Will artificial intelligence be, one day, powerful enough to obviate the need of randomized clinical trials?

Artificial Intelligence (AI) currently occupies the headlines in the media as well as the medical press, with messages of its emerging unlimited potential, but also tales of doom and gloom predicting risks for the extinction of humanity! One such headline in the London TIMES of 6th June 2023 reads: - "Two years to save the world, says AI adviser". To the uninformed, AI is nothing more than the processing of a colossal amount of data with lightning speed, now achievable with the latest spectacular developments in computing. However, could such power be harnessed to accurately predict the therapeutic potential of a new treatment emerging from Phase I, or Phase II trials, without the need to proceed to Phase III randomised, at times placebo controlled, trials? The deontological and ethical concerns about randomised trials have frequently occupied the medical literature as several clinical researchers feel uncomfortable with this kind of clinical research, especially when a placebo is allocated to patients with cancer, enlisted in a Phase III trial. Others have argued that in contrast to the belief that randomised controlled trials are more reliable estimators of the efficacy of a treatment, investigators have found that, in some settings, observational studies did not overestimate the size of the treatment effect compared with their randomised counterparts. An accurate prediction of the true potential of a novel treatment with AI, thus obviating the need of a phase III, randomised trial, could save time, effort, and finances, as well as relieve the ethical burden of allocating treatment at random to patients with cancer and limited life expectancy.

Medical Historians and Historians of Medicine: Time for a Truce

It could be argued that the first medical historian in the Western Medical Tradition, is the author of the treatise On Ancient Medicine, included in the Hippocratic Corpus, in all probability, Hippocrates himself. In our time, the domain of the history of medicine is inhabited by two factions, often indifferent towards each other's contributions, if not occasionally confrontational. One faction is represented by medical practitioners who, usually upon retirement from clinical care, research and seek to understand the practice and evolution of their craft in the recent and distant past. They are the medical historians. The other, by academic historians with a background in humanities who view and research the history of medicine from a different perspective. Historiography, the philosophy of science, philological concerns, the provenance of manuscripts, textual scrutiny, the cultural and social parameters relevant to their historical subject, are the focus of the work of these historians of medicine. Rarely, researchers of the history of medicine combine optimally humanities with a medical background. Many will recognize Sir William Osler (1849-1919) as the best representative of this happy cohabitation. The opportunity now arises for a fruitful collaboration between medical historians and historians of medicine in recording the unprecedented times and the global challenges of the COVID-19 pandemic. Now is the time for truce.

Clinical trials and the COVID-19 pandemic.

"...but why think? Why not try the experiment?..." John Hunter (1728-1793), in a letter to Edward Jenner. August 2nd, 1775. When Galen of Pergamum (2nd c. A.D.), physician, philosopher and experimentalist, sought to ascertain the therapeutic properties of Theriac, an antidote of repute against poisons, he resorted to an experiment. Theriac or Theriaca was a compound drug, containing in some versions used in antiquity numerous components; Galen's own composition included over 70 ingredients! One of its uses was as an antidote against snakebites, a frequent peril for the Roman armies marching on in sandals. Galen spent most of his life in Rome and was elevated to Imperial Physician at the court of Marcus Aurelius, who apparently took daily doses of Theriac, which among other components included opium. Describing the experiment to his friend Pison, Galen wrote, "as I could not possibly conduct a trial on humans, I experimented on roosters" For his experiment, Galen, studied two groups of roosters, but he doesn't tell us how many animals he included in each category. Both groups were exposed to poisonous snakebites. All roosters who were fed with theriac prior to exposure to viper bites survived, whereas in the second group that had not received prophylactic Theriac, all roosters died. Not only is Galen's methodology remarkable, preceding the modern randomised trial by eighteen centuries, but more importantly, it is notable for his ethical stance at a time when sensitivities about human rights, prevalent in our times, were largely absent in societies of widespread slavery. For example, Mithridates VI (132-63 BC), the King of Pontus who is credited with the first use of Theriac, tested its efficacy on criminals and slaves. For his experiment Galen used the random allocation of treatment, today's prospective randomised clinical trial, implemented in the evaluation of novel therapies, widely used internationally, particularly in cancer research! This experimental method used for ascertaining the efficacy of new drugs became established after the second half of the 20th century and is now firmly entrenched as a research tool. On the other hand, the retrieval of information from observational studies or non-randomised series is considered scientifically inferior and is often dismissed or ignored as irrelevant or anecdotal. Such is the compulsion for the randomised study that in the midst of the COVID-19 pandemic, respected physicians and scientists appeared in the media hesitant to recommend the use of protective facial masks, as there was no evidence of benefit for their use from prospective randomised studies in the general population! Logic had no place in the argument! COVID-19, caused by the SARS-CoV-2 new corona virus, brought to the fore the randomised trial, as well as, the ethical dilemmas that surround the allocation of treatment at random, in the face of a devastating pandemic. Anthony Fauci, distinguished infectious diseases expert and an adviser to the President of the USA, at a recent briefing from the Situation Room of the White House, endorsed categorically and unreservedly the randomised trial for the evaluation of drugs potentially effective against SARS-CoV-2, in patients afflicted with COVID-19. A few days later on April 8th, 2020, Professor Sotiris Tsiodras, scientific advisor to the Greek Government for COVID-19 and an expert on infectious diseases, when asked by a journalist about chloroquine, he responded, "Antony Fauci is correct. Nevertheless, we give the drug to everyone, that is, not half of the patients will receive it, and the other half will not". If we accept that the randomised trial represents the unique, impregnable method of evaluating new treatments-several clinicians dispute this dogma. -the question arises how will treatments be allocated to patients? According to the Declaration of Helsinki participation of a subject in a clinical trial requires their explicit written consent. Will, a potentially hypoxic patient rapidly deteriorating, be able to understand what is being asked of them, and will that patient be in a position to provide consent? And if that patient refuses to be randomised, what are the options? Is it his/her right to request the active treatment that a fellow patient is receiving in the next bed? Although the Declaration of Helsinki allows the option of no treatment or even placebo, where no known treatment is available for a certain condition, such as COVID-19, it also emphasizes that "while the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects". Consider now the physicians and nurses on the first line of the battle against the pandemic; to the enormous pressures and risks that they experience daily, they may have to endure the added psychological burden of the randomised trial, knowing that half of their patients are receiving the promising drug, whilst the other half are denied the chance of potential benefit. When during the Medical Research Council's randomized trial of streptomycin, one senior physician contracted tuberculosis, the Medical Research Council obtained supplies for him outside the trial. In this brief instance of medical history, the equipoise, the scientific imperative, all arguments and other justifications for providing treatment at random, were thrown out of the window in favour of the human factor! Why is randomization necessary? Because-it is presumed-the process of randomising subjects, protects the study from the selective inclusion of patients with favourable characteristics, thus inadvertently allowing or facilitating a falsely favourable result for the drug or treatment under investigation. However, the process of randomising patients does not necessarily result in the randomisation of the characteristics of their disease. Exactly because of this, at the end of a randomised study, even if the prognostic variables are evenly represented and balanced in the strata, further confirmation of the result is sought with a statistical multifactorial analysis. Such multifactorial analyses can also be applied to a non-randomised group of patients engaged in the trial of a new drug. Since the middle of the 20th century a generation of physicians have been trained to dismiss, or are incapable of evaluating the validity of a treatment beyond the established etiquette of the randomised study. This, some have argued, constitutes intellectual indolence, it is not scientific robustness. Pandits foresee that the world will be different after the end of this pandemic. Perhaps human ingenuity will seek new investigative methods that will render the randomised clinical trial obsolete, both, on methodological and ethical grounds. Until then and even if we have to accept the scientific supremacy of the randomised study in the evaluation of novel therapies, the ethical considerations in the unprecedented circumstances of a relentless pandemic demand a more humane approach, befitting the beneficent precepts of the Hippocratic tradition.

