Jiri Polivka

Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway.

Aberrations in various cellular signaling pathways are instrumental in regulating cellular metabolism, tumor development, growth, proliferation, metastasis and cytoskeletal reorganization. The fundamental cellular signaling cascade involved in these processes, the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR), closely related to the mitogen-activated protein kinase (MAPK) pathway, is a crucial and intensively explored intracellular signaling pathway in tumorigenesis. Various activating mutations in oncogenes together with the inactivation of tumor suppressor genes are found in diverse malignancies across almost all members of the pathway. Substantial progress in uncovering PI3K/AKT/mTOR alterations and their roles in tumorigenesis has enabled the development of novel targeted molecules with potential for developing efficacious anticancer treatment. Two approved anticancer drugs, everolimus and temsirolimus, exemplify targeted inhibition of PI3K/AKT/mTOR in the clinic and many others are in preclinical development as well as being tested in early clinical trials for many different types of cancer. This review focuses on targeted PI3K/AKT/mTOR signaling from the perspective of novel molecular targets for cancer therapy found in key pathway members and their corresponding experimental therapeutic agents. Various aberrant prognostic and predictive biomarkers are also discussed and examples are given. Novel approaches to PI3K/AKT/mTOR pathway inhibition together with a better understanding of prognostic and predictive markers have the potential to significantly improve the future care of cancer patients in the current era of personalized cancer medicine.

Length of Occlusion Predicts Recanalization and Outcome After Intravenous Thrombolysis in Middle Cerebral Artery Stroke

Background and Purpose— The length of large vessel occlusion is considered a major factor for therapy in patients with ischemic stroke. We used 4D-CT angiography evaluation of middle cerebral artery occlusion in prediction of recanalization and favorable clinical outcome and after intravenous thrombolysis (IV-tPA). Methods— In 80 patients treated with IV-tPA for acute complete middle cerebral artery/M1 occlusion determined using CT angiography and temporal maximum intensity projection, calculated from 4D-CT angiography, the length of middle cerebral artery proximal stump, occlusion in M1 or M1 and M2 segment were measured. Univariate and multivariate analyses were performed to define independent predictors of successful recanalization after 24 hours and favorable outcome after 3 months. Results— The length of occlusion was measureable in all patients using temporal maximum intensity projection. Recanalization thrombolysis in myocardial infarction 2 to 3 was achieved in 37 individuals (46%). The extension to M2 segment as a category (odds ratio, 4.58; 95% confidence interval, 1.39–15.05; P=0.012) and the length of M1 segment occlusion (odds ratio, 0.82; 95% confidence interval, 0.73–0.92; P=0.0007) with an optimal cutoff value of 12 mm (sensitivity 0.67; specificity 0.71) were significant independent predictors of recanalization. Favorable outcome (modified Rankin scale 0–2) was achieved in 25 patients (31%), baseline National Institutes of Health Stroke Scale (odds ratio, 0.82; 95% confidence interval, 0.72–0.93; P=0.003) and the length of occlusion M1 in segment (odds ratio, 0.79; 95% confidence interval, 0.69–0.91; P=0.0008) with an optimal cutoff value of 11 mm (sensitivity 0.74; specificity 0.76) were significant independent predictors of favorable outcome. Conclusions— The length of middle cerebral artery occlusion is an independent predictor of successful IV-tPA treatment.

“Pre-metastatic niches” in breast cancer: are they created by or prior to the tumour onset? “Flammer Syndrome” relevance to address the question

