Citations

Abstract Recent reports show that three-dimensional cone-beam (CB) imaging with a floor-mounted (or ceiling-mounted) C-arm system has become a valuable tool in interventional radiology. Currently, a circular short scan is used for data acquisition, which inevitably yields CB artifacts and a short coverage in the direction of the patient table. To overcome these two limitations, a more sophisticated data acquisition geometry is needed. This geometry should be complete in terms of Tuy’s condition and should allow continuous scanning, while being compatible with the mechanical constraints of mounted C-arm systems. Additionally, the geometry should allow accurate image reconstruction from truncated data. One way to ensure such a feature is to adopt a trajectory that provides full R-line coverage within the field-of-view (FOV). An R-line is any segment of line that connects two points on a source trajectory, and the R-line coverage is the set of points that belong to an R-line. In this work, we propose a novel geometry called the extended ellipse-line-ellipse (ELE) for long-object imaging with a mounted C-arm system. This trajectory is built from modules consisting of two elliptical arcs connected by a line. We demonstrate that the extended ELE can be configured in many ways so that full R-line coverage is guaranteed. Both tight and relaxed parametric settings are presented. All results are supported by extensive mathematical proofs provided in appendices. Our findings make the extended ELE trajectory attractive for axially-extended FOV imaging in interventional radiology.

Purpose Fluorouracil plus leucovorin (FU + LV) adjuvant chemotherapy reduced the risk of recurrence and death across all time points in a pooled analysis of 20,898 patients with colon cancer from 18 randomized studies. The impact of oxaliplatin added to FU + LV on the time course of recurrence and survival remains unknown. Patients and Methods A total of 12,233 patients enrolled to the randomized trials C-07, C-08, N0147, MOSAIC (Adjuvant Treatment of Colon Cancer), and XELOXA (Adjuvant XELOX) were pooled to examine the impact of oxaliplatin and tumor-specific factors on the time course of recurrence and death. For each end point, continuous-time risk was modeled over 6 years post treatment in all oxaliplatin-treated patients and patients concurrently randomized to FU + LV with or without oxaliplatin; the latter analyses supported time-dependent treatment comparisons. Results Addition of oxaliplatin significantly reduced the risk of recurrence within the first 14 months post treatment for patients with stage II disease and within the first 4 years for patients with stage III disease. Oxaliplatin also significantly reduced risk of death from 2 to 6 years post treatment for patients with stage III disease, with no differences in timing of outcomes between treatment groups (ie, oxaliplatin did not simply postpone recurrence or death compared with FU + LV alone). Patients with stage II disease receiving oxaliplatin did not exhibit a significant reduction in risk of death in the first 6 years post treatment. Recurrence risk peaked near 14 months for both treatments, and risk of recurrence and death increased with increased tumor and nodal burden. Conclusions These analyses support the addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy in patients with stage III disease and underscore the need for adequate surveillance of patients with colon cancer during the first 3 years after adjuvant therapy.

ObjectivesTo investigate the dose‐dependent effect of androgen deprivation therapy on community‐acquired respiratory infections in patients with localized prostate cancer.MethodsWe identified 52 905 men diagnosed with localized prostate cancer within the Surveillance, Epidemiology and End Results‐Medicare database between 1991 and 2006. We compared those who did not receive androgen deprivation therapy with those who received androgen deprivation therapy within 2 years of diagnosis, calculated as monthly equivalent doses (<7, 7–11, >11 doses), or orchiectomy. Adjusted Cox hazard models were fitted to predict the risk of community‐acquired respiratory infections (acute sinusitis, acute bronchitis, [severe] pneumonia) in patients treated with medical androgen deprivation therapy versus orchiectomy versus none.ResultsOverall, 43.4% received medical androgen deprivation therapy. These patients more likely experienced respiratory events compared with those who did not receive androgen deprivation therapy or who underwent orchiectomy (62.2% vs 54.5% vs 47.8%, P < 0.001). The risk of experiencing any respiratory event increased with the number of doses received. For example, men receiving >11 doses of androgen deprivation therapy were at greatest risk of acute sinusitis, acute bronchitis and pneumonia (HR 1.13, 1.26 and 1.15, respectively, all P < 0.001), except severe pneumonia. Furthermore, we did not detect any relationship between orchiectomy and respiratory events. Study limitations include the utilization of a retrospective population‐based dataset.ConclusionsIncreased exposure to medical androgen deprivation therapy for men with localized prostate cancer is associated with a higher risk of community‐acquired respiratory infections. Our results suggest that respiratory complications represent potentially underreported complications of medical androgen deprivation therapy.

