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.     

Comparing reconstruction with ileocecal graft to jejunal interposition pouch after total gastrectomy in rats.

After total gastrectomy, the ileocecal graft may act as a reservoir and protect against reflux but give rise to transposition of the ileum and cause possible changes in bile acid metabolism and nutrition. This study compared the ileocecal graft and jejunal pouch. Male Wistar rats weighing 265 +/- 22 g were submitted to sham operation (S), ileocecal interposition graft (IIG), and jejunal pouch interposition graft (JP) after total gastrectomy. Eight weeks later, the esophagus was examined for evidence of esophagitis. Nutritional biochemistry and weight profile were documented preoperatively and 8 weeks after surgery. The oral glucose tolerance test was performed. Thirty-three rats were operated on and 30 survived for 8 weeks. Esophagitis occurred in seven JP rats. Body weight was significantly higher in IIG than in JP rats (p < .05). Normal glucose tolerance to intragastric glucose load was observed in sham and operated rats. JP rats had a significant decrease in serum albumin, glucose, transferrin, hemoglobin, iron, folate, and calcium, compared to sham (p < .05). Cobalamine was significantly lower in IIG rats than in JP rats (p < .05). In the IIG and JP groups, serum/hepatic total bile acid did not differ significantly from preoperative and sham values. In conclusion, the IIG interposition graft in rats prevented esophagitis, preserved nutrition, and did not interfere with enterohepatic total bile acid circulation.     

Genotype/phenotype of familial pancreatic cancer.

It is estimated that 5% to 10% of pancreatic cancer cases are attributable to hereditary factors. We believe that the number of cases that are genetic in etiology are even greater, however, based not on a classic autosomal dominant pattern of inheritance but rather when one takes into account low-penetrant inherited susceptibility factors. There is also a growing recognition that the development of pancreatic cancer in pancreatic cancer-prone families is dependent not only on genetic variables but on nongenetic factors. The aim of this article is to review the challenges in identifying pancreatic cancer-prone families and how environmental factors interact with genetic factors in these families.     

The parenting partnership: The evaluation of a human service/corporate workplace collaboration for the prevention of substance abuse and mental health problems,and the promotion of family and work adjustment

A partnership between corporate worksites, a community-based prevention agency, and families in those worksites is described. Its primary goals were the reduction of family risk and enhancement of family protective factors that predispose children and youth to substance abuse and related social and emotional difficulties. A related goal of the program is to reduce family stress levels and attitudes that may influence the parents' levels of risk for substance abuse and related disorder. The program delivery strategy is conceived of as part of the necessart efforts of prevention programs to reach target populations in host settings in which they may naturally participate, thereby reducing obstacles and barriers to participation that often impede prevention efforts. Evaluation revealed that the program was generally better able to retain parents for a fairly lengthy period, and with high rates of attendance. Program attendance was also not affected by parental background characteristics that, in other delivery approaches, are often associated with poor attendance and high drop-out levels. Results also indicated that levels of program exposure (dosage) do make a significant difference in the efficacy of such efforts as those parents in the program who participated in higher percentages and numbers of sessions (i.e. more than 80% of sessions) showed both short-term and longer-term (i.e. across 18 month follow-ups) gains in their ratings of the target child's behavior problems and strengths, substance abuse resistance related knowledge and attitudes, reduced parental stress, depression and irritability, and increased utilization of social support. By contrast, parents who received a low program exposure exhibited a more restricted set of short-term gains. The findings are discussed in terms of their importance for consideration of program dosage for prevention programs, and the need to attend to the context in which programming is offered as it may facilitate or impede efforts to provide levels of dosage and fidelity to create enduring impacts     

Randomised double blind placebo controlled trial of prednisolone in children admitted to hospital with respiratory syncytial virus bronchiolitis

BACKGROUND: Experimental and clinical evidence suggests that respiratory syncytial virus (RSV) bronchiolitis is an immune mediated disease. Corticosteroids might therefore be effective in the treatment of RSV bronchiolitis. METHODS: A randomised double blind trial was conducted in children up to two years of age admitted to hospital with RSV bronchiolitis to compare prednisolone (1 mg/ kg/day orally for seven days) with placebo. Variables used for the efficacy analysis were a daily symptom score and the length of time in hospital in the non- ventilated patients, and the duration of mechanical ventilation and the length of time in hospital in the ventilated patients. RESULTS: Fifty four patients were included in the trial, 40 of whom were non- ventilated (20 in each group) and 14 were ventilated (seven in each group). During the first three days of treatment the symptom score decreased significantly faster in the prednisolone group than in the placebo group (mean (SE) decrease -1.2 (0.2) points/day versus -0.6 (0.2) points/day; mean (95% confidence interval (CI)) for difference = - 0.6 (-0.1 to -1.2); p = 0.02). The mean duration of hospital stay of all 40 non-ventilated patients was not significantly different between the two groups. In the ventilated patients the duration of mechanical ventilation was not significantly different, but the length of time in hospital was six days shorter in the prednisolone group than in the placebo group (mean (SE) 11.0 (0.7) versus 17.0 (2.0) days; mean (95% CI) difference = 7.0 (1.8 to 10.2) days; p < 0.01). CONCLUSIONS: These results suggest that prednisolone may be effective in accelerating the clinical recovery of children admitted to hospital with RSV bronchiolitis.


     

Management of psychopharmacologic agents in children and adolescents

This article summarizes the ways in which a clinician should think about medication use in children and describes practical usage of the most frequently used child psychopharmacologic agents.Leena Ranade, M.D., and Aftab Qadir, M.D., were Fellows in Child Psychiatry, State University of New York at Stony Brook at the time of writing this article.