Breast cancer (BC) epidemic in the twenty-first century is characterised by around half a million deaths and 1.7 million new cases registered annually worldwide. Metastatic disease is the major cause of death in BC patient cohorts. Current statistics are much alarming from the viewpoint of the early mortality amongst BC patients with de novo metastatic disease. A new paradigm of so-called “pre-metastatic niches” may sufficiently promote our knowledge regarding potential pathomechanisms, individual predisposition and prognosis in development and progression of the metastatic disease. However, the crucial question remains unaddressed, whether hypoxic pre-metastatic niches in BC are created by or prior to the tumour onset. So far, the current interpretation of the “Seed and Soil” theory of metastasis proposing that the pre-metastatic niches are formed by primary tumours which “induce and guide” the process is incomplete, since it does not provide satisfactory explanations towards several facts overviewed in the article. The overall results of this study clearly support the working hypothesis presented by the authors proposing that the epi/genetic predisposition of individuals at risk to form the systemic hypoxic pre-metastatic niches can be established a long time before breast malignancy is clinically manifested. “Flammer Syndrome” (FS) phenotype may strongly contribute to particularly poor outcomes of metastatic breast cancer. Significance and relevance of individual FS symptoms for breast cancer metastatic disease are discussed in extenso.

Testing for oncogenic molecular aberrations in cell-free DNA-based liquid biopsies in the clinic: Are we there yet?

The optimal choice of cancer therapy depends upon analysis of the tumor genome for druggable molecular alterations. The spatial and temporal intratumor heterogeneity of cancers creates substantial challenges, as molecular profile depends on time and site of tumor tissue collection. To capture the entire molecular profile, multiple biopsies from primary and metastatic sites at different time points would be required, which is not feasible for ethical or economic reasons. Molecular analysis of circulating cell-free DNA offers a novel, minimally invasive method that can be performed at multiple time-points and plausibly better represents the prevailing molecular profile of the cancer. Molecular analysis of this cell-free DNA offers multiple clinically useful applications, such as identification of molecular targets for cancer therapy, monitoring of tumor molecular profile in real time, detection of emerging molecular aberrations associated with resistance to particular therapy, determination of cancer prognosis and diagnosis of cancer recurrence or progression.

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

The breast cancer (BC) diagnosis currently experiences the epidemic evolution with more than half of million deaths each year. Despite screening programmes applied and treatments available, breast cancer patients frequently develop distant metastases. The brain is one of the predominant sites of the metastatic spread recorded for more than 20% of BC patients, in contrast to the general population, where brain tumours are rarely diagnosed. Although highly clinically relevant, the brain tumour mystery in the cohort of breast cancer patients has not been yet adequately explained. This review summarises currently available information on the risk factors predicting brain metastases in BC patients to motivate the relevant scientific areas to explore the data/facts available and elucidate disease-specific mechanisms that are of a great clinical utility.

Isocitrate Dehydrogenase-1 Mutations as Prognostic Biomarker in Glioblastoma Multiforme Patients in West Bohemia

Introduction. Glioblastoma multiforme (GBM) is the most malignant primary brain tumor in adults. Recent whole-genome studies revealed novel GBM prognostic biomarkers such as mutations in metabolic enzyme IDH—isocitrate dehydrogenases (IDH1 and IDH2). The distinctive mutation IDH1 R132H was uncovered to be a strong prognostic biomarker for glioma patients. We investigated the prognostic role of IDH1 R132H mutation in GBM patients in West Bohemia. Methods. The IDH1 R132H mutation was assessed by the RT-PCR in the tumor samples from 45 GBM patients treated in the Faculty Hospital in Pilsen and was correlated with the progression free and overall survival. Results. The IDH1 R132H mutation was identified in 20 from 44 GBM tumor samples (45.4%). The majority of mutated tumors were secondary GBMs (16 in 18, 89.9%). Low frequency of IDH1 mutations was observed in primary GBMs (4 in 26, 15.3%). Patients with IDH R132H mutation had longer PFS, 136 versus 51 days (P < 0.021, Wilcoxon), and OS, 270 versus 130 days (P < 0.024, Wilcoxon test). Summary. The prognostic value of IDH1 R132H mutation in GBM patients was verified. Patients with mutation had significantly longer PFS and OS than patients with wild-type IDH1 and suffered more likely from secondary GBMs.

