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     

Radiation dose reduction in CT-guided cryoablation of renal tumors

PURPOSEWe aimed to evaluate the effect on the radiation dose to the patient by reducing the tube current during the placement of the ablation needles (reduced dose group) compared with the patient doses delivered when scanning at the standard fully diagnostic level (full dose group) in computed tomography (CT)-guided percutaneous cryoablation.METHODSWe conducted a retrospective study of 103 patients undergoing cryoablation in a tertiary cancer center. Overall, 62 patients were scanned with standard exposure parameters (full dose group) set on a 64-slice multidetector CT scanner, while 41 patients were scanned on a reduced dose protocol. Dose levels were retrieved from the hospital picture and archiving communication system including the volumetric CT dose index (CTDIvol), total dose length product (DLP), length of cryoablation procedure, number of cryoablation needles and patient size. Wilcoxon Mann-Whitney (rank-sum) tests were used to compare the median DLP, CTDIvol and skin dose between the two groups.RESULTSMedian total DLP for the full dose group was 6025 mGy·cm (1909–13353 mGy·cm) compared with 3391 mGy·cm (1683–6820 mGy·cm) for the reduced dose group. The reduced dose group had a 44% reduction in total DLP and 42% reduction in total CTDIvol (p < 0.001). The estimated skin doses were 384 mGy for the full dose group and 224 mGy for the reduced dose group (42% reduction) (p < 0.001). At 12-month follow-up, the technical success for the full dose (n=62) was 97% with 2 patients requiring a further cryoablation treatment for residual tumor. The technical success for the reduced dose group (n=41) was 100%.CONCLUSIONCT dose reduction technique during image-guided cryoablation treatment of renal tumors can achieve significant radiation dose reduction whilst maintaining sufficient image quality.

Renal cell carcinoma is the most common kidney cancer and has a rising incidence (1–4), with obesity and smoking being major risk factors (5–8).Image-guided ablation offers a more minimally invasive option compared with surgery and the current evidence base shows that it is a safe and effective treatment for T1a tumors, with a low rate of complications (9–11). The major advantage of cryoablation over other modalities is the ability to accurately visualize the iceball and therefore zone of ablation on intraprocedural imaging, either with computed tomography (CT) or magnetic resonance imaging (MRI) (12, 13). However, renal cryoablation involves the placement of more ablation probes and can have almost three times the radiation exposure compared with CT-guided radiofrequency ablation procedures (14).In addition to this substantial radiation dose per cryoablation, estimated to be between 32 and 39.7 mSv, the follow-up CT imaging will also add to the total radiation burden (15, 16). Whilst this level of radiation dose and associated stochastic risk may be a lesser concern in the older patients, greater consideration needs to be given to younger patients (<50 years old) and in patients requiring lifelong follow-up imaging, in particular those with hereditary diseases such as Von Hippel-Lindau syndrome (15). To our knowledge, the potential for reducing radiation dose for cryoablation patients.The principle aim of this study was to evaluate the effect on the radiation dose to the patient by reducing the tube current during the placement of the ablation needles (reduced dose group) compared with the patient doses delivered when scanning at the standard fully diagnostic level (full dose group) in CT-guided percutaneous cryoablation.     

Treatment of Tobacco Use in Preconception Care

Maternal and Child Health Journal -     

The Volk steady mount holder for the +90D lens

Since its introduction in early 1985, the Volk +90D lens has become a very popular auxiliary lens for biomicroscopic fundus evaluation. The Volk +90D lens provides a wide field of view which is accessible by simple scanning of the biomicroscope. The necessity to hand hold the lens, however, has not always provided enough stability, particularly for the novice user. This article describes a newly introduced holder for the Volk +90D lens which mounts on the base of the biomicroscope headrest providing rapid and stable lens placement. Use of this holder improves the technique of retinal examination and photography by stabilizing the image and by freeing both hands to operate the slit lamp biomicroscope. The enhanced stability afforded by this holder also gives the examiner the practical capability of viewing the posterior pole without mydriasis.     

The precision of positron emission tomography: theory and measurement

The limits of quantitation with positron emission tomography (PET) are examined with respect to the noise propagation resulting from radioactive decay and other sources of random error. Theoretical methods for evaluating the statistical error have been devised but seldom applied to experimental data obtained on human subjects. This paper extends the analysis in several ways: (1) A Monte Carlo method is described for tracking the propagation of statistical error through the analysis of in vivo measurements; (2) Experimental data, obtained in phantoms, validating the Monte Carlo method and other methods are presented; (3) A difference in activation paradigm, performed on regional CBF (rCBF) data from five human subjects, was analyzed on 1.6-cm diameter regions of interest to determine the mean fractional statistical error in PET tissue concentration and in rCBF before and after stereotactic transformation; and (4) A linear statistical model and calculations of the various statistical errors were used to estimate the magnitude of the subject-specific fluctuations under various conditions. In this specific example, the root mean squared (RMS) noise in flow measurements was about three times higher than the RMS noise in the concentration measurements. In addition, the total random error was almost equally partitioned between statistical error and random fluctuations due to all other sources.     

Coagulation screening before epidural analgesia in pre-eclampsia

A questionnaire survey of current practice at a small cross-section of obstetric units, covering 22% of all United Kingdom deliveries, revealed a marked lack of standard practice regarding requests for coagulation screens on pre-eclamptic patients who require epidural procedures. A retrospective audit was therefore carried out on 434 coagulation screens requested for pre-eclamptic patients in whom epidural analgesia might have been considered. Borderline abnormalities of coagulation were found in only 10 patients (2%). Platelet counts of less than 150 x 10(9)/litre were present in 28% of cases. 'Significant' thrombocytopenia (less than 100 x 10(9)/litre) and all coagulation abnormalities were only encountered in severe pre-eclampsia (diastolic blood pressure of greater than 110 mmHg and proteinuria of + + or greater). Furthermore, coagulation abnormality was always associated with a reduced platelet count (mean, 97 x 10(9)/litre). This study would therefore support anaesthetic practice which restricted any requests for coagulation testing to severe pre-eclamptic patients only. For these patients first line testing could be limited to a platelet count.     

Phosphoinositide hydrolysis linked 5-HT2 receptors in fibroblasts from choroid plexus

A serotonin (5-HT)-mediated phosphoinositide hydrolysis response was characterized in fibroblasts cultured from rabbit choroid plexus. 5-HT elicited a maximum 8-fold increase in [³H]inositol-phosphate ([³H]IP) formation, while the partial agonists, (+)-lysergic acid diethylamide and (−)-1-(4-bromo-2,5-dimethyoxyphenyl)-2-aminopropane caused 2- and 5-fold increases, respectively. Mianserin, ketanserin, and spiperone were equipotent at blocking the 5-HT-mediated response. Thus, agonist and antagonist profiles indicate interactions with 5-HT₂ receptors.