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.     

Hood versus mask nebulization in infants with evolving bronchopulmonary dysplasia in the neonatal intensive care unit.

OBJECTIVE: To compare infants' discomfort, nursing-time and caregiver preference, and assess the clinical efficiency (as a secondary outcome) of hood versus facemask nebulization in infants with evolving bronchopulmonary dysplasia (BPD) in the neonatal intensive care unit. STUDY DESIGN: A prospective, open, randomized, controlled crossover clinical trial. In total, 10 infants with BPD who were on inhaled beta-agonist bronchodilators and corticosteroids were randomly assigned to receive their nebulized treatments either by a facemask, or by a hood for 2-3 days, and then crossover to receive the same treatments with the other technique for another 2-3 days. Infants' discomfort, nursing-time, caregiver preference and clinical efficiency were compared. RESULTS: At baseline there was no significant clinical difference between the groups. Nurse-time required for administering the hood nebulization (mean+/-s.e.m.: 1.9+/-0.1 min) was significantly shorter than the time for mask nebulization (12.0+/-0.6 min, P<0.0001). Infants' discomfort score was significantly lower (0.1+/-0.04) for hood versus mask nebulization (2.5+/-0.2, P<0.0001). Nurses and parents unequivocally preferred the hood treatment. During both mask and hood nebulization therapies (2-3 days) clinical efficiency was comparable. While both methods caused an immediate (20 min post) clinical improvement, the immediate respiratory assessment change score was significantly greater for the hood versus the mask nebulization (0.62+/-0.27 versus 0.13+/-0.14, P<0.05). CONCLUSIONS: Nebulization of aerosolized medications in infants with evolving BPD by hood was less time-consuming for caregivers and was much better tolerated by the infants while being at least as effective as the conventional facemask nebulization.     

HIV transmission by needle stick and eczematous lesion — Three cases from Germany

Summary Two cases of documented HIV-1 transmission by needle stick and one case of probable transmission by eczematous lesion in three nurses in Germany are reported in the period 1988 to 1991. In two of the cases the nurse knew of the AIDS status of the index patient. A review of the three cases reiterates the importance of repeated training on the prevention of accident and on measures to be taken after an accident, as well as the need to keep the workplace free of additional burden when AIDS or HIV-infected patients are treated.

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HIV-Übertragung durch Nadelstichverletzung und über offenes Ekzem. Drei Fälle aus Deutschland

Zusammenfassung Zwei dokumentierte HIV-Übertragungen über Nadelstichverletzung und eine Übertragung über ein offenes Hautekzem der Hand bei zwei Krankenschwestern und einem Pfleger aus den Jahren 1988 bis 1991 werden geschildert. Diese Übersicht der drei Fälle weist auf die Bedeutung von wiederholten Übungen hin, um einen Unfall zu verhüten und auf Maßnahmen die nach einem Unfall zu ergreifen sind. Unter anderem auf die Notwendigkeit den Arbeitsplatz von zusätzlichen Gegenständen freizuhalten, wenn AIDS- oder HIV-infizierte Patienten behandelt werden.

     

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.     

Zur Kenntniss der sogenannten Dehiscenz des Tegmen tympani

Ohne Zusammenfassung     

Psychologie und Psychiatrie

International Journal of Legal Medicine -