We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

A highly effective one-pot Friedländer quinoline synthesis from o-nitroarylcarbaldehydes and ketones or aldehydes was developed and the scope and limitations of the method were examined. The o-nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of a catalytic amount of aqueous hydrochloric acid; the amino compounds were then condensed in situ with ketones or aldehydes to form mono-or disubstituted quinolines, respectively, in good-to-excellent yields (58-100%).Quinolines are an important class of heterocycles that have long been used antimalarial agents, 1 and more recently have been used as protein kinase inhibitors for the treatment of cancer. 2 These beneficial biological activities continue to make quinolines attractive targets for both synthetic and medicinal chemists. Among the many methods available for constructing the quinoline ring, the Friedländer quinoline synthesis has proven to be a very powerful tool. 3 This reaction typically requires two steps: reduction of an o-nitro aldehyde or ketone I into an o-amino aldehyde or ketone II followed by condensation of this intermediate with a ketone or aldehyde III (Scheme 1).Often the amino carbonyl intermediate II is unstable, especially when R 2 = H, and it may undergo self-condensation. To overcome this potential problem and make this century-old reaction more practical, several laboratories have attempted to develop one-pot procedures involving the use of II generated in situ. 4,5 Of particular interest is the one-pot method developed by Miller and McNaughton, 4a which uses a tin(II) chloride/zinc chloride system to convert o-nitro aldehydes or ketones into 2-monosubstituted or 2,3-disubstituted quinolines. This method works well with a range of aliphatic ketones but, unfortunately, it is not applicable to aromatic ketones such as acetophenone. 5 We therefore attempted to develop a method that would permit the preparation of 2-aryl-substituted quinolines. As reported in our previous preliminary communication, 5 we have discovered a practical one-pot Friedländer quinoline synthesis that uses inexpensive and readily available reagents such as iron powder, aqueous hydrochloric acid, and solid potassium hydroxide. Our method successfully condensed a variety of o-nitro aldehydes (or ketones) with various carbonyl co-reactants. Herein, we report a study of the scope and limitations of the one-pot Friedländer quinoline synthesis.In a typical operation, 2-nitrobenzaldehyde was reduced with 4.0 equivalents of iron powder in the presence of 5 mol% of aqueous hydrochloric acid in refluxing ethanol. The reduction was usually complete within 30-40 minutes (as monitored by thin-layer chromatography). After this time, 1.0 equivalents of a carbonyl compound and 1.2 equivalents of powdered potassium hydroxide were added. The mixture was then stirred at reflux for a further 40-60 minutes to complete the condensation reaction. A classical aqueous workup followed by chromatography over silica gel or by recrystallization afforded the desir...

Although ipilimumab has been shown to improve survival in patients with metastatic melanoma and cause regression of metastatic renal cell carcinoma, the associated immune-related toxicities are of concern. The resultant T cell activation by this monoclonal antibody causes an increased immune response, which has been associated with many immune-regulated adverse effects. One of the most concerning effects is the development of colitis. Upwards to 8% of patients have been reported to develop colitis, with 5% being severe (Grades 3-4). While initial treatment of such adverse effects is generally comprised of supportive and symptomatic treatment, more severe cases warrant the use of high dose steroids. Furthermore, use of anti-TNF agents is usually reserved for those cases that prove to be refractory to steroids. We describe a systematic case review of seven patients who developed gastrointestinal symptoms following initiation of ipilimumab immunotherapy, and present the steps in their evaluation, treatment and outcomes at our institution.

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The goals in acoustic tumor surgery are total tumor removal and preservation of neurologic function, with primary emphasis placed on preserving the anatomic integrity and function of the facial nerve. The combination of improved surgical technique and advances in intraoperative neurophysiologic monitoring methods have made these goals attainable."2 With the advent and use of magnetic resonance imaging (MRI), it is now possible to find smaller tumors in patients who still have normal or near-normal hearing threshold levels. This technologic advance is fundamental toward achieving the next challenge, hearing preservation. The use of intraoperative neurophysiologic monitoring, that is, brainstem auditory evoked potentials (BAEPs) and transtympanic electrocochleography (ECoG), have also been advocated when hearing preservation is attempted.12 Despite these improvements in technology, hearing preservation remains an elusive goal. Although various authors report hearing preservation rates ranging from 10 to 65%, controversy exists regarding which preoperative factors are most predictive of postoperative hearing outcome.4'0To address this issue, we retrospectively evaluated nine variables, including auditory perceptual, auditory neurophysiologic, and imaging-related characteristics of acoustic tumor dimensions to validate those univariate relationships typically reported in the literature, and to determine which of these variables, either alone or in combination, are best predictors of postoperative hearing using logistic regression analysis.