Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group.

BACKGROUND: Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice. METHODS: The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility. RESULTS: As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available. CONCLUSION: Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer.

Differences in molecular sensitization profiles between a Spanish and Latin American mite allergic patients.

BACKGROUND AND OBJECTIVE: To analyze the sensitization pattern to Dermatophagoides pteronyssinus and to associate the diagnostic findings and clinical severity in 218 allergic patients from two different continents. METHODS: Mite allergic patients were recruited by the Allergology departments from Latin America (n=88: Colombia, Costa Rica and Guatemala) and Spain (N=130). All patients had allergic rhinitis with or without asthma and positive skin prick test results to D. pteronyssinus. Specific IgE levels to D. pteronyssinus, D. farinae, Der p 1, Der p 2, and Der p 23 were quantified by ImmunoCAP system (ThermoFisher Scientific). Allergenic profile was also determined by western blot. Comparative Statistical analysis was performed by GraphPad software. RESULTS: Patients recognized most frequently Der p 2 (79%) followed by Der p 1 (73%), and Der p 23 (69%) allergens. The percentage of asthmatic patients increases with the number of sensitizations however none statistically significant differences were found. Interestingly, asthmatic patients presented the highest median levels of total IgE and specific IgE levels of D. pteronyssinus and molecular allergens, mainly Der p 2. Analysing the two different populations, Spanish patients were predominantly sensitized to Der p 2 (88.46%) and Der p 1 (83.84%), whereas Latin American population were more sensitized to Der p 23. CONCLUSION: Our data support the relevance of Der p 2 in mite allergy as the major allergen, with the high number of patients sensitized to it and its importance in the development of asthma. Sensitization to Der p 23 was more important in Latin America.

Circulating tumor DNA analysis of the phase III VOYAGER trial: KIT mutational landscape and outcomes in patients with advanced gastrointestinal stromal tumor treated with avapritinib or regorafenib.

BACKGROUND: The current treatment paradigm of imatinib-resistant metastatic gastrointestinal stromal tumor (GIST) does not incorporate KIT/PDGFRA genotypes in therapeutic drug sequencing, except for PDGFRA exon 18-mutant GIST that is indicated for avapritinib treatment. Here, circulating tumor DNA (ctDNA) sequencing was used to analyze plasma samples prospectively collected in the phase III VOYAGER trial to understand how the KIT/PDGFRA mutational landscape contributes to tyrosine kinase inhibitor (TKI) resistance and to determine its clinical validity and utility. PATIENTS AND METHODS: VOYAGER (N = 476) compared avapritinib with regorafenib in patients with KIT/PDGFRA-mutant GIST previously treated with imatinib and one or two additional TKIs (NCT03465722). KIT/PDGFRA ctDNA mutation profiling of plasma samples at baseline and end of treatment was assessed with 74-gene Guardant360® CDx. Molecular subgroups were determined and correlated with outcomes. RESULTS: A total of 386/476 patients with KIT/PDGFRA-mutant tumors underwent baseline (pre-trial treatment) ctDNA analysis; 196 received avapritinib and 190 received regorafenib. KIT and PDGFRA mutations were detected in 75.1% and 5.4%, respectively. KIT resistance mutations were found in the activation loop (A-loop; 80.4%) and ATP-binding pocket (ATP-BP; 40.8%); 23.4% had both. An average of 2.6 KIT mutations were detected per patient; 17.2% showed 4-14 different KIT resistance mutations. Of all pathogenic KIT variants, 28.0% were novel, including alterations in exons/codons previously unreported. PDGFRA mutations showed similar patterns. ctDNA-detected KIT ATP-BP mutations negatively prognosticated avapritinib activity, with a median progression-free survival (mPFS) of 1.9 versus 5.6 months for regorafenib. mPFS for regorafenib did not vary regardless of the presence or absence of ATP-BP/A-loop mutants and was greater than mPFS with avapritinib in this population. Secondary KIT ATP-BP pocket mutation variants, particularly V654A, were enriched upon disease progression with avapritinib. CONCLUSIONS: ctDNA sequencing efficiently detects KIT/PDGFRA mutations and prognosticates outcomes in patients with TKI-resistant GIST treated with avapritinib. ctDNA analysis can be used to monitor disease progression and provide more personalized treatment.

