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.     

Transvaginal ultrasound and diagnostic hysteroscopy as a predictor of endometrial polyps: risk factors for premalignancy and malignancy

The aim of this study is to assess accuracy of transvaginal ultrasound (TVUS) and diagnostic hysteroscopy in diagnosing endometrial polyps and to determine premalignancy and malignancy rates in asymptomatic women. The study was designed to retrospectively analyze 438 women who underwent operative hysteroscopy in a day-care unit when endometrial polyp was suspected after TVUS and diagnostic hysteroscopy. Multivariate logistic regression modeling showed effects of age, previous breast cancer with tamoxifen treatment, and menopause with or without bleeding on pathologic results. The results indicate that positive predictive value of TVUS with diagnostic hysteroscopy was 79.9%. Premalignancy or malignancy occurred in 3.2% and was significantly related to menopause with abnormal bleeding (P < 0.001), which carried a 20-fold higher risk of pathology than any other group. Age was also a risk factor. It was concluded that TVUS with diagnostic hysteroscopy reliably evaluates endometrial polyps. The low incidence of endometrial tumors in asymptomatic (especially premenopausal) women suggests that their operative evaluation may not be cost effective. Larger studies are needed to support this tentative conclusion.     

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.     

Factors controlling immunoglobulin production and B cell proliferation

The proliferation and the differentiation of B lymphocytes is under the control of T cell and macrophage produced cytokines which drive resting B cells to the state of antibody-producing plasma cells. Antibodies exert a feedback control of their own production via their interaction with Fc receptor (FcR) bearing cells and the production of Immunoglobulin-Binding Factors (IBF). The fact that some malignant B cells are sensitive to the same factors as normal B lymphocytes opens the possibility to use cytokines as prognostic or therapeutic tools.     

Influence of the length of the small bowel graft on the severity of graft versus host disease

The influence of the length and origin of a small bowel graft on graft versus host disease (GVHD) was studied in 33 (Lewis x brown Norway) F1 hybrids transplanted with different types of Lewis small bowel grafts. Recipients of an entire small bowel graft (N = 9), a jejunal graft (N = 6), or an ileal graft (N = 6) displayed a similar acute lethal GVHD, with 100% mortality rate and equivalent survival time (15 +/- 0.7, 16.8 +/- 0.9, and 16 +/- 0.6 days, respectively) (P greater than 0.01). On the other hand, 80% of the recipients of a segmental jejunal graft (N = 10) recovered from a transitory form of GVHD and regained weight similarly to the isografted rats (N = 4). It was concluded that the entire small bowel, jejunum, and ileum can provoke an equivalent GVHD after transplantation, whereas a segment of jejunum decreases the intensity of GVHD, probably by reducing the amount of transplanted lymphoid tissue.     

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.