How I Treat Relapsed Multiple Myeloma

Despite recent advances multiple myeloma remains an incurable disease for most of the patients and initial remission will be followed by relapses requiring therapy. For many, there will be several remissions and relapses until resistance develops to all available therapies. With the introduction of several new agents, myeloma treatment has changed drastically and there are new options for the management of relapsed or refractory disease, including new drug classes with distinct mechanisms of action and cellular therapies. However, resistance to major drug classes used in first line remain the most critical factor for the choice of treatment at relapse. Continuous lenalidomide-based therapy is used extensively at first line and resistance to lenalidomide has become the key factor for the choice of salvage therapy. Daratumumab is increasingly used in first line and soon patients that relapse while on daratumumab will become a common challenge. Three-drug regimens are standard approach to manage relapsed disease. Adding drugs with new mechanisms of activity can improves outcomes and overcomes class resistance but, until now, while the biology is important, can offer only limited guidance for the choice of therapy.

Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1

Chronic lymphocytic leukemia (CLL) has experienced a clinical revolution—thanks to the discovery of crucial pathogenic mechanisms. CLL is still an incurable disease due to intrinsic or acquired resistance of the leukemic clone. Venetoclax is a Bcl-2 inhibitor with a marked activity in CLL, but emerging patterns of resistance are being described. We hypothesize that intrinsic features of CLL cells may contribute to drive mechanisms of resistance to venetoclax. We analyzed the expression of Interferon Regulatory Factor 4 (IRF4), Notch2, and Mcl-1 in a cohort of CLL patients. We evaluated CLL cell viability after genetic and pharmaceutical modulation of Notch2 expression in patients harboring trisomy 12. We tested venetoclax in trisomy 12 CLL cells either silenced or not for Notch2 expression or in combination with an inhibitor of Mcl-1, AMG-176. Trisomy 12 CLL cells were characterized by low expression of IRF4 associated with high levels of Notch2 and Mcl-1. Notch2 and Mcl-1 expression determined protection of CLL cells from spontaneous and drug-induced apoptosis. Considering the involvement of Mcl-1 in venetoclax resistance, our data demonstrated a contribution of high levels of Notch2 and Mcl-1 in a reduced response to venetoclax in CLL cells carrying trisomy 12. Furthermore, reduction of Mcl-1 expression by silencing Notch2 or by treatment with AMG-176 was able to restore the response of CLL cells to venetoclax. The expression of Notch2 identifies a subset of CLL patients, mainly harboring trisomy 12, characterized by high levels of Mcl-1. This biological mechanism may compromise an effective response to venetoclax.

Commercial and Scientific Solutions for Blood Glucose Monitoring—A Review

Diabetes is a chronic and, according to the state of the art, an incurable disease. Therefore, to treat diabetes, regular blood glucose monitoring is crucial since it is mandatory to mitigate the risk and incidence of hyperglycemia and hypoglycemia. Nowadays, it is common to use blood glucose meters or continuous glucose monitoring via stinging the skin, which is classified as invasive monitoring. In recent decades, non-invasive monitoring has been regarded as a dominant research field. In this paper, electrochemical and electromagnetic non-invasive blood glucose monitoring approaches will be discussed. Thereby, scientific sensor systems are compared to commercial devices by validating the sensor principle and investigating their performance utilizing the Clarke error grid. Additionally, the opportunities to enhance the overall accuracy and stability of non-invasive glucose sensing and even predict blood glucose development to avoid hyperglycemia and hypoglycemia using post-processing and sensor fusion are presented. Overall, the scientific approaches show a comparable accuracy in the Clarke error grid to that of the commercial ones. However, they are in different stages of development and, therefore, need improvement regarding parameter optimization, temperature dependency, or testing with blood under real conditions. Moreover, the size of scientific sensing solutions must be further reduced for a wearable monitoring system.

Saturation Transfer MRI for Detection of Metabolic and Microstructural Impairments Underlying Neurodegeneration in Alzheimer’s Disease

Alzheimer’s disease (AD) is one of the most common causes of dementia and difficult to study as the pool of subjects is highly heterogeneous. Saturation transfer (ST) magnetic resonance imaging (MRI) methods are quantitative modalities with potential for non-invasive identification and tracking of various aspects of AD pathology. In this review we cover ST-MRI studies in both humans and animal models of AD over the past 20 years. A number of magnetization transfer (MT) studies have shown promising results in human brain. Increased computing power enables more quantitative MT studies, while access to higher magnetic fields improves the specificity of chemical exchange saturation transfer (CEST) techniques. While much work remains to be done, results so far are very encouraging. MT is sensitive to patterns of AD-related pathological changes, improving differential diagnosis, and CEST is sensitive to particular pathological processes which could greatly assist in the development and monitoring of therapeutic treatments of this currently incurable disease.

