Real-time PCR detection of PI*S and PI*Z alleles of SERPINA1 gene using SYBR green.

BACKGROUND: Alpha-1 antitrypsin deficiency is an underdiagnosed genetic condition that predisposes to pulmonary complications and is mainly caused by rs28929474 (PI*Z allele) and rs17580 (PI*S allele) mutations in the SERPINA1 gene. OBJECTIVE: Development of a homogeneous genotyping test for detection of PI*S and PI*Z alleles based on the principles of allele-specific PCR and amplicon melting analysis with a fluorescent dye. METHODS: Sixty individuals, which included all possible genotypes that result from combinations of rs28929474 and rs17580 single nucleotide variants, were assayed with tailed allele-specific primers and SYBR Green dye in a real-time PCR machine. RESULTS: A clear discrimination of mutant and wild-type variants was achieved in the genetic loci that define PI*S and PI*Z alleles. Specific amplicons showed a difference of 2.0 °C in melting temperature for non-S and S variants and of 2.9 °C for non-Z and Z variants. CONCLUSIONS: The developed genotyping method is robust, fast, and easily scalable on a standard real-time PCR platform. While it overcomes the handicaps of non-homogeneous approaches, it greatly reduces genotyping costs compared with other homogeneous approaches.

Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas.

KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.

Imatinib plasma levels in patients with gastrointestinal stromal tumour under routine clinical practice conditions.

OBJECTIVES: Imatinib is the first therapeutic option for the treatment of unresectable or metastatic gastrointestinal stromal tumours. Previous studies have shown an improvement in patient survival rates following the use of imatinib. Nevertheless, adequate plasma concentrations of imatinib are necessary to achieve such improvement in survival and limit the toxicity of the drug. This study aims to analyse the influence of imatinib plasma concentrations on efficacy and safety in the treatment of gastrointestinal stromal tumour. MATERIALS AND METHODS: This descriptive, multicentre study analysed plasma levels of imatinib in patients diagnosed with gastrointestinal stromal tumour in the period 2019-2020. An optimal therapeutic range of 750-1500 ng/mL was established for the patient stratification based on their minimum plasma concentrations measured at the steady state. RESULTS: This study included 11 patients with metastatic disease in total, among whom only 54.5% (n = 6) had a minimum plasma concentrations measured at the steady state value within the therapeutic range. A median progression-free survival of 7.0 months was recorded for those patients with minimum plasma concentrations measured at the steady state < 750 ng/mL, while that median progression-free survival value remained unachieved for the group with minimum plasma concentrations measured at the steady state > 750 ng/mL (p = 0.005). The toxicity rate was 25% and 14.3% for patients with minimum plasma concentrations measured at the steady state > 1500 ng/mL and minimum plasma concentrations measured at the steady state ≤1500 ng/mL, respectively (p = 0.66). CONCLUSIONS: The present study aims to describe the correlation between the toxicity and effectiveness of imatinib as a function of minimum plasma concentrations measured at the steady state under routine clinical practice conditions. The results described here show the usefulness of imatinib plasma concentrations monitoring as part of the standard daily routine in our hospitals.

Imatinib plasma levels in patients with chronic myeloid leukaemia under routine clinical practice conditions.

INTRODUCTION: The addition of imatinib to the therapeutic arsenal for chronic myeloid leukaemia (CML) has changed the natural course of the disease, in such a way that it is now considered a chronic pathology. However, to achieve therapeutic success, it is necessary to reach adequate plasma concentrations to ensure efficacy and safety.In this study, we aimed to evaluate the plasma concentration of imatinib, analysing its influence on effectiveness and safety in patients with CML. METHODS: We performed a descriptive, multicentre study in which imatinib plasma levels from patients diagnosed with CML between 2019-2020 were analysed. An optimal therapeutic range of 750-1500 ng/mL was established for the stratification of patients, according to their minimum plasma concentrations measured at steady state (Cssmin). RESULTS: A total of 28 patients were included, of whom only 39.3% (n = 11) showed Cssmin within the therapeutic range. 100% of patients with Cssmin >750 ng/mL achieved an optimal molecular response, while only 50% of patients with Cssmin <750 ng/mL achieved an optimal molecular response (p = 0.0004). The toxicity rate was 36.4% for patients with Cssmin >1500 ng/mL and 5.9% for those with Cssmin <1500 ng/mL (p = 0.039). CONCLUSIONS: This study aimed to describe the correlation between the toxicity and effectiveness of imatinib according to its Cssmin in routine clinical practice conditions. Based on our findings, it would be certainly justified to monitor patient plasma concentrations of imatinib on a daily routine basis in our hospitals.

