Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo-controlled, randomised clinical trial of efficacy and safety of 1:1 delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

BACKGROUND:Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids but little high-quality evidence to guide clinicians. This study aims to define the role of a 1:1 delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) cannabinoid preparation in the management of symptom burden in patients with advanced cancer undergoing standard palliative care. METHODS AND DESIGN:One hundred fifty participants will be recruited from five sites within the Queensland Palliative Care Research Group (QPCRG) and randomly assigned to an active treatment or placebo group. This study is a pragmatic multicentre, randomised, placebo-controlled, two-arm trial of escalating doses of an oral 1:1 THC/CBD cannabinoid preparation. It will compare efficacy and safety outcomes of a titrated dose (10 mg/10 mg/mL oral solution formulation, dose range 2.5 mg/2.5 mg-30 mg/30 mg/day) against placebo. There is a 2-week patient-determined titration phase, using escalating doses of 1:1 THC/CBD or placebo, to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians. The primary objective is to assess the effect of escalating doses of a 1:1 THC/CBD cannabinoid preparation against placebo on change in total symptom score, with secondary objectives including establishing a patient-determined effective dose, the change in total physical and emotional sores, global impression of change, anxiety and depression, opioid use, quality of life and adverse effects. DISCUSSION:This will be the first placebo-controlled clinical trial to rigorously evaluate the efficacy, safety and acceptability of 1:1 THC/CBD for symptom relief in advanced cancer patients. This study will allow the medical community to have some evidence to present to patients wishing to access cannabis for their symptoms caused by advanced malignancy. TRIAL REGISTRATION:ACTRN, ACTRN12619000037101 . Registered on 14 January 2019. Trial Sponsor: Mater Misericordiae Limited (MML) and Mater Medical Research Institute Limited (MMRI)-Raymond Terrace, South Brisbane, Brisbane, QLD, Australia

Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: A double-blind, placebo controlled, randomised clinical trial of efficacy and safety of cannabidiol (CBD)

© 2019 The Author(s). Background: Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids, but there is little high quality evidence to guide clinicians. This study aims to define the role of cannabidiol (CBD) in the management of symptom burden in patients with advanced cancer undergoing standard palliative care. Methods and design: This study is a multicentre, randomised, placebo controlled, two arm, parallel trial of escalating doses of oral CBD. It will compare efficacy and safety outcomes of a titrated dose of CBD (100 mg/mL formulation, dose range 50 mg to 600 mg per day) against placebo. There is a 2-week patient determined titration phase, using escalating doses of CBD or placebo to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians. Discussion: A major strength of this study is that it will target symptom burden as a whole, rather than just individual symptoms, in an attempt to describe the general improvement in wellbeing previously reported by some patients in open label, non controlled trials of medicinal cannabis. Randomisation with placebo is essential because of the well-documented over reporting of benefit in uncontrolled trials and high placebo response rates in cancer pain trials. This will be the first placebo controlled clinical trial to evaluate rigorously the efficacy, safety and acceptability of CBD for symptom relief in advanced cancer patients. This study will provide the medical community with evidence to present to patients wishing to access medicinal cannabis for their cancer related symptoms. Trial registration number: ALCTRN12618001220257 Registered 20/07/2018

Risk Classification of Bladder Cancer by Gene Expression and Molecular Subtype

This study evaluated a panel including the molecular taxonomy subtype and the expression of 27 genes as a diagnostic tool to stratify bladder cancer patients at risk of aggressive behavior, using a well-characterized series of non-muscle invasive bladder cancer (NMIBC) as well as muscle-invasive bladder cancer (MIBC). The study was conducted using the novel NanoString nCounter gene expression analysis. This technology allowed us to identify the molecular subtype and to analyze the gene expression of 27 bladder-cancer-related genes selected through a recent literature search. The differential gene expression was correlated with clinicopathological variables, such as the molecular subtypes (luminal, basal, null/double negative), histological subtype (conventional urothelial carcinoma, or carcinoma with variant histology), clinical subtype (NMIBC and MIBC), tumor stage category (Ta, T1, and T2–4), tumor grade, PD-L1 expression (high vs. low expression), and clinical risk categories (low, intermediate, high and very high). The multivariate analysis of the 19 genes significant for cancer-specific survival in our cohort study series identified TP53 (p = 0.0001), CCND1 (p = 0.0001), MKI67 (p < 0.0001), and molecular subtype (p = 0.005) as independent predictors. A scoring system based on the molecular subtype and the gene expression signature of TP53, CCND1, or MKI67 was used for risk assessment. A score ranging from 0 (best prognosis) to 7 (worst prognosis) was obtained and used to stratify our patients into two (low [score 0–2] vs. high [score 3–7], model A) or three (low [score 0–2] vs. intermediate [score 3–4] vs. high [score 5–7], model B) risk categories with different survival characteristics. Mean cancer-specific survival was longer (122 + 2.7 months) in low-risk than intermediate-risk (79.4 + 9.4 months) or high-risk (6.2 + 0.9 months) categories (p < 0.0001; model A); and was longer (122 + 2.7 months) in low-risk than high-risk (58 + 8.3 months) (p < 0.0001; model B). In conclusion, the molecular risk assessment model, as reported here, might be used better to select the appropriate management for patients with bladder cancer

