Use of the European Organisation for Research and Treatment of Cancer multiple myeloma module (EORTC QLQ-MY20): a review of the literature 25 years after development.

The European Organisation for Research and Treatment of Cancer Quality of Life Multiple Myeloma Questionnaire (EORTC QLQ-MY20) was developed in 1996 to assess health-related quality of life (HRQoL) in patients with multiple myeloma. Since its development new therapies have prolonged survival in patients with myeloma and new combination agents are likely to impact HRQoL outcomes and its measurement.The aim of this review was to explore the use of the QLQ-MY20 and reported methodological issues.An electronic database search was conducted (1996-June 2020) to identify clinical studies/research that used the QLQ-MY20 or assessed its psychometric properties. Data were extracted from full-text publications/conference abstracts and checked by a second rater.The search returned 65 clinical and 9 psychometric validation studies. The QLQ-MY20 was used in interventional (n = 21, 32%) and observational (n = 44, 68%) studies and the publication of QLQ-MY20 data in clinical trials increased over time. Clinical studies commonly included relapsed patients with myeloma patients (n = 15, 68%) and assessed a range of combinations therapies.QLQ-MY20 subscales (disease symptoms [DS], side effects of treatment [SE], future perspectives [FP], body image [BI]) were defined as secondary (n = 12, 55%) or exploratory (n = 7, 32%) trial endpoints, particularly DS (n = 16, 72%) and SE (n = 16, 72%). Validation articles demonstrated that all domains performed well regarding internal consistency reliability (>0.7), test-reset reliability (intraclass correlation coefficient > =0.85), internal and external convergent and discriminant validity. Four articles reported a high percentage of ceiling effects in the BI subscale; all other subscales performed well regarding floor and ceiling effects.The EORTC QLQ-MY20 remains a widely used and psychometrically robust instrument. While no specific problems were identified from the published literature, qualitative interviews are ongoing to ensure new concepts and side effects are included that may arise from patients receiving novel treatments or from longer survival with multiple lines of treatment.

Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study.

Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T0). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study. Median age at T0 was 62 years (range 31-87); 61% were males. The median duration between diagnosis and T0 was 3.1 years. The median number of lines of therapy before T0 was 4 (range 3-13). The median overall survival (OS) from T0 for the entire cohort was 13 (95% confidence interval (CI) 11, 15) months. At least one regimen recorded after T0 in 462 (85%) patients, with a median (95% CI) progression-free survival and OS from T0 of 5 (4, 6), and 15.2 (13, 17) months, respectively. The study provides the expected outcome of relapsed multiple myeloma that is refractory to a PI and an IMiD, a benchmark for comparison of new therapies being evaluated.

Prospective longitudinal study on quality of life in relapsed/refractory multiple myeloma patients receiving second- or third-line lenalidomide or bortezomib treatment.

Treatment advances for multiple myeloma (MM) that have prolonged survival emphasise the importance of measuring patients' health-related quality of life (HRQoL) in clinical studies. HRQoL/functioning and symptoms of patients with relapsed/refractory MM (RRMM) receiving second- or third-line lenalidomide or bortezomib treatment were measured in a prospective European multicentre, observational study at different time points. At baseline, patients in the lenalidomide cohort were frailer than in the bortezomib cohort with more rapid disease progression at study entry (more patients with Eastern Cooperative Oncology Group performance status >2, shorter time from diagnosis, more chronic heart failure, higher serum creatinine levels, more patients with dialysis required). About 40% of the patients receiving lenalidomide discontinued the study in <6 months while 55% in the bortezomib cohort discontinued. No substantial HRQoL deterioration was observed for the first 6 months in patients with RRMM receiving one or the other treatment. For patients still on treatment at study completion (month 6), only the European Organization for Research and Treatment of Cancer Quality-of-Life Core domains of Diarrhoea and Global Health Status/QoL had worsened in the lenalidomide and bortezomib cohorts, respectively. A clinically meaningful deterioration in HRQoL was more often observed for patients who discontinued the study prior to 6 months in the bortezomib cohort than in the lenalidomide cohort.

