Placebos, placebo effect, and the response to the healing situation: The evolution of a concept

In spite of its impressive progress, medicine has been strongly criticized for relying on its modern biomedical tradition to the neglect of the psychosocial aspects of health. This neglect may account for patients’ dissatisfaction and eventual use of alternative health approaches. The concept of placebo has sustained dramatic ‘’protean” metamorphoses through the ages. For centuries, placebos have been regarded as powerful deceptive therapies. From the middle of the twentieth century, however, conventional medicine has used placebos as methodologic tools to distinguish the specific from the nonspecific ingredients in treatments. In modern medical research, the double-blind, placebo-controlled, randomized clinical trial has been established as the gold standard for the assessment of any new treatment. Recently a new trend regarding placebos seems to have emerged. The placebo and other nonspecific effects elicited by the “healing situation” have been independently subjected to scientific study. Progress in this area may promote useful clinical applications, enabling physicians to broaden their perspectives on the healing process. We present the historical changes of the concept of placebo and the ethical issues raised by their use

Horse madness (hippomania) and hippophobia

Anthropophagic horses have been described in classical mythology. From a current perspective, two such instances are worth mentioning and describing: Glaucus of Potniae, King of Efyra, and Diomedes, King of Thrace, who were both devoured by their horses. In both cases, the horses’ extreme aggression and their subsequent anthropophagic behaviour were attributed to their madness (hippomania) induced by the custom of feeding them with flesh. The current problem of ‘mad cow’ disease (bovine spongiform encephalopathy) is apparently related to a similar feeding pattern. Aggressive behaviour in horses can be triggered by both biological and psychological factors. In the cases cited here, it is rather unlikely that the former were the cause. On the other hand, the multiple abuses imposed on the horses, coupled with peoples’ fantasies and largely unconscious fears (hippophobia), may possibly explain these mythological descriptions of the ‘horse-monsters’

ExacTrac X-Ray 6D Imaging During Stereotactic Body Radiation Therapy of Spinal and Nonspinal Metastases

The objective was to investigate the possibility of using ExacTrac X-ray (ETX) for 6D image guidance in stereotactic body radiation therapy (SBRT) of bone metastasis and to propose a patient management protocol. The analyses were first obtained from measurements on a pelvic phantom and on 19 patients treated for bone metastasis. The phantom study consisted of applying known offsets and evaluating the ETX level of accuracy, where results were compared with kV-cone beam computed tomography (kV-CBCT). Two groups of patients, 10 spinal and 9 nonspinal SBRT cases, were analyzed to evaluate ETX imaging for different bone localisations. A comparison was made between kV-CBCT and ETX prior to the treatment fractions. During treatments, two other kV-CBCT/ETX image pairs were also acquired and a total of 224 shifts were compared. A second study, using the ETX monitoring module, analyzed the intrafraction motion of 8 other patients. In the phantom study, the root mean square (RMS) of the translational and rotational discrepancies between ETX and kV-CBCT were < 0.6 mm and < 0.4°, respectively. For both groups of patients, the RMS of the discrepancies observed between the two imaging systems were greater than the phantom experiment while still remaining < 1 mm and < 0.7°. In the nonspinal group, three patients (2 scapulas and 1 humerus) did not have consistent shift values with ETX due to a lack of anatomical information. When ETX monitoring was used during irradiation, the setup errors measured were on average less than 1 mm/1°. The results obtained validated the use of ETX for 6D image guidance during bone SBRT. Real-time tracking of the target position improves the accuracy of the irradiation. This strategy allowed for faster correction of out-of-tolerance positioning errors. The registration of bone lesions with poor anatomical information is a limitation of this 2D-kV imaging system

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406)

Movement Disorders and Liver Disease

The association of movement disorders with structural or functional hepatic disease occurs in three principal scenarios: (1) combined involvement of both organ systems from a single disease entity, (2) nervous system dysfunction resulting from exposure to toxic compounds in the setting of defective hepatic clearance, or (3) hepatic and/or neurological injury secondary to exposure to exogenous drugs or toxins. An important early step in the workup of any patient with combined movement disorders and liver disease is the exclusion of Wilson's disease. Diagnostic delay remains common for this treatable disorder, and this has major implications for patient outcomes. Thereafter, a structured approach integrating variables such as age of onset, tempo of progression, nature and severity of liver involvement, movement disorder phenomenology, exposure to drugs/toxins and laboratory/neuroimaging findings is key to ensuring timely diagnosis and disease‐specific therapy. Herein, we provide an overview of disorders which may manifest with a combination of movement disorders and liver disease, structured under the three headings as detailed above. In each section, the most common disorders are discussed, along with important clinical pearls, suggested diagnostic workup, differential diagnoses and where appropriate, treatment considerations