Combining germline, tissue and liquid biopsy analysis by comprehensive genomic profiling to improve the yield of actionable variants in a real-world cancer cohort.

BACKGROUND: Comprehensive next-generation sequencing is widely used for precision oncology and precision prevention approaches. We aimed to determine the yield of actionable gene variants, the capacity to uncover hereditary predisposition and liquid biopsy appropriateness instead of, or in addition to, tumor tissue analysis, in a real-world cohort of cancer patients, who may benefit the most from comprehensive genomic profiling. METHODS: Seventy-eight matched germline/tumor tissue/liquid biopsy DNA and RNA samples were profiled using the Hereditary Cancer Panel (germline) and the TruSight Oncology 500 panel (tumor tissue/cfDNA) from 23 patients consecutively enrolled at our center according to at least one of the following criteria: no available therapeutic options; long responding patients potentially fit for other therapies; rare tumor; suspected hereditary cancer; primary cancer with high metastatic potential; tumor of unknown primary origin. Variants were annotated for OncoKB and AMP/ASCO/CAP classification. RESULTS: The overall yield of actionable somatic and germline variants was 57% (13/23 patients), and 43.5%, excluding variants previously identified by somatic or germline routine testing. The accuracy of tumor/cfDNA germline-focused analysis was demonstrated by overlapping results of germline testing. Five germline variants in BRCA1, VHL, CHEK1, ATM genes would have been missed without extended genomic profiling. A previously undetected BRAF p.V600E mutation was emblematic of the clinical utility of this approach in a patient with a liver undifferentiated embryonal sarcoma responsive to BRAF/MEK inhibition. CONCLUSIONS: Our study confirms the clinical relevance of performing extended parallel tumor DNA and cfDNA testing to broaden therapeutic options, to longitudinally monitor cfDNA during patient treatment, and to uncover possible hereditary predisposition following tumor sequencing in patient care.

Review of electrical impedance tomography in the pediatric patient.

Electrical impedance tomography (EIT) is a new method of monitoring non-invasive mechanical ventilation, at the bedside and useful in critically ill patients. It allows lung monitoring of ventilation and perfusion, obtaining images that provide information on lung function. It is based on the physical principle of impedanciometry or the body's ability to conduct an electrical current. Various studies have shown its usefulness both in adults and in pediatrics in respiratory distress syndrome, pneumonia and atelectasis in addition to pulmonary thromboembolism and pulmonary hypertension by also providing information on pulmonary perfusion, and may be very useful in perioperative medicine; especially in pediatrics avoiding repetitive imaging tests with ionizing radiation.

The management of paediatric acute pain in Spain in 2021: Results of a national survey among paediatric anaesthesiologists.

OBJECTIVE: To improve knowledge about routine clinical practice in the management of paediatric acute pain in Spain. METHODS: A telematic survey was conducted via the Internet on a representative sample of healthcare professionals involved in the management of paediatric acute pain (specifically anaesthesiologists) in Spain. The survey included 28 questions about their usual clinical practice in the assessment and treatment of acute pain, and also training and organisational aspects in paediatric acute pain. RESULTS: The survey was completed during March 2021 by 150 specialists in anaesthesiology. The respondents widely experienced in the management of acute paediatric pain (mean years of experience: 14.3: SD: 7.8), essentially in acute postoperative pain (97% of cases). Although 80% routinely used validated paediatric acute pain assessment scales, only 2.6% used specific scales adapted for patients with cognitive impairment. Most of the respondents routinely used analgesic drugs such as paracetamol (99%) or metamizole (92%), but only 84% complemented these drugs with a loco-regional blocking technique or other non-steroidal anti-inflammatory drugs (62%). Furthermore, only 62.7% acknowledged having received specific training in paediatric acute pain, only 45% followed hospital institutional protocols, and a scant 28% did so through paediatric pain units. CONCLUSIONS: The survey identified important points for improvement in the training and organisation of acute pain management in Spanish paediatric patients.

Food-grade titanium dioxide can affect microbiota physiology, adhesion capability, and interbacterial interactions: A study on L. rhamnosus and E. faecium.