Clinical applications of sodium oxybate (GHB): from narcolepsy to alcohol withdrawal syndrome.

Gamma-hydroxybutyrate (GHB) is a short chain fatty acid endogenously produced within the central nervous system (CNS) and acts as a precursor and metabolite of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Although, it is an illegal recreational drug of abuse, its sodium salt (sodium oxybate) has been utilized as a medication for a number of medical conditions. The first aim of this review was to focus on current applications of sodium oxybate for the treatment of narcolepsy, with a particular emphasis on the key symptoms of this disorder: cataplexy and excessive daytime sleepiness (EDS). Secondly, the effectiveness of sodium oxybate therapy for the treatment of alcohol withdrawal syndrome (AWS) and the maintenance of alcohol abstinence has been assessed. Nowadays, sodium oxybate is the first-line treatment for narcolepsy and it is highly effective in meliorating sleep architecture, decreasing EDS and the frequency of cataplexy attacks in narcoleptic patients. Sodium oxybate currently finds also application in the treatment of AWS and the maintenance of alcohol abstinence in alcoholics. Most of the studies evaluating the efficacy of GHB in the treatment of AWS use a dosage of 50 mg/kg divided in three or four administrations per day. Human studies showed that GHB (dose of 50 mg/kg, divided in three administrations per day) is capable to increase the number of abstinent days, reduce alcohol craving and decrease the number of drinks per day. However, there is limited randomized evidence and, thus, GHB cannot be reliably compared to clomethiazole or benzodiazepines. Some randomized data suggest that GHB is better than naltrexone and disulfiram regarding abstinence maintenance and prevention of craving in the medium term i.e. 3-12 months. It is recommended that GHB should be used only under strict medical supervision, since concerns about the abuse/misuse of the drug and the addiction potential have been arisen.

Assessment of the stability of exogenous gamma hydroxybutyric acid (GHB) in stored blood and urine specimens.

OBJECTIVE: The aim of this work is to test the stability of exogenous GHB in whole blood and urine samples collected from living and deceased GHB free-users, spiked with known concentrations of GHB and stored at different temperatures (-20°C, 4°C and 20°C) up to 4 weeks. MATERIALS AND METHODS: GHB was added to GHB-free ante-mortem blood and urine samples at the concentration of 5 and 10 mg/L, respectively whereas in post-mortem blood and urine specimens at 50 and 10 mg/L respectively. All samples were stored at three different temperatures: -20°C, 4°C and 20°C and extracted and analyzed at three days, 1 week, 2 weeks, 3 and 4 weeks in duplicate. No preservatives were added. GHB was quantified by GC-MS after LLE according to a previously published method. RESULTS: Post-mortem blood specimens showed a reduction of GHB levels higher than 10% only after a period of 4 weeks of storage for samples kept at +4°C and +20°C, whereas samples stored at -20°C showed a mean reduction of 8.7%. In post-mortem urine samples, there was a mean reduction of GHB levels higher than 20% at all storage temperatures, after 4 weeks of storage. Ante-mortem blood samples showed a reduction of GHB levels lower than 10% only after 3 days of storage at -20°C and at +4°C (samples stored at +20°C showed a mean reduction of 10.4%). After 4 weeks of storage, there was a mean reduction of GHB concentrations higher than 20% at all storage temperatures. Ante-mortem urine samples showed a reduction of GHB levels higher than 10% after just 3 days of storage for samples kept at all tested temperatures. After 4 weeks of storage, there was a mean reduction of GHB concentrations higher than 25% at all storage temperatures. CONCLUSIONS: According to our findings, it would be useful to perform GHB analysis both in blood and urine specimens within 3 days of sampling and the specimens should be stored at -20°C or 4°C in order to avoid instability issues.

Mephedrone related fatalities: a review.

