Clinical utility of comprehensive circulating tumor DNA genotyping compared with standard of care tissue testing in patients with newly diagnosed metastatic colorectal cancer.

BACKGROUND: Comprehensive biomarker testing is essential in selecting optimal treatment for patients with metastatic colorectal cancer (mCRC); however, incomplete genotyping is widespread, with most patients not receiving testing for all guideline-recommended biomarkers, in part due to reliance on burdensome sequential tissue-based single-biomarker tests with long waiting times or availability of only archival tissue samples. We aimed to demonstrate that liquid biopsy, associated with rapid turnaround time (TAT) and lower patient burden, effectively identifies guideline-recommended biomarkers in mCRC relative to standard of care (SOC) tissue testing. PATIENTS AND METHODS: Prospectively enrolled patients with previously untreated mCRC undergoing physician discretion SOC tissue genotyping submitted pretreatment blood samples for comprehensive circulating tumor DNA (ctDNA) analysis with Guardant360 and targeted RAS and BRAF analysis with OncoBEAM. RESULTS: Among 155 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 82 patients, versus 88 identified with comprehensive ctDNA (52.9% versus 56.8%, noninferiority demonstrated down to α = 0.005) and 69 identified with targeted PCR ctDNA analysis (52.9% versus 44.5%, noninferiority rejected at α = 0.05). Utilizing ctDNA in addition to tissue increased patient identification for a guideline-recommended biomarker by 19.5% by rescuing those without tissue results either due to tissue insufficiency, test failure, or false negatives. ctDNA median TAT was significantly faster than tissue testing when the complete process from sample acquisition to results was considered (median 10 versus 27 days, P < 0.0001), resulting in accelerated biomarker discovery, with 52.0% biomarker-positive patients identified by ctDNA versus 10.2% by SOC tissue 10 days after sample collection (P < 0.0001). CONCLUSIONS: Comprehensive ctDNA genotyping accurately identifies guideline-recommended biomarkers in patients with mCRC at a rate at least as high as SOC tissue genotyping, in a much shorter time. Based on these findings, the addition of ctDNA genotyping to clinical practice has significant potential to improve the care of patients with mCRC.

Defining left bundle branch block according to the new 2021 European Society of Cardiology criteria.

Correctly diagnosing left bundle branch block (LBBB) is fundamental, as LBBB occurs frequently in heart failure and may trigger a vicious cycle of progressive left ventricular dysfunction. Moreover, a correct diagnosis of LBBB is pivotal to guide cardiac resynchronisation therapy. Since the LBBB diagnostic criteria were recently updated by the European Society of Cardiology (ESC), we assessed their diagnostic accuracy compared with the previous ESC 2013 definition. We further discuss the complexity of defining LBBB within the context of recent insights into the electromechanical pathophysiology of LBBB.

Aortic valve implantation-induced conduction block as a framework towards a uniform electrocardiographic definition of left bundle branch block.

INTRODUCTION: New-onset left bundle branch block (LBBB) following transcatheter or surgical aortic valve replacement (LBBBAVI) implies a proximal pathogenesis of LBBB. This study compares electrocardiographic characteristics and concordance with LBBB definitions between LBBBAVI and non-procedure-induced LBBB controls (LBBBcontrol). METHODS: All LBBBAVI patients at Ghent University Hospital between 2013 and 2019 were enrolled in the study. LBBBAVI patients were matched for age, sex, ischaemic heart disease and ejection fraction to LBBBcontrol patients in a 1:2 ratio. For inclusion, a non-strict LBBB definition was used (QRS duration ≥ 120 ms, QS or rS in V1, absence of Q waves in V5-6). Electrocardiograms were digitally analysed and classified according to three LBBB definitions: European Society of Cardiology (ESC), Strauss and American Heart Association (AHA). RESULTS: A total of 177 patients (59 LBBBAVI and 118 LBBBcontrol) were enrolled in the study. LBBBAVI patients had more lateral QRS notching/slurring (100% vs 85%, p = 0.001), included a higher percentage with a QRS duration ≥ 130 ms (98% vs 86%, p = 0.007) and had a less leftward oriented QRS axis (-15° vs -30°, p = 0.013) compared to the LBBBcontrol group. ESC and Strauss criteria were fulfilled in 100% and 95% of LBBBAVI patients, respectively, but only 18% met the AHA criteria. In LBBBcontrol patients, concordance with LBBB definitions was lower than in the LBBBAVI group: ESC 85% (p = 0.001), Strauss 68% (p < 0.001) and AHA 7% (p = 0.035). No differences in electrocardiographic characterisation or concordance with LBBB definitions were observed between LBBBAVI and LBBBcontrol patients with lateral QRS notching/slurring. CONCLUSION: Non-uniformity exists among current LBBB definitions concerning the detection of proximal LBBB. LBBBAVI may provide a framework for more consensus on defining proximal LBBB.

Diffuse shear wave spectroscopy for soft tissue viscoelastic characterization.

