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     

Epilepsie,Schlaf und plötzlicher unerwarteter Tod

Clinical Epileptology - Der plötzliche unerwartete Tod stellt eine seltene, aber schwerwiegende Komplikation für Epilepsiepatienten dar. Das Risiko hierfür ist u. a. nachts und...     

Dexamethasone as an adjuvant for peripheral nerve blockade: a randomised,triple-blinded crossover study in volunteers

Background

The efficacy of dexamethasone in extending the duration of local anaesthetic block is uncertain. In a randomised controlled triple blind crossover study in volunteers, we tested the hypothesis that neither i.v. nor perineurally administered dexamethasone prolongs the sensory block achieved with ropivacaine.

Application of an augmented reality tool for maxillary positioning in orthognathic surgery – A feasibility study

BACKGROUND: An augmented reality tool for computer assisted surgery named X-Scope allows visual tracking of real anatomical structures in superposition with volume rendered CT or MRI scans and thus can be used for navigated translocation of bony segments. METHODS: In a feasibility study X-Scope was used in orthognathic surgery to control the translocation of the maxilla after Le Fort I osteotomy within a bimaxillary procedure. The situation achieved was compared with the pre-operative situation by means of cephalometric analysis on lateral and frontal cephalograms. RESULTS: The technique was successfully utilized in 5 patients. Maxillary positioning using X-Scope was accomplished accurately within a range of 1mm. The tool was used in all cases in addition to the usual intra-operative splints. A stand-alone application without conventional control does not yet seem reasonable. CONCLUSION: Augmented reality tools like X-Scope may be helpful for controlling maxillary translocation in orthognathic surgery. The application to other interventions in cranio-maxillofacial surgery such as Le Fort III osteotomy, fronto-orbital advancement, and cranial vault reshaping or repair may also be considered.     

Reevaluation of procarbazine for the treatment of recurrent malignant central nervous system tumors

Ninety-nine patients with primary recurrent malignant tumors of the central nervous system were treated with procarbazine as a single agent. Procarbazine was not given as a specified protocol, but for patients who were ineligible or refused other protocols. All patients had been treated previously with radiotherapy and 96 patients had also received previous chemotherapy. Twenty-five patients were treated at the first progression of their tumor, 47 were treated at the second progression, and 27 were treated at the third progression of their tumor. For the aggregate, the response plus stabilization rate was 27% for glioblastoma multiforme with median time to tumor progression of 30 weeks, and 28% for other anaplastic gliomas with a median time to tumor progression of 49 weeks. With respect to the percent of patients who responded or stabilized to treatment, these results are inferior to those reported previously for patients treated with procarbazine at recurrence. With respect to duration of response and stabilization, the data are comparable.     

Effect of anoxia on in vitro bladder function.

Previous studies have demonstrated that the ability of the in vitro whole bladder to empty in response to bethanechol administration was inhibited by anoxia while its ability to generate pressure decreased only slightly. One question was not addressed by these early studies: Is the anoxic effect selective for receptor-mediated contractile stimulation (as opposed to non-receptor-mediated contractile stimulation)? The present study was designed to compare the effect of anoxia on the ability of the in vitro bladder to generate pressure, sustain pressure, and empty in response to field stimulation (FS), bethanechol and KC1 administration. Each New Zealand white rabbit was anesthetized with pentobarbital and the bladder removed. The bladder was mounted as a whole-bladder preparation in a 300-ml isolated bath containing Tyrode's solution at 37 degrees C and equilibrated with 95% O2, 5% CO2. Anoxia was produced by changing the gas mixture to 95% nitrogen, 5% CO2. The effect of anoxia on the response to FS, bethanechol, and KCl was determined at different times after the initiation of anoxia. The results of these studies can be summarized as follows. (1) Anoxia induced a time-dependent decrease in the rate of pressure generation, the magnitude of pressure generation, and the percent volume emptied in response to FS and bethanechol. (2) At all time periods of anoxia, the ability of the bladder to empty was inhibited to a significantly greater degree than either the rate of magnitude of pressure generation (for both FS and bethanechol administration).(ABSTRACT TRUNCATED AT 250 WORDS)     

Clonidine in the treatment of Tourette's syndrome exacerbation due to haloperidol withdrawal

A patient with long-standing Tourette's syndrome had a dramatic exacerbation of symptoms following the rapid withdrawal of haloperidol. Clonidine administration resulted in a disappearance of tics, which recurred 6 days later. The role of clonidine in blocking withdrawal-induced symptoms in patients with Tourette's syndrome treated with long-term neuroleptics is discussed from a clinical and neurobiological perspective. The implications of this case for the treatment of supersensitivity psychosis and tricyclic withdrawal states with clonidine are also discussed.