Trends in the Incidence of Cancer Among Adolescent and Young Adults in Alberta, 1983-2017: A Population-Based Study Using Cancer Registry Data.

Purpose: To describe the cancer incidence burden and trends among adolescent and young adults (AYAs) in Alberta, Canada over a 35-year period. Methods: We obtained data from the Alberta Cancer Registry on all first primary cancers, excluding non-melanoma skin cancer, diagnosed at ages 15-39 years among residents in Alberta from 1983 to 2017. Cancers were classified by using Barr's AYA cancer classification system. Age-standardized incidence rates (ASIR) and the average annual percentage change (AAPC) in incidence rates were calculated. Statistically significant changes in the AAPC during the study period were assessed using Joinpoint regression. Results: Overall, 23,652 incident cases of AYA cancer were diagnosed in Alberta. Females accounted for ∼60% of the diagnoses. AYA cancer increased significantly over the study period overall (AAPC: 0.5%; 95%CI: 0.3%-0.7%), for each sex (AAPCmale: 0.7%; 95%CI: 0.4%-0.9%; AAPCfemale: 0.4%; 95%CI: 0.2%-0.6%), and among male and female 20-39 year-olds. Although statistically significant increases were observed in 11 out of 29 cancer sites for at least a portion of the study period, with significant AAPCs ranging from 0.8% (95%CI: 0.01%-1.5%) to 6.6% (95%CI: 4.6%-8.5%), the main driver was thyroid cancer (AAPC: 3.7%; 95%CI: 3.2%-4.2%). Statistically significant decreases were observed for six cancer sites, with AAPCs ranging from -6.4% (95%CI: -8.7% to -4.1%) to -1.1% (95%CI: -1.8% to -0.5%). Conclusions: There is a growing cancer burden among AYAs in Alberta, which is driven primarily by thyroid cancer and early-onset cancers in males. These results highlight the need for etiological studies and tertiary strategies to prevent and mitigate morbidity and mortality in the AYA population.

[Skeletal maturation of the hand and wrist and ossification of the mid palate suture in adolescents: a literature review]. / Maduración esquelética de mano y muñeca y osificación de sutura media palatina en adolescentes: una revisión de literatura.

Introduction: The evaluation of skeletal age is an important factor in orthodontic planning to anticipate changes in growth, with the analysis of hand and wrist radiographs showing the degree of bone and facial growth potential. The objective was to evaluate the relationship between skeletal maturation of the hand and wrist and ossification of the midpalatal suture (MPS) in adolescents. Materials and methods: A search was carried out in four databases such as Pubmed, Scopus, Science Direct and Embase were reviewed until December 13, 2022. The included studies were descriptive and comparative articles on the skeletal maturation of the hand and wrist and ossification of the midpalatal suture of patients aged 7 to 18 years. Two researchers carefully selected the articles evaluated and analyzed the different key topics related to the topic. Results: Four articles were included in this study; According to the studies, it was found that the greater the degree of bone maturation there is an increase in the approximation of the SMP, especially in late stages, with high and positive correlations; Furthermore, there were greater evaluation results with the Fishman analysis method as opposed to the Hagg and Taranger and Björk methods. The critical limit stages in SMI7-9, a greater approach to the closure of SMP compatible with stage D-E was found. The completion of maturation in women occurs up to 2 years earlier than in men. Conclusions: Diagnostic evaluation methods using carpal analysis can be used for predictive evaluations of the maturation stage of SMP; However, the results were not absolute in all cases so they cannot be generalized.

Psychiatric Disorder Incidence Among Adolescents and Young Adults Aged 15-39 With Cancer: Population-Based Cohort.

