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.     

Long-term results in the treatment of menorrhagia and hypermenorrhea with a thermal balloon endometrial ablation technique.

BACKGROUND AND OBJECTIVES: Evaluation of long-term results using a thermal balloon endometrial ablation technique to treat menorrhagia and hypermenorrhea, considered dysfunctional uterine bleedings. METHODS: A single-arm, prospective study with long-term follow-up of 48 months at the department of obstetrics and gynecology, University of Kiel, Germany. Following hysteroscopic evaluation of the uterine cavity and fractionated curettage, the Cavaterm endometrial thermal ablation technique was performed on 70 patients over the age of 40 with menorrhagia and hypermenorrhea in whom medical treatment had previously failed. The study included a group of 10 patients with adenomyosis and uterine fibroids. RESULTS: In 65 patients, a complete 48-month follow-up evaluation was possible: 58% of patients reported amenorrhea and 33% hypomenorrhea. Nine percent of patients remained eumenorrheic. Fifty percent of the small group with failed indications for the procedure had to undergo a hysterectomy. CONCLUSIONS: The Cavaterm thermal coagulation system in the earlier mode of application (15 minutes at a temperature of 70 degrees C and a pressure of 200 mm Hg) is a safe and highly effective method of endometrial ablation resulting in a minimal amount of posttreatment menstrual bleeding.     

Role and value of laparoscopic training devices in assessing nondominant and two-handed dexterity

Background and objectives: To determine improvement in hand dexterity with targeted laparoscopic skill exercises desirable for use in the operating rooms among in-training laparoscopic gynaecological surgeons and medical students. Design: Cross-sectional study with paired analysis. Setting: Kiel School of Gynaecological Endoscopy and Reproductive Medicine, Germany, between February and April 2005. Subjects: Twenty third-year medical students and 20 in-training gynaecological endoscopic surgeons from various parts of the world. Interventions: Demonstration and explanation of a set of five laparoscopic skill exercises desirable for use in the operating rooms before administering a pretest. This was followed by voluntary practice of these exercises for at least 10 times over 1 day. The posttest was performed the next day once the participant was comfortable performing the skill. Pre- and posttest assessments were conducted by independent supervisors. Main outcome measures: Time to completion of tasks with minimal errors. Results: There was significant reduction in mean time for all the laparoscopic skill exercises performed with dominant, nondominant, and both hands, before and after the training and practice (p-value <0.01; paired t-test). Moderate to high correlation (0.617–0.901) was seen with the intermediate and complex/difficult tasks, whereas low correlation was seen with the simple/easy task (0.200–0.336). Medical students and gynaecologists both showed improvement in performance from pretest to posttest in terms of reduction in mean time taken to perform all the tasks with minimal errors. Conclusions: Simple laparoscopic training devices can substantially help an individual hand’s improvement and acquisition of laparoscopic skills. Simple laparoscopic training devices along with animal models will continue to provide an efficient and effective environment for learning and teaching laparoscopic surgical skills. With this training, performance improves progressively with practice.     

Realität der operativen endoskopischen Chirurgie in der gynäkologischen Chirurgie

Zusammenfassung Das Spektrum der gyn?kologisch-operativen Endoskopie hat sich seit den Tagen von RaoulPalmer in Frankreich 1964 mit den gut 25-j?hrigen Aktivit?ten von KurtSemm zum h?ufigsten gyn?kologischen Eingriff überhaupt entwickelt. Am gesamten Genitale, am Uterus, den Tuben und an den Ovarien lassen sich fast alle benignen Ver?nderungen endoskopisch diagnostizieren und therapieren. Selbst die endoskopischee supracervikale Hysterektomie stellt heutzutage keine schwierige Operation mehr dar. Die atypisch lokalisierte Schwangerschaft kann pelviskopisch diagnostiziert und therapiert werden. Bei malignen Ver?nderungen raten wir derzeit von einer endoskopischen Therapie ab, da das Metastasierungsrisiko noch nicht ausdiskutiert ist. Die pelvine Lymphonodektomie ist endoskopisch leicht m?glich und die Chirurgen und Urologen gehen uns dabei bereits endoskopisch voran. Die „Minimal Invasive Chirurgie“ per endoskopiam ist keine Schlüssel-Loch-Chirurgie mehr, sondern wird auf dem Videoschirm bereits allen im Operationssaal anwesenden ?rzten und Schwestern zur Kritik und Verbesserung zug?nglich gemacht. Ein echtes Teamwork von Operateur, Assistent, Kameramann und Schwester führt zu einer für die Patientin bei Einhalten der Sicherheitsschritte befriedigenden und sicheren Operation. Das gesamte Spektrum der Operationen in der Gyn?kologie hat sich auch per laparotomiam in den letzten Jahren der Organerhaltung zugewandt. Eine kombinierte medikament?s-operative Therapie erlaubt jetzt selbst die Uteruserhaltung bei Myomen, die knapp s?uglingskopfgro? werden k?nnen. Grenzen zur endoskopischen Chirurgie setzt heute immer noch das Instrumentarium, obwohl dieses der modernen Zeit zunehmend angepa?ter von vielen Firmen weiter entwickelt wird. Beispiele dafür bietet der Serrated Edged Macro-Morcellator S.E.M.M. zur Entfernung von bis zu faustgro?en Myonen und verbesserte Nahttechniken. End-Zu-End-Anastomosen an den Tuben, die noch vor einigen Jahren Dom?nen der Mikrochirurgie waren, sind mit der gleichen Erfolgsrate pelviskopisch durchführbar. Ovarialtumoren werden unter zu Hilfenahme verschiedener Technologien (Laser, Koagulation etc.) aus ihrem Bett ausgesch?lt und aus der K?rperh?hle extrahiert. Die Ovarialnaht wird durch eine Endonaht oder durch Fibrinkleber adaptiert.     

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.     

Role of laparoscopy in identifying the clinical significance and cause of adhesions and chronic pelvic pain: a retrospective review at the Kiel School of Gynecological Endoscopy.

OBJECTIVES: We sought to define the role of laparoscopy in identifying the clinical significance, cause, and association between adhesions and chronic pelvic pain. METHODS: A retrospective chart review was conducted from October 2004 to July 2005, at the Kiel School of Gynecological Endoscopy, University Hospitals Schleswig-Holstein, Campus Kiel, Germany. Included in the study was the analysis of 462 laparoscopic procedures; 275 (59.5%) of the patients undergoing these procedures had pelvic or abdominal adhesions. Of these, 84 (30.5%) patients were admitted with the main complaint of chronic pelvic pain. Further evaluation and assessment of this group was carried out. RESULTS: Among those patients with adhesions, the second most frequent reason for admission was chronic pelvic pain (30.5%) (P<0.0005). In our study, adhesions were found in 79.2% (n=84) of patients (n=106) with chronic pelvic pain. These adhesions were thin-filmy (19.0%) or thick-fibrous (81.0%) adhesions containing blood vessels. Thick-fibrous adhesions were present in 50.0% of patients at multiple abdominopelvic sites (P<0.005). CONCLUSIONS: Thick-fibrous adhesions that extend beyond the pelvic sidewall can cause significant chronic abdominopelvic pain.     

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.