Genetic aberrations have become a dominant factor in the stratification of myeloid malignancies. Cytogenetic and a few mutation studies are the backbone of risk assessment models of myeloid malignancies which are a major consideration in clinical decisions, especially patient assignment for allogeneic stem cell transplantation. Progress in our understanding of the genetic basis of the pathogenesis of myeloid malignancies and the growing capabilities of mass sequencing may add new roles for the clinical usage of genetic data. A few recently identified mutations recognized to be associated with specific diseases or clinical scenarios may soon become part of the diagnostic criteria of such conditions. Mutational study may also advance our capabilities for a more efficient patient selection process, assigning the most effective therapy at the best timing for each patient. The clinical utility of genetic data is anticipated to advance further with the adoption of deep sequencing and next-generation sequence techniques. We herein suggest some future potential applications of sequential genetic data to identify pending deteriorations at time points which are the best for aggressive interventions such as allogeneic stem cell transplantation. Genetics is moving from being mostly a prognostic factor to become a multitasking decision support tool for hematologists. Physicians must pay attention to advances in molecular hematology as it will soon be accessible and influential for most of our patients.
Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code was transcribed to RNA and translated to proteins, but how proteins were degraded had remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis was largely non-lysosomal, but the mechanisms involved have remained obscure. The discovery of the ubiquitin-proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanism-based drugs.
Otto Heinrich Warburg (1883–1970; not to be confused with the Zionist of the same name) was a member of an illustrious Jewish family, known for some five centuries. From humble beginnings, the family became prominent in the world for their contributions to all aspects of society. The son of a German mother and a Jewish (converted) father, Otto H. Warburg became a major contributor to medical science in the field of cancer research. Considered for Nobel Prize more than once, he finally received it in 1931 for his discovery of the nature and mode of action of the cellular respiratory enzyme. Warburg’s personality was controversial: he was intolerant of opposing scientific views yet tolerant toward Nazi abuses. Accused of collaboration under the Nazi regime, Otto H. Warburg was nevertheless readmitted to the global scientific community after World War II. His contribution to cancer research remains influential to this day and has been superseded by discoveries that have built upon his work.
This paper presents the full debate held on October 1, 2014, which focused on the following resolution: “Publications which promote political agendas have no place in scientific and medical journals, and academics should refrain from publishing in such journals.”
The debate moderator was Professor Shimon Glick. Taking the pro stance was Professor A. Mark Clarfield; the con stance was held by Professor Rael D. Strous. Following the first part of the debate, Dr Richard Horton, Editor-in-Chief of The Lancet, gave his thoughts on the topic. This was followed by the opportunity for rebuttal by Professors Clarfield and Strous. The debate was summarized and closed by Professor Glick.
This paper provides a slightly edited text of the debate, for ease of reading.
In August of 2014, Manduca P et al. published “An open letter for the people in Gaza” in The Lancet. This letter was the response of those authors to their perspective of what was happening in Gaza during the summer-long conflict between Israel and Gaza. Israel was finally responding to years of bombardment from Gaza into civilian areas in the south of Israel. Two of the authors of the letters were known anti-Semites, and held connections with David Duke, a former Ku Klux Klan Grand Wizard in Louisiana and advocate of Nazism. Both these authors expressed sympathy and support for Duke’s rabidly anti-Jewish positions. In their letter they accused Israel’s medical community of complicity in committing terrible atrocities and even implied that chemical warfare was being used by Israel.
The Jewish principle concerning a decision with regard to a dangerous treatment is as following: A patient who is estimated to die within 12 months because of a fatal illness is permitted to undergo a treatment that on the one hand may extend his life beyond 12 months, but on the other hand may hasten his death. There are, however, several limitations to this ruling related to the chances of success with the proposed treatment, the nature of the treatment, whether it is intended to be curative or merely to postpone the danger and death, whether the treatment is absolutely necessary, and others. One is not obligated to undergo a dangerous treatment, but one is permitted to do so. The permissibility to forfeit a short life expectancy in order to achieve more prolonged life applies only with the patient’s consent. That consent is valid and is not considered a form of attempted suicide. Neither is a refusal to submit to treatment considered an act of suicide; the patient has the right to refuse a dangerous procedure. In all situations where a permissive ruling is granted for a patient to endanger his short life expectancy, the ruling should be arrived at after careful reflection and with the approval of the rabbinic authorities acting on the recommendation of the most expert physicians.
Suicidal phenomena in the general hospital can take a variety of forms that can be parsed by taking into account whether or not the patient 1) intended to hasten death, and 2) included collaborators, including family and health care providers, in the decision to act. These two criteria can be used to distinguish entities as diverse as true suicide, non-compliance, euthanasia/physician-assisted suicide, and hospice/palliative care. Characterizing the nature of “suicide” events facilitates appropriate decision-making around management and disposition.
