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BACKGROUND: This study aimed to compare the cost-effectiveness of coronavirus disease 2019 (COVID-19) mass testing, carried out in November 2020 in the Italian Bolzano/Südtirol province, to scenarios without mass testing in terms of hospitalizations averted and quality-adjusted life-year (QALYs) saved. METHODS: We applied branching processes to estimate the effective reproduction number (Rt) and model scenarios with and without mass testing, assuming Rt = 0.9 and Rt = 0.95. We applied a bottom-up approach to estimate the costs of mass testing, with a mixture of bottom-up and top-down methodologies to estimate hospitalizations averted and incremental costs in case of non-intervention. Lastly, we estimated the incremental cost-effectiveness ratio (ICER), denoted by screening and related social costs, and hospitalization costs averted per outcome derived, hospitalizations averted and QALYs saved. RESULTS: The ICERs per QALY were 24 249 under Rt = 0.9 and 4604 under Rt = 0.95, considering the official and estimated data on disease spread. The cost-effectiveness acceptability curves show that for the Rt = 0.9 scenario, at the maximum threshold willingness to pay the value of 40 000, mass testing has an 80% probability of being cost-effective compared to no mass testing. Under the worst scenario (Rt = 0.95), at the willingness to pay threshold, mass testing has an almost 100% probability of being cost-effective. CONCLUSIONS: We provide evidence on the cost-effectiveness and potential impact of mass COVID-19 testing on a local healthcare system and community. Although the intervention is shown to be cost-effective, we believe the initiative should be carried out when there is initial rapid local disease transmission with a high Rt, as shown in our model.
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OBJECTIVE: To evaluate, under replicable, blinded and standardised conditions, the effect of acute exposure to hypobaric hypoxia (HH) (equivalent to 200 or 3000 or 5000 m above sea level (asl)) on selected cognitive domains and physiological parameters in personnel of helicopter emergency medical service (HEMS). METHODS: We conducted a randomized clinical trial using a single-blind crossover design in an environmental chamber (terraXcube) to induce HH in 48 HEMS personnel. Participants performed cognitive tests (CT) before the ascent, after 5 min at altitude, and after simulated cardiopulmonary resuscitation (SCR). CT evaluated: sustained attention using the psychomotor vigilance test (PVT) that included measurement of reaction time (RT); risky decision making using the balloon analogue risk task (BART), and attention and speed of processing using the digit symbol substitution test (DSST). CT performance was subjectively rated with a visual analogue scale (VAS). Physiological data were recorded with a physiological monitoring system. Data were analysed using a linear mixed model and correlation analysis. RESULTS: Mean reaction time was significantly slower (p = 0.002) at HH (5000 m asl), but there were no independent effects of HH on the other parameters of the PVT, BART or DSST. Participants did not detect subjectively the slower RT at altitude since VAS performance results showed a positive correlation with mean RT (p = 0.009). DSST results significantly improved (p = 0.001) after SCR. CONCLUSION: Acute exposure of HEMS personnel to HH induced a slower RT but no changes in any other investigated measures of cognition. The reduced RT was not detected subjectively by the participants. Trial number 3489044136, ClinicalTrials.gov trial registration.
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BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic overwhelming the health care systems worldwide. Lung ultrasound (LUS) use has been proposed to identify suspected COVID-19 patients and direct them to the isolation area in the emergency department (ED) or to discharge them for outpatient treatment. OBJECTIVE: Our aim was to retrospectively investigate the use of LUS in the ED to identify COVID-19 pneumonia (CP). METHODS: We performed a retrospective single-center study including all patients accessing the ED who underwent LUS examination for suspicion of COVID-19 during the initial outbreak. Demographics, clinical parameters, laboratory values, imaging features, and outcome variables were collected. The receiver operating characteristic (ROC) curve was used to evaluate diagnostic accuracy. RESULTS: A total of 41% patients were COVID-19-positive; 67% of them were diagnosed with CP. The ROC curve of the LUS score showed an area under the curve of 0.837 (95% CI 0.75-0.92) and with a cutoff value ≥3 identified 28 of 31 patients with CP and 11 of 15 without (sensitivity 90%, 95% CI 74-97%; specificity 75%, 95% CI 56-76%). LUS in combination with nasopharyngeal swab has a sensitivity of 100% (95% CI 74-97%) and a specificity of 61% (95% CI 44-67%). CONCLUSIONS: LUS is a promising technique for early identification of CP in patients who accessed the ED in an active epidemic time. The LUS score shows a sensitivity of 90% for CP, allowing to quickly direct patients with COVID-19 to the ED isolation area or to discharge them for outpatient treatment.
