 3673–85. ©2011 AACR.
Baseline Circulating Tumor Cell Counts Significantly Enhance a Prognostic Score for Patients Participating in Phase I Oncology Trials
Authors: Olmos David , Baird Richard D. , Yap Timothy A. , Massard Christophe , Pope Lorna , Sandhu Shahneen K. , Attard Gerhardt , Dukes Juliet , Papadatos-Pastos Dionysis , Grainger Philippa , Kaye Stan B. , de Bono Johann S. 
Published: April 2011

Abstract
Background: High circulating tumor cell (CTC) counts are associated with poor prognosis in several cancers. Enrollment of patients on phase I oncology trials requires a careful assessment of the potential risks and benefits. Many patients enrolled on such trials using established eligibility criteria have a short life expectancy and are less likely to benefit from trial participation. We hypothesized that the incorporation of CTC counts might improve patient selection for phase I trials.
Methods: This retrospective analysis evaluated patients who had baseline CTCs enumerated prior to their starting on a phase I trial. CTCs were enumerated using the CellSearch System.
Results: Between January 2006 and December 2009 a total of 128 patients enrolled in phase I trials had CTC counts evaluated. Higher CTC counts as a continuous variable independently correlated with risk of death in this patient population (P = 0.006). A multivariate point-based risk model was generated using CTCs as a dichotomous variable (≥3 or &lt;3), and incorporated other established prognostic factors, including albumin &lt;35 g/L, lactate dehydrogenase greater than upper limit of normal, and &gt;2 metastatic sites. Comparison of receiver operating characteristic curves demonstrated that the addition of baseline CTC counts improved the performance of the prospectively validated Royal Marsden Hospital phase I prognostic score, which now identifies three risk groups (P &lt; 0.0001): good prognosis [score 0–1, median overall survival (OS) 63.7 weeks], intermediate prognosis (score 2–3, median OS 37.3 weeks), and poor prognosis (score 4, median OS 13.4 weeks).
Conclusion: CTC enumeration improved the performance of a validated prognostic score to help select patients for phase I oncology trials. Clin Cancer Res; 17(15); 5188–96. ©2011 AACR.
Detection of Tumor DNA at the Margins of Colorectal Cancer Liver Metastasis
Authors: Holdhoff Matthias , Schmidt Kerstin , Diehl Frank , Aggrawal Nishant , Angenendt Philipp , Romans Katharine , Edelstein Daniel L. , Torbenson Michael , Kinzler Kenneth W. , Vogelstein Bert , Choti Michael A. , Diaz Luis A. 
Published: April 2011

Abstract
Purpose: Defining an adequate resection margin of colorectal cancer liver metastases is essential for optimizing surgical technique. We have attempted to evaluate the resection margin through a combination of histopathologic and genetic analyses.
Experimental Design: We evaluated 88 samples of tumor margins from 12 patients with metastatic colon cancer who each underwent partial hepatectomy of one to six liver metastases. Punch biopsies of surrounding liver tissue were obtained at 4, 8, 12, and 16 mm from the tumor border. DNA from these biopsies was analyzed by a sensitive PCR-based technique, called BEAMing, for mutations of KRAS, PIK3CA, APC, or TP53 identified in the corresponding tumor.
Results: Mutations were identified in each patient's resected tumor and used to analyze the 88 samples circumscribing the tumor-normal border. Tumor-specific mutant DNA was detectable in surrounding liver tissue in 5 of these 88 samples, all within 4 mm of the tumor border. Biopsies that were 8, 12, and 16 mm from the macroscopic visible margin were devoid of detectable mutant tumor DNA and of microscopically visible cancer cells. Tumors with a significant radiologic response to chemotherapy were not associated with any increase in mutant tumor DNA in beyond 4 mm of the main tumor.
Conclusions: Mutant tumor-specific DNA can be detected beyond the visible tumor margin, but never beyond 4 mm, even in patients whose tumors were larger prior to chemotherapy. These data provide a rational basis for determining the extent of surgical excision required in patients undergoing resection of liver metastases. Clin Cancer Res; 17(11); 3551–7. ©2011 AACR.
Effectiveness of Tyrosine Kinase Inhibitors on “Uncommon” Epidermal Growth Factor Receptor Mutations of Unknown Clinical Significance in Non–Small Cell Lung Cancer
Authors: Wu Jenn-Yu , Yu Chong-Jen , Chang Yeun-Chung , Yang Chih-Hsin , Shih Jin-Yuan , Yang Pan-Chyr 
Published: April 2011

