Infections of the Neck.

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Infections of the Neck.

Emerg Med Clin North Am. 2019 Feb;37(1):95-107

Authors: Li RM, Kiemeney M

Abstract
Infection of the neck is a relatively common emergency department complaint. If not diagnosed and managed promptly, it may quickly progress to a life-threatening infection. These infections can result in true airway emergencies that may require fiberoptic or surgical airways. This article covers common, as well as rare but emergent, presentations and uses an evidence-based approach to discuss diagnostic and treatment modalities.

PMID: 30454783 [PubMed - indexed for MEDLINE]

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Contributors to authors

Publication date: December 2018

Source: Seminars in Spine Surgery, Volume 30, Issue 4

Author(s):

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Molecular Subtypes and the Evolution of Treatment Decisions in Metastatic Colorectal Cancer.

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Molecular Subtypes and the Evolution of Treatment Decisions in Metastatic Colorectal Cancer.

Am Soc Clin Oncol Educ Book. 2018 May 23;(38):231-238

Authors: Dienstmann R, Salazar R, Tabernero J

Abstract
Colorectal cancer (CRC) has clinically relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics, and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations define a population refractory to epidermal growth factor receptor monoclonal antibodies, BRAFV600E mutations associate with poor outcomes under standard therapies and response to targeted inhibitors in combinations, and HER2 amplifications confer unique sensitivity to double HER2 blockade. Multiple rare gene alterations driving resistance to epidermal growth factor receptor monoclonal antibodies have been described, with substantial overlap in primary and acquired mechanisms, in line with a clonal selection process. In this context, sequential analysis of circulating tumor DNA has the potential to guide drug development in a treatment-refractory setting. Rare kinase fusion events and complex alterations in genes involved in DNA damage repair have been described, with emerging evidence for targetability. On the other hand, transcriptomic subtypes and pathway activation signatures have also shown prognostic and potential predictive value in metastatic CRC. These markers reflect stromal and immune microenvironment interactions with cancer cells. For example, the microsatellite instable or POLE ultramutant CRC population is particularly sensitive to immune checkpoint inhibitors, whereas tumors with a mesenchymal phenotype are characterized by activation of immunosuppressive molecules that mandate stratified development of novel immunotherapy combinations. Here, we review the expanding landscape of targetable oncogenic alterations and signatures in metastatic CRC and discuss the clinical implementation of novel molecular diagnostic tests.

PMID: 30231342 [PubMed - indexed for MEDLINE]

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MGMT promoter methylation is not correlated with integrin expression in malignant gliomas: clarifying recent clinical trial results.

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MGMT promoter methylation is not correlated with integrin expression in malignant gliomas: clarifying recent clinical trial results.

Med Oncol. 2018 Jun 07;35(7):103

Authors: Schnell O, Albrecht V, Pfirrmann D, Eigenbrod S, Krebs B, Romagna A, Siller S, Giese A, Tonn JC, Schichor C

Abstract
Integrin alpha-v-beta-3 (αvβ3) is important for invasive tumor growth and angiogenesis in glioblastomas (GBM). However, recent clinical trials on inhibition of this integrin led to ambiguous results whether patients with methylated or unmethylated 6O-methylguanine methyltransferase (MGMT) promoter might profit from this kind of therapy. Therefore, we addressed the still unanswered question about a possible correlation between integrin αvβ3 expression and MGMT promoter methylation in GBM. For this purpose, tumor samples from newly diagnosed and untreated GBM patients with methylated (n = 22) or unmethylated (n = 17) MGMT promoter were simultaneously analyzed for integrin αvβ3 expression by an automated immunohistochemical staining platform. Interestingly, subsequent semi-quantitative analysis by a special imaging software did not show any difference in integrin expression between patients with methylated or unmethylated MGMT promoter status. Moreover, further analysis of the integrin subunits via ELISA from histologic sections revealed that there is no difference in integrin subunit expression between these patients. Hence, our results are important for designing future clinical trials with respect to treatment stratification, while it still has to be identified which other molecular factors determine differential responses to targeted anti-integrin αvβ3 treatment.

