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.     

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.     

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.     

Both CD4+ and CD8+ human lymphocytes are activated and proliferate in response to Cryptococcus neoformans.

The current studies were performed to determine the contribution of T-cell subsets to lymphocyte proliferation in response to Cryptococcus neoformans, the most common invasive mycosis in acquired immune deficiency syndrome. We demonstrate for the first time that both human CD4 and CD8 cells are activated in response to C. neoformans. Both CD4 and CD8 cells express interleukin-2 receptor alpha (IL-2R alpha) and transferrin receptor and proliferate in response to C, neoformans, however proliferation of CD8 cells was dependent upon CD4 cells. The requirement for CD4 cells was complex, since CD8 enriched cells failed to express mRNA for IL-2, suggesting that CD4-dependent IL-2 production was required for CD8-cell proliferation. However, IL-2 was not sufficient to restore CD8-cell proliferation. These studies provide experimental evidence in humans to support the clinical impression that CD4 cells are important in cryptococcosis, and suggest that the appropriate CD4-derived signals could allow CD8 cells to assist in host defence.     

Primary cerebral neuroblastoma (neurocytoma) in adults

Summary We report a case of a third ventricular neuroblastoma (neurocytoma) in a 66 year old man. A stereotactic needly biopsy was performed to obtain a tissue diagnosis and was followed by total resection. We elected not to give radiation or chemotherapy and to follow the patient closely with serial CT scans. Presently, 48 months postoperatively, the patient is free of tumor by head CT scan and able to live independently. We reviewed the literature of primary cerebral neuroblastomas/neurocytomas occurring in adults (15 years of age) and found 32 cases. Our patient is the oldest of this group with a mean age of 32 ± 14 years (S.D.). The location of the 33 neoplasms was intraventricular in 17 cases (52%) and intraparenchymal in 16 cases. The male to female ratio was 2: 1. Of the 17 patients having a minimal follow-up period of 5 months (mean 51 months), five developed recurrences after 5 to 144 months (mean 50 months) compared to 12 patients without recurrence after a 6- to 72-month follow-up period (mean 52 months). Recurrences occurred statistically significantly more often in parenchymal neuroblastomas/neurocytomas than in intraventricular tumor locations.     

West Nile virus encephalitis with myositis and orchitis

This report documents the hospital course and autopsy findings of a 43-year-old man with a renal allograft who died of West Nile virus (WNV) encephalitis. Central nervous system (CNS) findings were those of severe necrotizing and hemorrhagic encephalitis affecting gray matter regions limited to the diencepahlon, rhombencephalon, spinal cord, and limbic system. The bilateral process exhibited preferential involvement of motor neurons. Brain imaging obtained 6 days before death demonstrated an unusual pattern of involvement corresponding with the autopsy findings, confirming that imaging may be a specific diagnostic guide in WNV encephalitis. Extra-CNS findings include myositis with T-lymphocyte infiltration of nerve fibers, suggesting that the virus may reach the CNS via peripheral nerves. Orchitis with dense T-lymphocyte infiltration and syncytial cell formation thought to be due to WNV were also noted.     

Chloride transport in the renal proximal tubule

The renal proximal tubule is responsible for most of the renal sodium, chloride, and bicarbonate reabsorption. Micropuncture studies and electrophysiological techniques have furnished the bulk of our knowledge about the physiology of this tubular segment. As a consequence of the leakiness of this epithelium, paracellular ionic transport--in particular that of Cl(-)--is of considerable importance in this first part of the nephron. It was long accepted that proximal Cl(-) reabsorption proceeds solely paracellularly, but it is now known that transcellular Cl(-) transport also exists. Cl(-) channels and Cl(-)-coupled transporters are involved in transcellular Cl(-) transport. In the apical membrane, Cl(-)/anion (formate, oxalate and bicarbonate) exchangers represent the first step in transcellular Cl(-) reabsorption. A basolateral Cl(-)/HCO(3)(-) exchanger, involved in HCO(3)(-) reclamation, participates in the rise of intracellular Cl(-) activity above its equilibrium value, and thus also contributes to the creation of an outwardly directed electrochemical Cl(-) gradient across the cell membranes. This driving force favours Cl(-) diffusion from the cell to the lumen and to the interstitium. In the basolateral membrane, the main mechanism for transcellular Cl(-) reabsorption is a Cl(-) conductance, but a Na(+)-driven Cl(-)/HCO(3)(-) exchanger may also participate in Cl(-) reabsorption.