Intervention is Urgently Needed to Address Poor Awareness of South Asian Family Caregivers for Dementia Care: A Qualitative Study

Introduction: “The National Dementia Strategies” in Canada emphasizes improving the knowledge of formal and informal caregivers for better care for the person living with dementia. Aim: This study aimed at exploring awareness and the attitudes of South Asian Bangladeshi family caregivers towards dementia care. Methods: It was purposive sampling and a qualitative study. The study included 45 family caregivers (>55 years) for the face-to-face interviews in Toronto, Ontario. The study used semi-structured questions. The duration of the data collection was between February and March 2020. Results: The study included the three areas related to dementia, such as a) the awareness of dementia, b: awareness of prevention and treatment as well as the awareness of caregivers about what is needed for better dementia care, and c) attitudes of caregivers towards dementia care. Many caregivers described dementia as memory loss and forgetfulness. According to the caregivers, anxiety, depression, and aging were the risk factors of dementia. The caregivers commonly perceived dementia as an unpreventable and incurable disease. Moreover, many caregivers did not know about the appropriate health providers who diagnosed and treated dementia, and they were not aware of non-pharmacological care of dementia. The caregivers perceived dementia as a shameful disease. They would not go for diagnosis if they had risks for dementia and would hide their dementia after diagnosis. Many caregivers confessed that training was essential to improve knowledge about dementia, but they did not want to be a caregiver for the person living with dementia. Conclusion: The South Asian Bangladeshi family caregivers had not enough awareness about dementia, prevention, and treatment. Dementia was associated with shame, and they had less interest in dementia care. Urgent educational training is needed in their language to improve knowledge, reduce stigma, engage them in dementia care, and achieve the goals of the National Dementia Strategies.

INTERNATIONAL TERRORISM: A STUDY IN FORMS AND EFFEETS

Terrorism is known as one of the most dangerous phenomena that has the negatively influence the reality of ‎human societies. Despite human history has never been free from acts of terrorism in all its forms, modern ‎terrorism has exceeded in its magnitude, image and impact all that has been found since human existence. In ‎addition, this phenomenon becomes a matter of concern to human beings wherever it may be exist. ‎Nevertheless, politicians, sociologists, lawmakers and philosophers, as well as various intellectuals and writers ‎alike, accept without hesitation the recognition of the difficulties of identifying and placing terrorism within a ‎comprehensive background that is acceptable to all. The disagreement and the lack of understanding that ‎accompanied and kept pace with all the attempts that were made and are taking place discuss the term of ‎terrorism. The problem of the terrorism under study revolves primarily around a phenomenon that is now ‎plaguing the entire world. This paper discusses a diagnosis of incurable disease called international terrorism to ‎reveal some of the uncertainties and uncertainties in this phenomenon. The importance of the topic is about ‎highlighting the important and effective role played by the international community and the Islamic societies ‎in the fight against terrorism. Furthermore, this paper aims to clarify the concept of international terrorism and ‎and identify the most important forms and dangers resulting from it, which has been increasing rapidly in ‎recent times and the consequent threat to the integrated human security system, whether moral security, ‎economic security, social security, or Political security or environmental security‎.‎

A New and Worrisome Predictor of Attitudes Toward Suicide: Self-Rated Health

Do people have the right to end their own lives? The General Social Survey has monitored the attitudes of Americans towards suicide since 1977 using four questions: Do you think a person has the right to end his or her own life if this person has an incurable disease, has gone bankrupt, has dishonored his or her family, or is tired of living and ready to die? These four responses can be combined into a reliable index representing an individual’s attitude toward suicide. As average population education levels have increased and religiosity has fallen, attitudes favoring the right to suicide have increased across the population. This research project introduces a previously understudied predictor of attitudes toward suicide: self-rated health. Using logistic and ordinal logistic regression, and controlling for age, education level, religiosity, marital status, survey year, race, and sex, I find that, over time, self-rated health has become a significant predictor of attitudes toward suicide. Since 2002, respondents who perceived themselves to be in poor health are significantly more likely to favor the right to end one’s life, especially if the individual has an incurable disease. After stratifying by age and race, I find that the relationship between self-rated health and attitudes toward suicide is strongest among individuals in the mid-life and is equally significant as a predictor for White and Black Americans after 2010. These findings provide further evidence that mental health screening is an increasingly vital component of physician/patient interactions and highlight the importance of continuity of care.

