BACKGROUND Recurrent brain tumors are the leading cause of cancer death in children. We conducted a first-in-children, two-institution, Phase 1 open-label dose-confirmation study using a 3 + 3 design, with expansion cohorts, to determine the recommended pediatric dose of the IDO pathway-inhibitor indoximod (NCT02502708). DESIGN/ METHODS Eligible patients were 3-22 years old with either recurrent malignant brain tumor or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Palliative radiation, surgery or dexamethasone were allowed as needed for patient management. Separate dose-finding arms were performed for indoximod plus temozolomide (200 mg/m2/day orally for 5 days of each 28-day cycle) and for indoximod plus conformal radiation (in patients for whom re-irradiation was planned as standard-of-care). At progression, patients who were otherwise clinically stable were offered crossover to indoximod plus a second-line chemotherapy regimen (cyclophosphamide 2.5 mg/kg/day orally and etoposide 50 mg/m2/day orally for 21 days of each 28-day cycle). RESULTS Between December 2015 and January 2019, the study enrolled 81 brain tumor patients, including newly-diagnosed DIPG (n = 13) or recurrent ependymoma (n = 27), glioblastoma/high-grade glioma (n = 19), medulloblastoma (n = 13), or other CNS tumors ( n= 9). Median follow-up was 52 months (range 39-77 months). No dose-limiting toxicities were observed, and the pediatric indoximod dose was determined (19.2 mg/kg/dose, given twice daily). Indoximod was well tolerated and did not affect the ability to deliver chemotherapy or radiation as planned. Median overall survival was 13.6 months (n = 81). Median overall survival was 34.7 months for the subset of patients who continued indoximod with second-line chemotherapy after progression on indoximod plus temozolomide (n = 18). CONCLUSIONS Indoximod was well tolerated and could be combined with a variety of standard treatments for pediatric brain tumors. Preliminary anti-tumor activity and overall survival suggest that indoximod with standard therapy should be further evaluated in pediatric brain tumors, and potentially other pediatric solid tumors.

Abstract BACKGROUND Recurrent brain tumors are the leading cause of cancer death in children. We conducted a first-in-children, two-institution, Phase 1 open-label dose-confirmation study using a 3 + 3 design, with expansion cohorts, to determine the recommended pediatric dose of the IDO pathway-inhibitor indoximod (NCT02502708). DESIGN/ METHODS Eligible patients were 3-22 years old with either recurrent malignant brain tumor or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). Palliative radiation, surgery or dexamethasone were allowed as needed for patient management. Separate dose-finding arms were performed for indoximod plus temozolomide (200 mg/m2/day orally for 5 days of each 28-day cycle) and for indoximod plus conformal radiation (in patients for whom re-irradiation was planned as standard-of-care). At progression, patients who were otherwise clinically stable were offered crossover to indoximod plus a second-line chemotherapy regimen (cyclophosphamide 2.5 mg/kg/day orally and etoposide 50 mg/m2/day orally for 21 days of each 28-day cycle). RESULTS Between December 2015 and January 2019, the study enrolled 81 brain tumor patients, including newly-diagnosed DIPG (n = 13) or recurrent ependymoma (n = 27), glioblastoma/high-grade glioma (n = 19), medulloblastoma (n = 13), or other CNS tumors ( n= 9). Median follow-up was 52 months (range 39-77 months). No dose-limiting toxicities were observed, and the pediatric indoximod dose was determined (19.2 mg/kg/dose, given twice daily). Indoximod was well tolerated and did not affect the ability to deliver chemotherapy or radiation as planned. Median overall survival was 13.6 months (n = 81). Median overall survival was 34.7 months for the subset of patients who continued indoximod with second-line chemotherapy after progression on indoximod plus temozolomide (n = 18). CONCLUSIONS Indoximod was well tolerated and could be combined with a variety of standard treatments for pediatric brain tumors. Preliminary anti-tumor activity and overall survival suggest that indoximod with standard therapy should be further evaluated in pediatric brain tumors, and potentially other pediatric solid tumors.