Abstract
Purpose: Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non–small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance.
Patients and Methods: Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations.
Results: Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months).
Conclusions: Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed. Clin Cancer Res; 17(11); 3812–21. ©2011 AACR.
Antitumor and Antiangiogenic Activities of BMS-690514, an Inhibitor of Human EGF and VEGF Receptor Kinase Families
Authors: Wong Tai W. , Lee Francis Y. , Emanuel Stuart , Fairchild Craig , Fargnoli Joseph , Fink Brian , Gavai Ashvinikumar , Hammell Amy , Henley Benjamin , Hilt Christine , Hunt John T. , Krishnan Bala , Kukral Daniel , Lewin Anne , Malone Harold , Norris Derek , Oppenheimer Simone , Vite Gregory , Yu Chiang 
Published: April 2011

Abstract
Purpose: The extensive involvement of the HER kinases in epithelial cancer suggests that kinase inhibitors targeting this receptor family have the potential for broad spectrum antitumor activity. BMS-690514 potently inhibits all three HER kinases, and the VEGF receptor kinases. This report summarizes data from biochemical and cellular pharmacology studies, as well as antitumor activity of BMS-690514.
Experimental Design: The potency and selectivity of BMS-690514 was evaluated by using an extensive array of enzymatic and binding assays, as well as cellular assays that measure proliferation and receptor signaling. Antitumor activity was evaluated by using multiple xenograft models that depend on HER kinase signaling. The antiangiogenic properties of BMS-690514 were assessed in a matrigel plug assay, and effect on tumor blood flow was measured by dynamic contrast-enhanced MRI.
Results: BMS-690514 is a potent and selective inhibitor of epidermal growth factor receptor (EGFR), HER2, and HER4, as well as the VEGF receptor kinases. It inhibits proliferation of tumor cells with potency that correlates with inhibition of receptor signaling, and induces apoptosis in lung tumor cells that have an activating mutation in EGFR. Antitumor activity was observed with BMS-690514 at multiple doses that are well tolerated in mice. There was evidence of suppression of tumor angiogenesis and endothelial function by BMS-690514, which may contribute to its efficacy.
Conclusions: By combining inhibition of two receptor kinase families, BMS-690524 is a novel targeted agent that disrupts signaling in the tumor and its vasculature. Clin Cancer Res; 17(12); 4031–41. ©2011 AACR.
Molecular Chemotherapy and Chemotherapy: A New Front against Late-Stage Hormone-Refractory Prostate Cancer
Authors: Singh Preetiner Pal , Joshi Swapna , Russell Pamela J. , Verma Nirupama D. , Wang Xiaochun , Khatri Aparajita 
Published: April 2011

Abstract
Purpose: Stemming from its inherent heterogeneity, single-agent treatments are essentially ineffective against castration-resistant prostate cancer (CRPC). Thus, clinically relevant regimens that harness different modalities to maximize treatment efficacy without increasing cumulative toxicities are urgently needed. Based on this rationale, we investigated whether a novel combination of purine nucleoside phosphorylase–mediated, gene-directed enzyme-prodrug therapy (PNP-GDEPT) with docetaxel against CRPC has superior efficacy in comparison with individual treatments.
Methods: The in vitro cell growth inhibition in differentially treated murine and human CRPC cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The local and systemic effects of docetaxel and/or PNP-GDEPT were tested in both immunodeficient and immunocompetent mice against human and murine CRPC tumors, respectively. Subsequently, immunohistochemical analyses and an evaluation of serum cytokine and serum toxicity profiles were conducted to characterize the differential host responses to treatment.
Results: The combined use of PNP-GDEPT and docetaxel led to strong synergistic cell killing in vitro. Compared with the individual modalities, a combination of the 2 led to a marked reduction in “local and distant” tumor growth in vivo, and importantly, with lowered doses and without additional toxicities. Immunomodulation was indicated by enhanced immune cell infiltration and altered serum cytokine levels. Furthermore, a lowering of T-helper type 2 cytokines, MCP-1, interleukin (IL)-4, IL-6, and IL-10 marked lower tumor burden and enhanced treatment efficacy.
Conclusion: PNP-GDEPT and docetaxel are a potent combination against CRPC in immunocompetent and immunodeficient settings; these outcomes have implications of translational potential for improved treatment and management of CRPC patients. Clin Cancer Res; 17(12); 4006–18. ©2011 AACR.
Initial Impact of the Acute Otitis Externa Clinical Practice Guideline on Clinical Care
Authors: Bhattacharyya Neil , Kepnes Lynn J. 
Published: April 2011