Purpose In recent retrospective analyses of early-stage colorectal cancer (CRC), low and high body mass index (BMI) scores were associated with worsened outcomes. Whether BMI is a prognostic or predictive factor in metastatic CRC (mCRC) is unclear. Patients and Methods Individual data from 21,149 patients enrolled onto 25 first-line mCRC trials during 1997 to 2012 were pooled. We assessed both prognostic and predictive effects of BMI on overall survival and progression-free survival, and we accounted for patient and tumor characteristics and therapy type (targeted v nontargeted). Results BMI was prognostic for overall survival (P < .001) and progression-free survival (P < .001), with an L-shaped pattern. That is, risk of progression and/or death was greatest for low BMI; risk decreased as BMI increased to approximately 28 kg/m 2 , and then it plateaued. Relative to obese patients, patients with a BMI of 18.5 kg/m 2 had a 27% increased risk of having a PFS event (95% CI, 20% to 34%) and a 50% increased risk of death (95% CI, 43% to 56%). Low BMI was associated with poorer survival for men than women (interaction P < .001). BMI was not predictive of treatment effect. Conclusion Low BMI is associated with an increased risk of progression and death among the patients enrolled on the mCRC trials, with no increased risk for elevated BMI, in contrast to the adjuvant setting. Possible explanations include negative effects related to cancer cachexia in patients with low BMI, increased drug delivery or selection bias in patients with high BMI, and potential for an interaction between BMI and molecular signaling pathways.

AbstractBackgroundActinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing.ObjectivesThe goal of these evidence‐ and consensus‐based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus‐based recommendations for the histopathological definition, diagnosis and the assessment of patients.MethodsThe guidelines development followed a pre‐defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies.ResultsVarious interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately.ConclusionsInternational guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).

Abstract Introduction: QSOX1 is a flavin-dependent sulfhydryl oxidase and the only known human enzyme with both disulfide generating and transferring activities. Using tissue microarrays, we previously demonstrated that QSOX1 is over-expressed in multiple tumor types including breast, pancreas, prostate and myeloma. Loss of QSOX1 leads to a significant decrease in tumor cell proliferation and invasion. The over-expression of QSOX1 in tumor cells compared to non-malignant cells combined with its role in tumor cell proliferation and invasion make it an attractive target for potential anti-neoplastic agents. Methods: Using a high throughput screening assay to detect sulfhydryl oxidase activity, we screened a library of compounds for inhibition of the QSOX1 enzyme. We used ROS-GloTM, a luciferase-based assay that detects H2O2, to determine if any compounds in the library inhibited QSOX1-mediated disulfide bond formation using reduced RNAse A as a substrate. QSOX1 generates H2O2 as a by-product of disulfide bond formation. To determine if compounds that showed activity in the enzymatic assay were also active against tumor cells, we treated pancreatic, breast, and myeloma cells with the compounds in a dose-dependent fashion, using non-malignant cells as controls. We assayed growth/viability by MTT and CellTiter-Glo assays. Invasive activity of tumor cells was assessed using matrigel-coated inserts in a modified Boyden chamber assay. Results: High throughput library screening identified 4 compounds that specifically inhibited QSOX1 activity (designated A-D) compared to a glucose oxidase counter-screen. Growth/viability assays showed that compound D suppressed the growth of tumor cells with IC50s between 300nM-750nM, depending on tumor cell line. In non-malignant cells the IC50s for compound D were more than 10-fold higher than in tumor cells. Compounds A and D also inhibited invasion of breast and pancreatic tumor cells through Matrigel. Conclusion: This is the first report of chemical compounds that inhibit QSOX1 enzymatic activity. The discovery of QSOX1 inhibitors with cellular efficacy establishes the chemical tractability of the target. Our data demonstrate that these First-In-Class compounds have potential as anti-neoplastic therapeutics via inhibition of QSOX1. Citation Format: Paul D. Hanavan, Douglas O. Faigel, Chen-Ting Ma, Eduard Sergienko, Nathalie Meurice, Joachim L. Petit, Yvette W. Ruiz, Benjamin A. Katchman, Douglas F. Lake. Small molecule inhibitors of QSOX1 suppress tumor cell growth and invasion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1790. doi:10.1158/1538-7445.AM2014-1790