The D647N mutation of FGFR1 induces ligand-independent receptor activation

The activation loop (A-loop) of kinases, a key regulatory region, is recurrently mutated in several kinase proteins in cancer resulting in dysregulated kinase activity and response to kinase inhibitors. FGFR1 receptor tyrosine kinase represents an important oncogene and therapeutic target for solid and hematological tumors. Here we investigate the biochemical and molecular effects of D647N mutation lying in the A-loop of FGFR1.When expressed in normal and tumoral in vitro cell models, FGFR1D647N is phosphorylated also in the absence of ligands, and this is accompanied by the activation of intracellular signaling. The expression of FGFR1D647N significantly increases single and collective migration of cancer cells in vitro and in vivo, when compared to FGFR1WT. FGFR1D647N expression exacerbates the aggressiveness of cancer cells, increasing their invasiveness in vitro and augmenting their pro-angiogenic capacity in vivo.Remarkably, the D647N mutation significantly increases the sensitivity of FGFR1 to the ATP-competitive inhibitor Erdafitinib suggesting the possibility that this mutation could become a specific target for the development of new inhibitors. Although further efforts are warranted for an exhaustive description of the activation mechanisms, for the identification of more specific inhibitors and for confirming the clinical significance of mutated FGFR1D647N, overall our data demonstrate that the D647N substitution of FGFR1 is a novel pro-oncogenic activating mutation of the receptor that, when found in cancer patients, may anticipate good response to erdafitinib treatment

The Modeling of Anisotropic Fuselage Lining Material

In this paper a theoretical model that can account for the effect of lining anisotropy on sound transmission through fuselage structures is developed. The model allows for anisotropic flow resistivity, tortuosity and elastic moduli. Implicit to the theory is a characteristic dispersion relation of sixth order that yields the allowed wave numbers for wave propagation in anisotropic elastic porous media. In addition, explicit expressions for field variables such as displacements and stresses appropriate for anisotropic foams are derived. Predictions of random incidence sound transmission loss for double panels with anisotropic linings have been performed. To verify the prediction, the theoretical results have been compared with random incidence transmission loss measurements

Intraprocedural, intra-arterial CT foot perfusion examination for assessment of endovascular therapy in patients with critical limb ischemia: a prospective pilot study

Background: Current techniques to evaluate computed tomography (CT) foot perfusion in patients with critical limb ischemia use high contrast doses and cannot be used during endovascular procedures. CT perfusion of the foot with intra-arterial contrast injection during endovascular treatment in a hybrid angiography CT suite might solve these problems. Purpose: The main objective of this study was to evaluate whether intra-arterial CT foot perfusion using a hybrid CT angiosystem is feasible during endovascular treatment for critical limb ischemia. Material and Methods: This prospective pilot study investigated intraprocedural, intra-arterial CT perfusion of the foot using a hybrid CT angiosystem in 12 patients before and after endovascular treatment for critical limb ischemia. Time to peak (TTP) and arterial blood flow were measured before and after treatment and compared using a paired t test. Results: All 24 CT perfusion maps could be calculated adequately. The contrast volume used for one perfusion CT scan was 4.8 ml. The mean TTP before treatment was 12.8 seconds (standard deviation [SD] 2.8) and the mean TTP posttreatment was 8.4 seconds (SD 1.7), this difference being statistically significant (p=.001). Tendency toward increased blood flow after treatment, 340 ml/min/100 ml (SD 174) vs 514 ml/min/100 ml (SD 366) was noticed (p=.104). The mean effective radiation dose was 0.145 mSv per scan. Conclusion: Computed tomography perfusion of the foot with low contrast dose intra-arterial contrast injection during endovascular treatment in a hybrid angiography CT suite is a feasible technique. Clinical Impact Intra-arterial CT foot perfusion using a hybrid CT-angiography system is a feasible new technique during endovascular therapy for critical limb ischemia to assess the results of the treament. Future research is necessary in defining endpoints of endovascular treatment and establishing its role in limb salvage prognostication.Radiolog

The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53

p53 is an important tumor-suppressor protein that is mutated in more than 50% of cancers. Strategies for restoring normal p53 function are complicated by the oncogenic properties of mutant p53 and have not met with clinical success. To counteract mutant p53 activity, a variety of drugs with the potential to reconvert mutant p53 to an active wildtype form have been developed. However, these drugs are associated with various negative effects such as cellular toxicity, nonspecific binding to other proteins, and inability to induce a wildtype p53 response in cancer tissue. Here, we report on the effects of a curcumin analog, HO-3867, on p53 activity in cancer cells from different origins. We found that HO-3867 covalently binds to mutant p53, initiates a wildtype p53-like anticancer genetic response, is exclusively cytotoxic toward cancer cells, and exhibits high anticancer efficacy in tumor models. In conclusion, HO-3867 is a p53 mutant-reactivating drug with high clinical anticancer potential