Search

For chronic myeloid leukemia (CML) patients with a known risk of cardiovascular events (CVE), imatinib is often recommended for first-line tyrosine kinase inhibitor (TKI) treatment rather than a second-generation TKI (2G-TKI) such as nilotinib or dasatinib. To date, very few studies have evaluated the genetic predisposition associated with CVE development on TKI treatment. In this retrospective study of 102 CML patients, 26 CVEs were reported during an average follow-up of over 10 years. Next-generation sequencing identified pathogenic/likely pathogenic mutations in genes associated with myeloid malignancies in 24.5% of the diagnostic samples analyzed. Patients with a recorded CVE had more myeloid mutations (0.48 vs. 0.14, p = 0.019) and were older (65.1 vs. 55.7 years, p = 0.016). Age ≥ 60 years and receiving a 2G-TKI in first-line were CVE risk factors. The presence of a pathogenic somatic myeloid mutation was an independent risk factor for CVE on any TKI (HR 2.79, p = 0.01), and significantly shortened the CV event-free survival of patients who received first-line imatinib (by 70 months, p = 0.011). Indeed, 62% of patients on imatinib with mutations had a CVE vs. the 19% on imatinib with a mutation and no CVE. In conclusion, myeloid mutations detectable at diagnosis increase CVE risk, particularly for patients on imatinib, and might be considered for first-line TKI choice.

Clinical trials have demonstrated that some patients with chronic myeloid leukemia (CML) treated for several years with tyrosine kinase inhibitors (TKIs) who have maintained a molecular response can successfully discontinue treatment without relapsing. Treatment free remission (TFR) can be reached by approximately 50% of patients who discontinue. Despite having similar levels of deep molecular response and an identical duration of treatment, the factors that influence the successful discontinuation of CML patients remain to be determined. In this review we will explore the factors identified to date that can help predict whether a patient will successfully achieve TFR. We will also discuss the need for the identification of predictive biomarkers associated with a high probability of achieving TFR for the future personalized identification of patients who are suitable for the discontinuation of TKI treatment.

Advances in Next-Generation Sequencing technologies (NGS) are revealing germline and somatic mutations that, together with karyotype, determine the diagnosis and subtype of Acute Myeloid Leukemia (AML). Molecular testing is also essential for the genetic risk stratification of patients with AML, in particular for those with normal karyotype AML (CN-AML), a large and highly heterogeneous group of patients. Patients determined to be at high risk could benefit from a more aggressive first-line therapy, or a more directed therapy, such as midostaurin (for FLT3-mutated AML) or ivosidenib (for IDH1-mutated AML). Here, we will summarize the molecular testing currently recommended in AML and introduce new mutations that may have prognostic value and clinical application in the near future.

Recent advances in sequencing technologies and genomics have led to the development of several targeted therapies such as BCL2 and Bromodomain and extra-terminal (BET) protein inhibitors for a more personalized treatment of patients with acute myeloid leukemia (AML), yet the majority of patients still receive standard induction chemotherapy. The molecular profiles of patients who are likely to respond to induction therapy and novel directed therapies remain to be determined. The expression of AML-related genes that are targeted by novel therapies such as

Advances in acute myeloid leukemia (AML) genomics and targeted therapies include the recently approved BCL2 inhibitor venetoclax. The association between BCL2 expression and patient outcome was analyzed in a series of 176 consecutive AML patients at diagnosis (Dx), post-induction (PI), complete remission (CR) and relapse (RL). Levels increased significantly at relapse (mean 1.07 PI/0.96 CR vs. 2.17 RL, p = 0.05/p = 0.03). In multivariate analysis, high BCL2-Dx were marginally associated with worse progression-free survival, while high PI levels or at CR had an independent negative impact on outcome (PI: HR 1.58, p = 0.014, CR: HR 1.96, p = 0.008). This behavior of high PI or CR BCL2 levels and increased risk was maintained in a homogeneous patient subgroup of age &lt, 70 and intermediate cytogenetic risk (PI: HR 2.44, p = 0.037, CR: HR 2.71, p = 0.049). Finally, for this subgroup, high BCL2 at relapse indicated worse overall survival (OS, HR 1.15, p = 0.05). In conclusion, high BCL2 levels PI or at CR had an independent negative impact on patient outcome. Therefore, BCL2 expression is a dynamic marker that may be useful during AML patient follow up, and BCL2 levels at PI and/or CR may influence response to anti-BCL2 therapy.