Gods behaving badly.

This paper addresses the myths surrounding the birth and death of Asclepios, the popular healing God of the Greeks and his place among other deities of the Greek Pantheon. The enigmatic invocation of Asclepios by Socrates, the Athenian philosopher condemned to take the hemlock, in his final moments is also discussed.

Medicinal use of earths and minerals from Hippocrates to Sir Hans Sloane and beyond.

In 1931 two pharmaceutical drawers containing mineral specimens, belonging to Sir Hans Sloane, the 18th century collector, Royal Physician, President of the Royal Society and of the Royal College of Physicians of London, were found in the Department of Botany of the Natural History Museum (NHM) of London. The drawers, each divided into 49 compartments, contained a total of 107 mineral pharmaceutical specimens, some labelled as mercury or white arsenic. Their registration, identification with the Sloane Manuscript Catalogues and subsequent transfer to the Mineralogy department of the NHM where one of these drawers is now on public display, had been documented by 1935. In antiquity therapeutic empiricism attributed medicinal properties to animal products, plants and minerals, including the soil of specific geographic locations. This communication traces the medicinal use of certain earths and minerals, listed in Sir Hans Sloane's manuscript catalogues, to classical antiquity with a reference to Arsenic compounds, which in our time are finding application in the treatment of acute promyelocytic leukaemia and to Terra Lemnia, a celebrated antidote of repute spanning twenty centuries, also included in the Sloane collections.

Alexander's (356-323 BC) expeditionary Medical Corps 334-323 BC.

Alexander had a profound interest in medicine and healing. Original Greek texts survive mainly from the works of Plutarch and Arrian. This paper examines original sources naming the physicians who participated in Alexander's expedition in Asia, the battle injuries he sustained and his final illness in Babylon.

Reflecting on the 2001 American Joint Committee on Cancer Staging System for melanoma.

The Melanoma Staging Committee of the American Joint Committee on Cancer (AJCC) promulgated in 2001 major revisions of the melanoma tumor-node-metastasis (TNM) categories and stage grouping criteria, for a new staging system of cutaneous melanoma. The Committee invited data analyses relevant to the proposed new melanoma staging for validation of the system. Validation studies that were published subsequently confirmed most of the parameters of the new staging system, identified new prognostic factors that had not been included in the revised AJCC staging, whereas the prognostic power of some parameters could not be confirmed in the data of other institutions. This article provides an in-depth analysis of the current AJCC staging for melanoma, addresses areas of controversy, and offers proposals for consideration at the next revision of the system.

Integration of gamma knife surgery in the management of cerebral metastases from melanoma.

The aim of this study was to investigate the effect of gamma knife surgery on the local control of cerebral metastases from melanoma and to assess survival. In 29 patients, 105 of 178 cerebral metastases were treated with gamma knife surgery. Only five patients had metastases confined to the brain. Of the 96 metastases with magnetic resonance imaging follow-up, 61.5% regressed by more than 50% of the pretreatment volume, 25% regressing by more than 90% and 13.5% completely. The median survival from gamma knife surgery was 5.7 months (longest survival, 38 months). In multivariate analyses, a larger number of lesions requiring treatment (P < 0.001), recursive partitioning analysis class (P = 0.009) and a long time interval from initial melanoma diagnosis to detection of cerebral metastases (P = 0.001) influenced survival. It can be concluded that gamma knife surgery is a useful adjunct in the management of cerebral metastases from melanoma and has a significant impact on local control. Its greatest potential may be achieved in conjunction with systemic chemotherapy, especially in the presence of extracerebral metastases.