Repurposing drugs in oncology (ReDO)—cimetidine as an anti-cancer agent

Cimetidine, the first H2 receptor antagonist in widespread clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical and clinical studies for a number of different cancer types. These data are summarised and discussed in relation to a number of distinct mechanisms of action. Based on the evidence presented, it is proposed that cimetidine would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of cimetidine as an anti-cancer therapeutic is warranted. Furthermore, there is compelling evidence that cimetidine administration during the peri-operative period may provide a survival benefit in some cancers. A number of possible combinations with other drugs are discussed in the supplementary material accompanying this paper

Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent

Mebendazole, a well-known anti-helminthic drug in wide clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical studies across a number of different cancer types. Significantly, there are also two case reports of anti-cancer activity in humans. The data are summarised and discussed in relation to suggested mechanisms of action. Based on the evidence presented, it is proposed that mebendazole would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of mebendazole as an anti-cancer therapeutic is warranted. A number of possible combinations with other drugs are discussed in the Appendix

The nocebo effect and tobacco control : first, do no harm?

Since tobacco remains a leading cause of global morbidity and mortality, emphasis needs to be given to preventive approaches to tobacco consumption. Environmental and policy strategies with fear appeals are important contributors to reductions in smoking prevalence. Fear appeals are persuasive messages-often using graphic and emotionally evocative imagery and language-that attempt to scare their audiences into tobacco cessation. While the intentions of fear appeals are benign, their effects are not necessarily so; here, we argue that some fear appeals carry a significant risk of backfiring by eliciting nocebo effects among its viewers. In this context, it is important to recognize that there is currently no justification for disregarding potential nocebo effects. Therefore, we should improve our understanding of nocebo effects in the field of preventive medicine, as well as the impact of strategies aimed at mitigating their negative health effects

The Repurposing Drugs in Oncology (ReDO) Project

The Repurposing Drugs in Oncology (ReDO) Project seeks to repurpose well-known and well-characterised non-cancer drugs for new uses in oncology. The rationale for this project is presented, examining current issues in oncological drug development, challenges for health systems, and existing and future patient needs. In addition to discussing the advantages of repurposing, the paper also outlines some of the characteristics used in the selection of drug candidates by this project. Challenges in moving candidate drugs into clinical trial and subsequent practice are also discussed

Repurposing Drugs in Oncology (ReDO)—nitroglycerin as an anti-cancer agent

Nitroglycerin (NTG), a drug that has been in clinical use for more than a century, has a range of actions which make it of particular interest in an oncological setting. It is generally accepted that the main mechanism of action of NTG is via the production of nitric oxide (NO), which improves cardiac oxygenation via multiple mechanisms including improved blood flow (vasodilation), decreased platelet aggregation, increased erythrocyte O2 release and decreased mitochondrial utilization of oxygen. Its vasoactive properties mean that it has the potential to exploit more fully the enhanced permeability and retention effect in delivering anti-cancer drugs to tumour tissues. Moreover NTG can reduce HIF-1α levels in hypoxic tumour tissues and this may have anti-angiogenic, pro-apoptotic and anti-efflux effects. Additionally NTG may enhance anti-tumour immunity. Pre-clinical and clinical data on these anti-cancer properties of NTG are summarised and discussed. While there is evidence of a positive action as a monotherapy in prostate cancer, there are mixed results in NSCLC where initially positive results have yet to be fully replicated. Based on the evidence presented, a case is made that further exploration of the clinical benefits that may accrue to cancer patients is warranted. Additionally, it is proposed that NTG may synergise with a number of other drugs, including other repurposed drugs, and these are discussed in the supplementary material appended to this paper

Intraoperative ketorolac in high-risk breast cancer patients : A prospective, randomized, placebo-controlled clinical trial

Funding: This work is financed by grants received by PF, in the name of his institution: the Anticancer Fund (no grant number) (www.anticancerfund.org); the Belgian Society of Anaesthesia and Resuscitation (no grant number) (www.sarb.be); the Fondation Saint-Luc (no grant number) (www.uclouvain.be); the Commission du Patrimoine of the Université catholique de Louvain, St-Luc Hospital (exceptional grant, no number) (www.uclouvain.be). None of the funders had any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript except the scientific advise of GB, scientific director of the Anticancer Fund.Peer reviewedPublisher PD

High mean arterial pressure target to improve sepsis-associated acute kidney injury in patients with prior hypertension: a feasibility study

Background : The optimal mean arterial pressure (MAP) in cases of septic shock is still a matter of debate in patients with prior hypertension. An MAP between 75 and 85 mmHg can improve glomerular filtration rate (GFR) but its effect on tubular function is unknown. We assessed the effects of high MAP level on glomerular and tubular renal function in two intensive care units of a teaching hospital. Inclusion criteria were patients with a history of chronic hypertension and developing AKI in the first 24 h of septic shock. Data were collected during two 6 h periods of MAP regimen administered consecutively after haemodynamic stabilisation in an order depending on the patient's admission unit: a high-target period (80–85 mmHg) and a low-target period (65–70 mmHg). The primary endpoint was the creatinine clearance (CrCl) calculated from urine and serum samples at the end of each MAP period by the UV/P formula. Results : 26 patients were included. Higher urine output (+0.2 (95%:0, 0.4) mL/kg/h; P = 0.04), urine sodium (+6 (95% CI 0.2, 13) mmol/L; P = 0.04) and lower serum creatinine (− 10 (95% CI − 17, − 3) µmol/L; P = 0.03) were observed during the high-MAP period as compared to the low-MAP period, resulting in a higher CrCl (+25 (95% CI 11, 39) mL/mn; P = 0.002). The urine creatinine, urine–plasma creatinine ratio, urine osmolality, fractional excretion of sodium and urea showed no significant variation. The KDIGO stage at inclusion only interacted with serum creatinine variation and low level of sodium excretion at inclusion did not interact with these results. Conclusions : In the early stage of sepsis-associated AKI, a high-MAP target in patients with a history of hypertension was associated with a higher CrCl, but did not affect the kidneys' ability to concentrate urine, which may reflect no effect on tubular function