ON CRITICAL THINKING AND MODERN LIMITS TO HUMAN KNOWLEDGE

: We are currently living in a world literally flooded with all types of information, and people have ended up dealing with various kinds of limitations to how much they can or choose to know. We can, thus, identify modern limits to human knowledge falling under (at least) two large categories: either limitations imposed by others (such as authorities, mass media, bosses or leaders, etc), or what we may call self-imposed limitations, i.e. choosing to disregard some information or another, refusing to keep up to date with a state of facts, rejecting scientifically proved data, etc. We are actually talking about outer manipulation (in option A above), or inner manipulation, if we may call it as such, namely the protection of personal comfort even over irrefutable evidence (in option B above). “Ignorance is bliss” (The Matrix, 1999), right? At least for some people. Yet, in this intricate matrix of human knowledge some of us are plagued with an incurable disease: critical thinking. A genuine bogeyman of any authoritarian system or regime, critical thinking is responsible for many glitches in this matrix, always at war against any sort of limitations imposed on human knowledge and rationale. We need to keep critical thinking alive and encourage it, and, in this process, identify the decisive vectors capable of disseminating the concept and its value, as well as its applications in everyday life.

Bendamustine-Based Regimens as Salvage Therapy in Refractory/Relapsed Multiple Myeloma Patients: A Retrospective Real-Life Analysis by the Polish Myeloma Group

Multiple myeloma (MM) is an incurable disease and patients become refractory to the treatment in the course of the disease. Bendamustine-based regimens containing steroids and other agents are among the therapeutic options offered to MM patients. Here, we investigated the safety and the efficacy of bendamustine used in patients with refractory/relapsed MM (RRMM). The patients were treated with bendamustine and steroids (n = 52) or bendamustine, steroids and immunomodulatory agents or proteasome inhibitors (n = 53). Response rates, progression-free survival (PFS), overall survival (OS) and frequency of adverse events were compared between both study groups. Most efficacy measurements were better in patients treated with three-drug regimens: overall response rate (55% versus 37%, p = 0.062), median PFS (9 months versus 4 months, p < 0.001), median OS survival (18 months versus 12 months, p = 0.679). The benefit from combining bendamustine and steroids with an additional agent was found in subgroups previously treated with both lenalidmide and bortezomib, with stem cell transplant and with more than two previous therapy lines. Toxicity was similar in both study groups and bendamustine-based therapies were generally well-tolerated. Our study suggests that bendamustine may be an effective treatment for patients with RRMM. Three-drug regimens containing bendamustine, steroids and novel agents produced better outcomes and had acceptable toxicity. The efficacy of bendamustine combined with steroids was limited.

LEGAL CULTURE AND LEGISLATION ON EUTHANASIA: A NEW LEVEL OF LEGAL REGULATION OR THE COLLAPSE OF THE LEGAL SYSTEM?

Euthanasia is a voluntary withdrawal from the life of a person suffering from an incurable disease or having a disease that causes him physical and mental suffering. This practice has been used since the period of antiquity, when in Ancient Rome and Sparta, the elderly and the disabled were thrown from the mountains. The need for such a policy was explained by the inability of the state to support weak members in the conditions of regular military campaigns. A similar position was supported by the Nazis of nazi Germany, who created gas chambers as an analogue of "easy death" for disabled citizens, which included people with mental disorders; people suffering from epilepsy; disabled people with any health abnormalities; patients who had been treated for more than 5 years. In addition to persons with various pathologies, representatives of Gypsy, Jewish, and Polish nationalities were included in the same group. It becomes obvious that in such a context, euthanasia is perceived as a clear abuse of the state to dispose of the lives of its citizens. In modern foreign countries and the Russian Federation, this procedure seems to be a way to satisfy the desire of a person suffering from an incurable or severe disease of both a somatic and mental nature, in a dignified and rapid termination of his existence. To what extent such a desire to classify oneself as deceased is voluntary and conscious and whether it fits into modern legal norms is considered in the presented publication, which at the same time offers more constructive ways to help individuals in need.