New insights into the role of the RNA binding proteins CPEBs in cancer

Cytoplasmic polyadenylation binding proteins (CPEB) are a family of RNA binding proteins which control the translation of its target mRNAs by modulating the length poly(A) mRNA tail. Cytoplasmic polyadenylation was originally discovered in oocytes, during meiotic progression, and more recently it has also been described in neuronal synapsis and in other somatic contexts. Currently, it has been proposed that 20% of the transcriptome can be potential targets to be regulated by this cytoplasmic polyadenylation. These mRNAs have a Cytoplasmic Polyadenylation Element (CPE) in its 3’ UnTranslated Regions (3’UTR) that is recognized by CPEBs. Although, several studies show that CPEBs have an important role in cancer progression and metastasis, its mechanistic role remain incomplete or unknown. In this study we describe the contribution of CPEB1 in pancreatic cancer progression and the role of CPEB4 in endometrial cancer metastasis. On one hand, CPEB1 acts both as a tumour suppressor or oncogene depending on the basal amounts of this protein inside the cell. On the other hand, CPEB4 impairs the metastatic potential of endometrial cancer cells by inhibiting the translation of key metastatic genes.Les proteïnes d'unió a elements de poliadenilació citoplasmàtica (CPEB) són una família de proteïnes d'unió a ARN que controlen la traducció dels seus ARN missatger objectiu mitjançant la modulació de la longitud de la cua de poly(A) del ARN missatger. La poliadenilació citoplasmàtica va ser descoberta orginàriament in oòcits, durant la progressió meiòtica. Recentment, també s’ha descrit el seu rol en la sinapsi neuronal i altres contexts somàtics. Actualment, s’ha predit que al voltant del 20% del transcriptoma es, potencialment, una diana de la poliadenilació citoplasmàtica. Aquests ARN missatgers tenen un Element de Poliadenilació Citoplasmàtica (CPE) a la seva regió no traduïda al 3’ (3’UTR) que es reconeguda per les proteines CPEB. Tot i que diversos estudis mostren que les CPEBs tenen un paper important en la progressió i la metàstasi del càncer, el seu paper i mecanisme roman incomplet o desconegut. En aquest estudi es descriu l'aportació de CPEB1 en la progressió del càncer de pàncrees i el paper de CPEB4 en la metàstasi del càncer d'endometri. D'una banda, CPEB1 actua tant com a supressor tumoral o oncogèn en funció de les quantitats basals d'aquesta proteïna dins de la cèl·lula. D'altra banda, CPEB4 impedeix el potencial metastàtic de les cèl·lules del càncer d’endometri inhibint la traducció de gens clau en la metàstasi

Machine learning risk prediction model of 90-day mortality after gastrectomy for cancer

Objective: to develop and validate a risk prediction model of 90-day mortality (90DM) using machine learning in a large multicenter cohort of patients undergoing gastric cancer resection with curative intent. Background: the 90DM rate after gastrectomy for cancer is a quality of care indicator in surgical oncology. There is a lack of well-validated instruments for personalized prognosis of gastric cancer. Methods: consecutive patients with gastric adenocarcinoma who underwent potentially curative gastrectomy between 2014 and 2021 registered in the Spanish EURECCA Esophagogastric Cancer Registry database were included. The 90DM for all causes was the study outcome. Preoperative clinical characteristics were tested in four 90DM predictive models: Cross Validated Elastic regularized logistic regression method (cv-Enet), boosting linear regression (glmboost), random forest, and an ensemble model. Performance was evaluated using the area under the curve by 10-fold cross-validation. Results: a total of 3182 and 260 patients from 39 institutions in 6 regions were included in the development and validation cohorts, respectively. The 90DM rate was 5.6% and 6.2%, respectively. The random forest model showed the best discrimination capacity with a validated area under the curve of 0.844 [95% confidence interval (CI): 0.841-0.848] as compared with cv-Enet (0.796, 95% CI: 0.784-0.808), glmboost (0.797, 95% CI: 0.785-0.809), and ensemble model (0.847, 95% CI: 0.836-0.858) in the development cohort. Similar discriminative capacity was observed in the validation cohort. Conclusions: a robust clinical model for predicting the risk of 90DM after surgery of gastric cancer was developed. Its use may aid patients and surgeons in making informed decisions

Comprehensive NGS profiling to enable detection of ALK gene rearrangements and MET amplifications in non-small cell lung cancer