Psychosocial risk in healthcare workers after one year of COVID-19.

BACKGROUND: The COVID-19 pandemic overwhelmed the capacity of the healthcare system, affecting the volume of demands and the care tasks of healthcare workers. AIMS: To examine the health indicators and exposure to psychosocial risks of Spanish healthcare workers 1 year into the COVID-19 pandemic and compare them with the results of the first wave. METHODS: We conducted a cross-sectional study using an online questionnaire (April-May 2020 and 2021). The data stem from the COTS 1 project database, corresponding to the first wave of COVID-19 (n = 1989) and COTS 2 (n = 1716) corresponding to 1 year later. The samples were independent. The prevalence of exposure to psychosocial risks and adverse health indicators was estimated for every occupational group, segregating the data by sex. RESULTS: Professionals of all types presented worse perception of health. In general, the results were worse for women, while geriatric assistants presented the greatest exposure to psychosocial risk in COTS 2 compared to COTS 1. Sleep problems, high quantitative demands and high concern about becoming infected and spreading COVID-19 were cross-disciplinary in COTS 1, while worse perception of health, high pace of work, high work-life conflict and low development opportunities stood out in COTS 2. CONCLUSIONS: Exposure to psychosocial risks was already high during the first wave and a significant decline in working conditions was observed. The prolongation of the pandemic exacerbated these results and seems to have multiplied the pre-existing inequalities between the axes of segregation in the labour market.

Analysis of outcomes of emergency general and gastrointestinal surgery during the COVID-19 pandemic.

BACKGROUND: Few surgical studies have provided adjusted comparative postoperative outcome data among contemporary patients with and without COVID-19 infection and patients treated before the pandemic. The aim of this study was to determine the impact of performing emergency surgery in patients with concomitant COVID-19 infection. METHODS: Patients who underwent emergency general and gastrointestinal surgery from March to June 2020, and from March to June 2019 in 25 Spanish hospitals were included in a retrospective study (COVID-CIR). The main outcome was 30-day mortality. Secondary outcomes included postoperative complications and failure to rescue (mortality among patients who developed complications). Propensity score-matched comparisons were performed between patients who were positive and those who were negative for COVID-19; and between COVID-19-negative cohorts before and during the pandemic. RESULTS: Some 5307 patients were included in the study (183 COVID-19-positive and 2132 COVID-19-negative during pandemic; 2992 treated before pandemic). During the pandemic, patients with COVID-19 infection had greater 30-day mortality than those without (12.6 versus 4.6 per cent), but this difference was not statistically significant after propensity score matching (odds ratio (OR) 1.58, 95 per cent c.i. 0.88 to 2.74). Those positive for COVID-19 had more complications (41.5 versus 23.9 per cent; OR 1.61, 1.11 to 2.33) and a higher likelihood of failure to rescue (30.3 versus 19.3 per cent; OR 1.10, 0.57 to 2.12). Patients who were negative for COVID-19 during the pandemic had similar rates of 30-day mortality (4.6 versus 3.2 per cent; OR 1.35, 0.98 to 1.86) and complications (23.9 versus 25.2 per cent; OR 0.89, 0.77 to 1.02), but a greater likelihood of failure to rescue (19.3 versus 12.9 per cent; OR 1.56, 95 per cent 1.10 to 2.19) than prepandemic controls. CONCLUSION: Patients with COVID-19 infection undergoing emergency general and gastrointestinal surgery had worse postoperative outcomes than contemporary patients without COVID-19. COVID-19-negative patients operated on during the COVID-19 pandemic had a likelihood of greater failure-to-rescue than prepandemic controls.

Modelling of photosynthesis, respiration, and nutrient yield coefficients in Scenedemus almeriensis culture as a function of nitrogen and phosphorus.

