Dabrafenib and Trametinib Therapy for Advanced Anaplastic Thyroid Cancer - Real-World Outcomes From UK Centres.

AIMS: Anaplastic thyroid cancer (ATC) is a rare but aggressive form of thyroid cancer with a median survival of 4 months. Recent advances in molecular profiling have shown that up to half of ATCs harbour the BRAF-V600E mutation. The aim of this study was to provide real-world data and experience on the use of combination therapy dabrafenib and trametinib in patients with BRAF-V600E-mutated advanced ATC. MATERIALS AND METHODS: We retrospectively evaluated patients with confirmed BRAF-V600E-mutated ATC, defined as patients with locally advanced or metastatic ATC with no locoregional, radical treatment options. Outcomes measured were overall survival, progression-free survival, response rate, discontinuation rate, dose reduction rate and toxicity data. RESULTS: Seventeen patients were evaluated and the mean age was 68 years. Ten patients died by the time of censoring. The median duration of follow-up was 12 months (3-43 months). The estimated median overall survival was 6.9 months (95% confidence interval 2.46 months - upper confidence interval not reached) and the median progression-free survival was 4.7 months (95% confidence interval 1.4-7.8 months). Dose interruptions and/or reductions were common, but none of the patients had to permanently discontinue treatment because of toxicities. Severe toxicities (grades 3 and 4) were uncommon. CONCLUSIONS: This study supports the indication of dabrafenib and trametinib in BRAF-V600E-mutated ATC as an effective and well-tolerated treatment in an historically difficult to treat cancer.

Doping and ion substitution in colloidal metal halide perovskite nanocrystals.

The past decade has witnessed tremendous advances in synthesis of metal halide perovskites and their use for a rich variety of optoelectronics applications. Metal halide perovskite has the general formula ABX3, where A is a monovalent cation (which can be either organic (e.g., CH3NH3+ (MA), CH(NH2)2+ (FA)) or inorganic (e.g., Cs+)), B is a divalent metal cation (usually Pb2+), and X is a halogen anion (Cl-, Br-, I-). Particularly, the photoluminescence (PL) properties of metal halide perovskites have garnered much attention due to the recent rapid development of perovskite nanocrystals. The introduction of capping ligands enables the synthesis of colloidal perovskite nanocrystals which offer new insight into dimension-dependent physical properties compared to their bulk counterparts. It is notable that doping and ion substitution represent effective strategies for tailoring the optoelectronic properties (e.g., absorption band gap, PL emission, and quantum yield (QY)) and stabilities of perovskite nanocrystals. The doping and ion substitution processes can be performed during or after the synthesis of colloidal nanocrystals by incorporating new A', B', or X' site ions into the A, B, or X sites of ABX3 perovskites. Interestingly, both isovalent and heterovalent doping and ion substitution can be conducted on colloidal perovskite nanocrystals. In this review, the general background of perovskite nanocrystals synthesis is first introduced. The effects of A-site, B-site, and X-site ionic doping and substitution on the optoelectronic properties and stabilities of colloidal metal halide perovskite nanocrystals are then detailed. Finally, possible applications and future research directions of doped and ion-substituted colloidal perovskite nanocrystals are also discussed.

Thermodynamic Routes to Ultralow Thermal Conductivity and High Thermoelectric Performance.

Thermoelectric (TE) research is not only a course of materials by discovery but also a seedbed of novel concepts and methodologies. Herein, the focus is on recent advances in three emerging paradigms: entropy engineering, phase-boundary mapping, and liquid-like TE materials in the context of thermodynamic routes. Specifically, entropy engineering is underpinned by the core effects of high-entropy alloys; the extended solubility limit, the tendency to form a high-symmetry crystal structure, severe lattice distortions, and sluggish diffusion processes afford large phase space for performance optimization, high electronic-band degeneracy, rich multiscale microstructures, and low lattice thermal conductivity toward higher-performance TE materials. Entropy engineering is successfully implemented in half-Huesler and IV-VI compounds. In Zintl phases and skutterudites, the efficacy of phase-boundary mapping is demonstrated through unraveling the profound relations among chemical compositions, mutual solubilities of constituent elements, phase instability, microstructures, and resulting TE properties at the operation temperatures. Attention is also given to liquid-like TE materials that exhibit lattice thermal conductivity at lower than the amorphous limit due to intensive mobile ion disorder and reduced vibrational entropy. To conclude, an outlook on the development of next-generation TE materials in line with these thermodynamic routes is given.