BACKGROUND: Adolescent and young adult (AYA) cancer survivors face physical and psychological sequelae related to having cancer decades after treatment completion. It is unclear if AYA cancer survivors are at increased risk for late psychiatric disorders. METHODS: We used the Alberta AYA Cancer Survivor Study that includes 5-year survivors of cancer diagnosed at age 15-39 years during 1991 to 2013. The primary outcome was incidence of psychiatric disorder (composite outcome) including anxiety, depressive, trauma- and stressor-related, psychotic, and substance use disorders that were identified using coding algorithms for administrative health databases. A validated coding algorithm identified people who experienced a suicide attempt or event of self-harm. Secondary outcomes were incidences of diagnoses by type of psychiatric disorder. RESULTS: Among 12 116 AYA 5-year cancer survivors (n = 4634 [38%] males; n = 7482 [62%] females), 7426 (61%; n = 2406 [32%] males; n = 5020 [68%] females) were diagnosed with at least 1 of 5 psychiatric disorders occurring at least 3 years after cancer diagnosis. Survivors of all cancer types were most often diagnosed with anxiety (males: 39.0%, 95% confidence interval [CI] = 37.6% to 40.4%; females: 54.5%, 95% CI = 53.3% to 55.6%), depressive (males: 32.7%, 95% CI = 31.3% to 34.0%; females: 47.0%, 95% CI = 45.8% to 48.1%), and trauma- and stressor-related disorders (males: 13.5%, 95% CI =12.5% to 14.5%; females: 22.5%, 95% CI = 21.6% to 23.5%). CONCLUSIONS: Anxiety, depressive, and trauma- and stressor-related disorders are common among 5-year survivors of AYA cancer. Primary, secondary, or tertiary preventive strategies for AYAs diagnosed with cancer, particularly at an early age, are needed to mitigate risk of potentially severe outcomes because of psychiatric disorders.

Evaluación de la relación exposición-respuestade cetuximab en pacientes con cáncer colorrectal metastásico y cáncer de cabeza y cuello / Assessment of exposure-response relationship for cetuximab in patients with metastatic colorectal cancer and head and neck cancer

Objetivo: Evaluar, en condiciones de vida real, la relación entre lasconcentraciones valle en estado estacionario de cetuximab y el control dela enfermedad, así como buscar la relación entre estas concentraciones y lasupervivencia. Además, estudiar si existe una concentración límite que sepueda asociar con la probabilidad de beneficio clínico.Método: Estudio observacional prospectivo llevado a cabo en pacientescon cáncer colorrectal metastásico o cáncer de cabeza y cuello entratamiento con cetuximab. Se realizó un análisis de regresión de ecuacionesde estimación generalizadas para evaluar la asociación entre laconcentración valle en estado estacionario de cetuximab y la respuesta altratamiento (progresión o beneficio clínico). Mediante modelos de riesgosproporcionales de Cox, se evaluó la asociación entre la mediana de concentracionesvalle en estado estacionario de cetuximab en cada pacienteo la última medida con la supervivencia global y la supervivencia librede progresión, en cada una de las patologías. Asimismo, se buscó unpunto de corte óptimo a través del área bajo la curva de característicasoperativas del receptor. Resultados: Se analizaron 30 muestras de 16 pacientes. La concentraciónvalle en estado estacionario mediana fue 26,86 mg/l y se encontróuna gran variabilidad inter e intraindividual (desviación estándar de 32,4 y16,9 mg/l, respectivamente). Se observó una asociación positiva entre laconcentración valle en estado estacionario y el beneficio clínico (odds ratio1,24; intervalo de confianza del 95%: 0,95-1,63; p = 0,113), aunque noalcanzó significación estadística debido a la baja potencia.

