Fibroblast growth factor receptors in cancer: genetic alterations,diagnostics, therapeutic targets and mechanisms of resistance

Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3-mutated urothelial carcinoma and FGFR2-fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.Subject terms: Cancer, Cancer     

Does stroke impair academic achievement in children? The role of metacognition in math and spelling outcomes following pediatric stroke

Introduction: Current research suggests that pediatric stroke is associated with a reduction in intellectual functioning. However, less is known about academic achievement and the contribution of specific executive functions to math and literacy in this population. The current study investigates behavioral ratings of executive functioning and their relationship to math and spelling performance in children with a history of unilateral arterial ischemic stroke.

Method: Thirty-two pediatric patients with stroke (M_age = 9.5 ± 2.7 years) and 32 demographically equivalent, healthy controls were tested on standardized measures of arithmetic, spelling, and intelligence. Executive functioning data were collected via standardized parent questionnaire.

Results: Relative to controls, stroke participants demonstrated significantly poorer functioning in math, spelling, metacognition, and behavioral-regulation. Pencil and paper arithmetic was particularly challenging for the stroke group, with 40% of patients reaching levels of clinical impairment. Hierarchical regression in stroke participants further revealed that metacognition was a robust predictor of academic deficits. Stroke occurring in later childhood and affecting cortical and subcortical brain regions also presented as potential clinical risk factors.

Conclusions: Children with stroke were especially vulnerable to math achievement deficits. Metacognition made a substantial contribution to academic achievement abilities among stroke patients, and results underscore the importance of early metacognitive skills in the completion of schoolwork. Results also emphasize that pediatric stroke patients are a heterogeneous group with regard to functioning and that there is value in examining standard score distributions of clinical participant samples.     

Behavioral neurology of multi-infarct dementia

Multi-infarct dementia (MID) is a heterogeneous entity in which a variety of cerebrovascular disorders leads to intellectual impairment. A variety of patterns of behavioral changes may be observed in MID, depression, psychosis, and personality change are common. The neurobehavioral syndromes of MID are determined by the specific arteries involved and the location and extent of tissue infarction.     

Passenger seating position and the risk of passenger death in traffic crashes: a matched cohort study

OBJECTIVE: To estimate the association of passenger seating position with the risk of death for passengers in traffic crashes. Design, setting, PARTICIPANTS: Matched cohort analysis of data from the National Highway Traffic Safety Administration Fatality Analysis Reporting System regarding 56 644 passengers in 23 308 passenger cars, light trucks, vans, and sport utility vehicles that crashed during 1990-2001. MAIN OUTCOME MEASURE: The adjusted risk ratio (aRR) for death of a rear seat passenger compared with a front seat passenger within 30 days of a crash. RESULTS: The aRR for all passengers in the rear seat in a crash was 0.79 (95% CI 0.77 to 0.82). This estimate varied by age, restraint use, and the presence of a front passenger airbag (p<0.001). For restrained passengers in cars with a front passenger airbag, the aRR was 0.62 (95% CI 0.48 to 0.81) for children 0-12 years, 0.96 (95% CI 0.88 to 1.06) for passengers 13-29 years, 1.03 (95% CI 0.93 to 1.15) for passengers 30-59 years, and 1.06 (95% CI 0.90 to 1.26) for passengers 60 years or older. The rear seat was associated with more protection in cars without front airbags and more protection for unrestrained passengers compared with restrained passengers. CONCLUSIONS: Previous studies have reported that the rear seat was safer for persons of all ages; thus seating a young child in the rear has often meant that older children and adults had to assume an increased risk of death by sitting in the front. These results suggest that when front passenger airbags are present and passengers are restrained, putting adults in front and children in back enhances child safety without sacrificing adult safety.     

Fracture-dislocation of the lunotriquetral coalition.

Bony fusions involving the carpus have a much higher prevalence in blacks relative to whites. This article describes a case of lunotriquetral coalition fracture-dislocation in an African American. This lesion is best treated through open reduction and pin fixation.     

Ketoconazole Impairs Early Pregnancy and the Decidual Cell Response via Alterations in Ovarian Function

Ketoconazole (KCZ) is an imidazole antifungal agent that alsoaffects P450 enzymes of the mammalian steroidogenic system.Several steps in the ovarian steroidogenesis pathway are knownto be inhibited by KCZ, but previous work has failed to addressthe ramifications of such inhibition with respect to early pregnancy.In initial studies, Holtzman rats (8–10/group) were administered10–100 mg/kg KCZ during days 1–8 of pregnancy. Onday 9, evaluations revealed a reduction at both 75 and 100 mgKCZ/kg in the number of implantation sites and serum progesteronelevels as well as an increase in ovarian weight The decidualcell response (DCR) was blocked by KCZ in parallel with decreasedserum progesterone and increased ovarian weight, indicatingdirect interference with uterine function. KCZ had no effectwhen given to long-term-ovariectomized rats that were hormonesupplemented to permit the DCR, indicating that the ovary wasat least one site of KCZ action on early pregnancy. Measurementof ovarian progesterone production in vitro from ovaries removedfrom rats treated in vivo with KCZ indicated a decline in progesteroneproduction, suggesting a direct effect of KCZ on ovarian steroidogenesis.These data demonstrate that KCZ can compromise early pregnancyand appears to do so by inhibiting progesterone synthesis inthe ovary.