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COVID-19/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Ultrassonografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , Teste de Ácido Nucleico para COVID-19 , Diagnóstico Precoce , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isolamento de Pacientes , Pneumonia Viral/diagnóstico por imagem , Curva ROC , Estudos Retrospectivos , SARS-CoV-2 , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Over the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1st-generation (reversible) EGFR TKI and later the 2nd -generation irreversible EGFR TKI Afatinib were aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy. Here, we evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI. METHODS: Rebiopsies of patients after progression to EGFR TKI therapy (> 6 months) were targeted to histological and molecular analysis. Multiplexed targeted sequencing (NGS) was conducted to identify acquired resistance mutations (e.g. EGFR p.T790M). Further, Fluorescence in situ hybridisation (FISH) was applied to investigate the status of bypass mechanisms like, MET or HER2 amplification. RESULTS: One hundred twenty-three rebiopsy samples of patients that underwent first-line EGFR TKI therapy (PFS ≥6 months) were histologically and molecularly profiled upon clinical progression. The EGFR p.T790M mutation is the major mechanism of acquired resistance in patients treated with reversible as well as irreversible EGFR TKI. Nevertheless a statistically significant difference for the acquisition of T790M mutation has been identified: 45% of afatinib- vs 65% of reversible EGFR TKI treated patients developed a T790M mutation (p-value 0.02). Progression free survival (PFS) was comparable in patients treated with irreversible EGFR irrespective of the sensitising primary mutation or the acquisition of p.T790M. CONCLUSIONS: The EGFR p.T790M mutation is the most prominent mechanism of resistance to reversible and irreversible EGFR TKI therapy. Nevertheless there is a statistically significant difference of p.T790M acquisition between the two types of TKI, which might be of importance for clinical therapy decision.
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Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
AIM: Medijet nasal continuous positive airway pressure (CPAP) generators are a family of devices developed from the Benveniste valve. Previous studies have shown that the in vitro performance of the Medijet disposable generator was similar to the Neopuff resistor system. We hypothesised that resistance would be the main mechanism of CPAP generation in the Medijet disposable generator. METHODS: The in vitro performance of the Medijet reusable and disposable systems, the Neopuff resistor system and the Benveniste and Infant Flow nonresistor systems were investigated using static and dynamic bench tests. RESULTS: Large differences in performance were found between the different systems. The disposable Medijet demonstrated high resistance, low pressure stability and high imposed work of breathing. The results also showed that encapsulating the Benveniste valve changed it into a resistor system. CONCLUSION: The main mechanism of CPAP generation for the disposable Medijet generator was resistance. The Medijet device family showed increasing resistance with each design generation. The high resistance of the Medijet disposable generator could be of great value when examining the clinical importance of pressure stability. Our results suggest that this device should be used cautiously in patients where pressure-stable CPAP is believed to be clinically important.
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Pressão Positiva Contínua nas Vias Aéreas/instrumentação , Humanos , Recém-Nascido , Ventilação PulmonarRESUMO
OBJECTIVE: To describe the prehospital management and safety of search and rescue (SAR) teams involved in a large-scale rockfall disaster and monitor the acute and chronic health effects on personnel with severe dolomitic dust exposure. METHODS: SAR personnel underwent on-site medical screening and lung function testing 3 months and 3 years after the event. RESULTS: The emergency dispatch center was responsible for central coordination of resources. One hundred fifty SAR members from multidisciplinary air- and ground-based teams as well as geotechnical experts were dispatched to a provisionary operation center. Acute exposure to dolomite dust with detectable silicon and magnesium concentrations was not associated with (sub)acute or chronic sequelae or a clinically significant impairment in lung function in exposed personnel. CONCLUSIONS: The risk for personnel involved in mountain SAR operations is rarely reported and not easily investigated or quantified. This case exemplifies the importance of a multiskilled team and additional considerations for prehospital management during natural hazard events. Safety plans should include compulsory protective measures and medical monitoring of personnel.
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Carbonato de Cálcio/toxicidade , Desastres , Poeira/análise , Pessoal de Saúde , Deslizamentos de Terra , Magnésio/toxicidade , Medicina Ambiental/organização & administração , Medicina Ambiental/estatística & dados numéricos , Itália , SegurançaRESUMO
BACKGROUND: The PACIFIC study showed that after radio-chemotherapy, patients with NSCLC derived a benefit in PFS and OS when treated with durvalumab. This effect was limited to patients with a PD-L1 expression of >1%, partly because the outcome in the observational control arm was surprisingly favorable. Thus, it could be speculated that a lack of PD-L1 expression confers a favorable outcome for patients with stage III NSCLC. METHODS: Clinical data, PD-L1 expression, predictive blood markers, and the outcomes of 99 homogeneously treated patients with stage III NSCLC were retrospectively captured. Statistical analyses using the log rank test were performed. RESULTS: The median OS of patients with an expression of PD-L1 < 1% was 20 months (CI 10.5-29.5) and the median OS of patients with an expression of PD-L1 ≥ 1% was 28 months (CI 16.5-39.2) (p = 0.734). The median PFS of patients with an expression of PD-L1 < 1% was 9 months (CI 6.3-11.6) and the median PFS of patients with an expression of PD-L1 ≥ 1% was 12 months (CI 9.8-14.2) (p = 0.112). CONCLUSIONS: The assumption that the lack of PD-L1 expression represents a favorable prognostic factor after radio-chemotherapy vs. PD-L1 expression > 1% was not confirmed.
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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent first-line standard of care in unresectable EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). However, 10-20% of patients with EGFRm+ NSCLC have uncommon EGFR variants, defined as mutations other than L858R substitutions or exon 19 deletions. NSCLC harboring uncommon EGFR mutations may demonstrate lower sensitivity to targeted agents than NSCLC with L858R or exon 19 deletion mutations. Prospective clinical trial data in patients with NSCLC uncommon EGFR mutations are lacking. Afatinib is a second-generation TKI and the only Food and Drug Administration-approved drug for some of the more prevalent uncommon EGFR mutations. We present a series of seven case reports describing clinical outcomes in afatinib-treated patients with NSCLC harboring a diverse range of extremely rare mutations with or without co-mutations affecting other genes. EGFR alterations included compound mutations, P-loop αC-helix compressing mutations, and novel substitution mutations. We also present a case with NSCLC harboring a novel EGFR::CCDC6 gene fusion. Overall, the patients responded well to afatinib, including radiologic partial responses in six patients during treatment. Responses were durable for three patients. The cases presented are in line with a growing body of clinical and preclinical evidence that indicating that NSCLC with various uncommon EGFR mutations, with or without co-mutations, may be sensitive to afatinib.
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Background: Capmatinib, a potent and selective MET tyrosine kinase inhibitor (TKI), holds promise as a therapeutic agent due to its potentially elevated intracranial efficacy in metastatic non-small cell lung cancer (NSCLC) patients harboring exon 14 skipping alterations in MET (MET Proto-Oncogene). This study aims to evaluate a targeted therapeutic approach to an MET exon 14 skipping (METex14) advanced NSCLC patient that progressed on Crizotinib and developed off target resistance alteration in PIK3CA. Case Discription: We present a case of advanced METex14 NSCLC patient wherein central nervous system (CNS) relapse occurred post complete surgical resection and remission of the lung tumor under first-line crizotinib treatment. Subsequent disease monitoring demonstrated a profound intracranial response to capmatinib in a crizotinib-resistant brain lesion. Molecular analysis unveiled the original METex14 D1028N driver mutation and a newly arisen PIK3CA bypass mutation, potentially contributing to off-target resistance. Conclusions: Before capmatinib was approved as a first line treatment option for metastatic NSCLC harboring somatic METex14 mutations, crizotinib conferred a potential option for targeted treatment. Switching to a selective MET-TKI like capmatinib with a better CNS penetration, it appears to be a promising approach for CNS metastasized NSCLC patients with METex14 mutations that failed on crizotinib. Further research is needed to more effectively understand and monitor resistance mechanisms using advanced diagnostic techniques such as DNA-based hybrid-capture (HC) next generation sequencing (NGS) to guide molecularly stratified therapy beyond the first line setting.
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IMPORTANCE: Emergency medical services (EMS) providers transiently ascend to high altitude for primary missions and secondary transports in mountainous areas in helicopters that are unpressurised and do not have facilities for oxygen supplementation. The decrease in cerebral oxygen saturation can lead to impairment in attention and reaction time as well as in quality of care during acute exposure to altitude. OBJECTIVE: The primary aim of the current study was to investigate the effect of oxygen supplementation on cognitive performance in Helicopter EMS (HEMS) providers during acute exposure to altitude. DESIGN, SETTING, AND PARTICIPANTS: This interventional, randomized, controlled, double-blind, cross-over clinical trial was conducted in October 2021. Each trial used a simulated altitude scenario equivalent to 4000 m, in which volunteers were exposed to hypobaric hypoxia with a constant rate of ascent of 4 m/s in an environmental chamber under controlled, replicable, and safe conditions. Trials could be voluntarily terminated at any time. Inclusion criteria were being members of emergency medical services and search and rescue services with an age between 18 and 60 years and an American Society of Anesthesiologists physical status class I. EXPOSURES: Each participant conducted 2 trials, one in which they were exposed to altitude with oxygen supplementation (intervention trial) and the other in which they were exposed to altitude with ambient air supplementation (control trial). MAIN OUTCOMES AND MEASURES: Measurements included peripheral oxygen saturation (SpO2), cerebral oxygenation (ScO2), breathing and heart rates, Psychomotor Vigilance Test (PVT), Digit-Symbol Substitution Test (DSST), n-Back test (2-BACK), the Grooved Pegboard test, and questionnaires on subjective performance, stress, workload, and positive and negative affect. Paired t-tests were used to compare conditions (intervention vs. control). Data were further analyzed using generalized estimating equations (GEE). RESULTS: A total of 36 volunteers (30 men; mean [SD] age, 36 [9] years; mean [SD] education, 17 [4] years) were exposed to the intervention and control trials. The intervention trials, compared with the control trials, had higher values of SpO2 (mean [SD], 97.9 [1.6] % vs. 86 [2.3] %, t-test, p = 0.004) and ScO2 (mean [SD], 69.9 [5.8] % vs. 62.1 [5.2] %, paired t-test, p = 0.004). The intervention trials compared with the control trials had a shorter reaction time (RT) on the PVT after 5 min (mean [SD], 277.8 [16.7] ms vs. 282.5 [15.3] ms, paired t-test, p = 0.006) and after 30 min (mean [SD], 276.9 [17.7] ms vs. 280.7 [15.0] ms, paired t-test, p = 0.054) at altitude. While controlling for other variables, there was a RT increase of 0.37 ms for each % of SpO2 decrease. The intervention trials showed significantly higher values for DSST number of correct responses (with a difference of mean [SD], 1.2 [3.2], paired t-test, p = 0.035). Variables in the intervention trials were otherwise similar to those in the control trials for DSST number of incorrect responses, 2-BACK, and the Grooved Pegboard test. CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that oxygen supplementation improves cognitive performance among HEMS providers during acute exposure to 4000 m altitude. The use of oxygen supplementation may allow to maintain attention and timely reaction in HEMS providers. The impact of repeated altitude ascents on the same day, sleep-deprivation, and additional stressors should be investigated. Trial registration NCT05073406, ClinicalTrials.gov trial registration.
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Altitude , Estudos Cross-Over , Humanos , Masculino , Adulto , Método Duplo-Cego , Feminino , Oxigenoterapia/métodos , Cognição/fisiologia , Oxigênio/sangue , Pessoa de Meia-Idade , Resgate Aéreo , Doença da Altitude/terapia , Serviços Médicos de EmergênciaRESUMO
BACKGROUND: During nasal continuous positive airway pressure (nCPAP) treatment in neonates, leakage is inevitable and can lead to reduced distending pressure in the lungs of the infant. In current practice, neither leakage nor expiratory flow is measured, which makes it difficult to assess if exhalation is through the device or entirely through leakages. OBJECTIVE: To examine if infants treated with nCPAP exhale through the CPAP system. DESIGN AND SETTING: Secondary data analyses from the ToNIL trial on leakages during nCPAP treatment. We retrospectively examined respiratory curves for the 50 infants included in the trial, using NI LabVIEW 2015. Each infant was measured with both prongs and nasal masks. A flow recording was classified as exhalation through the system if more than 50% of all expirations showed reverse flow, each for a minimum duration of 0.1 s. PATIENTS: 50 infants were included, born with a mean gestational age (GA) of 34 weeks, median birth weight of 1948 g and mean age at measurement 6.5 days. Inclusion criteria were CPAP treatment and a postmenstrual age (PMA) of 28-42 weeks. RESULTS: In our measurements, 32/50 infants exhaled through the CPAP system in at least one recording with either nasal mask or prongs. Leakages exceeding 0.3 L/min were seen in 97/100 recordings. CONCLUSIONS: During nCPAP treatment, infants can exhale through the CPAP system and leakage was common. Measuring expiratory flows and leakages in clinical settings could be valuable in optimising CPAP treatment of infants. TRIAL REGISTRATION NUMBER: NCT03586856.
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Pressão Positiva Contínua nas Vias Aéreas , Síndrome do Desconforto Respiratório do Recém-Nascido , Recém-Nascido , Humanos , Lactente , Recém-Nascido Prematuro , Estudos Cross-Over , Estudos Retrospectivos , Ventilação com Pressão Positiva Intermitente , Síndrome do Desconforto Respiratório do Recém-Nascido/terapiaRESUMO
HER2-targeted therapy is currently the subject of several studies in lung cancer and other solid tumors using either tyrosine kinase inhibitors (TKI) or targeted-antibody-drug conjugates. We describe a 61-year-old female patient with HER2 mutated adenocarcinoma of the lungs who received chemo-immunotherapy, followed by trastuzumab deruxtecan (T-DXd) and third-line Ramucirumab/Docetaxel at disease progression. Plasma ctDNA monitoring was obtained at 12 timepoints during therapy and revealed HER2 mutation allele frequencies that corresponded to the clinical course of disease. HER2-targeted T-DXd therapy resulted in a profound clinical response and may be an option for NSCLC patients carrying an activated HER2 mutation. Longitudinal liquid biopsy quantification of the underlying driver alteration can serve as a powerful diagnostic tool to monitor course of therapy.
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Carcinoma Pulmonar de Células não Pequenas , Imunoconjugados , Neoplasias Pulmonares , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoconjugados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Biópsia LíquidaRESUMO
EGFR-mutant lung cancers develop a wide range of potential resistance alterations under therapy with the third-generation EGFR tyrosine kinase inhibitor osimertinib. MET amplification ranks among the most common acquired resistance alterations and is currently being investigated as a therapeutic target in several studies. Nevertheless, targeted therapy of MET might similarly result in acquired resistance by point mutations in MET, which further expands therapeutic and diagnostic challenges. Here, we report a 50-year-old male patient with EGFR-mutant lung adenocarcinoma and stepwise acquired resistance by a focal amplification of MET followed by D1246N (D1228N), D1246H (D1228H), and L1213V (L1195V) point mutations in MET, all detected by NGS. The patient successfully responded to the combined and sequential treatment of osimertinib, osimertinib/crizotinib, and third-line osimertinib/cabozantinib. This case highlights the importance of well-designed, sequential molecular diagnostic analyses and the personalized treatment of patients with acquired resistance.
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Neoplasias Pulmonares , Humanos , Masculino , Pessoa de Meia-Idade , Crizotinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/genéticaRESUMO
Osimertinib has become the preferred first-line therapy for epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small cell lung cancer (NSCLC) in recent years. Originally, it was approved for second-line treatment after epidermal growth factor receptor EGFR tyrosine kinase inhibitors (TKIs) of the first and second generations had failed and EGFR T790M had emerged as a mode of resistance. Osimertinib itself provokes a wide array of on- and off-target molecular alterations that can limit therapeutic success. Liquid biopsy ctDNA (circulating tumor DNA) analysis by hybrid capture (HC) next-generation sequencing (NGS) can help to identify alterations in a minimally invasive way and allows for the detection of common as well as rare resistance alterations. We describe a young female patient who was initially diagnosed with metastatic EGFR L858R-positive NSCLC. She received EGFR TKI therapy at different timepoints during the course of the disease and developed sequential EGFR resistance alterations (EGFR T790M and C797S). In the course of her disease, resistance alteration became undetectable, and the tumor was successfully rechallenged with the original first-generation EGFR TKI as well as osimertinib and altogether showed prolonged response despite a prognostically negative TP53 alteration. To date, the patient has been alive for more than seven years, though initially diagnosed with a heavy metastatic burden.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores ErbB/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. We therefore established a DNA-based hybrid capture NGS assay and an associated bioinformatic pipeline that fulfils our institution's specific needs. The assay´s target regions cover the full exonic territory of relevant cancer-related genes and HRR genes and more than 20,000 evenly distributed single nucleotide polymorphism (SNP) loci to allow for the detection of genome-wide allele specific copy number alterations (CNA). To determine GI status, we implemented an %CNA score that is robust across a broad range of tumor cell content (25-85%) often found in routine FFPE samples. The assay was established using high-grade serous ovarian cancer samples for which BRCA1 and BRCA2 mutation status as well as Myriad MyChoice homologous repair deficiency (HRD) status was known. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS (GI-Score) v1 assay was clinically validated on more than 400 samples of the ENGOT PAOLA-1 clinical trial as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative. The "NOGGO GIS v1 assay" performed using highly robust hazard ratios for progression-free survival (PFS) and overall survival (OS), as well a significantly lower dropout rate than the Myriad MyChoice clinical trial assay supporting the clinical utility of the assay. We also provide proof of a modular and scalable routine diagnostic method, that can be flexibly adapted and adjusted to meet future clinical needs, emerging biomarkers, and further tumor entities.
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Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)/receptor tyrosine kinase inhibitor (ROS1), demonstrated efficacy in ROS1 positive (ROS1+) non-small cell lung cancer (NSCLC), although approval is currently limited to the treatment of ALK+ patients. However, lorlatinib-induced resistance mechanisms, and its efficacy against the resistance mutation G2032R in ROS1, respectively, have not yet been fully understood. Furthermore, concomitant tumor suppressor gene p53 (TP53) mutations occur in driver alteration positive NSCLC, but their prognostic contribution in the context of ROS1 inhibition remains unclear. Here we report a ROS1+ NSCLC patient who developed an on target G2032R resistance mutation during second-line lorlatinib treatment, indicating the lack of activity of lorlatinib against ROS1 G2032R. The resistance mutation was detected in plasma-derived ctDNA, signifying the clinical utility of liquid biopsies.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Aminopiridinas , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Lactamas , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/uso terapêutico , Biópsia Líquida , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Pirazóis , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/uso terapêuticoRESUMO
Introduction: This experimental in vitro study aimed to identify and characterize hypothermia-associated coagulopathy and to compare changes in mild to severe hypothermia with the quantitative measurement of rotational thromboelastometry (ROTEM) and multiple-electrode aggregometry (MULTIPLATE). Methods: Whole blood samples from 18 healthy volunteers were analyzed at the target temperatures of 37, 32, 24, 18, and 13.7°C with ROTEM (ExTEM, InTEM and FibTEM) and MULTIPLATE using the arachidonic acid 0.5 mM (ASPI), thrombin receptor-activating peptide-6 32 µM (TRAP) and adenosine diphosphate 6.4 µM (ADP) tests at the corresponding incubating temperatures for coagulation assessment. Results: Compared to baseline (37°C) values ROTEM measurements of clotting time (CT) was prolonged by 98% (at 18°C), clot formation time (CFT) was prolonged by 205% and the alpha angle dropped to 76% at 13.7°C (p < 0.001). At 24.0°C CT was prolonged by 56% and CFT by 53%. Maximum clot firmness was only slightly reduced by ≤2% at 13.7°C. Platelet function measured by MULTIPLATE was reduced with decreasing temperature (p < 0.001): AUC at 13.7°C -96% (ADP), -92% (ASPI) and -91% (TRAP). Conclusion: Hypothermia impairs coagulation by prolonging coagulation clotting time and by decreasing the velocity of clot formation in ROTEM measurements. MULTIPLATE testing confirms a linear decrease in platelet function with decreasing temperatures, but ROTEM fails to adequately detect hypothermia induced impairment of platelets.
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BACKGROUND: The negative prognostic and predictive value of TP53 co-mutations (TP53 mt+) in EGFR mutated (EGFR mt+) non-small cell lung cancer (NSCLC) is increasingly being acknowledged. Data consistently show that TP53 mt+ impact negatively on 1st line objective response rate (ORR), progression free survival (PFS) and overall survival (OS) with 1st and 2nd generation tyrosine kinase inhibitors (TKI). However, a negative predictive impact has not been shown for the 3rd generation TKI Osimertinib. Therefore, we investigated the impact of TP53 mt+ in EGFR mt+ NSCLC carrying a T790M resistance mutation and treated in 2nd/further lines with Osimertinib. METHODS: A total of 77 EGFR mt+ NSCLC IV patients carrying a T790M resistance mutation from two institutions were analyzed for TP53 mt+. Clinical data including sex, age, presence of CNS metastases, etc., as well as types of EGFR and TP53 mt+ were captured. PFS and OS were calculated from the start of Osimertinib. RESULTS: TP53 mt+ were found in 32/77 patients (42%). TP53 mt+ was a statistically significant independent negative predictive factor for PFS and OS. PFS for TP53 mt+ patients were 9 months vs. 14 months for patients with TP53 wild-type (TP53WT) (P<0.008). OS for TP53 mt+ patients was 16 months vs. 24 months patients with TP53WT (P<0.025). CONCLUSIONS: TP53 mt+ have a negative impact on PFS and OS in a group of patients carrying a sensitizing EGFR mt+ and a T790M resistance mutation treated with Osimertinib. These data, together with the data for 1st/2nd generation TKI in 1st line treatment call for additional therapeutic and management concepts for this subgroup of patients.
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BACKGROUND/AIM: Polymorphous adenocarcinoma (PAC) is a low-grade salivary gland malignancy in contrast to variants with papillary (PAP) or cribriform (CASG) architecture and confers the second most common malignancy of minor salivary glands. Our study aimed to identify prognostic factors and to evaluate histomorphological and molecular diagnostic criteria of PACs. PATIENTS AND METHODS: A series of 155 PACs, including 10 PAPs and 12 CASGs from the population-based Cancer Registry of North Rhine-Westphalia (LKR-NRW) and the Hamburg Salivary Gland Reference Centre (HRC) were analyzed. RESULTS: One fifth of the tumors were located in the major salivary glands and PACS/CASGS invariably lacked p40 expression. Fifty-two percent of PACs showed a PRKD1 E710D mutation. Ordinary PACs had a disease-specific 10-year survival probability of 97% compared to 90% when combining PAPs and CASGs. T-stage at diagnosis was a prognostic factor with 98% for stages T1/T2 versus 75% for T3/T4. CONCLUSION: Diagnostic algorithms for the PAC/CASG spectrum of tumors need to be improved and should include molecular markers.
Assuntos
Adenocarcinoma Papilar , Adenocarcinoma , Biomarcadores Tumorais , Neoplasias das Glândulas Salivares , Adenocarcinoma/química , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma Papilar/química , Adenocarcinoma Papilar/genética , Adenocarcinoma Papilar/mortalidade , Adenocarcinoma Papilar/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Criança , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Sistema de Registros , Neoplasias das Glândulas Salivares/química , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/mortalidade , Neoplasias das Glândulas Salivares/patologia , Fatores Sexuais , Fatores de Tempo , Carga Tumoral , Adulto JovemRESUMO
BACKGROUND: Current recommendations for rescue and resuscitation of people buried in avalanches are based on Swiss avalanche survival data. We analyzed Canadian survival patterns and compared them with those from Switzerland. METHODS: We extracted relevant data for survivors and nonsurvivors of complete avalanche burials from Oct. 1, 1980, to Sept. 30, 2005, from Canadian and Swiss databases. We calculated survival curves for Canada with and without trauma-related deaths as well as for different outdoor activities and snow climates. We compared these curves with the Swiss survival curve. RESULTS: A total of 301 people in the Canadian database and 946 in the Swiss database met the inclusion criteria. The overall proportion of people who survived did not differ significantly between the two countries (46.2% [139/301] v. 46.9% [444/946]; p = 0.87). Significant differences were observed between the overall survival curves for the two countries (p = 0.001): compared with the Swiss curve, the Canadian curve showed a quicker drop at the early stages of burial and poorer survival associated with prolonged burial. The probability of survival fell quicker with trauma-related deaths and in denser snow climates. Poorer survival probabilities in the Canadian sample were offset by significantly quicker extrication (median duration of burial 18 minutes v. 35 minutes in the Swiss sample; p < 0.001). INTERPRETATION: Observed differences in avalanche survival curves between the Canadian and Swiss samples were associated with the prevalence of trauma and differences in snow climate. Although avoidance of avalanches remains paramount for survival, the earlier onset of asphyxia, especially in maritime snow climates, emphasizes the importance of prompt extrication, ideally within 10 minutes. Protective devices against trauma and better clinical skills in organized rescue may further improve survival.