Postmenopausal breast cancer: European challenge and innovative concepts

Breast cancer (BC) epidemic is recognised now worldwide as the reality of the early twenty-first century. Increasing trends in the postmenopausal BC prevalence, even for the European countries earlier demonstrating relatively stable incidence rates of the disease, are highly alarming for the healthcare givers. This new actuality requires a substantial revision of the paradigm currently applied to the BC management and creation of highly innovative concepts. Current multi-centred study highlights new complex mechanisms of the development and progression of the postmenopausal BC. Innovative concepts are presented which argue for more effective predictive and preventive approaches well justified in view of the clusters of the symptoms analysed here and demonstrated as highly prevalent in the postmenopausal breast cancer versus BC-free individuals. Another conceptual novelty presented here is a new interpretation of the “Seed and Soil” theory of metastasis in BC. According to the new concept, the “pre-metastatic niches” (“Soil”) are created by a systemic hypoxia a long time before the breast malignancy is clinically manifested.

Current status of biomarker research in neurology

Neurology is one of the typical disciplines where personalized medicine has been recently becoming an important part of clinical practice. In this article, the brief overview and a number of examples of the use of biomarkers and personalized medicine in neurology are described. The various issues in neurology are described in relation to the personalized medicine and diagnostic, prognostic as well as predictive blood and cerebrospinal fluid biomarkers. Such neurological domains discussed in this work are neuro-oncology and primary brain tumors glioblastoma and oligodendroglioma, cerebrovascular diseases focusing on stroke, neurodegenerative disorders especially Alzheimer’s and Parkinson’s diseases and demyelinating diseases such as multiple sclerosis. Actual state of the art and future perspectives in diagnostics and personalized treatment in diverse domains of neurology are given.

Pregnancy-associated breast cancer: the risky status quo and new concepts of predictive medicine

The paper is motivated by severe concerns regarding currently applied care of the pregnancy-associated breast cancer (PABC) characterised by particularly poor outcomes of the disease. Psychological and ethical aspects play a crucial role in PABC: the highest priority not to damage the foetus significantly complicates any treatment generally, and it is quite usual that patients disclaim undergoing any breast cancer treatment during pregnancy. Although, due to global demographic trends, PABC is far from appearing rarely now, severe societal and economic consequences of the disease are still neglected by currently applied reactive medical approach. These actualities require creating new strategies which should be better adapted to the needs of the society at large by advancing the PABC care based on predictive diagnostic approaches specifically in premenopausal women, innovative screening programmes focused on young female populations, targeted prevention in high-risk groups, and optimised treatment concepts. The article summarises the facts and provides recommendations to advance the field-related research and medical services specifically dedicated to the PABC care.

Pre-graduate and post-graduate education in personalized medicine in the Czech Republic: statistics, analysis and recommendations.

The main goal of personalized medicine is the individualized approach to the patient’s treatment. It could be achieved only by the integration of the complexity of novel findings in diverse “omics” disciplines, new methods of medical imaging, as well as implementation of reliable biomarkers into the medical care. The implementation of personalized medicine into clinical practice is dependent on the adaptation of pre-graduate and post-graduate medical education to these principles. The situation in the education of personalized medicine in the Czech Republic is analyzed together with novel educational tools that are currently established in our country. The EPMA representatives in the Czech Republic in cooperation with the working group of professionals at the Faculty of Medicine in Pilsen, Charles University in Prague have implemented the survey of personalized medicine awareness among students of Faculty of Medicine in Pilsen—the “Personalized Medicine Questionnaire”. The results showed lacking knowledge of personalized medicine principles and students’ will of education in this domain. Therefore, several educational activities addressed particularly to medical students and young physicians were realized at our facility with very positive evaluation. These educational activities (conferences, workshops, seminars, e-learning and special courses in personalized medicine (PM)) will be a part of pre-graduate and post-graduate medical education, will be extended to other medical faculties in our country. The “Summer School of Personalized Medicine in Plzen 2015” will be organized at the Faculty of Medicine and Faculty Hospital in Pilsen as the first event on this topic in the Czech Republic.