Chemotherapy-associated myocardial toxicity is increasingly recognized with the expanding armamentari¬um of novel chemotherapeutic agents. The onset of cardiotoxicity during cancer therapy represents a major concern and often involves clinical uncertainties and complex therapeutic decisions, reflecting a compro¬mise between potential benefits and harm. Furthermore, the improved cancer survival has led to cardio¬vascular complications becoming clinically relevant, potentially contributing to premature morbidity and mortality among cancer survivors. Specific higher-risk populations of cancer patients can benefit from pre¬vention and screening measures during the course of cancer therapies. The pathobiology of chemotherapy-induced myocardial dysfunction is complex, and the individual patient risk for heart failure entails a multifactorial interaction between the selected chemotherapeutic regimen, traditional cardiovascular risk factors, and individual susceptibility. Treatment with several specific chemotherapeutic agents, including anthracyclines, proteasome inhibitors, epidermal growth factor receptor inhibitors, vascular endothelial growth factor inhibitors, and immune checkpoint inhibitors imparts increased risk for cardiotoxicity that results from specific therapy-related mechanisms. We review the pathophysiology, risk factors, and imaging considerations as well as patient surveillance, prevention, and treatment approaches to mitigate cardiotox¬icity prior, during, and after chemotherapy. The complexity of decision-making in these patients requires viable discussion and partnership between cardiologists and oncologists aiming together to eradicate cancer while preventing cardiotoxic sequelae.
We are proud to introduce you to the Fifteenth Annual Rambam Research Day, now established as a key annual event at Rambam Health Care Campus, Haifa, Israel, reflecting the diverse research activities on our campus.
Background: United States (US) and European Union (EU) legislation attempts to counterbalance the presumed discrimination in pediatric drug treatment and development.
Methods: We analyzed the history of drug development, US/EU pediatric laws, and pediatric studies required by US/EU regulatory authorities and reviewed relevant literature.
Results: The US and EU definitions of a child are defined administratively (rather than physiologically) as being aged <17 years and <18 years, respectively. However, children mature physiologically well before their seventeenth or eighteenth birthdays. The semantic blur for these differing definitions may indicate certain conflicts of interest.
Conclusions: Pediatric healthcare today is better than ever. Regulatory-related requirements for “pediatric” studies focus on labeling. Most of these studies lack medical usefulness and may even harm pediatric patients through administration of placebo and/or substandard treatment, despite the resultant publications, networking, patent extensions, and strengthened regulatory standing. Clinicians, parents, and ethics committees should be aware of these issues. New rules are needed to determine new pharmaceutical dose estimates in prepubescent patients, and when/how to clinically confirm them. Internet-based structures to divulge this information should be established between drug developers, clinicians, and regulatory authorities. A prerequisite for the rational use of pharmaceuticals in children would be to correct the flawed concept that children are discriminated against in drug treatment and development, and to abandon separate pediatric drug approval processes.
To the Editor,
I am writing in response to Dr Sharon Galper Grossman’s recent fascinating article, “Vape Gods and Judaism—E-cigarettes and Jewish Law.”1 The author extrapolates from rabbinic literature regard-ing combustible cigarettes and suggests that the preliminary data establishing the dangers of e-cigarettes, and the government warnings against usage, would render these products prohibited under Jewish law, especially for youth and pregnant women.
United States (US) and European Union (EU) laws attempt to counterbalance the presumed discrimination of children in drug treatment and drug development. The US Food and Drug Administration (FDA)-rewarded pediatric studies with antidepressants triggered in 2004 an FDA black-box warning of suicidality in young patients. Fewer antidepressants were prescribed, and the number of completed suicides of young persons increased. The dilemma between this warning and the need to adequately treat young depressed patients remains unsolved. We analyzed the history of drug development, the evolving view of diseases in young patients, US/EU pediatric laws, and pediatric studies triggered by FDA/European Medicines Agency (EMA) in depression and other diseases on the background of developmental pharmacology; financial, institutional, and other interests; and the literature. The FDA/EMA define children administratively, not physio¬logically, as <17 (FDA)/<18 years old (EMA). But young persons mature physiologically well before their 17th/18th birthday. Depression occurs in young persons, has special characteristics, but is not fundamentally different from adult depression. Young persons are not another species. Regulatory requirements for “pediatric” studies focus on “pediatric” labels. Many “pediatric” studies, including those in depression, lacked and lack medical sense and harm patients by placebo treatment although effective drugs exist. The FDA has partially abandoned separate “pediatric” efficacy studies, but not in psychiatry. Clinicians, parents, institutional review boards, and ethics committees should become aware of questionable “pediatric” studies, should re-evaluate ongoing ones, consider to suspend them, and to reject new ones. The concept of separate “pediatric” drug approval needs to be abandoned.
To the Editor,
I thank Rabbi Spitz for his thoughtful analysis. However, I humbly disagree with his conclusion that it is premature to classify e-cigarettes as “downright prohibited.”