Objective: There is limited scientific evidence on the cetuximab exposure-response relationship and no concentration threshold has been associatedwith optimal disease control. The aims were to assess, in a real-lifesetting, the relationship between steady state cetuximab concentrations(Ctrough, SS) and disease control.Method: A prospective observational study in patients with metastaticcolorectal cancer or head and neck cancer treated with cetuximab. Steadystate trough concentrations were compared with the results of radiologicalassessment of response (progression or clinical benefit). Generalizedestimating equations analysis was performed. To test the association betweensteady state concentrations and overall survival and progression-freesurvival, Cox proportional hazard models were developed. An optimalcut-off point was searched using the area under the receiver operatingcharacteristic curve.Results: A total of 30 steady state cetuximab concentrations from16 patients were analysed. Median Ctrough, SS was 26.86 mg/L andthere was marked inter- and intraindividual variability (standard deviation 32.4 mg/L and 16.9 mg/L, respectively). A positive associationwas found between cetuximab Ctrough, SS and clinical benefit (odds ratio1.24, 95% confidence interval: 0.95-1.63, p = 0.113), although withoutreaching statistical significance. The area under the receiver operatingcharacteristic curve (n = 30) had moderate discrimination power (0.71;95% confidence interval 0.49‑0.93), and the empirical optimal cutoffpoint was 19.12 mg/L. However, no association was observed betweencetuximab Ctrough, SS and survival in metastatic colorectal cancer or neckcancer patients.

Patient-reported outcomes and digital literacy of patients treated in an oncology day hospital unit.

INTRODUCTION: Patient-reported outcomes (PROs) use, via a computer registry, allows patients to report their symptoms enabling the detection of early signs of progression of the disease. For such a record, the patient needs to show certain skills in new technologies use. The present study aimed to analyse the perception and degree of digital literacy of patients undergoing oncological treatment in an Oncology Day Hospital (ODH). METHODS: A cross-sectional descriptive study was performed, where the degree of literacy of patients attending antineoplastic treatment at the ODH was examined by means of an anonymous survey. RESULTS: A total of 122 patients have been included in the study. The proportion of subjects who use the electronic mail (TM) and the Internet on a daily basis was 45.1% and 70.5%, respectively, and up to 77.9% from the subjects considered that the use of digital 2.0 strategies could help improve communication between healthcare professional and patient.The TM was determined by the age, educational level and employment status of the individual. Furthermore, the age of the patients conditioned their perception of the usefulness of the web 2.0 tools (T2.0). CONCLUSION: This study allowed us to establish a target patient profile to conduct the efficient monitoring of cancer progression by PROs. The results have shown that approximately 60% of the patients in our population could be potential candidates to receive PROs-based health care. This approach enables earlier detection of symptoms and signs of progression and consequently, improves health outcomes for cancer patients.

Root resorption followed by orthodontic treatment in individuals with anterior open bite. A complete vision focused on different treatment alternatives: A review.

The aim of this review was to determine the incidence of different types of treatment and the prevalence of root resorption in incisors induced by orthodontic treatment in patients with open bite. Libraries and electronic databases were searched, with 322 articles being selected and 55 articles considered regarding PRISMA checklist. It has been shown that apical root resorption of the incisors is more frequent in patients with premolar extractions than in those treated without extractions, due to greater apical displacement during retraction of the anterior teeth in the space closure phase. On the other hand, it has been described that intrusion of posterior teeth is four times more likely to cause root resorption than extrusion movement, thereby increasing the risk of root resorption in posterior teeth compared to conventional orthodontic treatment not requiring molar intrusions. Finally, aligners, such as orthodontic treatments with fixed appliances, have not been shown to induce clinically significant root resorption in open bite individuals. Literature on root resorption in open bite treatments is scarce making difficult conclusions difficult. However, the amount of root loss in cases of open bite seems to be similar to that of individuals without open bite.

