Myocardial transcriptomic analysis of diabetic patients with aortic stenosis: key role for mitochondrial calcium signaling.

BACKGROUND: Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism. OBJECTIVES: We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease. METHODS: We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy. RESULTS: T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D. CONCLUSIONS: Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique Identifier: NCT01862237.

Is a severe preoperative condition a contraindication for aortic valve-sparing reimplantation in type A aortic dissection?

BACKGROUND: Type A aortic dissection (TAAD) surgical management is still under debate. The purpose of this study was to demonstrate the feasibility and safety of the aortic valve-sparing root reconstruction (AVSR) procedure in 92 consecutive patients operated for TAAD, even when preoperative condition was severe (malperfusion, shock or both). METHODS: Our hospital database was reviewed to identify all patients who underwent an AVSR procedure for TAAD over 14 years. From May 2000 to June 2014, 92 consecutive patients were studied regarding to their preoperative condition. RESULTS: Age (61±13 years) and logistic Euroscore (23.4±15.3%) as well as cross-clamping (113±39 min), cardiopulmonary bypass (142±49 min) and circulatory arrest (22±13 min) times were collected. Hospital mortality was 16.3%. Mean follow-up was complete for a mean period of 27.6 months. One patient had early reoperation for aortic insufficiency. Actuarial survival at 1 year was 82.5%. The analysis of each group showed comparable mortality and morbidity in between patients. CONCLUSIONS: Based upon our experience in the management of TAAD, a reimplantation procedure could be performed regardless preoperative malperfusion or shock, with an acceptable postoperative over mortality or morbidity. A word of caution should be brought to patients over 70 years old.

Liquid biopsy as a tool for KRAS/NRAS/BRAF baseline testing in metastatic colorectal cancer.

BACKGROUND: The absence of KRAS and NRAS gene mutations (RAS wild type) in metastatic colorectal cancer (mCRC), is associated with a good response to targeted therapy with anti-EGFR receptor antibodies. The current gold standard for RAS mutational status identification is genetic testing on tissue biopsy samples. OBJECTIVE: This study aimed to assess the relevance of liquid biopsy as a less invasive alternative to tissue biopsy for detecting KRAS/NRAS and BRAF mutations in patients with metastatic colorectal cancer (mCRC). The study also aimed to determine the concordance between liquid biopsy and tissue biopsy. METHODS: This is a phase IV, observational, uncontrolled, non-comparative, non-randomized, open label study. RAS/BRAF status will be tested at baseline using tissue and liquid biopsy using the Idylla/Biocartis PCR-based device. The primary endpoint is the comparison of the RAS status based on liquid biopsy with the RAS status based on tissue biopsy. RESULTS: 100 patients with mCRC were included in the study. 75% of patients showed concordant results between liquid biopsy and tissue biopsy, while 25% had discordant results. Liquid biopsy demonstrated a sensitivity of 62% and a specificity of 93%. The accuracy of liquid biopsy was 75%, with a moderate agreement between the two tests. The most frequent mutations in concordant cases were in KRAS (41%), followed by NRAS (4%) and BRAF (3%). Mutations were not detected in 42% of tissue biopsy samples and 60% of liquid biopsy samples. The presence of hepatic metastases did not significantly affect the concordance between the biopsy methods. CONCLUSION: Liquid biopsy using the Idylla™ system showed a relatively low sensitivity but high specificity for detecting KRAS/NRAS and BRAF mutations in mCRC patients. Despite some discordant cases, liquid biopsy remains a promising alternative to tissue biopsy due to its non-invasiveness, ability to provide multiple samples, and better representation of tumor heterogeneity.

Gastrointestinal stromal tumor in North Africa and the middle east: updates in presentation and management from an 11-year retrospective cohort.

OBJECTIVES: This study described the epidemiological, clinical, and survival profiles of patients with gastrointestinal stromal tumor (GIST) in North Africa and the Middle East (AfME). METHODS: This regional, multicenter, observational, retrospective study collected 11-year data on demographics, medical history, disease characteristics, current treatment approaches of GIST, the safety of the most common tyrosine kinase inhibitors (TKIs), second cancers, and survival status. RESULTS: Data of 201 eligible patients were analyzed: mean age was 56.9 ± 12.6 years; 111 (55.2%) patients were men, 21 (10.4%) patients had previous personal malignancy. The most common clinical presentation of GIST was dysphagia [92 (45.8%) patients]. The stomach was the most common primary site in 120 (60.7%) patients, 171 (85.1%) patients had localized disease at diagnosis. 198 (98.5%) GIST cases were CD117/CD34-positive. Imatinib was used in the neoadjuvant (18/21 patients), adjuvant (85/89 patients), and first-line metastatic treatment (28/33 patients) settings. The most common non-hematological toxicity associated with TKIs was vomiting in 32/85 (37.6%) patients. Overall, 100 (49.8%) patients (95%CI: 42.8-56.7%) were alive and disease-free while 30 (14.9%) patients were alive with active disease. CONCLUSION: Presentation of GIST in our AfME population is consistent with global reports, being more frequent in patients >50 years old and having the stomach as the most common primary site. Unlike what is usually reported, though, we did have more patients with lymphatic spread of the disease. Despite the global trend and advances in the treatment of GIST according to molecular profile, this is still far to happen in our population given the lack of access to molecular profiles and the high associated cost.