The development of the modern hospital is usually dated to the nineteenth century. During this time, many municipal and sectarian hospitals were established and developed, and Jewish hospitals were no exception. Such developments also occurred in the Netherlands. This essay describes the different histories of the Jewish hospitals in Rotterdam and The Hague during the nineteenth century. The Rotterdam institution lasted for more than 130 years (until it was closed by the Nazis during the Second World War), whereas the one in The Hague existed for only 31 years. This study will suggest a number of possible explanations for the relatively long and successful history of the Jewish hospital in Rotterdam and the contrastingly brief duration of the Jewish hospital in The Hague.
Beyond the increase in medical knowledge and biotechnology during the last decades, doctors have adopted professional norms that would have been considered heretical only two generations ago. The changes transpired between the 1970s and 1990s, and generated controversies between those who upheld the traditional values of patient care, and those who welcomed the new professional norms. Professor Dr Johannes Juda Groen (1903–1990) predicted and promoted some of these changes. As early as the 1940s through the 1960s, he recognized the need to teach interviewing skills and advocated an orientation to patients, rather than to diseases; he supported decision-making based on evidence, rather than on personal experience and pathophysiologic rationale; and he demonstrated that psychosocial determinants predict, rather than only correlate with, disease. These views led to confrontations with the medical establishments in the Netherlands and in Israel. Still, many of his colleagues recognized the value of his contributions. The author, for one, admires Groen’s commitment in challenging the prevailing clinical wisdom after the end of World War 2, and his courage in opposing the views of his colleagues.
Introduction: Completion thyroidectomy is defined as the surgical removal of the remnant thyroid tissue following procedures of less than total or near-total thyroidectomy. Whether thyroid reoperations are associated with an increased complication risk is controversial.
Objective: A retrospective analysis was done of patients undergoing completion thyroidectomy for cancer of the thyroid who had undergone surgery elsewhere for solitary thyroid nodule. The incidence of surgical complications in these patients after reoperation was investigated in this study.
Material and Methods: The study included a total of 53 patients who had undergone thyroid lobectomy for a solitary nodule as initial surgery elsewhere and were referred to our institute for completion thyroidectomy when the histopathology revealed malignancy.
Results: There were 53 patients, 43 females and 10 males. Their mean age was 34.7±12.12 years (range 19–65 years). After initial surgery, the histopathology revealed papillary carcinoma in 46 patients (86.8%), follicular carcinoma in 7 (13.2%). Fourteen out of 53 patients had recurrent laryngeal nerve palsy after initial surgery (26.4%). None of the patients had clinical hypocalcemia after the first surgery. One or more parathyroid glands were identified and preserved in 52 patients (98.1%) in the process of completion thyroidectomy. No patient had additional recurrent nerve injury at the second surgery. The mean serum calcium value preoperatively was 8.96±0.39 mg/dL, and six months after surgery serum calcium was 8.74±0.56 mg/dL. Mean follow-up was 18 months. Transient hypoparathyroidism occurred in 24.5% patients. Five patients were lost to follow-up. Permanent and symptomatic hyperparathyroidism occurred in eight patients (16.67%).
Conclusions: Completion thyroidectomy is a safe and appropriate option in the management of well-differentiated thyroid cancer. It removes disease on the ipsilateral and contralateral side of the thyroid and carries a low risk of recurrent laryngeal nerve damage, but a higher risk of permanent hypoparathyroidism.
Anti-citrullinated protein antibodies (ACPAs) are highly specific serologic markers for rheumatoid arthritis (RA) and can pre-date clinical disease onset by up to 10 years, also predicting erosive disease. The process of citrullination, the post-translational conversion of arginine to citrulline residues, is mediated by peptidylarginine deiminase (PAD) enzymes present in polymorphonuclear cells (PMNs). Calcium ions (Ca2+) are required for PAD activation, but the intracellular Ca2+ concentration in normal cells is much lower than the optimal Ca2+ concentration needed for PAD activation. For this reason, it has been proposed that PAD activation, and thus citrullination, occurs only during PMN cell death when PAD enzymes leak out of the cells into the extracellular matrix, or extracellular Ca2+ enters the cells, with the high Ca2+ concentration activating PAD. Recently, using artificial in vitro systems to corroborate their hypothesis, Romero et al. demonstrated that “hypercitrullination,” citrullination of multiple intracellular proteins, occurs within synovial fluid (SF) cells of RA patients, and that only modes of death leading to membranolysis such as perforin-granzyme pathway or complement membrane attack complex activation cause hypercitrullination. In order for Romero’s hypothesis to hold, it is reasonable to surmise that PMN-directed lysis should occur in the rheumatoid joint or the circulation of RA patients. Research conducted thus far has shown that immunoglobulin G (IgG) targeting PMNs are present in RA SF and mediate PMN activation. However, the role of anti-PMN IgG in mediating complement activation and subsequent PMN lysis and hypercitrullination has not been fully evaluated.