ObjectivesDetermine the influence of the acute otitis externa clinical practice guideline on clinical care.Study DesignCross‐sectional study with historical controls.SettingOutpatient departments in the United States.MethodsCases of acute otitis externa occurring in 2004‐2005 (before guideline publication) and 2007‐2008 (after guideline publication) were extracted from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Care Survey. Prescribing rates for ototopical medications, analgesic recommendations, and oral antibiotics were determined and compared before and after guideline publication and relative to guideline recommendations.ResultsAn estimated 5.50 (standard error of the estimated mean, 0.38) million visits (mean age, 27.7 [1.7] years; 49.8% male) with a primary and singular coded diagnosis of acute otitis externa were studied (2.64 [0.26] million visits for 2004‐2005 and 2.86 [0.28] million visits for 2007‐2008). Prescribing rates for ototopical preparations were 67.2% (5.3%) and 67.6% (5.0%) before and after guideline publication, respectively (P =. 955). Recommendation rates for analgesics were 14.2% (3.3%) and 20.6% (3.9%), respectively (P =. 248). Prescription rates for oral antibiotics were 21.7% (4.8%) and 30.5% (3.6%), before and after, respectively (P =. 166).ConclusionClinician behavior in the medical treatment of acute otitis externa has not significantly changed after guideline publication, despite clear, evidence‐based guideline recommendations. These data have important implications for performance measures based on the guideline. Further efforts toward guideline dissemination are likely needed.
Autologous Chondrocyte Implantation in the Adolescent Knee
Authors: Macmull Simon , (Ed) Michael T. R. Parratt , Bentley George , Skinner John A. , Carrington Richard W. J. , Morris Tim , Briggs Tim W. R. 
Published: April 2011

Background Autologous chondrocyte implantation (ACI) has been shown to have favorable results in the treatment of symptomatic chondral and osteochondral lesions. However, there are few reports on the outcomes of this technique in adolescents. Purpose The aim of this study was to assess pain relief and functional outcome in adolescents undergoing ACI. Study Design Case series; Level of evidence, 4. Methods Thirty-five adolescent patients undergoing ACI or matrix-assisted chondrocyte implantation (MACI) were identified from a larger cohort. Four patients were lost to follow-up, leaving 31 patients (24 ACI, 7 MACI). The mean age was 16.3 years (range, 14-18 years) with a mean follow-up of 66.3 months (range, 12-126 months). There were 22 male and 9 female patients. All patients were symptomatic; 30 had isolated lesions and 1 had multiple lesions. Patients were assessed preoperatively and post-operatively using the visual analog scale (VAS) score for pain, the Bentley Functional Rating Score, and the Modified Cincinnati Rating System. At 1 year postoperatively, patients were recalled for a diagnostic biopsy, which was successfully attained in 21 patients. Results The mean pain scores improved from 5 preoperatively to 1 postoperatively. The Bentley Functional Rating Score improved from 3 to 0, while the Modified Cincinnati Rating System improved from 48 preoperatively to 92 postoperatively with 84% of patients achieving excellent or good results. All postoperative scores exhibited significant improvement from preoperative scores. One patient underwent graft hypertrophy and 1 patient's graft failed and was revised. Biopsy results revealed hyaline cartilage in 24% of cases, mixed fibro/hyaline cartilage in 19%, and fibrocartilage in 57%. Conclusion Results show that, in this particular group who received ACI, patients experienced a reduction in pain and significant improvement in postoperative function after ACI or MACI. The authors believe that ACI is appropriate in the management of carefully selected adolescents with symptomatic chondral and osteochondral defects.