Lead-Free Halide Perovskite Nanocrystals: Crystal Structures, Synthesis, Stabilities, and Optical Properties.

In recent years, there have been rapid advances in the synthesis of lead halide perovskite nanocrystals (NCs) for use in solar cells, light emitting diodes, lasers, and photodetectors. These compounds have a set of intriguing optical, excitonic, and charge transport properties, including outstanding photoluminescence quantum yield (PLQY) and tunable optical band gap. However, the necessary inclusion of lead, a toxic element, raises a critical concern for future commercial development. To address the toxicity issue, intense recent research effort has been devoted to developing lead-free halide perovskite (LFHP) NCs. In this Review, we present a comprehensive overview of currently explored LFHP NCs with an emphasis on their crystal structures, synthesis, optical properties, and environmental stabilities (e.g., UV, heat, and moisture resistance). In addition, strategies for enhancing optical properties and stabilities of LFHP NCs as well as the state-of-the-art applications are discussed. With the perspective of their properties and current challenges, we provide an outlook for future directions in this rapidly evolving field to achieve high-quality LFHP NCs for a broader range of fundamental research and practical applications.

Unconventional route to dual-shelled organolead halide perovskite nanocrystals with controlled dimensions, surface chemistry, and stabilities.

The past few years have witnessed rapid advances in the synthesis of high-quality perovskite nanocrystals (PNCs). However, despite the impressive developments, the stability of PNCs remains a substantial challenge. The ability to reliably improve stability of PNCs while retaining their individual nanometer size represents a critical step that underpins future advances in optoelectronic applications. Here, we report an unconventional strategy for crafting dual-shelled PNCs (i.e., polymer-ligated perovskite/SiO2 core/shell NCs) with exquisite control over dimensions, surface chemistry, and stabilities. In stark contrast to conventional methods, our strategy relies on capitalizing on judiciously designed star-like copolymers as nanoreactors to render the growth of core/shell NCs with controlled yet tunable perovskite core diameter, SiO2 shell thickness, and surface chemistry. Consequently, the resulting polymer-tethered perovskite/SiO2 core/shell NCs display concurrently a stellar set of substantially improved stabilities (i.e., colloidal stability, chemical composition stability, photostability, water stability), while having appealing solution processability, which are unattainable by conventional methods.

Viral emergence in marine mammals in the North Pacific may be linked to Arctic sea ice reduction.

Climate change-driven alterations in Arctic environments can influence habitat availability, species distributions and interactions, and the breeding, foraging, and health of marine mammals. Phocine distemper virus (PDV), which has caused extensive mortality in Atlantic seals, was confirmed in sea otters in the North Pacific Ocean in 2004, raising the question of whether reductions in sea ice could increase contact between Arctic and sub-Arctic marine mammals and lead to viral transmission across the Arctic Ocean. Using data on PDV exposure and infection and animal movement in sympatric seal, sea lion, and sea otter species sampled in the North Pacific Ocean from 2001-2016, we investigated the timing of PDV introduction, risk factors associated with PDV emergence, and patterns of transmission following introduction. We identified widespread exposure to and infection with PDV across the North Pacific Ocean beginning in 2003 with a second peak of PDV exposure and infection in 2009; viral transmission across sympatric marine mammal species; and association of PDV exposure and infection with reductions in Arctic sea ice extent. Peaks of PDV exposure and infection following 2003 may reflect additional viral introductions among the diverse marine mammals in the North Pacific Ocean linked to change in Arctic sea ice extent.

