Plasmatic BRAF-V600E allele fraction as a prognostic factor in metastatic colorectal cancer treated with BRAF combinatorial treatments

BRAF inhibitor; Colorectal cancerInhibidor de BRAF; Cáncer colorrectalInhibidor de BRAF; Càncer colorectalBackground Combination of a BRAF inhibitor (BRAFi) and an anti-epidermal growth factor receptor (EGFR), with or without a MEK inhibitor (MEKi), improves survival in BRAF-V600E-mutant metastatic colorectal cancer (mCRC) over standard chemotherapy. However, responses are heterogeneous and there are no available biomarkers to assess patient prognosis or guide doublet- or triplet-based regimens. In order to better characterize the clinical heterogeneity observed, we assessed the prognostic and predictive role of the plasmatic BRAF allele fraction (AF) for these combinations. Patients and methods A prospective discovery cohort including 47 BRAF-V600E-mutant patients treated with BRAFi–anti-EGFR ± MEKi in clinical trials and real-world practice was evaluated. Results were validated in an independent multicenter cohort (n = 29). Plasmatic BRAF-V600E AF cut-off at baseline was defined in the discovery cohort with droplet digital PCR (ddPCR). All patients had tissue-confirmed BRAF-V600E mutations. Results Patients with high AF have major frequency of liver metastases and more metastatic sites. In the discovery cohort, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 10.1 months, respectively. Patients with high BRAF AF (≥2%, n = 23) showed worse PFS [hazard ratio (HR) 2.97, 95% confidence interval (CI) 1.55-5.69; P = 0.001] and worse OS (HR 3.28, 95% CI 1.58-6.81; P = 0.001) than low-BRAF AF patients (<2%, n = 24). In the multivariable analysis, BRAF AF levels maintained independent significance. In the validation cohort, high BRAF AF was associated with worse PFS (HR 3.83, 95% CI 1.60-9.17; P = 0.002) and a trend toward worse OS was observed (HR 1.86, 95% CI 0.80-4.34; P = 0.15). An exploratory analysis of predictive value showed that high-BRAF AF patients (n = 35) benefited more from triplet therapy than low-BRAF AF patients (n = 41; PFS and OS interaction tests, P < 0.01). Conclusions Plasmatic BRAF AF determined by ddPCR is a reliable surrogate of tumor burden and aggressiveness in BRAF-V600E-mutant mCRC treated with a BRAFi plus an anti-EGFR with or without a MEKi and identifies patients who may benefit from treatment intensification. Our results warrant further validation of plasmatic BRAF AF to refine clinical stratification and guide treatment strategies.This work was supported by the Fundación FERO; the Fondo Europeo de Desarrollo Regional (FEDER) ISCIII-FEDER [grant number PI20/00968]; and Fundación AECC [grant number CLSEN19001ELEZ], CRIS contra el Cancer and Mutual Medica Fellowship

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Colorectal cancer; Predictive markers; Tumour biomarkersCáncer colorrectal; Marcadores predictivos; Biomarcadores tumoralesCàncer colorrectal; Marcadors predictius; Biomarcadors tumoralsAnti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.VHIO would like to acknowledge the Cellex Foundation for providing research facilities and equipment, the FERO Foundation for their funding support, the Consorcio Centro de Investigación Biomédica en Red de Cáncer (CIBERONC, CB16/12/00259) from the Institute of Health Carlos III (ISCIII), Ministry of Science and Innovation, and the Department of Health (Generalitat de Catalunya, SLT008/18/00198 and SLT008/18/00205) for their support on this research. Authors acknowledge financial support from the State Agency for Research (Agencia Estatal de Investigación) (CEX2020-001024-S / AEI / 10.13039 /501100011033). This research is funded by the SCITRON program; Novartis funded the genomics characterization by WES of samples from 28 patients from the discovery cohort and had no influence on data analysis/interpretation or writing of the paper (3003145512 to R.A.T.). S.Li. is financially supported by a Chinese Scholarship Council PhD fellowship (201909370083 to S. Li). R.P.-L. is supported by a CRIS Foundation Talent Award (TALENT19-05), the FERO Foundation, the Instituto de Salud Carlos III-Investigación en Salud (PI18/01395 and PI21/01019 to R.P.-L.) and the Prostate Cancer Foundation (Young Investigator Award). This work was supported by the Miguel Servet-I Research Award from ISCIII of the Ministry of Economy (CP17/00199 to R.A.T.), the Olga Torres Foundation Award to emerging researchers (2601 to R.A.T.), the ISCIII-FEDER (PI17/00947 and PI20/00968 to E.E.), and the Fundación AECC (CLSEN19001ELEZ to E.E.) and Ministry of Science and Innovation (Europa Redes y Gestores, ECT2020-000827 to E.E.)

