Best practices in epidermal growth factor receptor T790M testing for advanced non-small-cell lung cancer in Hong Kong.

The T790M mutation in the epidermal growth factor receptor gene causes most acquired resistance to firstor second-line epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small-cell lung cancer. The results of T790M testing can guide subsequent treatment. Despite the availability of guidelines from international organisations, T790M testing practices in Hong Kong must be streamlined and adapted to the Hospital Authority setting. To address this issue, a panel of experts in oncology and pathology met for discussion of key topics regarding T790M testing practices in Hong Kong, including the appropriate timing of testing and re-testing, as well as optimal testing methods. All panel members voted on the results of the discussion to achieve consensus. Items supported by a majority vote were adopted as consensus statements regarding current best practices for T790M testing in Hong Kong. Among the topics discussed, the panel agreed that T790M testing should be initiated upon radiological progression, including symptomatic disease progression or central nervous system-only progression. The experts also preferred initial testing with liquid biopsy, using the widely available digital polymerase chain reaction platform. This document provides the final consensus statements, as well as a testing and treatment workflow, for clinicians in Hong Kong to use as guidance in T790M testing.

Bariatric surgery is expensive but improves co-morbidity: 5-year assessment of patients with obesity and type 2 diabetes.

BACKGROUND: Bariatric surgery can be effective in weight reduction and diabetes remission in some patients, but is expensive. The costs of bariatric surgery in patients with obesity and type 2 diabetes mellitus (T2DM) were explored here. METHODS: Population-based retrospectively gathered data on patients with obesity and T2DM from the Hong Kong Hospital Authority (2006-2017) were evaluated. Direct medical costs from baseline up to 60 months were calculated based on the frequency of healthcare service utilization and dispensing of diabetes medication. Charlson Co-morbidity Index (CCI) scores and co-morbidity rates were measured to compare changes in co-morbidities between surgically treated and control groups over 5 years. One-to-five propensity score matching was applied. RESULTS: Overall, 401 eligible surgical patients were matched with 1894 non-surgical patients. Direct medical costs were much higher for surgical than non-surgical patients in the index year (€36 752 and €5788 respectively; P < 0·001) mainly owing to the bariatric procedure. The 5-year cumulative costs incurred by surgical patients were also higher (€54 135 versus €28 603; P < 0·001). Although patients who had bariatric surgery had more visits to outpatient and allied health professionals than those who did not across the 5-year period, surgical patients had shorter length of stay in hospitals than non-surgical patients in year 2-5. Surgical patients had significantly better CCI scores than controls after the baseline measurement (mean 3·82 versus 4·38 at 5 years; P = 0·016). Costs of glucose-lowering medications were similar between two groups, except that surgical patients had significantly lower costs of glucose-lowering medications in year 2 (€973 versus €1395; P = 0.012). CONCLUSION: Bariatric surgery in obese patients with T2DM is expensive, but leads to an improved co-morbidity profile, and reduced length of hospitalization.

Differences Between the East and the West in Managing Advanced-Stage Non-small Cell Lung Cancer.

Lung cancer is a common cancer associated with high mortality rates worldwide. Unfortunately, it usually presents at a late stage, precluding the chance of curative therapy. The discovery of oncogenic driver mutations in patients with non-small cell lung cancer over the past 20 years has led to new molecular targeted therapies that have dramatically improved treatment efficacy and quality of life. New generations of therapy that target the drug-resistant mutations have also quickly evolved, benefiting patients who are refractory or intolerant to first-line targeted therapy. Eastern patients, from Southeast Asia, Japan and China, are known to have a higher incidence of epidermal growth factor receptor mutation. Therefore, compared with the West, more patients would benefit from these recent advances. In contrast, survival of patients without driver mutations has benefited from advances in novel therapeutics, including the immune checkpoint inhibitors. The current review aims to highlight the recent developments in the management of advanced-stage non-small cell lung cancer and to compare the differences in clinical practice between Eastern and Western countries.

An electromyographic investigation of the first six months of progressive mandibular advancement of the Herbst appliance in adolescents.

The effects of the progressive activation of the Herbst appliance on the activity of the masseter and temporalis elevator muscles of the mandible were monitored in a group of 14 consecutively treated 10-15-year-old subjects with an Angle Class II, division I malocclusion. A cast silver splint Herbst appliance was activated in multiple stages at a rate of 2 mm/2 mo. The functionality of the superficial masseter and anterior portion of the temporalis muscles was monitored at maximum bite force using surface electromyography (EMG). The EMG recordings were taken at an incisal edge-to-edge position and a retruded mandibular position, both at a vertical interincisal separation of 3 mm using an acrylic bite plate. Measurements of maximum voluntary isometric clenches were taken during adaptive functional changes at pretreatment (baseline) and during the first 6 months of Herbst appliance therapy. Results showed great individual and inter- and intrasessional differences in electromyographic activity of the muscles before and during treatment. At the retruded position, the masseteric activity increased by the sixth month while temporalis activity remained at the same level. Following treatment, the masseteric imbalance was reduced, but the temporalis imbalance was unchanged. At the edge-to-edge position, masseteric activity increased by the sixth month, while temporalis activity remained unchanged. The masseteric imbalance was reduced by the sixth month, while the temporalis imbalance was reduced from the fourth month into treatment. The results imply a favorable muscular response to a progressive regime of Herbst appliance activation.