Food-grade titanium dioxide (TiO2-FG) is a widespread metal oxide used in the food industries. Recently, the European Food Safety Authority concluded that TiO2-FG cannot be considered safe for consumption due to its genotoxicity; however, its effect on the gut microbiota has not yet been completely unraveled. We studied the effects of TiO2-FG (0.125 mg/mL) on Lactobacillus rhamnosus GG (LGG) and Enterococcus faecium NCIMB10415 (Ent), in particular some physiological and phenotypic traits (growth kinetics, bile salts, and ampicillin resistance) and their interactions with the host (auto-aggregation, biofilm formation, and adhesion on Caco-2/TC7 monolayers) and other gut microorganisms (antimicrobial activity towards pathogens). The results obtained revealed that TiO2-FG alters both LGG and Ent growth and lowers bile resistance (62 and 34.5%, respectively) and adhesion on Caco-2/TC7 monolayers (34.8 and 14.16%, respectively). The other outcomes were strictly species-specific: Ent showed a lower ampicillin sensitivity (14.48%) and auto-aggregation (38.1%), while LGG showed a reduced biofilm formation (37%) and antimicrobial activity towards Staphylococcus aureus (35.73%). Overall, these results suggest an adverse effect of TiO2-FG on both the endogenous and exogenously administered probiotics, contributing to the argument against using TiO2-FG as a food additive.

Clinical differences in a multidisciplinary pediatric pain unit between primary and secondary chronic pain.

INTRODUCTION: Chronic pain affects an important part of the pediatric population in developed countries. secondary chronic pain (SCP) can have a well-defined medical cause, but primary chronic pain (PCP) can have an unknown etiology. In Spain, there is as yet no information on the clinical differences between patients treated in multidisciplinary units. METHODS: Retrospective analysis of the clinical records of patients seen in 2018 at the Children's Chronic Pain Unit in University La Paz Hospital. RESULTS: A total of 92 patients were included, (age between 3 and 19 years), with a mean age of 12.4 (SD = 4.1) years, mostly female (55%), with a mean duration of pain of 11.3 (SD = 10.4) months. A comparison of patients with PCP (n = 31) and SCP (n = 61) showed that both groups, on average, presented intense pain (X = 5.9; SD = 2.2; range = 0-10), with similar duration and functional repercussions, although PCP was less likely to be associated with neuropathic descriptors than SCP (p = 0.040), and was more extensive (p < 0.001). Both groups received similar treatment, based on rehabilitation, psychotherapy, invasive techniques and analgesic medication, although patients in the PCP group received less analgesic medication (gabapentinoids and opioids) than the SCP (p = 0.011). CONCLUSION: Patients treated in a multidisciplinary Child Pain Unit for PCP or SCP present a very similar clinical profile, though with differences in the number and type of analgesic drugs used. This shows the importance of etiologic diagnosis for adequate pharmacological treatment.

Predictors of germline status for hereditary melanoma: 5 years of multi-gene panel testing within the Italian Melanoma Intergroup.

BACKGROUND: The incidence of cutaneous melanoma is increasing in Italy, in parallel with the implementation of gene panels. Therefore, a revision of national genetic assessment criteria for hereditary melanoma may be needed. The aim of this study was to identify predictors of susceptibility variants in the largest prospective cohort of Italian high-risk melanoma cases studied to date. MATERIALS AND METHODS: From 25 Italian centers, we recruited 1044 family members and germline sequenced 940 cutaneous melanoma index cases through a shared gene panel, which included the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP, MITF and ATM. We assessed detection rate according to familial status, region of origin, number of melanomas and presence and type of non-melanoma tumors. RESULTS: The overall detection rate was 9.47% (5.53% analyzing CDKN2A alone), ranging from 5.14% in sporadic multiple melanoma cases (spoMPM) with two cutaneous melanomas to 13.9% in familial cases with at least three affected members. Three or more cutaneous melanomas in spoMPM cases, pancreatic cancer and region of origin predicted germline status [odds ratio (OR) = 3.23, 3.15, 2.43, P < 0.05]. Conversely, age > 60 years was a negative independent predictor (OR = 0.13, P = 0.008), and was the age category with the lowest detection rate, especially for CDKN2A. Detection rate was 19% when cutaneous melanoma and pancreatic cancer clustered together. CONCLUSIONS: Gene panel doubled the detection rate given by CDKN2A alone. National genetic testing criteria may need a revision, especially regarding age cut-off (60) in the absence of strong family history, pancreatic cancer and/or a high number of cutaneous melanomas.