This brief introduction is followed by a published version of my Nobel Laureate lecture, re-published herein with the kind permission of the Nobel Foundation. Much has happened since my original research, for which that prize was awarded. Hence, I am pleased to offer a few thoughts about the future of my research and its possible impact on humankind.
Although the original work on nuclear transfer and reprogramming was done over half a century ago, advances continue to be made. In particular the Takahashi and Yamanaka induced pluripotent stem cells (iPS) procedure has opened up the field of cell replacement to a great extent. Now, more recently, further advances make this whole field come closer to actual usefulness for humans. Recently, in the UK, the government approved the use of mitochondrial replacement therapy to avoid the problems associated with genetically defective mitochondria in certain women. Although the House of Commons (members of Parliament) and the House of Lords had to debate and discuss whether to allow this kind of human therapy, I was very pleased to find that both bodies approved this procedure. This means that a patient can choose to make use of the procedure; it does not in any way force an individual to have a procedure that they are not comfortable with. In my view, this is a great advance in respect to giving patients a choice about the treatment they receive. I am told that the UK is the first country in the world to approve mitochondrial replacement therapy.
Now that the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPr) technology is being widely used and works well, one can foresee that there will be those who wish to use this technology to make genetic changes to humans. For example, if a human has a gene that makes it susceptible to infection or any other disorder, the removal of that gene might give such a person immunity from that disease. If this gene deletion is done within the germ line, the genetic change will be inherited. However, one can imagine that various people will strongly object and say that this technology should not be allowed. I would very much hope that various regulatory bodies, governments, etc. will allow the choice to remain with the individual. I can see no argument for such bodies to make a law that removes any choice whatsoever by an individual.
The number needed to treat (NNT) is a simple measure of a treatment’s impact, increasingly reported in randomized trials and observational studies. It has been found to be incorrectly calculated in several studies involving varying follow-up times. We discuss the NNT in these contexts and illustrate the concept using several published studies. The computation of the NNT is founded on the cumulative incidence of the outcome. Instead, several published studies use simple proportions that do not account for varying follow-up times, or use incidence rates per person-time. We show how these approaches can lead to erroneous values of the NNT and misleading interpretations. For example, a trial of 3,845 very elderly hypertensives randomized to a diuretic or placebo reported a NNT of 94 treated for 2 years to prevent one stroke, though the correct approach results in a NNT of 63. We also note that meta-analyses involve trials of differing lengths, but often report a single NNT. For example a meta-analysis of 22 trials of the anticholinergic tiotropium in chronic obstructive pulmonary disease reported a NNT of 16 patients “over one year,” even if the trials varied in duration from 3 to 48 months, with the more specifically computed NNTs varying widely from 72, 15, and 250 for the 3-month, 12-month, and 48-month trials, respectively. Finally, we describe the value of the NNT in assessing benefit–risk, such as low-dose aspirin use in secondary prevention, where prevention of mortality was assessed against the risk of gastrointestinal bleeding. As the “number needed to treat” becomes increasingly used in the comparative effectiveness and safety of therapies, its accurate estimation and interpretation become crucial to avoid distorting clinical, economic, and public health decisions.
Introduction. The current study evaluated the rate of ependymal enhancement and whether its presence influences survival of patients with malignant glioma (GBM).
Methods. A retrospective review of all patients who were treated in our institution from 2005 to 2011 was conducted. Data extracted from the medical records included age, date of diagnosis, co-morbidities, treatment regimen, and time of death. Magnetic resonance images (MRI) were evaluated for the presence of ependymal enhancement and its extent, and the correlation to survival was investigated.
Results. Between 2005 and 2011, 230 patients were treated for GBM. Eighty-nine patients were excluded from the study due to insufficient data, leaving 141 patients for analysis. Median age at diagnosis was 60 years. Sixty-seven (40.6%) patients had evidence of ependymal enhancement on MRI (group A), and 70 (42.4%) patients did not have evidence of enhancement. The assessment of ependymal enhancement was inconclusive due to mass effect and ventricular compression that precluded accurate assessment for 28 (17%) patients (group C). Median survival was 14 months for group A (range, 12–16 months), 15.9 months for group B (range, 14.28–17.65 months), and 11.7 months for group C (range, 6.47–16.92 months) (P>0.05). A multivariate analysis to predict survival indicated that male gender (P=0.039), hypertension (P=0.012), and biopsy only compared to complete gross tumor resection (P=0.001) were significant for poor survival.
Conclusions. Pretreatment ependymal enhancement on MRI was not found to be associated with poorer survival. These results might be due to better treatments options compared to prior reports.
