Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene.

Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein-ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein-coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (TP53, IDH1, FBXW7, SDH-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST

Genome-scale CRISPR/Cas9 screening identifies Hippo pathway as key determinant for susceptibility to BET inhibitors in lung cancer

Lung cancer is the main cause of cancer-related mortality worldwide. Despite the availability of different therapeutic options, including chemotherapy, target therapy, and immunotherapy, prognosis for lung cancer patients remains poor. Among innovative therapeutic approaches, inhibitors of the bromodomain and extraterminal domain containing proteins (BETi) have proven efficacy in preclinical settings and are currently in clinical trials for hematologic and solid tumors, including lung cancer. BETi downregulate key oncogenes to which cancer cells are addicted, causing a decrease in proliferation and an increase in apoptosis and differentiation. However, biomarkers that can help to select patients for this treatment are still lacking. To discover the mechanisms responsible of susceptibility and/or resistance to BETi, we performed a genome-scale knockout screening using the CRISPR/Cas9 technology in lung cancer cells. Through this approach, we identified three genes belonging to Hippo pathway, LATS2, TAOK1, and NF2, as mediators of susceptibility to BETi. Hippo pathway is an oncosuppressor pathway that converges on the phosphorylation of YAP1 and TAZ. YAP1 and TAZ are two transcriptional coactivators that interact with TEAD family proteins in nucleus for the activation of pro-oncogenic transcriptional programs. Phosphorylated YAP1 and TAZ are excluded from nucleus, degraded, and unable to enhance the expression of their target genes. We showed that LATS2, TAOK1, and NF2 support susceptibility to BETi, restraining TAZ nuclear localization and activity. We observed that TAZ knockout increases sensitivity whereas TAZ overexpression supports resistance to BETi. Furthermore, we showed that TAZ, YAP1, and TEAD are direct targets of BRD4 and their expression is downregulated by BETi treatment in a large panel of cancer cell lines. Noticeably, molecular alterations in YAP1, TAZ or in the Hippo genes LATS2, TAOK1, and NF2 are present in 19% of all non-small cell lung cancer patients, and overexpression or amplification of TAZ correlates with a worse outcome in lung adenocarcinoma patients. Our data demonstrate that Hippo pathway genes are required for susceptibility to BETi by restraining TAZ activity as transcriptional coactivator, and suggest that this mechanism can be exploited to detect and overcome drug resistance in lung cancer. BETi-mediated downregulation of the YAP1/TAZ/TEAD transcriptional activity provides a rationale for using these drugs to counteract the activity of these pro-oncogenic transcription factors

Paracoccidioidomycosis in the state of Maranhão, Brazil: geographical and clinical aspects

INTRODUCTION: The study aimed to show the situation of paracoccidioidomycosis in the state of Maranhão, Brazil. METHODS: This study is a descriptive case series developed in two stages. First, a survey of cases originating from the state of Maranhão at the Instituto de Doenças Tropicais Natan Portela, Piauí (IDTNP) from 1997 to 2007, and second, the clinical description of 29 cases diagnosed in the Centro de Referências em Doenças Infecciosas e Parasitárias, Maranhão (CREDIP) from 2004 to 2010. RESULTS: Two hundred and sixteen cases have been cataloged at the IDTNP. West, east, and central regions of the state of Maranhão recorded 90.3% of cases proving to be important areas for study. The western region, with a prevalence of 10.8/100,000 inhabitants, has a significantly higher proportion of cases than the northern, southern, and eastern regions (p < 0.05). The occurrence was higher in men with 89.3% of cases, and the male-to-female ratio was 8.4:1. The majority of patients were older than 20 years, lived in rural areas, and had farming or soil management as main occupation (73.8%). At CREDIP, 29 cases were diagnosed, of which 26 (89.6%) had multifocal manifestations. Mucous tissues were involved more (75.8%) frequently, followed by lymph nodes, skin, and lungs with 65.5%, 39% and 37.9 %, respectively. The diagnosis was made by combining direct examination, culture, and histopathology. CONCLUSIONS: The study shows the geographical distribution and the epidemiological and clinical aspects of paracoccidioidomycosis, revealing the significance of the disease to the state of Maranhão

Outcomes from elective colorectal cancer surgery during the SARS‐CoV‐2 pandemic

Aim This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic. Method This was an international cohort study of patients undergoing elective resection of colon or rectal cancer without preoperative suspicion of SARS-CoV-2. Centres entered data from their first recorded case of COVID-19 until 19 April 2020. The primary outcome was 30-day mortality. Secondary outcomes included anastomotic leak, postoperative SARS-CoV-2 and a comparison with prepandemic European Society of Coloproctology cohort data. Results From 2073 patients in 40 countries, 1.3% (27/2073) had a defunctioning stoma and 3.0% (63/2073) had an end stoma instead of an anastomosis only. Thirty-day mortality was 1.8% (38/2073), the incidence of postoperative SARS-CoV-2 was 3.8% (78/2073) and the anastomotic leak rate was 4.9% (86/1738). Mortality was lowest in patients without a leak or SARS-CoV-2 (14/1601, 0.9%) and highest in patients with both a leak and SARS-CoV-2 (5/13, 38.5%). Mortality was independently associated with anastomotic leak (adjusted odds ratio 6.01, 95% confidence interval 2.58–14.06), postoperative SARS-CoV-2 (16.90, 7.86–36.38), male sex (2.46, 1.01–5.93), age >70 years (2.87, 1.32–6.20) and advanced cancer stage (3.43, 1.16–10.21). Compared with prepandemic data, there were fewer anastomotic leaks (4.9% versus 7.7%) and an overall shorter length of stay (6 versus 7 days) but higher mortality (1.7% versus 1.1%). Conclusion Surgeons need to further mitigate against both SARS-CoV-2 and anastomotic leak when offering surgery during current and future COVID-19 waves based on patient, operative and organizational risks