Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential ...of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based “liquid biopsies”.
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•Tumors “educate” platelets (TEPs) by altering the platelet RNA profile•TEPs provide a RNA biosource for pan-cancer, multiclass, and companion diagnostics•TEP-based liquid biopsies may guide clinical diagnostics and therapy selection•A total of 100–500 pg of total platelet RNA is sufficient for TEP-based diagnostics
Best et al. show that mRNA sequencing of tumor-educated blood platelets distinguishes cancer patients from healthy individuals with 96% accuracy, differentiates between six primary tumor types of patients with 71% accuracy, and identifies several genetic alterations found in tumors.
The WHO 2007 classification of tumors of the CNS distinguishes between diffuse astrocytoma WHO grade II (A II
WHO2007
) and anaplastic astrocytoma WHO grade III (AA III
WHO2007
). Patients with A II
...WHO2007
are significantly younger and survive significantly longer than those with AA III
WHO2007
. So far, classification and grading relies on morphological grounds only and does not yet take into account
IDH
status, a molecular marker of prognostic relevance. We here demonstrate that WHO 2007 grading performs poorly in predicting prognosis when applied to astrocytoma carrying
IDH
mutations. Three independent series including a total of 1360 adult diffuse astrocytic gliomas with
IDH
mutation containing 683 A II
IDHmut
, 562 AA III
IDHmut
and 115 GBM
IDHmut
have been examined for age distribution and survival. In all three series patients with A II
IDHmut
and AA III
IDHmut
were of identical age at presentation of disease (36–37 years) and the difference in survival between grades was much less (10.9 years for A II
IDHmut
, 9.3 years for AA III
IDHmut
) than that reported for A II
WHO2007
versus AA III
WHO2007
. Our analyses imply that the differences in age and survival between A II
WHO2007
and AA III
WHO2007
predominantly depend on the fraction of
IDH
-non-mutant astrocytomas in the cohort. This data poses a substantial challenge for the current practice of astrocytoma grading and risk stratification and is likely to have far-reaching consequences on the management of patients with
IDH
-mutant astrocytoma.
Diffuse gliomas are up till now graded based upon morphology. Recent findings indicate that isocitrate dehydrogenase (IDH) mutation status defines biologically distinct groups of tumors. The role of ...tumor grade and mitotic index in patient outcome has not been evaluated following stratification by IDH mutation status. To address this, we interrogated 558 WHO grade II–III diffuse gliomas for
IDH1/2
mutations and investigated the prognostic impact of WHO grade within IDH-mutant and IDH-wild type tumor subsets independently. The prognostic impact of grade was modest in IDH-mutant hazard ratio (HR) = 1.21, 95 % confidence interval (CI) = 0.91–1.61 compared to IDH-wild type tumors (HR = 1.74, 95 % CI = 0.95–3.16). Using a dichotomized mitotic index cut-off of 4/1000 tumor cells, we found that while mitotic index was significantly associated with outcome in IDH-wild type tumors (log-rank
p
< 0.0001, HR = 4.41, 95 % CI = 2.55–7.63), it was not associated with outcome in IDH-mutant tumors (log-rank
p
= 0.5157, HR = 1.10, 95 % CI = 0.80–1.51), and could demonstrate a statistical interaction (
p
< 0.0001) between IDH mutation and mitotic index (i.e., suggesting that the effect of mitotic index on patient outcome is dependent on IDH mutation status). Patient age, an established prognostic factor in diffuse glioma, was significantly associated with outcome only in the IDH-wild type subset, and consistent with prior data, 1p/19q co-deletion conferred improved outcome in the IDH-mutant cohort. These findings suggest that stratification of grade II–III gliomas into subsets defined by the presence or absence of IDH mutation leads to subgroups with distinct prognostic characteristics. Further evaluation of grading criteria and prognostic markers is warranted within IDH-mutant versus IDH-wild type diffuse grade II–III gliomas as independent entities.