Introduction: Next-generation sequencing (NGS) is currently widely used for biomarker studies and molecular profiling to identify concurrent alterations that can lead to the better characterization of a tumor's molecular landscape. However, further evaluation of technical aspects related to the detection of gene rearrangements and copy number alterations is warranted. Methods: There were 12 ALK rearrangement-positive tumor specimens from patients with non-small cell lung cancer (NSCLC) previously detected via fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and an RNA-based NGS assay, and 26 MET high gene copy number (GCN) cases detected by FISH, selected for this retrospective study. All 38 pre-characterized cases were reassessed utilizing the PGDx™ elio™ tissue complete assay, a 505 gene targeted NGS panel, to evaluate concordance with these conventional diagnostic techniques. Results: The detection of ALK rearrangements using the DNA-based NGS assay demonstrated excellent sensitivity with the added benefit of characterizing gene fusion partners and genomic breakpoints. MET copy number alterations were also detected; however, some discordances were observed likely attributed to differences in algorithm, reporting thresholds and gene copy number state. TMB was also assessed by the assay and correlated to the presence of NSCLC driver alterations and was found to be significantly lower in cases with NGS-confirmed canonical driver mutations compared with those without (p=0.0019). Discussion: Overall, this study validates NGS as an accurate approach for detecting structural variants while also highlighting the need for further optimization to enable harmonization across methodologies for amplifications

Comparison of different methods for defining hyperprogressive disease in NSCLC

Introduction: Hyperprogressive disease (HPD) as a consequence of immune checkpoint inhibitors in NSCLC has been reported in multiple studies. However, inconsistent results in incidence and survival outcomes within studies, together with different assessment methods, have led to increasing controversy regarding the concept of HPD. Methods: Consecutive patients treated with nivolumab (N = 42) or docetaxel (N = 37) were evaluated. HPD was quantified by applying three different methods (tumor growth rate [TGR], tumor growth kinetics [TGK], and Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]). HPD rates were compared between and within both cohorts using the different methods. Results: Using TGR, TGK, and RECIST 1.1, we identified seven (16.7%), seven (16.7%), and six (14.3%) patients with HPD in the nivolumab cohort and three (8.1%), four (10.8%), and five (13.6%) in the docetaxel cohort, respectively. We observed a higher concordance between TGR and TGK (90.1%) compared with RECIST 1.1 (31.3% and 37.5% with TGR and TGK, respectively). We found no significant differences in the overall survival between patients with progressive disease and HPD in either cohort. Conclusions: TGR and TGK revealed high concordance rates for identifying patients with HPD in NSCLC. The incidence of HPD was numerically higher in patients treated with immune checkpoint inhibitors. Standardization of methods for measuring HPD and its exploration in larger studies are needed to establish its clinical meaning in NSCLC

MultiCOVID: a multi modal deep learning approach for COVID-19 diagnosis

The rapid spread of the severe acute respiratory syndrome coronavirus 2 led to a global overextension of healthcare. Both Chest X-rays (CXR) and blood test have been demonstrated to have predictive value on Coronavirus Disease 2019 (COVID-19) diagnosis on different prevalence scenarios. With the objective of improving and accelerating the diagnosis of COVID-19, a multi modal prediction algorithm (MultiCOVID) based on CXR and blood test was developed, to discriminate between COVID-19, Heart Failure and Non-COVID Pneumonia and healthy (Control) patients. This retrospective single-center study includes CXR and blood test obtained between January 2017 and May 2020. Multi modal prediction models were generated using opensource DL algorithms. Performance of the MultiCOVID algorithm was compared with interpretations from five experienced thoracic radiologists on 300 random test images using the McNemar-Bowker test. A total of 8578 samples from 6123 patients (mean age 66 ± 18 years of standard deviation, 3523 men) were evaluated across datasets. For the entire test set, the overall accuracy of MultiCOVID was 84%, with a mean AUC of 0.92 (0.89-0.94). For 300 random test images, overall accuracy of MultiCOVID was significantly higher (69.6%) compared with individual radiologists (range, 43.7-58.7%) and the consensus of all five radiologists (59.3%, P < .001). Overall, we have developed a multimodal deep learning algorithm, MultiCOVID, that discriminates among COVID-19, heart failure, non-COVID pneumonia and healthy patients using both CXR and blood test with a significantly better performance than experienced thoracic radiologists

Worse outcome and distinct mutational pattern in follicular lymphoma with anti-HBc positivity

Epidemiological studies have demonstrated the association between hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphoma (NHL), mainly for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). We studied a cohort of 121 patients with FL for HBV infection status, clinical features, and gene mutational profile. Anti-HBc was detectable in 16 patients (13.2%), although all had undetectable HBV DNA. Anti-HBcore+ (anti-HBc+) cases presented with older age at diagnosis than anti-HBc- cases (68.1 vs 57.2 years; P = .007) and higher β2-microglobulin (56.3% vs 28.9%; P = .04). All patients included in the study fulfilled criteria for treatment and received therapy with rituximab or rituximab-containing chemotherapy. There were no episodes of HBV reactivation or HBV hepatitis during treatment and/or maintenance. Remarkably, anti-HBc+ patients had significantly lower 10-year progression-free survival (PFS; 12.9% vs 58.3%; P < .0001) and overall survival (OS; 22.0% vs 86.2%; P < .0001), that remained at multivariate analysis. Gene mutational profiling of all cases showed that anti-HBc+ cases had higher incidence of ARID1A mutations and absence of EP300 mutations, 2 key epigenetic regulators in FL. Overall, our study shows that FL patients with resolved HBV infection have a worse outcome independently of other well-known clinical risk factors and a distinct gene mutational profile