Original and minimally invasive approach to a left-lung refractory atelectasis after reparation of an aortic recoarctation in a lactant: Selective endobronchial CPAP.

Atelectasis is one of the most common respiratory complications in pediatric patients after open-heart surgery, and may lead to weaning failure and increased morbidity. We report the use of an original, minimally invasive approach to refractory left lung atelectasis after repair of an aortic coarctation in a 2 month-old infant, in which a CPAP system connected to a flexible endobronchial tube resolved the atelectasis.

Perioperative management of patients with arrhythmogenic syndromes refractory to medical treatment: A clinical case report.

Family heart diseases related to sudden death are a group of cardiovascular diseases (cardiomyopathies, channelopathies, aortic diseases …) that require familiarity of the anesthesiologist with the perioperative treatment of complex hemodynamic disorders, as well as their surgical treatment.1 We present the case of a 12-year-old man diagnosed with non-obstructive hypertrophic cardiomyopathy (MHNO), after cardiorespiratory arrest (PCR), who underwent video-guided thoracoscopy-guided left sympathectomy (VATS) for frequent syncope, despite pharmacological treatment and implantation of an implantable automatic defibrillator (ICD). Whenever arrhythmic syncope occurs in the setting of familial heart disease, left heart denervation should be considered as the next step in the treatment plan.2.

Perioperative management of patients with arrhythmogenic syndromes refractory to medical treatment: A clinical case report. / Valoración y tratamiento perioperatorio de los pacientes con síndromes arritmogénicos refractarios a tratamiento médico: a propósito de un caso clínico.

Family heart diseases related to sudden death are a group of cardiovascular diseases (cardiomyopathies, channelopathies, aortic diseases...) that require familiarity of the anesthesiologist with the perioperative treatment of complex hemodynamic disorders, as well as their surgical treatment1. We present the case of a 12-year-old man diagnosed with non-obstructive hypertrophic cardiomyopathy, after cardiorespiratory arrest, who underwent video-guided thoracoscopy-guided left sympathectomy for frequent syncope, despite pharmacological treatment and implantation of an implantable automatic defibrillator. Whenever arrhythmic syncope occurs in the setting of familial heart disease, left heart denervation should be considered as the next step in the treatment plan2.

Painapple®. Validation and evaluation of an electronic application for the management of acute pain in pediatric patients. / PainAPPle. Validación y evaluación de una aplicación electrónica para el manejo del dolor agudo en pacientes pediátricos.

INTRODUCTION: The digital version of the assessment scales recommended for the pediatric patient could contribute to its improvement and to implement the quality indicators described for the management of acute pain. MATERIAL AND METHODS: Psychometric validation (validity and reliability) of pain assessment and treatment side effects scales incorporated in the electronic application PainAPPle. For this, both formats (paper and electronic) of all the scales were applied in two measurements with 30minutes of difference in 44 patients from 4 to 18years of the Acute Pain Unit in the immediate postoperative period. In addition, the data collected by PainAPPle was evaluated by retrospectively applying the quality indicators described for the management of acute postoperative pain. RESULTS: Reliability was studied analyzing the high correlation (Spearman greater than 0.5, P<.001) that we obtained for the values of each scale in two moments with 30minutes of difference, in the same patients. For validity, the high correlation (Spearman greater than 0.5, P<.001) between the values of the paper scales (gold rule) and PainAPPle at both minute 0 and 30 was analyzed. Concordance obtained taking into account the cut-off point of the scales that would force a treatment were also statistically significant (P<.005). CONCLUSIONS: PainAPPle is a validated instrument for the management of acute pain in pediatric patients. The collected data allow to apply the quality indicators described for the management of acute postoperative pain.

