This consensus document summarizes the current knowledge on the potential for precision medicine in food allergy, drug allergy, and anaphylaxis under the auspices of the PRACTALL collaboration ...platform. PRACTALL is a joint effort of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology, which aims to synchronize the European and American approaches to allergy care. Precision medicine is an emerging approach for disease treatment based on disease endotypes, which are phenotypic subclasses associated with specific mechanisms underlying the disease. Although significant progress has been made in defining endotypes for asthma, definitions of endotypes for food and drug allergy or for anaphylaxis lag behind. Progress has been made in discovery of biomarkers to guide a precision medicine approach to treatment of food and drug allergy, but further validation and quantification of these biomarkers are needed to allow their translation into practice in the clinical management of allergic disease.
OptimalTTF-2 is a randomized, comparative, multi-center, investigator-initiated, interventional study aiming to test skull remodeling surgery in combination with Tumor Treating Fields therapy ...(TTFields) and best physicians choice medical oncological therapy for first recurrence in glioblastoma patients. OptimalTTF-2 is a phase 2 trial initiated in November 2020. Skull remodeling surgery consists of five burrholes, each 15 mm in diameter, directly over the tumor resection cavity. Preclinical research indicates that this procedure enhances the effect of Tumor Treating Fields considerably. We recently concluded a phase 1 safety/feasibility trial that indicated improved overall survival and no additional toxicity. This phase 2 trial aims to validate the efficacy of the proposed intervention.
The trial is designed as a comparative, 1:1 randomized, minimax two-stage phase 2 with an expected 70 patients to a maximum sample size of 84 patients. After 12-months follow-up of the first 52 patients, an interim futility analysis will be performed. The two trial arms will consist of either a) TTFields therapy combined with best physicians choice oncological treatment (control arm) or b) skull remodeling surgery, TTFields therapy and best practice oncology (interventional arm). Major eligibility criteria include age ≥ 18 years, 1st recurrence of supratentorial glioblastoma, Karnofsky performance score ≥ 70, focal tumor, and lack of significant co-morbidity. Study design aims to detect a 20% increase in overall survival after 12 months (OS12), assuming OS12 = 40% in the control group and OS12 = 60% in the intervention group. Secondary endpoints include hazard rate ratio of overall survival and progression-free survival, objective tumor response rate, quality of life, KPS, steroid dose, and toxicity. Toxicity, objective tumor response rate, and QoL will be assessed every 3rd month. Endpoint data will be collected at the end of the trial, including the occurrence of suspected unexpected serious adverse reactions (SUSARs), unacceptable serious adverse events (SAEs), withdrawal of consent, or loss-to-follow-up.
New treatment modalities are highly needed for first recurrence glioblastoma. Our proposed treatment modality of skull remodeling surgery, Tumor Treating Fields, and best practice medical oncological therapy may increase overall survival significantly.
ClinicalTrials.gov Identifier: NCT0422399 , registered 13. January 2020.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims
We aimed to reclassify a population‐based cohort of 529 adult glioma patients to evaluate the prognostic impact of the 2016 World Health Organization (WHO) central nervous system tumour ...classification. Moreover, we evaluated the feasibility of gene panel next‐generation sequencing (NGS) in daily diagnostics of 225 prospective glioma patients.
Methods
The retrospective cohort was reclassified according to WHO 2016 criteria by immunohistochemistry for IDH‐R132H, fluorescence in situ hybridization for 1p/19q‐codeletion and gene panel NGS. All tumours of the prospective cohort were subjected to NGS analysis up‐front.
Results
The entire population‐based cohort was successfully reclassified according to WHO 2016 criteria. NGS results were obtained for 98% of the prospective patients. Survival analyses in the population‐based cohort confirmed three major prognostic subgroups, that is, isocitrate dehydrogenase (IDH)‐mutant and 1p/19q‐codeleted oligodendrogliomas, IDH‐mutant astrocytomas and IDH‐wildtype glioblastomas. The distinction between WHO grade II and III was prognostic in patients with IDH‐mutant astrocytoma. The survival of patients with IDH‐wildtype diffuse astrocytomas carrying TERT promoter mutation and/or EGFR amplification overlapped with the poor survival of IDH‐wildtype glioblastoma patients.
Conclusions
Gene panel NGS proved feasible in daily diagnostics. In addition, our study confirms the prognostic role of glioma classification according to WHO 2016 in a large population‐based cohort. Molecular features of glioblastoma in IDH‐wildtype diffuse glioma were linked to poor survival corresponding to IDH‐wildtype glioblastoma patients. The distinction between WHO grade II and III retained prognostic significance in patients with IDH‐mutant diffuse astrocytic gliomas.
Risk factors for systemic anticancer therapies (SACTs) administered close to death derived from existing quality indicators are not directly applicable in the clinic, because they condition on future ...events, which leads to selection bias. This study aimed to adapt a previously suggested indicator for its use in a clinical context and to evaluate it in a real-world, population-based cohort of cancer patients.
An improved version of the ‘30-day mortality after SACT’ indicator suggested by Wallington et al. (Lancet Oncol 2016; 17:1203–16) was defined. All SACTs (n = 16 622) for all patients (n = 10 213) treated for common malignancies between 2009 and 2019 in the North Denmark Region were included. The results for the improved and Wallington's indicators were calculated and compared.