Increasing the incidence of drain-free day-case mastectomies with the use of a fibrin tissue sealant; data from a single surgical center in the United Kingdom.

Day-case mastectomy surgery provides benefits to both patients and hospitals. Key barriers are the use of a drain and the risk of postoperative seroma formation. We introduced the use of a tissue sealant (Artiss) into the surgical site (post-mastectomy without immediate reconstruction and postaxillary clearance) and evaluated its effect on our practice, particularly day-case rates. A prospective audit of 177 patients who underwent a simple mastectomy with or without axillary surgery, or axillary node clearance with or without breast-conserving surgery was conducted at a single surgical center in the UK between November 2015 and November 2016. Artiss was used in all operations and, where appropriate, the drain was omitted to facilitate day-case surgery. The clinical outcomes were compared between patients undergoing different operations and duration of hospital stay. There was no statistically significant difference between day-case patients and inpatients in seroma aspiration rates (24.5% and 21.7%, respectively; P = 0.381) or other complications (22.4% and 16.1%, respectively; P = 0.106). The day-case mastectomy rate increased from 3.9% in the first quarter to 45.5% in the final quarter, which was a significant increase reaching well beyond the national target. The use of Artiss enabled us to increase the drain-free day-case surgery rates over a 1-year period, exceeding the 30% target recommended by the British Association of Day Surgery. We did not observe any increase in patient morbidity, and the change was cost-effective. We have now implemented the routine use of Artiss in women undergoing simple mastectomy with or without axillary surgery and stand-alone axillary node clearances as part of enhanced recovery clinical pathways.

Differentiated Thyroid Cancer in Children: A UK Multicentre Review and Review of the Literature.

AIMS: To obtain an overview of the management and outcomes of children aged 18 years or younger diagnosed with differentiated thyroid carcinoma of follicular cell origin across the UK, by collecting and analysing data from the limited number of centres treating these patients. This multicentre data might provide a more realistic perspective than single-institution series. MATERIALS AND METHODS: Six centres submitted data extracted from historical records on patients aged 18 years or younger, diagnosed between 1964 and 2017. The univariate and multivariable Cox proportional hazard model was used to identify potential predictors of progression-free survival, using national data as a control. RESULTS: Data on 166 patients were available for analysis. Females (74%) were predominant, and the age ranged from 3 to 19 years at diagnosis, mean 14.1 years. Nodal metastases were present in 51%; 12% had distant metastases. After surgery, 95% received radioactive iodine (39% on more than one occasion) and 4% received external beam radiotherapy. With a median follow-up duration of 5 years, 69% are alive with no evidence of disease; 20% are alive with a raised thyroglobulin level as the only evidence of residual disease; 6% have residual structural disease detectable on imaging; 2% have died, from cerebral metastases. CONCLUSION: Despite most patients having advanced disease at presentation, outcomes are very good. A national prospective registry should allow systematic collection of good-quality data and may facilitate research to further improve outcomes.

Can We Discharge Dynamically Risk-Stratified Low-Risk (Excellent Response to Treatment) Thyroid Cancer Patients After 5 Years of Follow-Up?