Neurocognitive disorders (NCD) affect over 50 million people globally. The detection biomarkers using brain imaging or cerebrospinal fluid are expensive procedures. Blood-based biomarkers such as plasma or serum present a cost-effective alternative. The work presented in this paper is focused on the use of hyperspectral (HS) imaging (HSI) to classify plasma samples in order to discriminate between patients with major NCD and healthy control subjects. HS images of plasma samples were obtained using a SWIR (Short-Wave Infrared) camera able to capture 273 bands within the 900-2,500 nm spectral range. A preliminary HSI database was obtained with 20 major NCD samples and 20 control samples. This data was segmented and classified using pixel-wise supervised classification algorithms, achieving 75% sensitivity and 100% specificity results with the best classifier in the test set.

The development of thrombotic events is common among patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We studied the influence of pathogenic mutations frequently associated with myeloid malignancies on thrombotic events using next-generation sequencing (NGS) in an initial cohort of 68 patients with myeloproliferative neoplasms (MPN). As expected, the presence of mutations in DNMT3A, TET2, and ASXL1 (DTA genes) was positively associated with age for the whole cohort (p = 0.025, OR: 1.047, 95% CI: 1.006&ndash, 1.090). Also, while not related with events in the whole cohort, DTA mutations were strongly associated with the development of vascular events in PV patients (p = 0.028). To confirm the possible association between the presence of DTA mutation and thrombotic events, we performed a case-control study on 55 age-matched patients with PV (including 12 PV patients from the initial cohort, 25 with event vs. 30 no event). In the age-matched case-control PV cohort, the presence of &ge, 1 DTA mutation significantly increased the risk of a thrombotic event (OR: 6.333, p = 0.0024). Specifically, mutations in TET2 were associated with thrombotic events in the PV case-control cohort (OR: 3.56, 95% CI: 1.15&ndash, 11.83, p = 0.031). Our results suggest that pathogenic DTA mutations, and particularly TET2 mutations, may be an independent risk factor for thrombosis in patients with PV. However, the predictive value of TET2 and DTA mutations in ET and PMF was inconclusive and should be determined in a larger cohort.

Microsatellite instability (MSI) and aneuploidy are inversely related phenomena. We tested whether ploidy status influences the clinical impact of MSI in endometrioid endometrial cancer (EEC). We analyzed 167 EECs for MSI and ploidy. Tumors were classified in three categories according to MSI and ploidy status. Associations with clinicopathological and molecular variables, survival, and treatment response were assessed. All MSI tumors (23%) were scored as diploid, and 14% of microsatellite stable (MSS) tumors presented aneuploidy. MSI tumors associated with older age at diagnosis, non-obesity, high histological grade, and advanced surgical stage. MSS-aneuploid tumors also associated with higher grade and advanced stage. In multivariate survival analysis MSI did not influence disease-free survival (DFS) or cancer-specific survival (CSS). However, when just diploid tumors were considered for the analysis, MSI significantly contributed to worse DFS and CSS, and the same was observed for aneuploidy when MSS tumors were analyzed alone. In diploid tumors, a differential response to postoperative radiotherapy (RT) was observed according to MSI, since it predicted poor DFS and CSS in the multivariate analysis. We conclude that ploidy status influences the clinical impact of MSI in EEC. Among diploid tumors those with MSI have poor clinical outcome and respond worse to RT.