OBJECTIVE: Synthetic cathinones are an emerging class of designer drugs abused of due to their psychostimulant and hallucinogenic effects, similar to those of cocaine, methylenedioxymethamphetamine (MDMA), amphetamines and methamphetamines. Mephedrone is a cathinone analogue (4-methyl aromatic analogue of methcathinone) that was reported to be implicated in several fatalities in the media across Europe, but only a few have actually resulted in mephedrone cited as the cause of death. In this paper, we aim to systematically review analytically confirmed cases of mephedrone-related fatalities. MATERIALS AND METHODS: Relevant scientific articles were identified from Medline, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE and Google Scholar, through May 2015 using the following keywords: "Mephedrone", "fatal intoxication," "fatalities", "acute intoxication" and "death". RESULTS: In total, 10 citations met the criteria for inclusion, representing 18 fatal cases with analytically confirmed mephedrone in biological sample/s of the deceased. The death was attributed to mephedrone intoxication in 9 cases (range of post-mortem blood mephedrone concentration: 1.33-22 mg/L), whereas multiple drug toxicity, involving mephedrone was cited as cause of death in 6 cases (range of post-mortem blood mephedrone concentration: 0.04-1.3 mg/L). CONCLUSIONS: Data suggest that the abuse of mephedrone remains to be a public health issue. Mephedrone appears to have a rather narrow therapeutic window that makes its use dangerous. Dosages which supposedly fall within recreational use limits could also lead to death when combined with other drugs in certain circumstances. Forensic Toxicology laboratories must assess their testing procedures to ensure they can achieve both an appropriate screening regime and targeted quantitative analysis for the detection of mephedrone in various biological matrices.

NBOMe: new potent hallucinogens--pharmacology, analytical methods, toxicities, fatalities: a review.

OBJECTIVE: NBOMe is a class of emerging new psychoactive substances that has recently gained prominence in the drug abuse market. NBOMes are N-2-methoxy-benzyl substituted 2C class of hallucinogens, currently being marked online as "research chemicals" under various names: N-bomb, Smiles, Solaris, and Cimbi. This article reviews available literature on the pharmacology; the analytical methods currently used for the detection and quantification of NBOMe in biological matrices and blotters, together with intoxication cases and NBOMe-related fatalities. MATERIALS AND METHODS: Relevant scientific articles were identified from Medline, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE and Google Scholar, through June 2015 using the following keywords: "NBOMe", "Nbomb", "Smiles", "intoxication", "toxicity" "fatalities", "death", "pharmacology", "5-HT2A receptor", "analysis" and "analytical methods". The main key word "NBOMe" was individually searched in association to each of the others. RESULTS: The review of the literature allowed us to identify 43 citations on pharmacology, analytical methods and NBOMe-related toxicities and fatalities. CONCLUSIONS: The high potency of NBOMes (potent agonists of 5-HT2A receptor) has led to several severe intoxications, overdose and traumatic fatalities; thus, their increase raises significant public health concerns. Moreover, due to the high potency and ease of synthesis, it is likely that their recreational use will become more widespread in the future. The publication of new data, case reports and evaluation of the NBOMes metabolites is necessary in order to improve knowledge and awareness within the forensic community.

A new xenograft model of myeloma bone disease demonstrating the efficacy of human mesenchymal stem cells expressing osteoprotegerin by lentiviral gene transfer.

We describe a new model of myeloma bone disease in which beta2m NOD/SCID mice injected with KMS-12-BM cells develop medullary disease after tail vein administration. Micro-computed tomography analysis demonstrated significant bone loss in the tibiae and vertebrae of diseased animals compared to controls, with loss of cortical bone (P<0.01), as well as trabecular bone volume, thickness and number (P<0.05 for all). Bone marrow of diseased animals demonstrated an increase in osteoclasts (P<0.01) and reduction in osteoblasts (P<0.01) compared to control animals. Both bone loss and osteoclast increase correlated with the degree of disease involvement. Mesenchymal stem cells (MSCs) were lentivirally transduced to express human osteoprotegerin (hOPG). Systemic administration of OPG expressing MSC reduced osteoclast activation (P<0.01) and trabecular bone loss in the vertebrae (P<0.05) and tibiae of diseased animals, to levels comparable to non-diseased controls. Because of its predominantly medullary involvement and quantifiable parameters of bone disease, the KMS-12-BM xenogeneic model provides unique opportunities to test therapies targeted at the bone marrow microenvironment.