El objetivo de esta revisión fue determinar la incidencia de los diferentes tipos de tratamiento y la prevalencia de la reabsorción radicular en los incisivos inducida por el tratamiento de ortodoncia en pacientes con mordida abierta. Se realizaron búsquedas en bibliotecas y bases de datos electrónicas, se seleccionaron 322 artículos y se consideraron 55 artículos de acuerdo con las guías PRISMA. Se ha demostrado que la reabsorción radicular apical de los incisivos es más frecuente en pacientes con extracciones de premolares que en los tratados sin extracciones, debido al mayor desplazamiento apical durante la retracción de los dientes anteriores en la fase de cierre de espacios. Por otro lado, se ha descrito que la intrusión de los dientes posteriores tiene cuatro veces más probabilidades de causar reabsorción radicular que el movimiento de extrusión, lo que aumenta el riesgo de reabsorción radicular en los dientes posteriores en comparación con el tratamiento de ortodoncia convencional que no requiere intrusiones molares. Finalmente, no se ha demostrado que los alineadores, como los tratamientos de ortodoncia con aparatos fijos, induzcan una reabsorción radicular clínicamente significativa en individuos con mordida abierta. La literatura sobre reabsorción radicular en tratamientos de mordida abierta es escasa, lo que dificulta conclusiones definitivas. Sin embargo, la cantidad de pérdida de raíz en los casos de mordida abierta parece ser similar a la de las personas sin mordida abierta.

The effect of interventions targeting gut microbiota on depressive symptoms: a systematic review and meta-analysis.

BACKGROUND: Despite their popularity, the efficacy of interventions targeting gut microbiota to improve depressive symptoms is unknown. Our objective is to summarize the effect of microbiome-targeting interventions on depressive symptoms. METHODS: We conducted a systematic review and meta-analysis. We searched MEDLINE, Embase, PsycINFO, Database of Abstracts of Reviews of Effects, Cochrane Database of Systematic Reviews and the Cochrane Controlled Register of Trials from inception to Mar. 5, 2021. We included studies that evaluated probiotic, prebiotic, synbiotic, paraprobiotic or fecal microbiota transplant interventions in an adult population (age ≥ 18 yr) with an inactive or placebo comparator (defined by the absence of active intervention). Studies must have measured depressive symptoms with a validated scale, and used a randomized controlled trial study design. We conducted a random effects meta-analysis of change scores, using standardized mean difference as the measure of effect. RESULTS: Sixty-two studies formed the final data set, with 50 included in the meta-analysis. Probiotic, prebiotic, and synbiotic interventions on depressive symptoms showed statistically significant benefits. In the single studies evaluating each of fecal microbiota transplant and paraprobiotic interventions, neither showed a statistically significant benefit. INTERPRETATION: Despite promising findings of benefit of probiotic, prebiotic and synbiotic interventions for depressive symptoms in study populations, there is not yet strong enough evidence to favour inclusion of these interventions in treatment guidelines for depression. Critical questions about species administered, dosage and timing relative to other antidepressant medications remain to be answered. STUDY REGISTRATION: PROSPERO no. 143178.

The Burden of Late Effects and Related Risk Factors in Adolescent and Young Adult Cancer Survivors: A Scoping Review.

Risk factors associated with late effects in survivors of adolescent and young adult (AYA) cancer are poorly understood. We conducted a systematic scoping review to identify cohort studies published in English from 2010-2020 that included: (1) cancer survivors who were AYAs (age 15-39 years) at diagnosis and (2) outcomes of subsequent malignant neoplasms (SMNs), chronic conditions, and/or late mortality (>5 years postdiagnosis). There were 652 abstracts identified and, ultimately, 106 unique studies were included, of which 23, 34, and 54 studies related to the risk of SMNs, chronic conditions, and mortality, respectively. Studies investigating late effects among survivors of any primary cancer reported that AYA cancer survivors were at higher risk of SMN, chronic conditions, and all-cause mortality compared to controls. There was an indication that the following factors increased risk: radiation exposure (n = 3) for SMNs; younger attained age (n = 4) and earlier calendar period of diagnosis (n = 3) for chronic conditions; and non-Hispanic Black or Hispanic (n = 5), low socioeconomic status (n = 3), and earlier calendar period of diagnosis (n = 4) for late mortality. More studies including the full AYA age spectrum, treatment data, and results stratified by age, sex, and cancer type are needed to advance knowledge about late effects in AYA cancer survivors.

KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.

In mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we have generated a mouse strain that carries a terminator codon in exon 4B that leads to the expression of an unstable KRAS4B154 truncated polypeptide, hence resulting in a bona fide Kras4B-null allele. In contrast, this terminator codon leaves expression of the KRAS4A isoform unaffected. Mice selectively lacking KRAS4B expression developed to term but died perinatally because of hypertrabeculation of the ventricular wall, a defect reminiscent of that observed in embryos lacking the Kras locus. Mouse embryonic fibroblasts (MEFs) obtained from Kras4B-/- embryos proliferated less than did wild-type MEFs, because of limited expression of KRAS4A, a defect that can be compensated for by ectopic expression of this isoform. Introduction of the same terminator codon into a KrasFSFG12V allele allowed expression of an endogenous KRAS4AG12V oncogenic isoform in the absence of KRAS4B. Exposure of Kras+/FSF4AG12V4B- mice to Adeno-FLPo particles induced lung tumors with complete penetrance, albeit with increased latencies as compared with control Kras+/FSFG12V animals. Moreover, a significant percentage of these mice developed proximal metastasis, a feature seldom observed in mice expressing both mutant isoforms. These results illustrate that expression of the KRAS4AG12V mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4BG12V oncoprotein may not have significant therapeutic consequences.

Assessment of exposure-response relationship for bevacizumab in patients with metastatic colorectal cancer.

Limited literature is available for bevacizumab exposure-response relationship and there is not a concentration threshold associated with an optimal disease control. This prospective observational study in patients with metastatic colorectal cancer (mCRC) aims to evaluate, in a real-life setting, the relationship between bevacizumab through concentrations at steady state (Ctrough, SS) and disease control. Ctrough, SS were drawn, coinciding with the radiological evaluation of the response (progression or clinical benefit). Generalized estimating equations (GEE) analysis was performed. To test the association between Ctrough, SS in each patient with overall survival (OS) or progression-free survival (PFS), Cox proportional hazard models were developed. Data included 50 bevacizumab Ctrough, SS from 27 patients. The GEE model did not suggest any positive association between bevacizumab Ctrough, SS and clinical benefit (OR 0.99, 95% CI: 0.98-1.02, p = 0.863). The Cox regression showed association between higher median Ctrough, SS with better OS (HR 0.86, 95% CI: 0.73-1.01, p = 0.060), but not with PFS. We cannot confirm a relationship between bevacizumab Ctrough, SS and clinical benefit but this is the first real-world study trying to show a relationship between bevacizumab Ctrough, SS and disease control in mCRC. It was conducted in a small sample size which reduces the level of evidence. Further controlled randomized studies with a sufficient number of patients are required.

Diabetic Retinopathy Screening: A Systematic Review of Qualitative Literature.

OBJECTIVES: Diabetic retinopathy is a common microvascular complication that leads to vision loss. Despite national and international organizations developing guidelines for diabetic retinopathy screening, patients with diabetes remain unscreened. Our aim was to understand facilitators and barriers influencing diabetic retinopathy screening attendance and to examine factors that promote program success. METHODS: MEDLINE, Embase, PsycINFO and CINAHL from inception until September 23, 2019, were used for data collection. Studies were included if they were original qualitative research articles, included adults >18 years of age and assessed diabetic retinopathy screening programs or retinopathy screening as a component of a general diabetes care program. A "best-fit" framework synthesis methodology was used for this analysis. RESULTS: Twenty-nine articles involving 1,433 participants were identified. Six themes of barriers to, and facilitators of, diabetic retinopathy screening were identified, including access to screening, knowledge and information sharing, training and skills competency, service delivery, cultural competency and psychological factors. Cost and competing interests were common barriers to access; lack of knowledge about screening services was also a frequently reported barrier. Both patients and providers identified the need for improved service delivery, especially the referral and follow-up process. Providers recognized the need for additional training, patients enumerated several psychological barriers to screening uptake and cultural considerations were believed to be important, particularly among Indigenous communities. CONCLUSIONS: To improve screening uptake, the identified challenges must be addressed while also reinforcing the facilitators. Furthermore, program administrators could model new and unsuccessful screening programs after the successful ones while also considering local peculiarities.

Capacity, confidence and training of Canadian educators and school staff to recognize and respond to sexual abuse and internet exploitation of their students.