Photo-respirometric tecniques are applied for evaluating photosynthetic activity in phototrophic organisms. These methods allow to evaluate photosynthetic response under different conditions. In this work, the influence of nutrient availability (nitrate, ammonium, and phosphate) on the photosynthesis and respiration of Scenedesmus almeriensis was studied using short photo-respirometric measurements. Both photosynthesis and respiration increasing until saturation value and consecutively diminishing, presenting inhibition by high concentrations. Regarding the influence of phosphorus concentration in microalgae cells, a similar hyperbolic trend was observed but no inhibition was observed at high concentration. Based on these experimental data, the respiration, and the photosynthesis rate of S. almeriensis were modelled using Haldane equation for nitrate and ammonium data, and Monod equation for phosphate data. In addition, experiments were performed to determine the yield coefficients for both nitrogen and phosphorus in S. almeriensis cultures. The data showed that the nitrogen and phosphorous coefficient yields are not constant, being modified as a function of nutrients concentration, presenting the luxury uptake phenomena. Finally, the proposed models were incorporated into a simulation tool to evaluate the photosynthetic activity and the nutrient yield coefficients of S. almeriensis when different culture media and wastewaters are used as a nitrogen and phosphorous source for its growth. Key points • Microalgal photosynthesis/respiration vary as a function of nutrients availability. • Photosynthesis inhibition appears at high N-NO 3 - and N-NH4+ concentrations. • Nutrient yield coefficients are influenced by luxury uptake phenomenon.

Thermography for the differential diagnosis of vascular malformations.

Vascular malformations classification may pose a diagnostic challenge for physicians. In the early stages, they are diagnosed clinically mainly by visual inspection. For a deeper analysis, Doppler ultrasonography is the preferred technique to determine the haemodynamic behaviour of the anomaly. However, this imaging method is not always available and it requires trained operators to acquire and interpret the images. There is a lack of portable and user-friendly systems that may help physicians in the assessment of vascular malformations. We propose a new diagnostic procedure, more affordable and easier to use, based on a portable thermal camera. This technique provides information about temperature, which has been found to be correlated with the flow rate of the lesion. In our study, > 60 vascular malformations of previously diagnosed patients were analysed with a thermal camera to classify them into low-flow and high-flow malformations. The value was 1 for both sensitivity and specificity of this technique.

Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.

Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.

Serum periostin is not related to asthma predictive index.

BACKGROUND: In contrast to adult asthmatic patients, studies on the role of serum periostin levels in schoolchildren with asthma are still conflictive, and very few studies have been performed in pre-schoolers. The aim of this study was to compare serum periostin levels in recurrent wheezer pre-schoolers according to their asthma predictive index (API) condition. METHODS: We performed a case-control study enrolling pre-schoolers with recurrent wheezing episodes (>3 episodes confirmed by physician) presented at one paediatric clinic in Santiago, Chile. The population was divided according to stringent API criteria into positive or negative. RESULTS: In a one-year period, 60 pre-schoolers were enrolled. After excluding 12 (due to not fulfilment of inclusion criteria or refusal of blood sample extraction), 48 remaining pre-schoolers (27 males, age range from 24 to 71 months) completed the study; 34 were API positive and 14 were API negative. There were no significant differences in demographics between groups. The level of serum periostin levels for pre-schoolers with positive API and negative API were (median 46.7 [25.5-83.1] and 67.5 [20.5-131.8], p=0.9, respectively). The area under the curve for the serum periostin levels for predict positive API was 0.5, 95% CI [0.29-0.70], p=0.9. No significant correlation between serum periostin levels and peripheral blood eosinophils was found. CONCLUSION: Serum periostin levels were no significantly different between wheezer pre-schoolers with positive and negative API. More studies are needed to confirm this finding.

Relation between serum CC16 levels and asthma predictive index in pre-schoolers with recurrent wheezing.

BACKGROUND: Low levels of serum CC16 were reported in asthmatic adults, but the studies on children were scarce and conflicting. The aim of this study was to compare serum CC16 levels in pre-school children with recurrent wheezing assessed using an asthma predictive index (API). METHODS: We performed a case-control study based on API, with all enrolled pre-school children who had recurrent wheezing episodes (>3 episodes/last year confirmed by a physician) and had presented at one paediatric clinic in Santiago, Chile. The population was divided according to stringent API criteria into positive or negative. RESULTS: In a one-year period, 60 pre-schoolers were enrolled. After excluding 12, 48 pre-schoolers remained (27 males, age range from 24 to 71 months) and completed the study; 34 were API positive and 14 were API negative. There were no significant differences in demographics between groups. The level of serum CC16 levels for pre-schoolers with a positive API and negative API were (median 9.2 [7.1-11.5] and 9.4 [5.5-10], p=0.26, respectively). The area under the curve for the serum CC16 levels to predict a positive API was 0.6, 95% CI [0.43-0.77], p=0.3. A correlation between serum CC16 levels and age was found (r=0.36 [0.07-0.59], p=0.01], but not between serum CC16 levels and peripheral eosinophils blood. CONCLUSION: There was no evidence that serum CC16 levels played a role in recurrent wheezing and a positive API in pre-school children. More studies are needed to confirm this finding.