// Cristina Bilbao-Sieyro 1,2 , Yanira Florido 1 and Maria Teresa Gomez-Casares 1 1 Hematology Department, Hospital Universitario de Gran Canaria Dr. Negrin, Las Palmas de Gran Canaria, Spain 2 Morfology Department, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain Correspondence to: Maria Teresa Gomez-Casares, email: // Cristina Bilbao-Sieyro, email: // Keywords : CALR, myeloproliferative neoplasms, type-1/2-like mutations Received : March 23, 2016 Accepted : June 13, 2016 Published : July 01, 2016 Abstract Identification of somatic frameshift mutations in exon 9 of the calreticulin gene (CALR) in myeloproliferative neoplasms (MPNs) in December of 2013 has been a remarkable finding. It has provided a new molecular diagnostic marker, particularly in essential thrombocythemia (ET) and primary myelofibrosis (PMF), where is the second most common altered gene after JAK2V617F. There are two main types of CALR mutants, type 1 and type 2, and there is evidence about their distinct clinical/prognostic implications, for instances, it is believed that favorable outcome might be restricted to type-1 in PMF. By using reasoned approaches, very recent publications have supported classifying the alternative mutants in type-1-like or type-2-like. If further studies confirm these results, new considerations may be taken into account in the molecular diagnosis of MPNs. This implies that precise mutation characterization must be performed and caution should be taken in screening technique selection. In this Editorial we summarize the current information regarding all this issues.

// Sergio Alonso 1, 2 , Yuichi Dai 1, 3, 4 , Kentaro Yamashita 1 , Shina Horiuchi 1 , Tomoko Dai 1, 3 , Akihiro Matsunaga 1 , Rosa Sanchez-Munoz 1 , Cristina Bilbao-Sieyro 5 , Juan Carlos Diaz-Chico 5 , Andrei V. Chernov 6 , Alex Y. Strongin 6 , Manuel Perucho 1, 2, 7 1 Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA 2 Institute of Predictive and Personalized Medicine of Cancer (IMPPC), IGTP, Badalona, Barcelona, Spain 3 Dept. of Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan 4 Dept. of Diagnostic Pathology, Tsukuba Memorial Hospital, Tsukuba, Ibaraki, Japan 5 Dept. of Biochemistry and Molecular Biology, Cancer Research Institute of The Canary Islands, University of Las Palmas de Gran Canaria, Spain 6 Cancer Research Center, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA 7 Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain Correspondence to: Manuel Perucho, e-mail: mperucho@imppc.org Keywords: KRAS mutations, TP53 mutations, MGMT , O 6 -methylguanine-DNA methyltransferase, ADAMTS14 , CRC, colorectal cancer Received: November 28, 2014 Accepted: December 04, 2014 Published: February 02, 2015 ABSTRACT Somatic hypermethylation of the O 6 -methylguanine-DNA methyltransferase gene ( MGMT ) was previously associated with G > A transition mutations in KRAS and TP53 in colorectal cancer (CRC). We tested the association of MGMT methylation with G > A mutations in KRAS and TP53 in 261 CRCs. Sixteen cases, with and without MGMT hypermethylation, were further analyzed by exome sequencing. No significant association of MGMT methylation with G > A mutations in KRAS, TP53 or in the whole exome was found ( p > 0.5 in all comparisons). The result was validated by in silico comparison with 302 CRCs from The Cancer Genome Atlas (TCGA) consortium dataset. Transcriptional silencing associated with hypermethylation and stratified into monoallelic and biallelic. We also found a significant clustering ( p = 0.001) of aberrant hypermethylation of MGMT and the matrix metalloproteinase gene ADAMTS14 in normal colonic mucosa of CRC patients. This suggested the existence of an epigenetic field defect for cancerization disrupting the methylation patterns of several loci , including MGMT or ADAMTS14 , that may lead to predictive biomarkers for CRC. Methylation of these loci in normal mucosa was more frequent in elder ( p = 0.001) patients, and particularly in African Americans ( p = 1 × 10 −5 ), thus providing a possible mechanistic link between somatic epigenetic alterations and CRC racial disparities in North America.