A Randomized Phase II Trial Comparing the Efficacy and Safety of Pioglitazone, Clarithromycin and Metronomic Low-Dose Chemotherapy with Single-Agent Nivolumab Therapy in Patients with Advanced Non-small Cell Lung Cancer Treated in Second or Further Line (ModuLung)

Background: Most non-small cell lung cancers occur in elderly and frequently comorbid patients. Therefore, it is necessary to evaluate the efficacy of biomodulatory active therapy regimen, concertedly interfering with tumor-associated homeostatic pathways to achieve tumor control paralleled by modest toxicity profiles. Patients and Methods: The ModuLung trial is a national, multicentre, prospective, open-label, randomized phase II trial in patients with histologically confirmed stage IIIB/IV squamous (n = 11) and non-squamous non-small cell (n = 26) lung cancer who failed first-line platinum-based chemotherapy. Patients were randomly assigned on a 1:1 ratio to the biomodulatory or control group, treated with nivolumab. Patients randomized to the biomodulatory group received an all-oral therapy consisting of treosulfan 250 mg twice daily, pioglitazone 45 mg once daily, clarithromycin 250 mg twice daily, until disease progression or unacceptable toxicity. Results: The study had to be closed pre-maturely due to approval of immune checkpoint inhibitors (ICi) in first-line treatment. Thirty-seven patients, available for analysis, were treated in second to forth-line. Progression-free survival (PFS) was significantly inferior for biomodulation (N = 20) vs. nivolumab (N = 17) with a median PFS (95% confidence interval) of 1.4 (1.2–2.0) months vs. 1.6 (1.4–6.2), respectively; with a hazard ratio (95% confidence interval) of 1.908 [0.962; 3.788]; p = 0.0483. Objective response rate was 11.8% with nivolumab vs. 5% with biomodulation, median follow-up 8.25 months. The frequency of grade 3–5 treatment related adverse events was 29% with nivolumab and 10% with biomodulation. Overall survival (OS), the secondary endpoint, was comparable in both treatment arms; biomodulation with a median OS (95% confidence interval) of 9.4 (6.0–33.0) months vs. nivolumab 6.9 (4.6–24.0), respectively; hazard ratio (95% confidence interval) of 0.733 [0.334; 1.610]; p = 0.4368. Seventy-five percent of patients in the biomodulation arm received rescue therapy with checkpoint inhibitors. Conclusions: This trial shows that the biomodulatory therapy was inferior to nivolumab on PFS. However, the fact that OS was similar between groups gives rise to the hypothesis that the well-tolerable biomodulatory therapy may prime tumor tissues for efficacious checkpoint inhibitor therapy, even in very advanced treatment lines where poor response to ICi might be expected with increasing line of therapy

Trends in International Cancer Research Investment 2006-2018.

The International Cancer Research Partnership (ICRP) is an active network of cancer research funding organizations, sharing information about funded research projects in a common database. Data are publicly available to enable the cancer research community to find potential collaborators and avoid duplication. This study presents an aggregated analysis of projects funded by 120 partner organizations and institutes in 2006-2018, to highlight trends in cancer research funding. Overall, the partners' funding for cancer research increased from $5.562 billion (bn) US dollars (USD) in 2006 to$8.511bn USD in 2018, an above-inflation increase in funding. Analysis by the main research focus of projects using Common Scientific Outline categories showed that Treatment was the largest investment category in 2018, followed by Early Detection, Diagnosis, and Prognosis; Cancer Biology; Etiology; Control, Survivorship, and Outcomes; and Prevention. Over the 13 years covered by this analysis, research funding into Treatment and Early Detection, Diagnosis, and Prognosis had increased in terms of absolute investment and as a proportion of the portfolio. Research funding in Cancer Biology and Etiology declined as a percentage of the portfolio, and funding for Prevention and Control, Survivorship and Outcomes remained static. In terms of cancer site-specific research, funding for breast cancer and colorectal cancer had increased in absolute terms but declined as a percentage of the portfolio. By contrast, investment for brain cancer, lung cancer, leukemia, melanoma, and pancreatic cancer increased both in absolute terms and as a percentage of the portfolio

Parental use of the Internet to seek health information and primary care utilisation for their child: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Using the Internet to seek health information is becoming more common. Its consequences on health care utilisation are hardly known in the general population, in particular among children whose parents seek health information on the Internet. Our objective was to investigate the relationship between parental use of the Internet to seek health information and primary care utilisation for their child.</p> <p>Methods</p> <p>This cross-sectional survey has been carried out in a population of parents of pre-school children in France. The main outcome measure was the self-reported number of primary care consultations for the child, according to parental use of the Internet to seek health information, adjusted for the characteristics of the parents and their child respectively, and parental use of other health information sources.</p> <p>Results</p> <p>A total of 1 068 out of 2 197 questionnaires were returned (response rate of 49%). No association was found between parental use of the Internet to seek health information and the number of consultations within the last 12 months for their child. Variables related to the number of primary care consultations were characteristics of the child (age, medical conditions, homeopathic treatment), parental characteristics (occupation, income, stress level) and consultation of other health information sources (advice from pharmacist, relatives).</p> <p>Conclusion</p> <p>We did not find any relationship between parental use of the Internet to seek health information and primary care utilisation for children. The Internet seems to be used as a supplement to health services rather than as a replacement.</p