BACKGROUND: Sexual exploitation of children online is an issue of growing public concern. This form of exploitation typically involves adults using the internet to communicate with children for sexual purposes or to distribute sexually explicit material involving children. To date, there is no research on the knowledge and skills of educators to recognize online sexual exploitation. This research is urgently needed since educators are well-positioned to detect, identify and report sexual exploitation of their students. OBJECTIVE: The study was conducted to understand the confidence and capacity of grade school educators to recognize and respond to online child sexual exploitation. PARTICIPANTS AND SETTING: This cross-sectional study surveyed 450 educators in Alberta, Canada between April and December 2018. METHODS: Vignettes were used to obtain experiences and attitudes surrounding four categories of exploitation or abuse: grooming, luring, sexual abuse, and sexual abuse imagery (also known as child pornography). RESULTS: Among school district staff, 28 % reported working with a student affected by sexual abuse in the last year, as compared to 25 % for grooming, 17 % for luring and 14 % for sexual abuse imagery. A minority of respondents expressed confidence in their ability to recognize if the internet was being employed for grooming (35 % of staff), luring (46 %) or sexual abuse (45 %) of their students. CONCLUSIONS: Educators encounter issues of online sexual exploitation of their students almost as often as contact sexual abuse. Child protection efforts in schools should be modernized to incorporate training in online safety of children and adolescents.

Assessment of exposure-response relationship for cetuximab in patients with metastatic colorectal cancer and head and neck cancer.

OBJECTIVE: There is limited scientific evidence on the cetuximab exposure-response relationship and no concentration threshold has been associated with optimal disease control. The aims were to assess, in a real-life setting, the  relationship between steady state cetuximab concentrations (Ctrough, SS) and  disease control. METHOD: A prospective observational study in patients with metastatic colorectal cancer or head and neck cancer treated with cetuximab.  Steady state trough concentrations were compared with the results of  radiological assessment of response (progression or clinical benefit).  Generalized estimating equations analysis was performed. To test the  association between steady state concentrations and overall survival and  progression-free survival, Cox proportional hazard models were developed. An  optimal cut-off point was searched using the area under the receiver operating  characteristic curve. RESULTS: A total of 30 steady state cetuximab concentrations from 16 patients  were analysed. Median Ctrough, SS was 26.86 mg/L and there was marked  inter- and intraindividual variability (standard deviation 32.4 mg/L and 16.9 mg/L, respectively). A positive association was found between cetuximab  Ctrough, SS and clinical benefit (odds ratio 1.24, 95% confidence interval:  0.95-1.63, p = 0.113), although without reaching statistical significance. The  area under the receiver operating characteristic curve (n = 30) had moderate  discrimination power (0.71; 95% confidence interval 0.49­0.93), and the  empirical optimal cutoff point was 19.12 mg/L. However, no association was  observed between cetuximab Ctrough, SS and survival in metastatic colorectal  cancer or neck cancer patients. CONCLUSIONS: We cannot confirm a relationship between cetuximab Ctrough,  SS and disease control despite a positive association. This study was  conducted with a small sample, which reduces the power analysis. Further  controlled randomised studies with a sufficient number of patients are needed.