Outcomes and molecular profile of oligomonocytic CMML support its consideration as the first stage in the CMML continuum

atients with oligomonocytic chronic myelomonocytic leukemia (OM-CMML) are currently classified according to the 2017 World Health Organization myelodysplastic syndromes classification. However, recent data support considering OM-CMML as a specific subtype of chronic myelomonocytic leukemia (CMML), given their similar clinical, genomic, and immunophenotypic profiles. The main purpose of our study was to provide survival outcome data of a well-annotated series of 42 patients with OM-CMML and to compare them to 162 patients with CMML, 120 with dysplastic type (D-CMML), and 42 with proliferative type (P-CMML). OM-CMML had significantly longer overall survival (OS) and acute myeloid leukemia-free survival than did patients with CMML, considered as a whole group, and when compared with D-CMML and P-CMML. Moreover, gene mutations associated with increased proliferation (ie, ASXL1 and RAS-pathway mutations) were identified as independent adverse prognostic factors for OS in our series. We found that at a median follow-up of 53.47 months, 29.3% of our patients with OM-CMML progressed to D-CMML, and at a median follow-up of 46.03 months, 28.6% of our D-CMML group progressed to P-CMML. These data support the existence of an evolutionary continuum of OM-CMML, D-CMML, and P-CMML. In this context, we observed that harboring more than 3 mutated genes, carrying ASXL1 mutations, and a peripheral blood monocyte percentage >20% significantly predicted a shorter time of progression of OM-CMML into overt CMML. These variables were also detected as independent adverse prognostic factors for OS in OM-CMML. These data support the consideration of OM-CMML as the first evolutionary stage within the proliferative continuum of CMML

Evaluation of four prognostic indices in follicular lymphoma treated in first line with immunochemotherapy

[AHEAD] Data de publicació electrónica: 19-10-2022Several clinical risk models have been proposed to predict outcome in follicular lymphoma (FL). The development of Next Generation Sequencing (NGS) technologies has allowed the integration of somatic gene mutations in clinical scores to build genotyped-based risk models, such as m7-FLIPI. We explored four clinical or clinicogenetic risk models in patients with symptomatic FL who received frontline immunochemotherapy. Out of 191 patients with FL grade 1-3a, 109 were successfully genotyped. Treatment consisted on rituximab (R) plus CVP/CHOP (72.5%) or R-bendamustine (R-B) (27.5%). The proportion of cases classified as high-risk in FLIPI, FLIPI-2, PRIMA-PI or m7-FLIPI were 39.3%, 14%, 30.3%, 22%, respectively. No case with low-intermediate FLIPI was upgraded in m7-FLIPI, but 18 out of 42 higher-risk patients in FLIPI were downgraded to low-risk m7-FLIPI. Sensitivity and specificity for the prediction of POD24 was highest for FLIPI. The discrimination for progression free survival (PFS) and overall survival (OS) was best for FLIPI (c-index: 0.644 and 0.727, respectively). When analyzed only R-B patients, m7-FLIPI had higher discrimination for PFS and OS. Thus, FLIPI remains as the clinical risk score with higher discrimination in advanced FL patients treated with immunochemotherapy, but the performance of m7-FLIPI should be further investigated in patients treated with R-B

Molecular and cytogenetic characterization of myelodysplastic syndromes in cell-free DNA

Molecular and cytogenetic studies are essential for diagnosis and prognosis in patients with myelodysplastic syndromes (MDSs). Cell-free DNA (cfDNA) analysis has been reported to be a reliable noninvasive approach for detecting molecular abnormalities in MDS; however, there is limited information about cytogenetic alterations and monitoring in cfDNA. We assessed the molecular and cytogenetic profile of a cohort of 70 patients with MDS by next-generation sequencing (NGS) of cfDNA and compared the results to sequencing of paired bone marrow (BM) DNA. Sequencing of BM DNA and cfDNA showed a comparable mutational profile (92.1% concordance), and variant allele frequencies (VAFs) strongly correlated between both sample types. Of note, SF3B1 mutations were detected with significantly higher VAFs in cfDNA than in BM DNA. NGS and microarrays were highly concordant in detecting chromosomal alterations although with lower sensitivity than karyotype and fluorescence in situ hybridization. Nevertheless, all cytogenetic aberrations detected by NGS in BM DNA were also detected in cfDNA. In addition, we monitored molecular and cytogenetic alterations and observed an excellent correlation between the VAFs of mutations in BM DNA and cfDNA across multiple matched time points. A decrease in the cfDNA VAFs was detected in patients responding to therapy, but not in nonresponding patients. Of note, cfDNA analysis also showed cytogenetic evolution in 2 nonresponsive cases. In summary, although further studies with larger cohorts are needed, our results support the analysis of cfDNA as a promising strategy for performing molecular characterization, detection of chromosomal aberrations and monitoring of patients with MDS