Cardiac arrest related to anaesthesia in Williams-Beuren syndrome. / Parada cardíaca relacionada con la anestesia en el síndrome Williams-Beuren.

Williams-Beuren syndrome is the clinical manifestation of a congenital genetic disorder in the elastin gene, among others. There is a history of cardiac arrest refractory to resuscitation manoeuvres in anaesthesia. The incidence of myocardial ischaemia is high during anaesthetic induction, but there are patients who do not have this condition yet also have had very serious cardiac events, and issues that are still to be resolved. Case descriptions will enable the common pathophysiological factors to be defined, and decrease morbidity and mortality. We report the case of a 3-year-old boy with cardiac arrest at induction, rescued with circulatory assistance with extracorporeal membrane oxygenation and hypothermia induced for cerebral protection.

The importance of bilateral monitoring of cerebral oxygenation (NIRS): Clinical case of asymmetry during cardiopulmonary bypass secondary to previous cerebral infarction. / Importancia de la monitorización bilateral de la oxigenación cerebral: caso clínico de asimetría durante el bypass cardiopulmonar secundaria a infarto cerebral previo.

Cerebral oximetry based on near infrared spectroscopy (NIRS) technology is used to determine cerebral tissue oxygenation. We hereby present the clinical case of a 12-month old child with right hemiparesis secondary to prior left middle cerebral artery stroke 8 months ago. The child underwent surgical enlargement of the right ventricular outflow tract (RVOT) with cardiopulmonary bypass. During cardiopulmonary bypass, asymmetric NIRS results were detected between both hemispheres. The utilization of multimodal neuromonitoring (NIRS-BIS) allowed acting on both perfusion pressure and anesthetic depth to balance out the supply and demand of cerebral oxygen consumption. No new neurological sequelae were observed postoperatively. We consider bilateral NIRS monitoring necessary in order to detect asymmetries between cerebral hemispheres. Although asymmetries were not present at baseline, they can arise intraoperatively and its monitoring thus allows the detection and treatment of cerebral ischemia-hypoxia in the healthy hemisphere, which if undetected and untreated would lead to additional neurological damage.

Clinical experience with desflurane for paediatric anaesthesia outside the operating room. / Experiencia clínica con desflurano para anestesia pediátrica fuera de quirófano.

BACKGROUND: Desflurane has been used in paediatric patients for several surgical indications. This article analyses the efficacy and safety of desflurane for diagnostic-therapeutic procedures in remote areas far from operating room in a group of selected patients with no known associated respiratory disease. MATERIAL AND METHODS: A retrospective analysis was performed on 2,072 general anaesthesia procedures stored in a computer database, in which desflurane was used in a Paediatric Pain Unit during the years 2013 and 2014. An analysis was also performed using the patient demographics, type of procedure, anaesthetic technique, type of airway management, patient cooperation, and incidence of anaesthetic complications. RESULTS: The study included 876 patients, with a mean age of 8.8 years. The main procedures were bone marrow aspirates (23%), lumbar punctures (20%), panendoscopies (15%), and colonoscopies (5%). Induction was intravenous with propofol (26%) or inhalation with sevoflurane in the remaining 74%. Maintenance consisted of remifentanil and desflurane at mean end tidal concentrations of 6.2±2.1%. The airway was managed through a nasal cannula or face mask in spontaneous ventilation. The effectiveness was 98%, and the incidence of side effects was 15%, which included agitation (6%), headache (4%), nausea-vomiting (3%), and laryngospasm (2%). CONCLUSION: The maintenance with desflurane (at concentrations close to the hypnotic-MAC in spontaneous ventilation) was effective, with a rapid recovery, and with a low incidence of adverse effects.

Agreement between child self-reported and parent-reported scores for chronic pain secondary to specific pediatric diseases. / Concordancia en pacientes con dolor crónico secundario a enfermedades pediátricas entre la autovaloración y las puntuaciones reportadas por sus padres.