AIMS: The 2014 British Thyroid Association thyroid cancer guidelines recommend lifelong follow-up of thyroid cancer patients. This is probably unnecessary, can cause patient anxiety, is time consuming and places significant demand on National Health Service resources. It has been suggested that low-risk differentiated thyroid cancer (DTC) patients could be discharged to primary care once they are 5 years from diagnosis and treatment. The aim of this study was to investigate the potential safety of this practice. MATERIALS AND METHODS: In total, 756 patients with dynamically risk-stratified (DRS) low-risk/excellent response to treatment DTC treated over 2001-2013 in the Leeds region were followed after diagnostic surgery and the recurrence rate calculated. RESULTS: The median follow-up time was nearly 10 years (5-17 years). Radiological recurrence occurred in 13/756 (1.7%) patients and was always preceded by raised thyroglobulin/ thyroglobulin antibody levels. In all 13 patients elevation of thyroglobulin occurred within 5 years of diagnosis. Two additional patients were found to have rising thyroglobulin at almost 9 and 10.5 years from diagnosis, although to date radiological recurrence has not been detected. Assuming these two patients developed recurrence with longer duration of follow-up, then 0.26% (2/756) of patients would not have their recurrence discovered within 5 years of diagnosis. To detect 100% of patients with a putative recurrence in our cohort would require 10.5 years of follow-up. Four patients had transiently raised thyroglobulin, which became undetectable within 2 years (in three patients), without any treatment and radiological recurrence was not discovered. CONCLUSION: Discharge of DRS low-risk DTC patients to primary care after 5 years of secondary care follow-up is reasonable, accepting that late recurrence may occur in a very small minority of individuals (0.26%, ∼1:400). A more cautious approach would be to continue monitoring for 10 years, although the frequency of assessments could be reduced with increasing duration of follow-up.

Patient perspectives on de-simplifying their single-tablet co-formulated antiretroviral therapy for societal cost savings.

OBJECTIVES: The incremental costs of expanding antiretroviral (ARV) drug treatment to all HIV-infected patients are substantial, so cost-saving initiatives are important. Our objectives were to determine the acceptability and financial impact of de-simplifying (i.e. switching) more expensive single-tablet formulations (STFs) to less expensive generic-based multi-tablet components. We determined physician and patient perceptions and acceptance of STF de-simplification within the context of a publicly funded ARV budget. METHODS: Programme costs were calculated for patients on ARVs followed at the Southern Alberta Clinic, Canada during 2016 (Cdn$). We focused on patients receiving Triumeq® and determined the savings if patients de-simplified to eligible generic co-formulations. We surveyed all prescribing physicians and a convenience sample of patients taking Triumeq® to see if, for budgetary purposes, they felt that de-simplification would be acceptable. RESULTS: Of 1780 patients receiving ARVs, 62% (n = 1038) were on STF; 58% (n = 607) of patients on STF were on Triumeq®. The total annual cost of ARVs was $26 222 760. The cost for Triumeq® was $8 292 600. If every patient on Triumeq® switched to generic abacavir/lamivudine and Tivicay® (dolutegravir), total costs would decrease by $4 325 040. All physicians (n = 13) felt that de-simplifying could be safely achieved. Forty-eight per cent of 221 patients surveyed were agreeable to de-simplifying for altruistic reasons, 27% said no, and 25% said maybe. CONCLUSIONS: De-simplifying Triumeq® generates large cost savings. Additional savings could be achieved by de-simplifying other STFs. Both physicians and patients agreed that selective de-simplification was acceptable; however, it may not be acceptable to every patient. Monitoring the medical and cost impacts of de-simplification strategies seems warranted.

Ten Year Experience of Radioiodine Dosimetry: is it Useful in the Management of Metastatic Differentiated Thyroid Cancer?