Changes in the stool and oropharyngeal microbiome in obsessive-compulsive disorder

Although the etiology of obsessive-compulsive disorder (OCD) is largely unknown, it is accepted that OCD is a complex disorder. There is a known bi-directional interaction between the gut microbiome and brain activity. Several authors have reported associations between changes in gut microbiota and neuropsychiatric disorders, including depression or autism. Furthermore, a pediatric-onset neuropsychiatric OCD-related syndrome occurs after streptococcal infection, which might indicate that exposure to certain microbes could be involved in OCD susceptibility. However, only one study has investigated the microbiome of OCD patients to date. We performed 16S ribosomal RNA gene-based metagenomic sequencing to analyze the stool and oropharyngeal microbiome composition of 32 OCD cases and 32 age and gender matched controls. We estimated different α- and β-diversity measures and performed LEfSe and Wilcoxon tests to assess differences in bacterial distribution. OCD stool samples showed a trend towards lower bacterial α-diversity, as well as an increase of the relative abundance of Rikenellaceae, particularly of the genus Alistipes, and lower relative abundance of Prevotellaceae, and two genera within the Lachnospiraceae: Agathobacer and Coprococcus. However, we did not observe a different Bacteroidetes to Firmicutes ratio between OCD cases and controls. Analysis of the oropharyngeal microbiome composition showed a lower Fusobacteria to Actinobacteria ratio in OCD cases. In conclusion, we observed an imbalance in the gut and oropharyngeal microbiomes of OCD cases, including, in stool, an increase of bacteria from the Rikenellaceae family, associated with gut inflammation, and a decrease of bacteria from the Coprococcus genus, associated with DOPAC synthesis

Impact of the COVID-19 pandemic in the early-onset colorectal cancer

COVID-19 pandemic; Early-onset colorectal cancerPandemia de COVID-19 Cáncer colorrectal precozPandèmia de COVID-19; Càncer colorectal precoçThe COVID19 pandemic has affected the spectrum of cancer care worldwide. Early onset colorectal cancer (EOCRC) is defined as diagnosis below the age of 50. Patients with EOCRC faced multiple challenges during the COVID19 pandemic and in some institutions it jeopardized cancer diagnosis and care delivery. Our study aims to identify the clinicopathological features and outcomes of patients with EOCRC in our Centre during the first wave of the pandemic in comparison with the same period in 2019 and 2021. Patients with EOCRC visited for the first time at Vall d'Hebron University Hospital in Spain from the 1st March to 31st August of 2019, 2020 and 2021 were included in the analysis. 177 patients with EOCRC were visited for the first time between 2019 and 2021, of which 90 patients met the inclusion criteria (2019: 30 patients, 2020: 29 patients, 2021: 31 patients). Neither differences in frequency nor in stage at diagnosis or at first visit during the given periods were observed. Of note, indication of systemic therapy in the adjuvant or metastatic setting was not altered. Days to treatment initiation and enrollment in clinical trials in this subpopulation was not affected due to the COVID-19 outbreak.This work was supported by the Cancer Research UK (CRUK) grant OPTIMISTICC (C10674/A27140)

A Comprehensive Biomarker Analysis of Microsatellite Unstable/Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy

Biomarkers; Colorectal cancer; ImmunotherapyBiomarcadors; Càncer colorectal; ImmunoteràpiaBiomarcadores; Cáncer colorrectal; InmunoterapiaThe search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial.This research was funded by Merck Research Grants (Call 2018) in the Area of Colorectal Cancer Clinical Investigation

Correction : Chaparro et al. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. J. Clin. Med. 2021, 10, 2885

The authors wish to make the following corrections to this paper [...]

Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain : Large-Scale Epidemiological Study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD-Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)-during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100,000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31-56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

Jardins per a la salut

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia. Assignatura: Botànica farmacèutica. Curs: 2014-2015. Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són el recull de les fitxes botàniques de 128 espècies presents en el Jardí Ferran Soldevila de l’Edifici Històric de la UB. Els treballs han estat realitzats manera individual per part dels estudiants dels grups M-3 i T-1 de l’assignatura Botànica Farmacèutica durant els mesos de febrer a maig del curs 2014-15 com a resultat final del Projecte d’Innovació Docent «Jardins per a la salut: aprenentatge servei a Botànica farmacèutica» (codi 2014PID-UB/054). Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pels professors de l’assignatura. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica. També s’ha pretès motivar els estudiants a través del retorn de part del seu esforç a la societat a través d’una experiència d’Aprenentatge-Servei, deixant disponible finalment el treball dels estudiants per a poder ser consultable a través d’una Web pública amb la possibilitat de poder-ho fer in-situ en el propi jardí mitjançant codis QR amb un smartphone

Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when = 50 years and symptomatic for <= 7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with <= 5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution