Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

Reliability of blood eosinophil count in steady-state bronchiectasis.

RATIONALE: The baseline value of eosinophils in peripheral blood (BEC) has been associated with different degrees of severity, prognosis and response to treatment in patients with bronchiectasis. It is not known, however, if this basal value remains constant over time. OBJECTIVES: The aim of this study was to assess whether the BEC remains stable in the long term in patients with bronchiectasis. METHODS AND MEASUREMENTS: Patients from the RIBRON registry of bronchiectasis diagnosed by computed tomography with at least 2 BEC measurements one year apart were included in the study. Patients with asthma and those taking anti-eosinophilic drugs were excluded. Reliability was assessed using the intra-class correlation coefficient (ICC). A patient with a BEC of at least 300 cells/uL or less than 100 cells/uL was considered eosinophilic or eosinopenic, respectively. Group changes over time were also calculated. MAIN RESULTS: Seven hundred and thirteen patients were finally included, with a mean age of 66.5 (13.2) years (65.8 % women). A total of 2701 BEC measurements were performed, with a median number of measurements per patient of 4 (IQR: 2-5) separated by a median of 12.1 (IQR: 10.5-14.3) months between two consecutive measurements. The ICC was good (>0.75) when calculated between two consecutive measurements (approximately one year apart) but had dropped significantly by the time of the next annual measurements. Similarly, the change from an eosinophilic or eosinopenic patient to a non-eosinophilic or non-eosinopenic patient, respectively, was less than 30 % during the first year with respect to the baseline value but was close to 50 % in later measurements. CONCLUSIONS: Given the significant changes observed in the baseline value of the BEC over time, its monitoring is necessary in patients with bronchiectasis in order to more reliably assess its usefulness.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Clinical standards for diagnosis, treatment and prevention of post-COVID-19 lung disease.

BACKGROUND: The aim of these clinical standards is to provide guidance on 'best practice' care for the diagnosis, treatment and prevention of post-COVID-19 lung disease.METHODS: A panel of international experts representing scientific societies, associations and groups active in post-COVID-19 lung disease was identified; 45 completed a Delphi process. A 5-point Likert scale indicated level of agreement with the draft standards. The final version was approved by consensus (with 100% agreement).RESULTS: Four clinical standards were agreed for patients with a previous history of COVID-19: Standard 1, Patients with sequelae not explained by an alternative diagnosis should be evaluated for possible post-COVID-19 lung disease; Standard 2, Patients with lung function impairment, reduced exercise tolerance, reduced quality of life (QoL) or other relevant signs or ongoing symptoms ≥4 weeks after the onset of first symptoms should be evaluated for treatment and pulmonary rehabilitation (PR); Standard 3, The PR programme should be based on feasibility, effectiveness and cost-effectiveness criteria, organised according to local health services and tailored to an individual patient's needs; and Standard 4, Each patient undergoing and completing PR should be evaluated to determine its effectiveness and have access to a counselling/health education session.CONCLUSION: This is the first consensus-based set of clinical standards for the diagnosis, treatment and prevention of post-COVID-19 lung disease. Our aim is to improve patient care and QoL by guiding clinicians, programme managers and public health officers in planning and implementing a PR programme to manage post-COVID-19 lung disease.

Validación de la ecografía Point-of-Care para el diagnóstico de hernia diafragmática: a propósito de un caso / Validation of Point-of-Care ultrasound in the diagnosis of a diaphragmatic hernia

La ecografía Point-of-Care (POCUS) es una herramienta sensible y específica para diagnosticar de manera precoz la patología del diafragma en pacientes críticos. Presentamos un caso clínico de un paciente con antecedentes de hernia diafragmática iatrogénica que ingresó en la unidad de reanimación tras una laparotomía exploradora de emergencia. Aprovechando el diagnóstico conocido de hernia diafragmática, describimos los signos clínicos que debemos encontrar en la evaluación POCUS para establecer el diagnóstico de hernia diafragmática: 1)fracción de acortamiento diafragmático normal bilateral; 2)excursión diafragmática reducida, y 3)posición cefálica de la cúpula diafragmática 4)mayor en supino que en sedestación. Igualmente, proponemos una sistemática de exploración ecográfica del diafragma y una clasificación diferencial de la disfunción diafragmática evaluada mediante POCUS en función de la correcta integridad y el buen funcionamiento del músculo periférico y del tendón central diafragmáticos en el paciente crítico.(AU)

Point-of-care ultrasound (POCUS) is a sensitive, specific tool for early diagnosis of diaphragm pathology in critically ill patients. We report the case of a patient with a history of iatrogenic diaphragmatic hernia who was admitted to the Resuscitation Unit after an emergency exploratory laparotomy. As the diagnosis of diaphragmatic hernia had already been confirmed, we determined the POCUS features that establish the diagnosis of diaphragmatic hernia: (1)normal bilateral diaphragmatic shortening fraction; (2)decreased diaphragmatic excursion, and (3)cephalic position of the diaphragmatic dome (4)greater in supine than in sitting position. We also outline a systematic ultrasound examination of the diaphragm and a POCUS-based differential classification of diaphragmatic dysfunction based on the functional integrity of the peripheral muscle and central diaphragmatic tendon in critically ill patients.(AU)

Validation of Point-of-Care ultrasound in the diagnosis of a diaphragmatic hernia.

Point-of-care ultrasound (POCUS) is a sensitive, specific tool for early diagnosis of diaphragm pathology in critically ill patients. We report the case of a patient with a history of iatrogenic diaphragmatic hernia who was admitted to the Resuscitation Unit after an emergency exploratory laparotomy. As the diagnosis of diaphragmatic hernia had already been confirmed, we determined the POCUS features that establish the diagnosis of diaphragmatic hernia: (1) normal bilateral diaphragmatic shortening fraction; (2) decreased diaphragmatic excursion; and (3) cephalic position of the diaphragmatic dome (4) greater in supine than in sitting position. We also outline a systematic ultrasound examination of the diaphragm and a POCUS-based differential classification of diaphragmatic dysfunction based on the functional integrity of the peripheral muscle and central diaphragmatic tendon in critically ill patients.

Refractory hypotension secondary to chronic treatment with high doses of quetiapine.

Quetiapine is an atypical antipsychotic used in the treatment of depressive, schizophrenic, or bipolar disorders. It acts on dopamine D1 and D2, histamine, and 5HT1A and 5HT2 receptors. However, it also acts as an antagonist for α1 receptors causing cardiovascular side effects, including hypotension. We present the case of a patient chronically medicated with Quetiapine who developed hypotension refractory to vasoconstrictors and intraoperative fluid therapy. Noradrenalin has a strong α1 effect with lower affinity for ß2 receptors unlike adrenalin. This translates into peripheral vasoconstriction and an improved clinical picture. Therefore, it should be considered the vasoactive drug of choice in patients on high doses of Quetiapine.

Hipotensión refractaria secundaria a tratamiento crónico con altas dosis de quetiapina / Refractory hypotension secondary to chronic treatment with high doses of quetiapine

La quetiapina es un antipsicótico atípico que se usa en el tratamiento del trastorno depresivo, esquizofrénico o bipolar. Su acción reside en su acción sobre los receptores de la dopamina D1 y D2, histamina y serotonina 5HT1A y 5HT2. Sin embargo, también tiene antagonismo para los receptores α1, provocando efectos secundarios cardiovasculares, entre ellos la hipotensión. Presentamos el caso de un paciente medicado crónicamente con quetiapina que presentó hipotensión refractaria a vasoconstrictores y fluidoterapia intraoperatoria. La noradrenalina tiene un fuerte efecto α1 con una menor afinidad para los receptores β2 a diferencia de la adrenalina. Esto se traduce en una vasoconstricción periférica y la resultante mejoría del cuadro clínico. Por lo tanto, se debe considerar el fármaco vasoactivo de elección en la hipotensión refractaria en pacientes que tomen altas dosis de quetiapina.(AU)

Quetiapine is an atypical antipsychotic used in the treatment of depressive, schizophrenic, or bipolar disorders. It acts on dopamine D1 and D2, histamine, and 5HT1A and 5HT2 receptors. However, it also acts as an antagonist for α1 receptors causing cardiovascular side effects, including hypotension. We present the case of a patient chronically medicated with quetiapine who developed hypotension refractory to vasoconstrictors and intraoperative fluid therapy. Noradrenalin has a strong α1 effect with lower affinity for β2 receptors unlike adrenalin. This translates into peripheral vasoconstriction and an improved clinical picture. Therefore, it should be considered the vasoactive drug of choice in patients on high doses of quetiapine.(AU)

Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism and masculinization of intermediate metabolism in women with polycystic ovary syndrome (PCOS).

BACKGROUND: The polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the art proton nuclear magnetic resonance spectroscopy metabolomics profiling, that androgen excess in women induces also a certain masculinization of intermediate metabolism that is modulated by obesity. METHODS: Participants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected in order to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity defined by a body mass index ≥ 30 kg/m2. Subjects maintained the same diet unrestricted in carbohydrates for 3 days before sampling and maintained their lifestyle and exercise patterns prior and during the study. Plasma samples were submitted to proton nuclear magnetic resonance spectroscopy metabolomics profiling. RESULTS: Obesity associated a metabolomics profile mainly characterized by increased branched chain and aromatic aminoacids. Regardless of obesity, this unfavorable profile also characterized men as compared with control women, and was shared by women with PCOS. Notably, the negative impact of obesity on metabolomics profile was restricted to women, with obese men showing no further deterioration when compared with their non-obese counterparts. CONCLUSIONS: Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism, and masculinization of intermediate metabolism in women with PCOS, further suggesting a role for sex and sex hormones in the regulation of intermediate metabolism.

Validation of circulating microRNAs miR-142-3p and miR-598-3p in women with polycystic ovary syndrome as potential diagnostic markers.

STUDY QUESTION: Circulating miRNAs previously associated with androgen excess in women might be used as diagnostic biomarkers for polycystic ovary syndrome (PCOS). SUMMARY ANSWER: Models based on circulating miR-142-3p and miR-598-3p expression show good discrimination among women with and without PCOS, particularly when coupled with easily available measurements such as waist-to-hip ratio (WHR) and circulating LH-to-FSH (LH/FSH) ratios. WHAT IS KNOWN ALREADY: The lack of standardization of the signs, methods, and threshold values used to establish the presence of the diagnostic criteria (hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology) complicates the diagnosis of PCOS. Certain biomarkers may help with such a diagnosis. We conducted a validation study to check the diagnostic accuracy for PCOS of several miRNAs that were associated with the syndrome in a small pilot study that had been previously carried out by our research group. STUDY DESIGN, SIZE, DURATION: This was a diagnostic test study involving 140 premenopausal women. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included 71 women with PCOS and 69 healthy control women in the study. Both groups were selected as to be similar in terms of body mass index. We used miRCURY LNA™ Universal RT microRNA PCR to analyse the five miRNAs that had shown the strongest associations with PCOS in a much smaller pilot study previously conducted by our group. We studied diagnostic accuracy using receiver operating characteristics (ROC) curve analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Only the expression of two miRNAs, miR-142-3p and miR-598-3p, of the five studied, was different between the women with PCOS and the non-hyperandrogenic controls. The diagnostic accuracy of the combination of these circulating miRNAs was good (area under the ROC curve (AUC) 0.801; 95% CI: 0.72-0.88) and was further improved when adding WHR (AUC 0.834, 95% CI: 0.756-0.912), LH/FSH ratio (AUC = 0.869, 95% CI: 0.804-0.934) or both (AUC = 0.895, 95% CI: 0.835-0.954). We developed several models by selecting different threshold values for these variables favouring either sensitivity or specificity, with positive and negative predictive values as high as 88% or 85%, respectively. LIMITATIONS, REASONS FOR CAUTION: Patients included here had the classic PCOS phenotype, consisting of hyperandrogenism and ovulatory dysfunction; hence, the present results might not apply to milder phenotypes lacking androgen excess. WIDER IMPLICATIONS OF THE FINDINGS: If confirmed in larger studies addressing different populations and PCOS phenotypes, these biomarkers may be useful to simplify the clinical diagnosis of this prevalent syndrome. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (grants PI15/01686, PIE16/00050, PI18/01122 & PI21/00116) and co-funded by European Regional Development Fund 'A way to make Europe'. Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) are also initiatives of the Instituto de Salud Carlos III. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Post-TB bronchiectasis: from pathogenesis to rehabilitation.

The destruction of lung parenchyma caused by TB can result in pulmonary sequelae that are classified as bronchiectasis due to traction (radiological sequelae), and bronchiectasis persisting with an inflammatory bronchial component and opportunistic bronchial infection. There is a lack of studies that comprehensively analyse whether post-TB bronchiectasis differs in clinical, prognostic or therapeutic aspects from bronchiectasis arising from other aetiologies. However, it has been noted that post-TB bronchiectasis tends to appear more frequently in the upper lung lobes. In many countries, TB is the most frequent known cause of bronchiectasis, but there is currently no targeted management of bronchiectasis due to TB as opposed to other aetiologies. It is imperative to first prevent TB, and when that fails to provide early diagnosis and adequate treatment for TB disease. In addition, efforts should be made to limit additional lung insults such as tobacco use and provide management of post TB bronchiectasis to minimise further pulmonary sequelae. The objective of this minireview was to provide an update on post-TB bronchiectasis, its definition, epidemiological data, pathophysiology, and clinical, diagnosis and therapeutic aspects.

Impact and treatment of exacerbations in adults with bronchiectasis.

Exacerbations have a negative impact on inflammatory diseases of the airways and, in patients with bronchiectasis, severe exacerbations are associated with increased morbidity and mortality. Exacerbations are also associated with a decline in quality of life and lung function, greater local and systemic inflammation and clinically more severe forms of the disease. As a consequence, the majority of therapeutic clinical trials carried out in patients with bronchiectasis are aimed at preventing exacerbations, but there is a scarcity of scientific evidence on the best treatment once they occur. All of these elements, combined with the great heterogeneity of bronchiectasis and the influence of geographical and microbiological factors on its clinical presentations and aetiologies, mean that the recommendations of therapeutic guidelines vary. An international group of experts has now reached agreement on the definition of exacerbation in bronchiectasis for the inclusion of patients in clinical trials, although its validity in clinical practice has yet to be demonstrated.

Neurosurgery in a patient with severe hemophilia B: an experience using eftrenonacog alfa as perioperative management.

Extended half-life FIX (EHL-FIX) concentrates have been developed with the purpose of reducing the frequency of infusions in patients with severe or moderate hemophilia B. We describe the case of a 63-year-old patient with severe hemophilia B (sHB) treated with FIX-Fc fusion protein (rFIXFc) who underwent neurosurgery.