Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors.

BACKGROUND: Avapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence-based guidance on management of avapritinib-associated adverse events (AEs), including cognitive effects and intracranial bleeding. MATERIALS AND METHODS: We performed a post hoc analysis of data from a two-part, single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30-600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression-free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose). RESULTS: Of 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started avapritinib at 300 mg. The most common treatment-related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment-related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all-cause cognitive effects rate (grade 1-2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3-3.1 weeks) than without (4.9-7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without. CONCLUSION: Tolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs. IMPLICATIONS FOR PRACTICE: Early recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment-related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events.

Mindfulness for adolescent chronic pain: a pilot feasibility study.

OBJECTIVE: Chronic pain is common in paediatric populations and many patients do not respond to the currently available evidence-based treatments. Mindfulness-based interventions (MBIs) have a growing evidence-base in adults, but evidence is limited in youth with chronic pain. METHODS: We conducted an open-label pilot study to test the feasibility of an 8-week MBI for this population. RESULTS: Seven adolescents (age range 14-17; median age 15; six female) completed the intervention. There were no dropouts. Median class attendance was seven of eight total sessions (SD = 0.76). Only one (14.3%) participant reported not finding it useful; five (71.4%) reported that they would recommend it to a friend; and the remaining two (28.6%) reported "maybe". There was no worsening of internalizing symptoms. Secondary outcomes included significant reduction of pain intensity, which was maintained at three-month follow-up. Somatic symptoms and functional disability were both non-significantly lower immediately following the intervention; but were significantly improved at three-month follow-up. CONCLUSION: An eight-week group MBI is a feasible intervention for adolescents with chronic pain, and warrants further investigation as a potential alternative to cognitive behavioural therapy in this population.

Patient Decision-Making About the Disposition of Surplus Cryopreserved Embryos in Canada.

OBJECTIVE: The objective of this study was to identify factors that contribute to patient decision-making for disposition of surplus cryopreserved embryos in Canada. METHODS: In 2013, interviews were conducted with 45 IVF patients from three clinic sites, representing a total of 33 households. Patients interviewed all had unused cryopreserved embryos in storage in 2010. Initial demographic data collection was followed by one in-depth semi-structured interview conducted in 2013. Data were managed and coded thematically. RESULTS: Most patients (21 patients, representing 16 households) renewed storage agreements to keep embryos in storage at the time of the interview. Among patients who did not renew their storage agreements at some point between 2010 and 2013, six patients (representing 5 households) had since used all their embryos, two patients (representing one household) had decided to keep their embryos in storage in perpetuity, three patients (representing 3 households) discarded their embryos outright, and 13 patients (representing 9 households) donated their embryos to research or clinical training. Among patients who donated to research or clinical training, three key themes emerged: a desire to "give back," to contribute to scientific progress, and to avoid "wasting" embryos. These patients were not always certain about whether they had chosen research or clinical training. CONCLUSION: This study demonstrates the applicability of international findings about embryo disposition decision-making to the Canadian setting. Moreover, it identifies that while patients making disposition decisions often choose to donate embryos to research and/or clinical training, they are not always certain about what these options entail. Clinicians, counsellors, and others must ensure that patients are not only aware of their embryo disposition options, but that they understand the nature of these options as well.

Analysis of agriculture-related life-threatening injuries presenting to emergency departments of rural generalist hospitals in Southern Queensland.

OBJECTIVE: Agricultural industries are among the most dangerous in Australia posing significant public health risks. This study analyses the nature and management of agriculture-related injuries presenting to EDs in selected hospitals in Southern Queensland. METHODS: Data on agricultural injury presentations over a 6 month period was collected at four rural hospitals by a dedicated onsite hospital data coordinator. Additionally, in two of the participating hospitals all injury presentations over the same 6 month period were recorded. A pre-tested survey instrument, modified for rural settings and designed and developed to export the abstracted data using an iPad application was used as the survey tool. RESULTS: The incidence of agriculture-related injuries was 11% of all injuries, most were males (73%), averaging 40 years. On presentation, 66.5% (n = 234) were categorised as imminently or potentially life threatening with 44% of those patients presenting to hospital ED >3 h after the injury. Large animals were more commonly reported as involved in the aetiology of the presenting injury, particularly using horses and handling cattle. CONCLUSIONS: Agricultural injuries are a significant group of primary care presentations to rural hospitals and training and resourcing for rural hospitals should reflect this. A better understanding of common injury types can lead to efficient allocation of available resources in rural hospitals and potentially improve ED practices. The delay in presentation must be considered in response planning both by farmers and hospital EDs.

Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status.

BACKGROUND: In addition to its role in adaptive thermogenesis, brown adipose tissue (BAT) may protect from weight gain, insulin resistance/diabetes, and metabolic syndrome. Prior studies have shown contradictory results regarding the influence of thyroid hormone (TH) levels on BAT volume and activity. The aim of this pilot study was to gain further insights regarding the effect of TH treatment on BAT function in adult humans by evaluating the BAT mass and activity prospectively in six patients, first in the hypothyroid and then in the thyrotoxic phase. METHODS: The study subjects underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scanning after cold exposure to measure BAT mass and activity while undergoing treatment for differentiated thyroid cancer, first while hypothyroid following TH withdrawal at the time of the radioactive iodine treatment and then three to six months after starting TH suppressive treatment when they were iatrogenically thyrotoxic. Thermogenic and metabolic parameters were measured in both phases. RESULTS: All study subjects had detectable BAT under cold stimulation in both the hypothyroid and thyrotoxic state. The majority but not all (4/6) subjects showed an increase in detectable BAT volume and activity under cold stimulation between the hypothyroid and thyrotoxic phase (total BAT volume: 72.0 ± 21.0 vs. 87.7 ± 16.5 mL, p = 0.25; total BAT activity 158.1 ± 72.8 vs. 189.0 ± 55.5 SUV*g/mL, p = 0.34). Importantly, circulating triiodothyronine was a stronger predictor of energy expenditure changes compared with cold-induced BAT activity. CONCLUSIONS: Iatrogenic hypothyroidism lasting two to four weeks does not prevent cold-induced BAT activation, while the use of TH to induce thyrotoxicosis does not consistently increase cold-induced BAT activity. It remains to be determined which physiological factors besides TH play a role in regulating BAT function.

Quantification of human and rodent brown adipose tissue function using 99mTc-methoxyisobutylisonitrile SPECT/CT and 18F-FDG PET/CT.

UNLABELLED: For brown adipose tissue (BAT) to be effective at consuming calories, its blood flow must increase enough to provide sufficient fuel to sustain energy expenditure and also transfer the heat created to avoid thermal injury. Here we used a combination of human and rodent models to assess changes in BAT blood flow and glucose utilization. METHODS: (99m)Tc-methoxyisobutylisonitrile (MIBI) SPECT (n = 7) and SPECT/CT (n = 74) scans done in adult humans for parathyroid imaging were reviewed for uptake in regions consistent with human BAT. Site-directed biopsies of subcutaneous and deep neck fat were obtained for electron microscopy and gene expression profiling. In mice, tissue perfusion was measured with (99m)Tc-MIBI (n = 16) and glucose uptake with (18)F-FDG (n = 16). Animals were kept fasting overnight, anesthetized with pentobarbital, and given intraperitoneally either the ß3-adrenergic receptor agonist CL-316,243, 1 mg/kg (n = 8), or saline (n = 8) followed by radiotracer injection 5 min later. After 120 min, the mice were imaged using SPECT/CT or PET/CT. Vital signs were recorded over 30 min during the imaging. BAT, white adipose tissue (WAT), muscle, liver, and heart were resected, and tissue uptake of both (99m)Tc-MIBI and (18)F-FDG was quantified by percentage injected dose per gram of tissue and normalized to total body weight. RESULTS: In 5.4% of patients (4/74), (99m)Tc-MIBI SPECT/CT showed increased retention in cervical and supraclavicular fat that displayed multilocular lipid droplets, dense capillary investment, and a high concentration of ovoid mitochondria. Expression levels of the tissue-specific uncoupling protein-1 were 180 times higher in BAT than in subcutaneous WAT (P < 0.001). In mice, BAT tissue perfusion increased by 61% (P < 0.01), with no significant changes in blood flow to WAT, muscle, heart, or liver. CL-316,243 increased glucose uptake in BAT even more, by 440% (P < 0.01). CONCLUSION: Pharmacologic activation of BAT requires increased blood flow to deliver glucose and oxygen for thermogenesis. However, the glucose consumption far exceeds the vascular response. These findings demonstrate that activated BAT increases glucose uptake beyond what might occur by increased blood flow alone and suggest that activated BAT likely uses glucose for nonthermogenic purposes.