AIMS: When a fixed activity of radioiodine is given for differentiated thyroid cancer (DTC), absorbed doses of radioiodine can vary widely and are not usually measured. Leeds Cancer Centre has routinely used a form of lesion-specific dosimetry for radioiodine patients. This study investigated if the results of dosimetry influenced treatment decisions for patients with advanced DTC. MATERIALS AND METHODS: Since 2005, patients with regionally advanced/metastatic DTC, who underwent radioiodine treatment together with dosimetry, were included in this study. Patients were excluded if their radioiodine post-treatment scan showed no abnormal uptake. Dosimetry was calculated using images taken 2, 3 and 7 days post-radioiodine. Regions of interest were drawn around lesions that required dosimetry and a time-dose activity curve was created. The total cumulative activity was equal to the area under the curve. Each patient's results were prospectively assessed by their oncologist regarding the usefulness of dosimetry in making management decisions. RESULTS: Thirty patients were studied and underwent 102 admissions of radioiodine between them. Dosimetry was carried out during 83 of 102 admissions. An absorbed dose of >20 Gy was taken as significant from dosimetry calculations, following which further radioiodine was considered. In 80% of patients, dosimetry was found to be useful when making treatment decisions. Only on 1/19 admissions did dosimetry calculate a minimum dose above 20 Gy in patients who had a total of four or more admissions for radioiodine. Ten per cent (3/30) had a complete response to radioiodine, both biochemically and radiologically, with a median follow-up of 6.7 months. Thirty-three per cent had a partial response/stable disease to radioiodine. The remainder had progressive disease. The decision to discontinue radioiodine therapy was often based on dosimetry and thyroglobulin results. Dosimetry was very useful for patients with thyroglobulin antibodies. CONCLUSION: Only 10% had a complete response. Therefore, a significant number of patients became refractory to radioiodine during a course of repeat admissions for treatment. Dosimetry (often together with thyroglobulin and anatomical scans) helped to identify these patients to avoid further futile radioiodine therapy.

Experiences of discrimination among people using mental health services in England 2008-2011.

BACKGROUND: Research suggests that levels of discrimination against people using mental health services are high; however, reports of these people's experiences are rare. AIMS: To determine whether the Time to Change (TTC) programme target of 5% reduction in discrimination has been achieved. METHOD: Separate samples of people using mental health services were interviewed annually from 2008 to 2011 using the Discrimination and Stigma Scale to record instances of discrimination. RESULTS: Ninety-one per cent of participants reported one or more experiences of discrimination in 2008 compared with 88% in 2011 (z = -1.9, P = 0.05). The median negative discrimination score was 40% in 2008 and 28% in 2011 (Kruskal-Wallis χ(2) = 83.4, P<0.001). CONCLUSIONS: The proportion of participants experiencing no discrimination increased significantly over the course of TTC but by less than the initial target. The overall median discrimination score fell by 11.5%. Data from 2010 and 2011 suggest that these gains may be hard to maintain during economic austerity.

Preliminary evidence for biologic activity of toceranib phosphate (Palladia(®)) in solid tumours.

The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia®, Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity.

Use of imiquimod 5% cream (Aldara) in cats with multicentric squamous cell carcinoma in situ: 12 cases (2002-2005).

Multicentric squamous cell carcinoma in situ (MSCCIS) is a variant of squamous cell carcinoma in cats, commonly referred to as Bowen's-like disease. Imiquimod 5% cream (Aldara) is a novel immune response modifier (IRM) that has been reported as a successful treatment for Bowen's disease in humans. The purpose of this study was to describe clinical findings, treatment protocols and survival in cats with MSCCIS treated with imiquimod 5% cream and to examine the effects of imiquimod 5% cream in cats with MSCCIS. The expression of papillomavirus group-specific antigen in the study population was also determined. From review of medical records, 12 cats were identified with a histologic diagnosis of MSCCIS and treatment with imiquimod 5% cream. Initial lesions responded to imiquimod 5% cream in all cats. Most cats (75%) developed new lesions. New lesions also responded to imiquimod 5% cream in all cats treated. Five cats (41%) had side effects suspected to be associated with the use of imiquimod 5% cream, including local erythema (25%), increased liver enzymes and neutropenia (8%), and partial anorexia and vomiting (8%). Kaplan-Meier median treatment duration and median survival time probabilities for cats in this study were 1189 days, respectively. A time to failure model was generated as many cats were censored from analysis well before the aforementioned projected median. This model resulted in a shorter median survival time of 243 days. No patient-related, tumour-related or treatment-related prognostic variables were identified. No expression for papilloma group-specific antigen was found. Imiquimod 5% cream appears to be well tolerated in the majority of cats, and further studies are warranted to further examine its usefulness in cats with this disease.