Predictive preventive personalized medicine Liver cancer is the fifth most common form of cancer worldwide [1], with an incidence rate almost equals the mortality rate and ranks 3 rd among causes of cancer related death [2]. The coexistence of two life threatening conditions, cancer and liver cirrhosis makes the staging challenging. However, there are some staging systems, e.g. the Barcelona staging system for Hepatocellular carcinoma (HCC) [3], that suggest treatment options and management. Whereas diagnosis in early stages gives hope for a curative outcome, the treatment regime for around 80 % [2] of the patients classified as severe stages only gears towards palliation [4]. An intra-arterial radiation approach, radioembolisation (RE) is ubiquitously applied as one of palliative approaches. Although, in general RE shows promising results in intermediate and advanced stage HCC [5], individual treatment outcomes are currently unpredictable. Corresponding stratification criteria are still unclear. We hypothesised that individual radioresistance/radiosensitivity may play a crucial role in treatment response towards RE strongly influencing individual outcomes. Further, HCC represents a highly heterogeneous group of patients which requires patient stratification according to clear criteria for treatment algorithms to be applied individually. Multilevel diagnostic approach (MLDA) is considered helpful to set-up optimal predictive and prognostic biomarker panel for individualised application of radioembolisation. Besides comprehensive medical imaging, our MLDA includes non-invasive multi-omics and sub-cellular imaging. Individual patient profiles are expected to give a clue to targeting shifted molecular pathways, individual RE susceptibility, treatment response. Hence, a dysregulation of the detoxification pathway (SOD2/Catalase) might indicate possible adverse effects of RE, and highly increased systemic activities of matrix metalloproteinases indicate an enhanced tumour aggressiveness and provide insights into molecular mechanisms/targets. Consequently, an optimal set-up of predictive and prognostic biomarker panels may lead to the changed treatment paradigm from untargeted "treat and wait" to the cost-effective predictive, preventive and personalised approach, improving the life quality and life expectancy of HCC patients. Keywords: Market access, Value, Strategy, Companion diagnostics, Cost-effectiveness, Reimbursement, Health technology assessment, Economic models, Predictive preventive personalized medicine Achieving and sustaining seamless "drug -companion diagnostic" market access requires a sound strategy throughout a product life cycle, which enables timely creation, substantiation and communication of value to key stakeholders [1, 2]. The study aims at understanding the root-cause of market access inefficiencies of companies by gazing at the "Rx-CDx" co-development process through the prism of "value", and developing a perfect co-development scenario based on the literature review and discussions with the ...
Introduction: Tension-type headache (TTH) is very common, with a lifetime prevalence in the general population ranging in different studies between 30% and 78%. TTH, divided into episodic and chronic types, introduced in the manual "International Classification of Headache Disorders"(ICHD-I), is of practical importance. Infrequent episodic headaches (no more than once a month) may not require drug therapy, but, on the contrary, frequent forms may require expensive treatment. Objective: To study the state of cerebral hemodynamics and cerebrovascular reactivity in patients with Tension-type headache and evaluate the efficacy of treatment with Phenibite using Doppler ultrasound. Materials and Methods: A retrospective analysis of the results of ultrasound dopplerography of the anterior, middle and posterior cerebral arteries (ACA, MCA and PCA), Vertebral and Basal (VA, BA) arteries was performed in 188 patients with TTH. Among them are infrequent episodic TTH - 68 (36,2%) patients, frequent episodic TTH - 64 (34,0%) patients, chronic TTH - 56 (29,8%) patients. The age of the subjects was 18-45 years, among them 85 (45.2%) men and 103 (54.8%) women. The maximum systolic velocity (Vs), the end diastolic velocity (Vd), the resistance and pulsativity indexes (RI, PI) in all vessels were determined. Patients were given consent to participate in the study. Results: Infrequent episodic (IFE) TTH were recorded in 86.4% of cases, frequent episodic (FE) — in 88.9%, and chronic (Ch) TTH — in 81.6% of cases. Bilateral TTH was noted in 39.2%, frontal localization - in 35.6%, in the occipital region - in 25–7% of cases. The asymmetry of the maximum systolic blood flow velocity (Vs) in the paired arteries within 20-30% was considered a violation of cerebral hemodynamics, which was detected in 38.7% of patients. An increase in Vs was noted in all cerebral vessels, especially in patients with FE TTH and chronic Ch TTH compared with the control group. In patients with IFE TTH the average value of RcFMt was 1.24±0.03, in patients with FE TTH - 1.25±0.02, in patients with Ch TTH - 1.27±0.03. In patients with TTH, hyper-responsiveness to hypercapnic test was detected: RcCO2 was 1.43±0.05 in the group with FE TTH; 1.39±0.07 in the group of Ch TTH and 1.37±0.04 in the group of IFE TTH, which indicates a tendency for the tension of the vasodilator regulation mechanism even in clinically insignificant forms of TTH. In the study of reactivity to the O2-test, a hyporeactive response was observed in the groups with FE TTH and Ch TTH (0.38±0.04 and 0.35±0.05, respectively. The treatment with Phenibut carried out in a step-by-step manner - during the first week the drug was applied at a dose of 250 mg 2 times a day, over the next 6 weeks the dose increased to 500 mg 2 times a day, then the dose was reduced back to 250 mg 2 times a day. Among patients with FE TTH, the frequency of headache decreased from 5.7±2.3 to 3.6±2.1 days/month, and in patients with Ch TTH - from 22.8±1.7 to 17.7±1,3 days/month (P<0,05). Influence of the drug was manifested at the initially increased RcFMt and RcCO2. A decrease in initially elevated RcCO2 was noted in all (FE TTH, ChTTH, IFETTH) clinical groups. However, this decrease was not statistically significant. Conclusion: In patients with TTH, an increase in the Vs is more often recorded, their asymmetry in the middle cerebral artery. Hyperreactivity on CO2-load is typical for patients with chronic TTH, and reflects the mobilization of metabolic regulation of cerebral blood flow. Conducting FMt was the most informative method for detecting autoregulatory disorders mainly in patients with IFE TTH. FE TTH in patients is characterized by the presence of a hyperactive reaction to hypercapnic and orthostatic tests, probably due to mobilization of humoral-metabolic and neurogenic links of regulation. In the group of patients with chronic TTH prevails hyporeactivity for hyperventilation test, reflecting the depletion of vasoconstriction reserve. The use of Phenibut(Noophen® (JSC Olainfarm Latvia in the treatment of TTH is accompanied by a decrease in the frequency of pain, and of pericranial muscle tone, most pronounced in patients with FE TTH. It's effectiveness is evident in the normalization of the coefficients of cerebrovascular reactivity in a patients with chronic TTH. The minimal statistical significance was observed on the dynamics of blood flow only in the VA.
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