Aminorex and rexamino as metabolites of levamisole in the horse.

Administration studies of levamisole in horses were carried out using two different levamisole preparations, namely, levamisole hydrochloride oral bolus and levamisole phosphate injectable solution. These preparations were analysed in detail for the presence of aminorex-like impurities. Both levamisole preparations were found to contain 1-(2-mercaptoethyl)-4-phenyl-2-imidazolidinone (I) and 4-phenyl-2-imidazolidinone (II) as degradation impurities, but neither aminorex nor rexamino was detected in these preparations. After the administration of these preparations to horses, aminorex, rexamino, in addition to levamisole and compound II, were detected in post-administration urine and plasma samples, among which compound II was found to have the longest detection time. Administration study of compound II was then performed on another horse to investigate whether it could be a metabolic precursor of aminorex and/or rexamino. However, no aminorex and rexamino was detected in the post-administration samples, suggesting that compound II was not a metabolic precursor of aminorex or rexamino. A metabolite (III) of compound II, tentatively identified to be a hydrolysis product of compound II, was observed instead. It has been established unequivocally that the normal use of levamisole products in horses can lead to the presence of aminorex, rexamino and 4-phenyl-2-imidazolidinone (II) in their urine and blood samples. As compound II has the longest detection time, the detection of aminorex (and in some cases rexamino) in some of the official samples from racehorses can be ascribed to the use of levamisole products as long as compound II is also present as a marker. These findings should be of direct relevance to the investigation of some of the cases of aminorex detection in official doping control samples from racehorses.

Metabolic studies of turinabol in horses.

Turinabol (4-chloro-17alpha-methyl-17beta-hydroxy-1,4-androstadien-3-one) is a synthetic oral anabolic androgenic steroid. As in the case of other anabolic steroids, it is a prohibited substance in equine sports. The metabolism of turinabol in human has been reported previously; however, little is known about its metabolic fate in horses. This paper describes the studies of both the in vitro and in vivo metabolism of turinabol in racehorses with an objective to identify the most appropriate target metabolites for detecting turinabol administration. For the in vitro studies, turinabol was incubated with fresh horse liver microsomes. Metabolites in the incubation mixture were isolated by liquid-liquid extraction and analysed by gas chromatography-mass spectrometry (GC-MS) after trimethylsilylation. The results showed that the major biotransformation of turinabol was hydroxylation at the C6, C16 and C20 sites to give metabolites 6beta-hydroxyturinabol (M1), 20-hydroxyturinabol (M2), two stereoisomers of 6beta,16-dihydroxyturinabol (M3a, M3b) and 6beta,20-dihydroxyturinabol (M4). The metabolite 6beta-hydroxyturinabol was confirmed using an authentic reference standard. The structures of all other turinabol metabolites were tentatively identified by mass spectral interpretation. For the in vivo studies, two horses were administered orally with turinabol. Pre- and post-administration urine samples were collected for analysis. Free and conjugated metabolites were isolated using solid-phase extraction and analysed by GC-MS as described for the in vitro studies. The results revealed that turinabol was extensively metabolised and the parent drug was not detected in urine. Two metabolites detected in the in vitro studies, namely 20-hydroxyturinabol and 6beta,20-dihydroxyturinabol, these were also detected in post-administration urine samples. In addition, 17-epi-turinabol (M5) and six other metabolites (M6a-M6c and M7a-M7c), derived from D-ring hydroxylation and A-ring reduction, were also detected. Except for 17-epi-turinabol, none of these metabolites has ever been reported in any species. All in vivo metabolites were detected within 48 h after administration.

Selective disruption of protein aggregation by cyclodextrin dimers.

Beta-cyclodextrin (CD) dimers (n = 11) were synthesized and tested against eight enzymes, seven of which were dimeric or tetrameric, for inhibitor activity. Initial screening showed that only L-lactate dehydrogenase and citrate synthase were inhibited but only by two specific CD dimers in which two beta-CDs were linked on the secondary face by a pyridine-2,6-dicarboxylic group. Further investigation suggested that these CD dimers inhibit the activity of L-lactate dehydrogenase and citrate synthase at least in part by disruption of protein-protein aggregation.

Cyclodextrin dimers as cleavable carriers of photodynamic sensitizers.

Several phthalocyanines carrying hydrophobic components have been synthesized and shown to bind to a group of cyclodextrin dimers with a carbon-carbon double bond in the linker. The complexes are soluble in water. On irradiation in the presence of oxygen, the singlet oxygen produced cleaves the olefinic linkers in the complexes, resulting in precipitation of the sensitizers. This process concentrates the sensitizers in the light beam, a process that has useful potential in photodynamic therapy.