In order to limit and slow the development of diseases, they have to be diagnosed early as possible to treat patients in a better and more rapid manner. In this paper, we focus on a noninvasive and quick method based on diffuse fields in elastography to detect diseases that affect the stiffness of organs. To validate our method, a phantom experiment numerically pre-validated is designed. It consists of seven vibrators that generate white noises in a bandwidth of [80-300] Hz and then a complex acoustic field in a phantom. Waves are tracked by a linear ultrasound probe L11-4v linked to a Verasonics Vantage System and are converted into a particle velocity 2D map as a function of time. The phase velocity of the shear waves is calculated using a temporal and 2D spatial Fourier transform and an adapted signal-processing method. Shear wave velocity dispersion measurement in the frequency bandwidth of the vibrators enables one to characterize the dynamic hardness of the material through the viscoelastic parameters µ and η in an acquisition time shorter than a second (Tacq = 300 ms). With the aim of estimating the consistency of the method, the experiment is performed N = 10 times. The measured elastic modulus and viscous parameter that quantify the dynamic properties of the medium correspond to the expected values: µ = 1.23 ± 0.05 kPa and η = 0.51 ± 0.09 Pa∙s.

Efficacy of trifluridine and tipiracil (TAS-102) versus placebo, with supportive care, in a randomized, controlled trial of patients with metastatic colorectal cancer from Spain: results of a subgroup analysis of the phase 3 RECOURSE trial

Purpose. TAS-102 is a combination of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer (mCRC) refractory or intolerant to standard therapies were evaluated in the phase 3 RECOURSE trial. Results of RECOURSE demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 versus placebo [hazard ratio (HR) = 0.68 and 0.48 for OS and PFS, respectively; both P < 0.001]. The current analysis evaluates efficacy and safety of TAS-102 in the RECOURSE Spanish subgroup. Methods. Primary and key secondary endpoints were evaluated in a post hoc analysis of the RECOURSE Spanish subgroup, using univariate and multivariate analyses. Safety and tolerability were reported with descriptive statistics. Results. The RECOURSE Spanish subgroup included 112 patients (mean age 61 years, 62 % male). Median OS was 6.8 months in the TAS-102 group (n = 80) versus 4.6 months in the placebo group (n = 32) [HR = 0.47; 95 % confidence interval (CI): 0.28-0.78; P = 0.0032). Median PFS was 2.0 months in the TAS-102 group and 1.7 months in the placebo group (HR = 0.47; 95 % CI: 0.30-0.74; P = 0.001). Eighty (100 %) TAS-102 versus 31 (96.9 %) placebo patients had adverse events (AEs). The most common drug-related ≥Grade 3 AE was neutropenia (40 % TAS-102 versus 0 % placebo). There was 1 (1.3 %) case of febrile neutropenia in the TAS-102 group versus none in the placebo group. Conclusions. In the RECOURSE Spanish subgroup, TAS-102 was associated with significantly improved OS and PFS versus placebo, consistent with the overall RECOURSE population. No new safety signals were identified (AU)

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Efficacy of trifluridine and tipiracil (TAS-102) versus placebo, with supportive care, in a randomized, controlled trial of patients with metastatic colorectal cancer from Spain: results of a subgroup analysis of the phase 3 RECOURSE trial.

PURPOSE: TAS-102 is a combination of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer (mCRC) refractory or intolerant to standard therapies were evaluated in the phase 3 RECOURSE trial. Results of RECOURSE demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 versus placebo [hazard ratio (HR) = 0.68 and 0.48 for OS and PFS, respectively; both P < 0.001]. The current analysis evaluates efficacy and safety of TAS-102 in the RECOURSE Spanish subgroup. METHODS: Primary and key secondary endpoints were evaluated in a post hoc analysis of the RECOURSE Spanish subgroup, using univariate and multivariate analyses. Safety and tolerability were reported with descriptive statistics. RESULTS: The RECOURSE Spanish subgroup included 112 patients (mean age 61 years, 62 % male). Median OS was 6.8 months in the TAS-102 group (n = 80) versus 4.6 months in the placebo group (n = 32) [HR = 0.47; 95 % confidence interval (CI): 0.28-0.78; P = 0.0032). Median PFS was 2.0 months in the TAS-102 group and 1.7 months in the placebo group (HR = 0.47; 95 % CI: 0.30-0.74; P = 0.001). Eighty (100 %) TAS-102 versus 31 (96.9 %) placebo patients had adverse events (AEs). The most common drug-related ≥Grade 3 AE was neutropenia (40 % TAS-102 versus 0 % placebo). There was 1 (1.3 %) case of febrile neutropenia in the TAS-102 group versus none in the placebo group. CONCLUSIONS: In the RECOURSE Spanish subgroup, TAS-102 was associated with significantly improved OS and PFS versus placebo, consistent with the overall RECOURSE population. No new safety signals were identified. CLINICALTRIALS. GOV STUDY NUMBER: NCT01607957.