Diffuse intrinsic pontine glioma (DIPG) is a uniformly fatal brain tumor with no available cure. Indoximod blocks the IDO (indoleamine 2,3-dioxygenase) pathway, thereby reversing IDO-mediated immune suppression in the tumor microenvironment. Patients aged 3 to 21 years with treatment-naive DIPG were eligible for this phase 1b dose-confirmation study of indoximod. The treatment regimen comprised continuous oral indoximod (38.4 mg/kg/day divided twice daily) with conformal photon radiation (54 Gy in 30 fractions), followed by cycles of indoximod with temozolomide (200 mg/m2/day, days 1–5 in 28-day cycles). Thirteen patients (median age 9 years, range 5 to 20 years) with DIPG were treated. Median OS was 14.5 months (follow-up ranged 4.8 to 29.3 months), 12-month OS was 61.5% (8/13), and 18-month OS was 30.8% (4/13), with 1 patient remaining in follow-up at the data cutoff. This compared favorably to expected median OS of approximately 10.8 months, 12-month OS of 45.3%, and 18-month OS of 16.2% taken from published historical data from the Pediatric Brain Tumor Consortium. Two patients showed near-complete responses lasting until relapsing after 7.6 months and 13.3 months of study therapy, respectively. Many patients had increased circulating non-classical monocytes (nc-Monos, CD16+, CD14neg, CD33+, HLA-DR+) within the first 3 treatment cycles, and elevation of this early pharmacodynamic marker was predictive of subsequent OS. Patients with nc-Monos >10% (n=7) had median OS of 19 months, whereas patients with nc-Monos below 10% (n=5) had median OS of 7 months (p=0.0047). No patients stopped therapy for toxicity. The most common indoximod-attributed adverse events were thrombocytopenia, neutropenia, nausea, vomiting, dizziness, and fatigue. Adding indoximod immunotherapy to conventional radiation and chemotherapy for front-line treatment of pediatric patients with DIPG was well-tolerated. Improved outcomes were observed in patients having evidence of pharmacodynamic response. A follow-on phase 2 study is in progress (NCT04049669).

Aims Management of coagulopathy in patients with cirrhosis presenting with variceal bleeding is challenging. TEG may offer a more targeted blood product transfusion approach. This study aims to evaluate the overall impact on patient care that a TEG guided blood product transfusion strategy made on patients admitted with variceal bleeding.

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Introduction. Book I: Adobe Creative Suite 2 Basics. Chapter 1: Introducing Adobe Creative Suite 2. Chapter 2: Using Common Menus and Commands. Chapter 3: Using Common Palettes. Chapter 4: Using Common Plug-Ins. Chapter 5: Importing and Exporting. Chapter 6: Handling Graphics, Paths, Text, and Fonts. Chapter 7: Using Color. Chapter 8: Printing Documents. Book II: InDesign CS2. Chapter 1: Introducing InDesign CS2. Chapter 2: Drawing in InDesign. Chapter 3: Working with Text and Text Frames. Chapter 4: Understanding Page Layout. Chapter 5: Clipping Paths, Transforming Objects, and Alignment. Chapter 6: Understanding Color and Printing. Chapter 7: Exporting Your Work. Chapter 8: Integrating InDesign. Book III: Illustrator CS2. Chapter 1: Discovering Illustrator CS2. Chapter 2: Using the Selection Tools. Chapter 3: Creating Basic Shapes. Chapter 4: Using the Pen Tool and Placing Images. Chapter 5: Using Type in Illustrator. Chapter 6: Organizing Your Illustrations. Chapter 7: Using Layers. Chapter 8: Livening Up Illustrations with Color. Chapter 9: The Transform and Distortions Tools. Chapter 10: Transparency and Special Effects Tools. Chapter 11: Using Filters and Effects. Chapter 12: Using Your Illustrator Image. Book IV: Photoshop CS2. Chapter 1: Photoshop CS2 Basics. Chapter 2: Mode Matters. Chapter 3: Creating a Selection. Chapter 4: Using the Photoshop Pen Tool. Chapter 5: Resolution Basics. Chapter 6: Creating a Good Image. Chapter 7: Painting and Retouching Tools. Chapter 8: Using Layers. Chapter 9: Saving Photoshop Images for Print and the Web. Book V: Acrobat 7.0. Chapter 1: Discovering Essential Acrobat Information. Chapter 2: Creating PDF Files. Chapter 3: Adding Interactivity to PDF Files. Chapter 4: Editing and Extracting Text and Graphics. Chapter 5: Using Commenting and Annotation Tools. Chapter 6: Securing Your PDF Files. Book VI: GoLive CS2. Chapter 1: Introducing GoLive CS2. Chapter 2: Creating a Web Site. Chapter 3: Working with Images. Chapter 4: Text and CSS. Chapter 5: Layout Grids, Tables, and Frames. Chapter 6: Links. Chapter 7: Layers. Chapter 8: Forms. Chapter 9: Multimedia. Chapter 10: Publishing Your Web Site. Index.

Costs less. Does more. Is easier to use: If this is the conclusion you've reached when comparing InDesign CS with its two long-time rivals (QuarkXPress and PageMaker), you're ready to make the switch. This guide shows you how! Throughout this compact guide, the focus is on leveraging your skill in the other leading desktop publishing packages to get up to speed fast in the new leading publishing package! As the perfect companion to the more comprehensive Real World InDesign CS, this tightly focused guide details the most common tasks and techniques you need to know to get your job done in InDesign CS. Clear, concise instructions enhanced by plenty of screen shots and sample layouts show you how to create and navigate documents, import and style text and objects, manage long projects, work with color, and more. Youï戮驴ll also find good coverage of all of InDesign's newest and most unique features: the Story Editor, a Separation Preview palette, nested styles, the Package for GoLive command, and more.

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