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     

Changes in Quality of Health Care Delivery after Vertical Integration

ObjectivesTo fill an empirical gap in the literature by examining changes in quality of care measures occurring when multispecialty clinic systems were acquired by hospital-owned, vertically integrated health care delivery systems in the Twin Cities area.ConclusionsMoving a clinic system into a vertically integrated delivery system resulted in limited increases in quality of care indicators. Caution is warranted when the acquisition causes disruption in referral patterns.     

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.     

Prevalence of vitamin D depletion among morbidly obese patients seeking gastric bypass surgery

BACKGROUND: Abnormalities in calcium and vitamin D metabolism have been reported after bariatric surgery. The purpose of this study was to evaluate vitamin D nutritional status among morbidly obese patients before gastric bypass surgery. METHODS: We prospectively studied 279 morbidly obese patients seeking gastric bypass surgery for vitamin D nutritional status as assessed by serum 25-hydroxyvitamin D level. In addition, serum samples were analyzed for calcium, alkaline phosphatase (AP), intact parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D. RESULTS: Mean patient age was 43 +/- 9 years; 87% of the study patients were women, and 72% were white. Serum calcium and AP levels were normal in 88% and 89% of the patients, respectively. Vitamin D depletion, defined as serum 25-hydroxyvitamin D level 相似文献   

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.     

Sulphasalazine inhibition of human granulocyte activation by inhibition of second messenger compounds.

The effects of sulphasalazine on the production of second messenger compounds in human granulocytes have been characterised by various stimuli. The increases in cytosolic calcium, inositol trisphosphate, diacylglycerol, and phosphatidic acid (all important mediators of intracellular signal transduction) triggered by stimulation were inhibited by sulphasalazine. The metabolites 5-amino-salicylic acid and sulphapyridine were less potent inhibitors than the mother compound. It is concluded that sulphasalazine inhibits the synthesis of phosphoinositide derived second messenger compounds at the level of phospholipase C or its regulatory guanosine 5'-triphosphate (GTP) binding protein. Inhibition of phosphatidic acid synthesis was either due to the same mechanism, or to interaction with a phospholipase D regulating GTP binding protein.     

Disposition and pharmacokinetics of [14C]finasteride after oral administration in humans.

The disposition of [14C]finasteride, a competitive inhibitor of steroid 5 alpha-reductase, was investigated after oral administration of 38.1 mg (18.4 microCi) of drug in six healthy volunteers. Plasma, urine, and feces were collected for 7 days and assayed for total radioactivity. Concentrations of finasteride and its neutral metabolite, omega-hydroxyfinasteride (monohydroxylated on the t-butyl side chain), in plasma and urine were determined by HPLC assay. Mean excretion of radioactivity equivalents in urine and feces equaled 39.1 +/- 4.7% and 56.8 +/- 5.0% of the dose, respectively. The mean peak plasma concentrations reached for total radioactivity (ng equivalents), finasteride, and omega-hydroxyfinasteride were 596.5 +/- 88.3, 313.8 +/- 99.4, and 73.7 +/- 11.8 ng/ml, respectively, at approximately 2 hr; the mean terminal half-life for drug and metabolite was 5.9 +/- 1.3 and 8.4 +/- 1.7 hr, respectively. Of the 24-hr plasma radioactivity, 40.9% was finasteride, 11.8% was the neutral metabolite, and 26.7% was characterized as an acidic fraction of radioactivity. Binding of [14C]finasteride to plasma protein was extensive (91.3 to 89.8%), with a trend suggesting concentration dependency (range 0.02 to 2 micrograms/ml). Little of the dose was excreted in urine as parent (0.04%) or omega-hydroxyfinasteride (0.4%). Urinary excretion of radioactivity was largely in the form of acidic metabolite(s)--18.4 +/- 1.7% of the dose was eliminated as the omega-monocarboxylic acid metabolite. Finasteride was scarcely excreted unchanged in feces. In humans, finasteride is extensively metabolized through oxidative pathways.(ABSTRACT TRUNCATED AT 250 WORDS)     

Double-crowned valved stents for off-pump mitral valve replacement.

OBJECTIVE: An animal model has been designed to assess the feasibility of off-pump mitral valve replacement using valved stents. METHODS: Glutaraldehyde-preserved homograft was sutured inside a prosthetic tube (Dacron). Then, two self-expandable nitinol Z-stents were sutured on the external surface of the prosthesis in such a way to create two self-expanding crowns for fixation. In adult pigs and under general anesthesia, the left atrium was exposed through a left thoracotomy and atrio-ventricular roadmapping was performed with intravascular ultrasound (IVUS) and fluoroscopy. The double-crowned valved stents were loaded into a delivery sheath. The sheath was then introduced into the left atrium and the valved stents was deployed in mitral position in such a way that the part in between the two stents was at the level of the mitral annulus. Intracardiac Unltrasound (ICUS) was used to assess the valve function. Hemodynamic parameters were gathered as well. Animal survived for no more than 3h after the valve deployment and gross anatomy examination of the left heart was carried out. RESULTS: The mean height of the valved stents was 29.4+/-0.2 mm, with an internal diameter of 20.4+/-1.0mm, and an external diameter of 25.5+/-0.8 mm. The procedure was successfully carried out in eight animals. In vivo evaluation showed a native mitral annulus diameter of 24.9+/-0.6 mm, and a mean mitral valve area of 421.4+/-17.5 mm2. ICUS showed a mild mitral regurgitation in three out of eight animals. Mean pressure gradient across the valved stents was 2.6+/-3.1 mmHg. Mean pressure gradient across the left ventricular outflow tract (LVOT) was 6.6+/-5.2 mmHg. The mean survival time was 97.5+/-56.3 min (survival time range was 40-180 min). One animal died due to the occlusion of the LVOT because of valved stents displacement. Postmortem evaluation confirmed correct positioning of the valved stent in the mitral position in seven out of eight animals. No atrial or ventricular lesions due to the valved stents were found. CONCLUSIONS: Off-pump implantation of a self-expandable valved stent in the mitral position is technically feasible. Further studies will assess if this procedure is also feasible in humans.