BACKGROUND: Parental report on a child's secondary chronic pain is commonly requested by anesthesiologists when the child cannot directly provide information. Daily pain intensity is reported as highest, average and lowest. However, it is unclear whether the parents' score is a valid indicator of the child's pain experience. METHODS: Nineteen children (aged 6-18years) with secondary chronic pain attending our anesthesiologist-run pediatric pain unit participated in this study. Identification of highest, average and lowest pain intensity levels were requested during initial screening interviews with the child and parents. Pain intensity was scored on a 0-10 numerical rating scale. Agreement was examined using: (i) intraclass correlation coefficient (ICC), and (ii) the Bland-Altman method. RESULTS: The ICC's between the children and the parents' pain intensity reports were: 0.92 for the highest, 0.68 for the average, and 0.50 for the lowest pain intensity domains. The limits of agreement set at 95% between child and parental reports were respectively +2.19 to -2.07, +3.17 to -3.88 and +5.15 to -5.50 for the highest, average and lowest pain domains. CONCLUSIONS: For the highest pain intensity domain, agreement between parents and children was excellent. If replicated this preliminary finding would suggest the highest pain intensity is the easiest domain for reporting pain intensity when a child cannot directly express him or herself.

[Anesthesia-related cardiac arrest in children. Data from a tertiary referral hospital registry]. / Parada cardiaca relacionada con la anestesia en pediatría. Registro en un hospital infantil terciario.

OBJECTIVES: The aim of this study is to analyze the cardiac arrests related to anesthesia in a tertiary children's hospital, in order to identify risk factors that would lead to opportunities for improvement. METHODS: A 5-year retrospective study was conducted on anesthesia related cardiac arrest occurring in pediatric patients. All urgent and elective anesthetic procedures performed by anesthesiologists were included. Data collected included patient characteristics, the procedure, the probable cause, and outcome of the cardiac arrest. Odds ratio was calculated by univariate analysis to determine the clinical factors associated with cardiac arrest and mortality. RESULTS: There were a total of 15 cardiac arrests related to anesthesia in 43,391 anesthetic procedures (3.4 per 10,000), with an incidence in children with ASA I-II versus ASA≥III of 0.28 and 19.27 per 10,000, respectively. The main risk factors were children ASA≥III (P<.001), less than one month old (P<.001), less than one year old (P<.001), emergency procedures (P<.01), cardiac procedures (P<.001) and procedures performed in the catheterization laboratory (P<.05). The main causes of cardiac arrest were cardiovascular (53.3%), mainly due to hypovolemia, and cardiovascular depression associated with induction of anesthesia, followed by respiratory causes (20%), and medication causes (20%). The incidence of mortality and neurological injury within the first 24h after the cardiac arrest was 0.92 and 1.38 per 10,000, respectively. The mortality in the first 3 months was 1.6 per 10,000. The main causes of death were ASA≥III, age under one year, pulmonary arterial hypertension, cardiac arrest in areas remote from the surgery area, a duration of cardiopulmonary resuscitation over 20min, and when hypothermia was not applied after cardiac arrest. CONCLUSION: The main risk factors for cardiac arrest were ASA≥III, age under one year, emergency procedures, cardiology procedures and procedures performed in the catheterization laboratory. The main cause of the cardiac arrest was due mainly to cardiovascular hypovolemia. All patients who died or had neurological injury were ASA≥III. Pulmonary arterial hypertension is a risk of anesthesia-related mortality.

Exact relativistic expressions for wave refraction in a generally moving fluid.

The law for the refraction of a wave when the two fluids and the interface are moving with relativistic velocities is given in an exact form, at the same time correcting a first order error in a previous paper [Cavalleri and Tonni, Phys. Rev. E 57, 3478 (1998)]. The treatment is then extended to a generally moving fluid with variable refractive index, ready to be applied to the refraction of acoustic, electromagnetic, or magnetohydrodynamic waves in the atmosphere of rapidly rotating stars. In the particular case of a gas cloud receding because of the universe expansion, our result can be applied to predict observable micro- and mesolensings. The first order approximation of our exact result for the deviation due to refraction of the light coming from a further quasar has a relativistic dependence equal to the one obtained by Einsteins' linearized theory of gravitation.