Overall, the association between clinical variables and 30-day mortality following SACT was similar for both indicators, except for the 75+ years age group. However, Wallington's indicator showed varying absolute risk when comparing values for quarterly and yearly observation intervals. The improved and Wallington's indicators showed large differences between curative (1.0% and 1.1%, respectively) and palliative SACTs (9.1% and 11.7%, respectively). For palliative SACTs, different types of malignancy presented with large variations for the improved indicator, ranging from above 10% for gastroesophageal, pancreatic and lung cancers to below 4% for prostate cancers. The value of the improved indicator was significantly lower in the last years of the study period compared with the 2009–2011 period. The type of malignancy was also associated with significant differences.
We defined an indicator adapted to the clinical context evaluating 30-day mortality following SACT. This indicator can be used to identify risk factors to help with clinical decision-making. A significant downward trend was observed in the 30-day mortality following palliative SACT over an 11-year period.
•We defined an improved quality indicator for the 30-day mortality following SACT.•This indicator can help identify clinical risk factors for increased 30-day mortality.•This indicator stays consistent across different choices of observation intervals.•Large variations in 30-day mortality following SACT between malignancies were found.•We report a significant downward trend in 30-day mortality following palliative SACT.
Background
Cerebral mitochondrial dysfunction is prominent in the pathophysiology of severe bacterial meningitis. In the present study, we hypothesize that the metabolic changes seen after ...intracisternal lipopolysaccharide (LPS) injection in a piglet model of meningitis is compatible with mitochondrial dysfunction and resembles the metabolic patterns seen in patients with bacterial meningitis.
Methods
Eight pigs received LPS injection in cisterna magna, and four pigs received NaCl in cisterna magna as a control. Biochemical variables related to energy metabolism were monitored by intracerebral microdialysis technique and included interstitial glucose, lactate, pyruvate, glutamate, and glycerol. The intracranial pressure (ICP) and brain tissue oxygen tension (PbtO
2
) were also monitored along with physiological variables including mean arterial pressure, blood glucose, lactate, and partial pressure of O
2
and CO
2
. Pigs were monitored for 60 min at baseline and 240 min after LPS/NaCl injection.
Results
After LPS injection, a significant increase in cerebral lactate/pyruvate ratio (LPR) compared to control group was registered (
p
= 0.01). This increase was due to a significant increased lactate with stable and normal values of pyruvate. No significant change in PbtO
2
or ICP was registered. No changes in physiological variables were observed.
Conclusions
The metabolic changes after intracisternal LPS injection is compatible with disturbance in the oxidative metabolism and partly due to mitochondrial dysfunction with increasing cerebral LPR due to increased lactate and normal pyruvate, PbtO
2
, and ICP. The metabolic pattern resembles the one observed in patients with bacterial meningitis. Metabolic monitoring in these patients is feasible to monitor for cerebral metabolic derangements otherwise missed by conventional intensive care monitoring.
A lobular capillary hemangioma, previously known as a pyogenic granuloma, is a benign vascular lesion of the skin or mucous membrane. We report a case of capillary hemangioma of lobular subtype in ...the calvarium of a 28-year-old pregnant woman which presented as a sore and rapidly growing bulge over the left fronto-parietal region. Magnetic resonance imaging of the brain and skull showed an expansive tumor with brain displacement, skull erosion, and scalp infiltration. The tumor was surgically removed, and histopathological examination showed a capillary hemangioma of lobular subtype. To the best of our knowledge, this is the first report of a lobular capillary hemangioma in the calvarium, and it represents a rarity to be considered among the many other differential diagnoses for neurosurgical lesions involving the skull, especially in pregnant women.
Less than half of anthropogenic carbon dioxide emissions remain in the atmosphere. While carbon balance models imply large carbon uptake in tropical forests, direct on-the-ground observations are ...still lacking in Southeast Asia. Here, using long-term plot monitoring records of up to half a century, we find that intact forests in Borneo gained 0.43 Mg C ha
per year (95% CI 0.14-0.72, mean period 1988-2010) above-ground live biomass. These results closely match those from African and Amazonian plot networks, suggesting that the world's remaining intact tropical forests are now en masse out-of-equilibrium. Although both pan-tropical and long-term, the sink in remaining intact forests appears vulnerable to climate and land use changes. Across Borneo the 1997-1998 El Niño drought temporarily halted the carbon sink by increasing tree mortality, while fragmentation persistently offset the sink and turned many edge-affected forests into a carbon source to the atmosphere.
It is well described that patients with pulmonary arteriovenous malformations (PAVMs) and Hereditary Hemorrhagic Telangiectasia (HHT) have an increased risk of cerebral abscess (CA). However, as both ...CA and HHT are rare, the proportion of patients with CA who are diagnosed with HHT has not been previously described. A retrospective study was carried out of all patients treated surgically for CA between January 1995 and September 2014 at the Department of Neurosurgery, Odense University Hospital. The cases were then cross-referenced with the Danish HHT database. Eighty patients aged 5–79 years were included. The incidence of CA was 0.33/100,000/year. Two patients (2.5%) were registered as having HHT. Bacterial pathogens were identified in 70% of all cases, most frequently streptococci species (46.3%). The most common predisposing condition was odontogenic infection (20%), followed by post-operative infection (13.8%) and post-trauma (6.3%). Patients undergoing a full diagnostic program to determine predisposing conditions causing CA increased over the 20-year period from 11.8% to 65.2%. The 3-month and 1-year mortality rates were 7.5% and 11.25%, respectively. There is an overrepresentation of HHT patients in a cohort of patients with CA, and HHT should be investigated as the cause of the CA if no other apparent cause can be identified.
Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of ...metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise ± metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g., the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260).
Novelty:
Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle.
Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle.
Metformin does not affect exercise-induced AMPK activation in human skeletal muscle.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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