Pharmaco-resistant temporal lobe epilepsy (TLE) is often treated with surgical intervention at some point. As epilepsy surgery is considered a last resort by most physicians, a long history of ...epileptic seizures prior to surgery is not uncommon. Little is known about the effects of ongoing TLE on neural functioning. A better understanding of these effects might influence the moment of surgical intervention. Functional connectivity (interaction between spatially distributed brain areas) and network structure (integration and segregation of information processing) are thought to be essential for optimal brain functioning. We report on the impact of TLE duration on temporal lobe functional connectivity and network characteristics.
Functional connectivity of the temporal lobe at the time of surgery was assessed by means of interictal electrocorticography (ECoG) recordings of 27 TLE patients by using the phase lag index (PLI). Graphs (abstract network representations) were reconstructed from the PLI matrix and characterized by the clustering coefficient C (local clustering), the path length L (overall network interconnectedness), and the "small world index" S (network configuration).
Functional connectivity (average PLI), clustering coefficients, and the small world index were negatively correlated with TLE duration in the broad frequency band (0.5-48 Hz).
Temporal lobe functional connectivity is lower in patients with longer TLE history, and longer TLE duration is correlated with more random network configuration. Our findings suggest that the neural networks of TLE patients become more pathological over time, possibly due to temporal lobe changes associated with long-standing lesional epilepsy.
Abstract Considering the brain as a complex network of interacting dynamical systems offers new insights into higher level brain processes such as memory, planning, and abstract reasoning as well as ...various types of brain pathophysiology. This viewpoint provides the opportunity to apply new insights in network sciences, such as the discovery of small world and scale free networks, to data on anatomical and functional connectivity in the brain. In this review we start with some background knowledge on the history and recent advances in network theories in general. We emphasize the correlation between the structural properties of networks and the dynamics of these networks. We subsequently demonstrate through evidence from computational studies, in vivo experiments, and functional MRI, EEG and MEG studies in humans, that both the functional and anatomical connectivity of the healthy brain have many features of a small world network, but only to a limited extent of a scale free network. The small world structure of neural networks is hypothesized to reflect an optimal configuration associated with rapid synchronization and information transfer, minimal wiring costs, resilience to certain types of damage, as well as a balance between local processing and global integration. Eventually, we review the current knowledge on the effects of focal and diffuse brain disease on neural network characteristics, and demonstrate increasing evidence that both cognitive and psychiatric disturbances, as well as risk of epileptic seizures, are correlated with (changes in) functional network architectural features.
Although epilepsy affects almost 1% of the world population, diagnosis of this debilitating disease is still difficult. The EEG is an important tool for epilepsy diagnosis and classification, but the ...sensitivity of interictal epileptiform discharges (IEDs) on the first EEG is only 30-50%. Here we investigate whether using 'functional connectivity' can improve the diagnostic sensitivity of the first interictal EEG in the diagnosis of epilepsy.
Patients were selected from a database with 390 standard EEGs of patients after a first suspected seizure. Patients who were later diagnosed with epilepsy (i.e. > or = two seizures) were compared to matched non-epilepsy patients (with a minimum follow-up of one year). The synchronization likelihood (SL) was used as an index of functional connectivity of the EEG, and average SL per patient was calculated in seven frequency bands. In total, 114 patients were selected. Fifty-seven patients were diagnosed with epilepsy (20 had IEDs on their EEG) and 57 matched patients had other diagnoses. Epilepsy patients had significantly higher SL in the theta band than non-epilepsy patients. Furthermore, theta band SL proved to be a significant predictor of a diagnosis of epilepsy. When only those epilepsy patients without IEDs were considered (n = 74), theta band SL could predict diagnosis with specificity of 76% and sensitivity of 62%.
Theta band functional connectivity may be a useful diagnostic tool in diagnosing epilepsy, especially in those patients who do not show IEDs on their first EEG. Our results indicate that epilepsy diagnosis could be improved by using functional connectivity.
