Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

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Cancer Genome Landscapes

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

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The cancer genome atlas pan-cancer analysis project

The Cancer Genome Atlas Pan-Cancer analysis project

Background Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non–small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. Methods After screening tumor samples from approximately 1500 patients with non–small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. Results Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. Conclusions The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.)

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Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer

https://www.hal.inserm.fr/inserm-00561753/document

International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma

Is video-assisted thoracoscopic surgery an optimal approach for descending necrotizing mediastinitis?

Cervical infections can cause neck phlegmonosa and occasionally develop lethal mediastinitis. We report a 52-year-old man with a retropharyngeal abscess causing descending mediastinis without cervical spread. Thoracoscopic drainage without cervicotomy was successful. Deep neck infections causing a descending mediastinitis should be considered in patients even without an abnormal neck appearance.

Descending necrotizing mediastinitis secondary to retropharyngeal abscess without cervical spread.

We report a case of intrathoracic desmoid tumor without familial adenomatous polyposis and demonstrate beta-catenin mutation of exon 3. A 15-year-old male presented with a desmoid tumor after having sustained an assault. In an examination for a mutation of the beta-catenin gene, an activating mutation from ACC (Thr) to GCC (Ala) at codon 41 was found. Immunohistochemical staining showed that accumulated beta-catenin protein was predominantly localized in the nuclei of desmoid cells, and cyclin D1 protein was also overexpressed. These findings might suggest that an activating mutation of the beta-catenin gene affected regulation of the cyclin D1 gene, resulting in the generation of intrathoracic sporadic desmoid tumor, which arose at the site of posttraumatic injury.

Intrathoracic Sporadic Desmoid Tumor with the Beta-Catenin Gene Mutation in Exon 3 and Activated Cyclin D1

Overproduction of interleukin (IL)-6 plays an important role in the pathophysiology of myasthenia gravis (MG), and thymectomy can cause myasthenic crisis because of surgically induced overproduction of IL-6 Preoperative steroid therapy is beneficial in preventing MG crisis during the perioperative period The purpose of this study was to clarify the effect of preoperative steroid therapy on proinflammatory mediators during the perioperative period of transsternal thymectomy for MG The study group comprised 20 consecutive MG patients undergoing transsternal thymectomy during the period March 2002 through March 2004 Seventeen of these patients received dose-escalated steroid therapy before thymectomy (steroid treatment group) and three did not (non-steroid treatment group) Serum concentrations of C-reactive protein (CRP) and IL-6 were determined during the perioperative period; clinical outcomes were reviewed, and the results were compared between the two groups Peak serum IL-6 and CRP concentrations were significantly lower in the steroid treatment group than in the non-steroid treatment group Amongst perioperative variables subjected to multiple regression analysis, preoperative steroid treatment were found to be the most significant independent predictor of inhibited IL-6 production on postoperative day 1 No postoperative respiratory failure occurred in the steroid treatment group, but it did occur in the non-steroid treatment group Preoperative steroid therapy can ameliorate IL-6 overproduction and may help stabilize the patient's postoperative condition

Inhibition of IL-6 overproduction by steroid treatment before transsternal thymectomy for myasthenia gravis: does it help stabilize perioperative condition?

Yasunori Sohara

Papers

Is video-assisted thoracoscopic surgery an optimal approach for descending necrotizing mediastinitis?

Descending necrotizing mediastinitis secondary to retropharyngeal abscess without cervical spread.

Intrathoracic Sporadic Desmoid Tumor with the Beta-Catenin Gene Mutation in Exon 3 and Activated Cyclin D1

Inhibition of IL-6 overproduction by steroid treatment before transsternal thymectomy for myasthenia gravis: does it help stabilize perioperative condition?

Phosphodiesterase type 4 inhibitor rolipram inhibits activation of monocytes during extracorporeal circulation