Functional gastrointestinal disorders in children from low socio-economic status and Helicobacter pylori infection.

BACKGROUND: Most studies on functional gastrointestinal disorders (FGIDs) in children are based on data from the northern hemisphere. Scientific reports are arising in South American population, but little is still known about children from low socio-economic status (SES), where Helicobacter pylori infection is endemic. Our objective was to evaluate the prevalence of FGIDs in school children from low SES and its relationship with H. pylori infection. METHODS: Children from 3 public schools of low SES from Santiago de Chile were included. Students completed the Rome III Questionnaire and a survey about other symptoms. Also, the 13 C urea breath test determined the presence of H. pylori infection. RESULTS: Five hundred six children were included, where 48% were male, with a median age of 15.7 years (range 7.1-19.6). Forty-two percent had some FGID, aerophagia and functional constipation being the most frequent. Females (adjusted OR 1.5, 95% CI [1.1, 2.2]), those children with parents within the lowest level of education (adjusted OR 1.6, 95% CI: 1.1-2.4), and family history of gastric cancer (adjusted OR 1.9, 95% CI: 1.2-3.1) were related to FGIDs. The prevalence of H. pylori infection was 55.9% (95% CI [50.7, 60.9]). In multivariable analysis, the presence of abdominal pain (OR 1.55, 95% CI [1.02, 2.36]), but not FGIDs, was related to H. pylori infection. CONCLUSIONS: FGIDs are common in low SES students. A low educational level of the household head, family history of gastric cancer. and being female are related to the development of FGIDs. In this study, no relationship between the presence of H. pylori and FGIDs was found.

Challenges in the transition to clinical training in dentistry: An ADEE special interest group initial report.

INTRODUCTION: Curricular integration in higher education has been widely supported in the educational literature. As a result, several health care and specifically dental curricula have evolved from compartmentalised disciplinary training to integrated modalities; however, in many courses, a pre-clinical-clinical watershed remains a barrier to integration in dental education. This article introduces a general description of the pre-clinical-clinical transition in dentistry according to the outcomes of the discussion held during the first working group session of the "Transition to Clinical Training" Special Interest Group during the 2016 annual meeting of the Association for Dental Education in Europe. MATERIALS AND METHODS: An online questionnaire was made available before the meeting to survey the curricular characteristics of the participants' schools. During the meeting, a working session related to the pre-clinical-clinical transition occurred. Conclusions from the discussion are summarised in this article. RESULTS: Fourteen dental schools from 12 countries participated in the online survey. The included programmes had an average duration of 5.3 years (SD = 0.48), with high school or the local equivalent as the required entrance level for dentistry. The hybrid curriculum was the leading curriculum design (n = 9) followed by competence-based curricula (n = 3), with patient treatment as the core of clinical training in every included programme. CONCLUSION: The pre-clinical-clinical transition in dentistry is a recognisable matter in dental education that requires assessment and research to ease the management of a stage with relevant influence on educational outcomes. This article presents an initial framework for further research and educational intervention.

Innovation in dental education: The "On-the-Fly" approach to simultaneous development, implementation and evidence collection.

INTRODUCTION: This study outlines an approach for education innovation and addresses the ambivalence between evidence-based and non-evidence-based conditions. The "on-the-fly" approach was described as involving implementation during the development of an innovation for dental education. MATERIALS AND METHODS: The process of designing and implementing cutting-edge technology of the MOOG Simodont Dental Trainer (DT) whilst systematically collecting evidence illustrates the "on-the-fly" approach. RESULTS: Using the "on-the-fly" approach for developing, implementing and collecting evidence simultaneously in an academic environment appears feasible in serving both the professionals, users and developers and system designers. During the implementation of the new technology, growing evidence stepwise strengthened its position; therefore, showing stakeholders that evidence was used to improve the technology seemed to support and increase acceptance of the new technology. CONCLUSIONS: When pioneering an innovative technology in a specialty field, the development stage often precedes evidence for its effectiveness. Consciously choosing the "on-the-fly" approach clarifies to stakeholders in advance about the lack of evidence in an innovation and the need of their support to collect such evidence for improvement and in order to facilitate implementation.