Alcohol-related emergency department admissions among adolescents in the Ghent and Sint-Niklaas areas.

Alcohol abuse is a major health concern. The aim of this retrospective study was to analyse the alcohol-related emergency department (ED) admissions among adolescents in all hospitals of distinct areas during a 1-year period. In each hospital, all ED patients with a blood alcohol concentration (BAC) of at least 0.5 g/l were surveyed in a standardised way. Of the 3918 included patients, only 146 (3.7%) were < 18  years. The male-to-female ratio was 1.5:1. There was a strong preponderance of weekend and night time admissions. Most of the patients were transported by ambulance (77% of 138 patients with information on this item). The main reason for ED admittance was depressed level of consciousness (64%), trauma (12%), vomiting and/or abdominal pain (12%), agitation or aggression (4%), syncope (4%) and psychological problems (4%). The context of the alcohol intoxication was related to some kind of festivity in 85%, mental problems in 14% and chronic abuse in 1%. Median BAC values (and range) were 2.08 g/l (0.73-3.70 g/l) for boys and 1.51 g/l (0.73-2.90 g/l) for girls. Most patients (87%) could be discharged home within 24  hours. Our study confirms that problematic alcohol use leading to ED admissions starts in adolescence. Although the numbers of cases below 18 years are low when compared to adults, the phenomenon is alarming as it is associated with substantial health problems. Therefore, Belgium urgently needs a global national alcohol plan, with youngsters being one of the target groups.

Budd-Chiari Syndrome Caused by TIPS Malposition: A Case Report.

Budd-Chiari syndrome refers to hepatic pathology secondary to diminished venous outflow, most commonly associated with venothrombotic disease. Clinically, patients with Budd-Chiari present with hepatomegaly, ascites, abdominal distension, and pain. On imaging, Budd-Chiari syndrome is hallmarked by occluded IVC and or hepatic veins, caudate lobe enlargement, heterogeneous liver enhancement, intrahepatic collaterals, and hypervascular nodules. Etiopathological factors for Budd-Chiari syndrome include several systemic thrombotic and nonthrombotic conditions that can cause venous outflow obstruction at hepatic veins and/or IVC. While the transjugular intrahepatic portosystemic shunt (TIPS) is used as a treatment option for Budd-Chiari syndrome, Budd-Chiari syndrome is not a well-known complication of TIPS procedure. We report a case of Budd-Chiari syndrome that occurred in a transplanted cirrhotic liver from malpositioned proximal portion of the TIPS in IVC causing occlusion of the ostia of hepatic veins which was subsequently diagnosed on contrast-enhanced CT.

Manifestaciones neurológicas en pacientes pediátricos con fenilcetonuria. Revisión bibliográfica / Neurological manifestations in pediatric patients with. phenylketonuria: bibliographic review

La fenilcetonuria (PKU) es una enfermedad congénita de herencia autosómica recesiva, en la que existe el déficit de la enzima fenilalanina hidroxilasa, que produce lesión del sistema nervioso central (SNC). La incidencia mundial es de 1:20.000 recién nacidos vivos. (1,2) El tratamiento es a base de dieta con restricción de fenilalanina que debe mantenerse para toda la vida para prevenir el deterioro intelectual. (3,4) OBJETIVO: Identificar manifestaciones neurológicas de pacientes pediátricos con PKU. METODOLOGIA: Revisión bibliográfica de la literatura acerca de las manifestaciones neurológicas para PKU mediante la búsqueda electrónica en varias bases de datos (MEDLINE, EMBASE, COCHRANE, LILACS, PubMed) con límites en inglés y español de enero de 1970 a 2012. RESULTADOS: Se identifica un estudio transversal, un caso clínico, tres revisiones narrativas en poblaciones pediátricas y un caso clínico combinado niños y adultos. La discapacidad intelectual es la principal manifestación neurológica, el criterio diagnóstico primordial fue el valor sérico de fenilalanina. Existen 29 clasificaciones distintas sobre el punto de corte para hiperfenilalaninemia y 23 para fenilcetonuria.

Phenylketonuria (PKU) is a congenital autosomal recessive disease in which there is a shortage of the enzyme phenylalanine hydroxylase, which produces an injury to the central nervous system (CNS). The global incidence is about 1:20,000 live newborns. (1.2) The treatment is based on phenylalanine restricted diet which should be maintained for lifelong to prevent intellectual impairment. OBJECTIVE: To identify neurological manifestations of pediatric patients with PKU. METHODOLOGY: A review of the literature on the neurological manifestations for PKU by searching several electronic databases (MEDLINE , EMBASE, Cochrane , LILACS , PubMed) with English and Spanish limits from January 1970-2012. RESULTS: One cross-sectional study, one clinical case, three narrative reviews in pediatric populations and one clinical case combine children and adults. Intellectual disability is the main neurological manifestation; the primary diagnostic criterion was the serum level of phenylalanine. There are 29 different classifications on the cutoff to hyperphenylalaninemia and 23 for phenylketonuria