Since the discovery of small-world and scale-free networks the study of complex systems from a network perspective has taken an enormous flight. In recent years many important properties of complex ...networks have been delineated. In particular, significant progress has been made in understanding the relationship between the structural properties of networks and the nature of dynamics taking place on these networks. For instance, the 'synchronizability' of complex networks of coupled oscillators can be determined by graph spectral analysis. These developments in the theory of complex networks have inspired new applications in the field of neuroscience. Graph analysis has been used in the study of models of neural networks, anatomical connectivity, and functional connectivity based upon fMRI, EEG and MEG. These studies suggest that the human brain can be modelled as a complex network, and may have a small-world structure both at the level of anatomical as well as functional connectivity. This small-world structure is hypothesized to reflect an optimal situation associated with rapid synchronization and information transfer, minimal wiring costs, as well as a balance between local processing and global integration. The topological structure of functional networks is probably restrained by genetic and anatomical factors, but can be modified during tasks. There is also increasing evidence that various types of brain disease such as Alzheimer's disease, schizophrenia, brain tumours and epilepsy may be associated with deviations of the functional network topology from the optimal small-world pattern.
Brain tumours frequently cause epileptic seizures. Medical antiepileptic treatment is often met with limited success. Pharmacoresistance, drug interactions and adverse events are common problems ...during treatment with antiepileptic drugs. The unpredictability of epileptic seizures and the treatment-related problems deeply affect the quality of life of patients with a brain tumour. In this review, we focus on both clinical and basic aspects of possible mechanisms in epileptogenesis in patients with a brain tumour. We provide an overview of the factors that are involved in epileptogenesis, starting focally at the tumour and the peritumoral tissue and eventually extending to alterations in functional connectivity throughout the brain. We correlate this knowledge to the known mechanisms of antiepileptic drugs. We conclude that the underlying mechanisms of epileptogenesis in patients with a brain tumour are poorly understood. The currently available antiepileptic drugs have little to no influence on the known epileptogenic mechanisms that could contribute to the poor efficacy. Better understanding of focal changes that are involved in epileptogenesis may provide new tools for optimal treatment of both the seizures and the underlying tumour. In our opinion, therapy for every patient with a brain tumour suffering from epilepsy should first and foremost aim at eliminating the tumour as well as the epileptic focus through resection combined with postoperative treatment, and only if this strategy does not result in adequate seizure control should medical antiepileptic treatment be intensified. If this strategy, however, results in sustained seizure freedom, tapering of antiepileptic drugs should be considered in the long term.
Summary The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. ...The guideline is based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline. The recommendations focus on pathological and radiological diagnostics, and the main treatment modalities of surgery, radiotherapy, and pharmacotherapy. In this guideline we have also integrated the results from contemporary clinical trials that have changed clinical practice. The guideline aims to provide guidance for diagnostic and management decisions, while limiting unnecessary treatments and costs. The recommendations are a resource for professionals involved in the management of patients with glioma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
Patient-reported outcomes (PROs), such as symptoms, function, and other health-related quality-of-life aspects, are increasingly evaluated in cancer randomised controlled trials (RCTs) to provide ...information about treatment risks, benefits, and tolerability. However, expert opinion and critical review of the literature showed no consensus on optimal methods of PRO analysis in cancer RCTs, hindering interpretation of results. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium was formed to establish PRO analysis recommendations. Four issues were prioritised: developing a taxonomy of research objectives that can be matched with appropriate statistical methods, identifying appropriate statistical methods for PRO analysis, standardising statistical terminology related to missing data, and determining appropriate ways to manage missing data. This Policy Review presents recommendations for PRO analysis developed through critical literature reviews and a structured collaborative process with diverse international stakeholders, which provides a foundation for endorsement; ongoing developments of these recommendations are also discussed.
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