[3D printed medical devices and anatomical models: What kind of distribution and which uses in French hospitals?] / Dispositifs médicaux et modèles anatomiques produits par impression 3D : quelle diffusion et quelles utilisations dans les établissements de santé français ?

3D printing plays an increasingly important role in the medical sector and particularly in surgery. Nowadays, numerous manufacturers benefit from this technology to produce their medical devices and some hospitals have also purchased 3D printers. In this context, the aim of the present study was to study the distribution and the use of 3D printing in French hospitals in order to its main features in surgery. By conducting a national survey, we targeted hospitals equipped with 3D printers and those using external providers to benefit from this technology. Forty-seven hospitals were identified as using 3D printing including eight equipped with in-house 3D printers. This work gives us a first picture of 3D printing for hospital use in France and it raises questions about hospital pharmacists' involvement in 3D printed medical device production.

[Real patients in virtual reality: the link between phantom heads and clinical dentistry]. / Echte patiënten in de virtuele realiteit: de schakel tussen fantoom en kliniek.

Preclinical training in phantom heads has until now been considered the 'gold standard' for restorative dental education, but the transition from preclinic to the treatment of real patients has remained a challenge. With the introduction of the latest generation of virtual reality simulators, students and dental practitioners can make digital impressions of their patients in virtual reality models and practice procedures in virtual reality before clinically performing them. In this way, clinical decisions can be investigated and practiced prior to actual treatment, enhancing the safety of the treatment and the self-confidence to perform it. With the 3M™ True Definition Scanner and the Moog Simodont Dental Trainer, 3 masters students and a general dental practitioner practiced their procedures in virtual reality prior to performing them on real patients. They were very satisfied with this preparation and the result of the treatment.

Wastewater treatment using microalgae: how realistic a contribution might it be to significant urban wastewater treatment?

Microalgae have been proposed as an option for wastewater treatment since the 1960s, but still, this technology has not been expanded to an industrial scale. In this paper, the major factors limiting the performance of these systems are analysed. The composition of the wastewater is highly relevant, and especially the presence of pollutants such as heavy metals and emerging compounds. Biological and engineering aspects are also critical and have to be improved to at least approximate the performance of conventional systems, not just in terms of capacity and efficiency but also in terms of robustness. Finally, the harvesting of the biomass and its processing into valuable products pose a challenge; yet at the same time, an opportunity exists to increase economic profitability. Land requirement is a major bottleneck that can be ameliorated by improving the system's photosynthetic efficiency. Land requirement has a significant impact on the economic balance, but the profits from the biomass produced can enhance these systems' reliability, especially in small cities.

Regulatory T-cell subsets in response to specific Mycobacterium tuberculosis antigens in vitro distinguish among individuals with different QTF and TST reactivity.

Regulatory T cells (Tregs), a subset of CD4+ T cells related with immune regulation, have been associated with active and latent tuberculosis infection (LTBI). Treg frequencies were evaluated by multicolor flow cytometry (FC) in peripheral blood mononuclear cells (PBMCs) stimulated with mycobacterial antigens ESAT-6, CFP-10, and TB7.7 to assess their capacity to distinguish subjects with different reactivity to the QuantiFERON-TB® Gold In-Tube (QFT-IT) test and the tuberculin skin test (TST). Increased frequencies of CD4+CD25highCD39+ cells were found for the [TST+, QTF+] compared with the [TST+, QTF-] group. Also, higher frequencies were observed for the [TST+, QTF+] compared with the [TST+, QTF-] and [TST-, QTF-] groups in CD4+CD25highFoxp3+ and CD4+CD25highCD39+Foxp3+ populations. Receiver operating characteristics (ROC curve) analysis confirmed these discriminating results. QFT-IT and TST quantitative values correlated with several Treg population frequencies.