PMID: 29882028 [PubMed - indexed for MEDLINE]

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Where We Stand With Immunotherapy in Colorectal Cancer: Deficient Mismatch Repair, Proficient Mismatch Repair, and Toxicity Management.

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Where We Stand With Immunotherapy in Colorectal Cancer: Deficient Mismatch Repair, Proficient Mismatch Repair, and Toxicity Management.

Am Soc Clin Oncol Educ Book. 2018 May 23;(38):239-247

Authors: Overman MJ, Ernstoff MS, Morse MA

Abstract
With the recent U.S. Food and Drug Administration approvals of pembrolizumab and nivolumab for refractory deficient mismatch repair metastatic colorectal cancer, immune checkpoint inhibitors have now entered into clinical care for gastrointestinal cancers. Extensive ongoing efforts are exploring additional combinations of therapy in both deficient and proficient mismatch repair colorectal cancer. This review will outline the current status of such efforts and discuss the critical aspects of recognition and management of immune-related toxicities from checkpoint inhibitors.

PMID: 30231358 [PubMed - indexed for MEDLINE]

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Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma.

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Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma.

Int J Mol Sci. 2018 Nov 29;19(12):

Authors: Fianco G, Contadini C, Ferri A, Cirotti C, Stagni V, Barilà D

Abstract
Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dependent phosphorylation of Caspase-8 on Tyr380. Loss of apoptotic signaling is a hallmark of cancer and indeed Caspase-8 expression is often lost in tumors. This event may account not only for cancer progression but also for cancer resistance to radiotherapy and chemotherapy. Intriguingly, other tumors, such as glioblastoma, preferentially retain Caspase-8 expression, and high levels of Caspase-8 expression may correlate with a worse prognosis, suggesting that in this context this protease loses its apoptotic activity and gains additional functions. Using different cellular systems, it has been clearly shown that in cancer Caspase-8 can exhibit non-canonical functions, including promotion of cell adhesion, migration, and DNA repair. Intriguingly, in glioblastoma models, Caspase-8 can promote NF-κB-dependent expression of several cytokines, angiogenesis, and in vitro and in vivo tumorigenesis. Overall, these observations suggest that some cancer cells may hijack Caspase-8 function which in turn promote cancer progression and resistance to therapy. Here we aim to highlight the multiple functions of Caspase-8 and to discuss whether the molecular mechanisms that modulate the balance between those functions may be targeted to dismantle the aberrant activity of Caspase-8 and to restore its canonical apoptotic functionality.

PMID: 30501030 [PubMed - in process]

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Allele-specific genome editing using CRISPR-Cas9 is associated with loss of heterozygosity in diploid yeast.

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Allele-specific genome editing using CRISPR-Cas9 is associated with loss of heterozygosity in diploid yeast.

Nucleic Acids Res. 2018 Dec 05;:

Authors: Gorter de Vries AR, Couwenberg LGF, van den Broek M, de la Torre Cortés P, Ter Horst J, Pronk JT, Daran JG

Abstract
Targeted DNA double-strand breaks (DSBs) with CRISPR-Cas9 have revolutionized genetic modification by enabling efficient genome editing in a broad range of eukaryotic systems. Accurate gene editing is possible with near-perfect efficiency in haploid or (predominantly) homozygous genomes. However, genomes exhibiting polyploidy and/or high degrees of heterozygosity are less amenable to genetic modification. Here, we report an up to 99-fold lower gene editing efficiency when editing individual heterozygous loci in the yeast genome. Moreover, Cas9-mediated introduction of a DSB resulted in large scale loss of heterozygosity affecting DNA regions up to 360 kb and up to 1700 heterozygous nucleotides, due to replacement of sequences on the targeted chromosome by corresponding sequences from its non-targeted homolog. The observed patterns of loss of heterozygosity were consistent with homology directed repair. The extent and frequency of loss of heterozygosity represent a novel mutagenic side-effect of Cas9-mediated genome editing, which would have to be taken into account in eukaryotic gene editing. In addition to contributing to the limited genetic amenability of heterozygous yeasts, Cas9-mediated loss of heterozygosity could be particularly deleterious for human gene therapy, as loss of heterozygous functional copies of anti-proliferative and pro-apoptotic genes is a known path to cancer.

PMID: 30517747 [PubMed - as supplied by publisher]

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