Abstract Deregulation of the TWEAK-Fn14 signaling pathway is observed in many diseases including inflammation, autoimmune diseases, and cancer, notably glioblastoma. Activation of Fn14 signaling by TWEAK binding triggers glioma cell invasion and survival and therefore represents an attractive pathway for therapeutic intervention. Based on structural studies of the TWEAK-binding cysteine rich domain of Fn14, several homology models of TWEAK were built to investigate plausible modes of TWEAK-Fn14 interaction. Two promising models, centered on different anchoring residues of TWEAK [Tyrosine 176 (Y176) and Tryptophan 231 (W231)], were prioritized using a data-driven strategy. Site-directed mutagenesis of TWEAK at Y176, but not W231, resulted in the loss of TWEAK binding to Fn14 substantiating Y176 as the anchoring residue. Importantly, mutation of TWEAK at Y176 did not disrupt TWEAK trimerization, but failed to induce Fn14 mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. The validated structural models were utilized in a virtual screen to design a targeted library of small molecules predicted to disrupt the TWEAK-Fn14 interaction. 129 small molecules were screened iteratively, with identification of molecules producing up to 37% inhibition of TWEAK-Fn14 binding. One specific compound, L524-0366 binds specifically to the Fn14 receptor and disrupt TWEAK-Fn14 interaction. Treatment of L524-0366 suppresses TWEAK-induced cell migration and survival in glioblastoma cells. In summary, we present a data-driven in silico study revealing key structural elements of the TWEAK-Fn14 interaction, followed by experimental validation, serving as a guide for the design of small molecule inhibitors of the TWEAK-Fn14 ligand-receptor interaction. Our results provide the foundation for further exploration utilizing L524-0366 as a small molecule inhibitor to the TWEAK-Fn14 signaling axis. Citation Format: Harshil D. Dhruv, Joseph C. Loftus, Pooja Narang, Joachim L. Petit, Donald Chow, Holly Yin, Michael Berens, Nathalie Meurice, Nhan L. Tran. Identification and characterization of L524-0366 as a small molecule inhibitor that disrupt TWEAK-Fn14 signaling in glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1780. doi:10.1158/1538-7445.AM2014-1780

The ubiquitin–proteasome system (UPS) is increasingly recognized as a therapeutic target for the development of anticancer therapies. The success of the 20S proteasome core particle (20S CP) inhibitor bortezomib in the clinical management of multiple myeloma has raised the possibility of identifying other UPS components for therapeutic intervention. We previously identified the small molecule b‐AP15 as an inhibitor of 19S proteasome deubiquitinase (DUB) activity. Building upon our previous data, we performed a structure–activity relationship (SAR) study on b‐AP15 and identified VLX1570 as an analog with promising properties, including enhanced potency and improved solubility in aqueous solution. In silico modeling was consistent with interaction of VLX1570 with key cysteine residues located at the active sites of the proteasome DUBs USP14 and UCHL5. VLX1570 was found to inhibit proteasome deubiquitinase activity in vitro in a manner consistent with competitive inhibition. Furthermore, using active‐site‐directed probes, VLX1570 also inhibited proteasome DUB activity in exposed cells. Importantly, VLX1570 did not show inhibitory activity on a panel of recombinant non‐proteasome DUBs, on recombinant kinases, or on caspase‐3 activity, suggesting that VLX1570 is not an overtly reactive general enzyme inhibitor. Taken together, our data shows the chemical and biological properties of VLX1570 as an optimized proteasome DUB inhibitor.

PurposeProgression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.MethodsIndividual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti–epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models.ResultsForty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy.ConclusionIn modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.