OBJETIVO: Evaluar, en condiciones de vida real, la relación entre las concentraciones valle en estado estacionario de cetuximab y el control de  la enfermedad, así como buscar la relación entre estas concentraciones y la supervivencia. Además, estudiar si existe una concentración límite que se  pueda asociar con la probabilidad de beneficio clínico.Método: Estudio observacional prospectivo llevado a cabo en pacientes con  cáncer colorrectal metastásico o cáncer de cabeza y cuello en tratamiento con  cetuximab. Se realizó un análisis de regresión de ecuaciones de estimación  generalizadas para evaluar la asociación entre la concentración valle en estado  estacionario de cetuximab y la respuesta al tratamiento (progresión o beneficio  clínico). Mediante modelos de riesgos proporcionales de Cox, se  evaluó la asociación entre la mediana de concentraciones valle en estado  estacionario de cetuximab en cada paciente o la última medida con la  supervivencia global y la supervivencia libre de progresión, en cada una de las  patologías. Asimismo, se buscó un punto de corte óptimo a través del área  bajo la curva de características operativas del receptor. RESULTADOS: Se analizaron 30 muestras de 16 pacientes. La concentración valle en estado estacionario mediana fue 26,86 mg/l y se  encontró una gran variabilidad inter e intraindividual (desviación estándar de  32,4 y 16,9 mg/l, respectivamente). Se observó una asociación positiva entre  la concentración valle en estado estacionario y el beneficio clínico (odds ratio  1,24; intervalo de confianza del 95%: 0,95-1,63; p = 0,113), aunque no alcanzó significación estadística debido a la baja potencia. El área bajo la  curva de características operativas del receptor de las concentraciones (n =  30) tuvo una moderada capacidad discriminatoria (área bajo la curva de  características operativas del receptor 0,710; intervalo de confianza del 95%:  0,49-0,93) y el punto de corte estimado fue de 19,12 mg/l. Sin embargo, no  se observó relación entre la supervivencia y las concentraciones valle en  estado estacionario en ninguna de las patologías. CONCLUSIONES: No se ha podido confirmar una relación entre exposición a  cetuximab y eficacia, a pesar de encontrar una tendencia positiva en el control  de la enfermedad con el aumento de la concentración valle en estado  estacionario. El nivel de evidencia se vio reducido por la pequeña muestra de  pacientes en cada grupo, por lo que se necesitan estudios aleatorizados y  controlados, con un número suficiente de pacientes, para evaluar  adecuadamente esta relación.

Extended enzymatic stability of reconstituted lyophilized PEG-asparaginase in vials.

Asparaginase (ASNase) use as a tumour-inhibitor drug has changed completely the natural course of paediatric acute lymphoblastic leukaemia (ALL) in such a way that it represents a paradigm shift in ALL management. ASNase treatment emergence has significantly improved pathologic responses and increased survival rates of ALL patients. Although different ASNase forms are currently available, only the pegylated form (PEG-ASNase) is recommended by relevant clinic guides. PEG-ASNase form shows longer elimination half-life, reducing the number of administrations, along with an enhanced safety profile. In spite of all of these advantages, PEG-ASNase elevated cost limits enormously its use. PEG-ASNase is commercialised as a lyophilised powder which according to the manufacturer it is stable for 24 hours once reconstituted, as a result, the leftover is usually discarded. In this study we analysed the enzymatic stability of reconstituted PEG-ASNase after conservation in three different temperature conditions for 5 and 14 days, aiming to take advantage of the remaining leftover for the subsequent administration. Our results have shown that PEG-ASNase is stable at 4°C, -20°C and -80°C for at least 14 days, retaining the 95% from the initial enzymatic activity in all three storage temperatures. According to our results, it is feasible to reuse the remaining content of PEG-ASNase vial after reconstitution, which means a 50% reduction of its cost for paediatric patient treatment and, consequently, removes the main barrier to use this drug in a wider population.

Anti-drug antibodies anti-trastuzumab in the treatment of breast cancer.

INTRODUCTION: Trastuzumab is a monoclonal antibody which could induce the activation of a humoral immune response generating anti-drug antibodies (ADAs). Such response depends of the protein nature and the route of administration (intravenous or subcutaneous). The formation of these antibodies could block the action of trastuzumab (ADA-Tras) and forming immune complexes which decrease its efficacy, so it would be interesting to determine the presence of ADA-Tras in patients treated with trastuzumab. MATERIAL AND METHODS: The blood samples were centrifuged to separate the plasma. The presence of ADA-Tras in plasma was determined using an ELISA-type automated immunoassay. RESULTS: Fifty-one women with non-metastatic HER2-positive breast cancer treated with trastuzumab were included. Two groups were studied: patients treated intravenously and subcutaneously. In neither case was there any presence of ADA-Tras. DISCUSSION: This study may be the first ever conducted under usual clinical practice conditions to detect the presence of ADA-Tras in patients with non-metastatic HER2-positive breast cancer. We have wanted to show the antibodies anti-trastuzumab determination as a possible tool that would enable comparison of potential differences in immunogenic behavior between trastuzumab and its biosimilars.