Infigratinib Reduces Fibroblast Growth Factor 23 (FGF23) and Increases Blood Phosphate in Tumor-Induced Osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25-dihydroxy-vitamin D (1,25D) production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1-fibroblast growth factor receptor 1 (FN1-FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs. Based on the presumptive role of FGFR1 signaling by chimeric FN1-FGFR1 proteins, the effectiveness of infigratinib, a FGFR1-3 tyrosine kinase inhibitor, was studied in an open-label, single-center, phase 2 trial. The primary endpoint was persistent normalization of blood phosphate and FGF23 after discontinuation. Four adults with TIO (two nonlocalized, two nonresectable PMTs) were treated with daily infigratinib for up to 24 weeks. All patients had a favorable biochemical response that included reduction in intact FGF23, and normalization of blood phosphate and 1,25D. However, these effects disappeared after drug discontinuation with biochemistries returning to baseline; no patients entered biochemical remission. In the two patients with identifiable tumors, 68Gallium (68Ga)-DOTATATE and 18Fluoride (18F)-Fluorodeoxyglucose (FDG) PET/CT scans showed a decrease in PMT activity without change in tumor size. Patients experienced mild to moderate, treatment-related, dose-limiting adverse events (AEs), but no serious AEs. Three patients had dose interruptions due to AEs; one patient continued on a low dose for the entire 24 weeks and one patient stopped therapy at 17 weeks due to an AE. The study closed early due to a failure to meet the primary endpoint and a higher-than-expected incidence of ocular AEs. Infigratinib treatment lowered FGF23, increased blood phosphate, and suppressed PMT activity, confirming the role of FGFR signaling in PMT pathogenesis. However, treatment-related AEs at efficacy doses and disease persistence on discontinuation support restricting the use of infigratinib to patients with life-limiting metastatic PMTs. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Novel Neonatal Umbilical Catheter Protection and Stabilization Device in In vitro Model of Catheterized Human Umbilical Cords: Effect of Material and Venting on Bacterial Colonization.

OBJECTIVE: Umbilical central lines deliver life-saving medications and nutrition for neonates; however, complications associated with umbilical catheters (UCs) occur more frequently than in adults with central lines (i.e., line migration, systemic infection). We have developed a device for neonatal UC protection and stabilization to reduce catheter exposure to bacteria compared with the standard of care: "goal post" tape configuration. This study analyzes the effect of device venting and material on bacterial load of human umbilical cords in vitro. STUDY DESIGN: Catheters were inserted into human umbilical cord segments in vitro, secured with plastic or silicone vented prototype versus tape, and levels of bacterial colonization were compared between groups after 7 days of incubation. RESULTS: Nonvented plastic prototype showed increased bacterial load compared with goal post (p = 0.04). Colonization was comparable between the goal post and all vented plastic prototypes (p ≥ 0.30) and when compared with the vented silicone device (p = 1). CONCLUSION: A novel silicone device does not increase external bacterial colonization compared with the current standard of care for line securement, and may provide a safe, convenient alternative to standard adhesive tape for UC stabilization. Future studies are anticipated to establish safety in vivo, alongside benefits such as migration and infection reduction.

Infigratinib in upper tract urothelial carcinoma versus urothelial carcinoma of the bladder and its association with comprehensive genomic profiling and/or cell-free DNA results.

BACKGROUND: Infigratinib (BGJ398) is a potent and selective fibroblast grown factor receptor 1 to 3 (FGFR1-3) inhibitor with significant activity in patients with advanced or metastatic urothelial carcinoma bearing FGFR3 alterations. Given the distinct biologic characteristics of upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB), the authors examined whether infigratinib had varying activity in these settings. METHODS: Eligible patients had metastatic urothelial carcinoma with activating FGFR3 mutations and/or fusions. Comprehensive genomic profiling was performed on formalin-fixed, paraffin-embedded tissues. Blood was collected for cell-free DNA analysis using a 600-gene panel. Patients received infigratinib at a dose of 125 mg orally daily (3 weeks on/1 week off) until disease progression or intolerable toxicity occurred. The overall response rate (ORR; partial response [PR] plus complete response [CR]) and disease control rate (DCR; CR plus PR plus stable disease [SD]) were characterized. RESULTS: A total of 67 patients were enrolled; the majority (70.1%) had received ≥2 prior antineoplastic therapies. In 8 patients with UTUC, 1 CR and 3 PRs were observed (ORR, 50%); the remaining patients achieved a best response of SD (DCR, 100%). In patients with UCB, 13 PRs were observed (ORR, 22%), and 22 patients had a best response of SD (DCR, 59.3%). Notable differences in genomic alterations between patients with UTUC and those with UCB included higher frequencies of FGFR3-TACC3 fusions (12.5% vs 6.8%) and FGFR3 R248C mutations (50% vs 11.9%), and a lower frequency of FGFR3 S249C mutations (37.5% vs 59.3%). CONCLUSIONS: Differences in the cumulative genomic profile were observed between patients with UTUC and those with UCB in the current FGFR3-restricted experience, underscoring the distinct biology of these diseases. These results support a planned phase 3 adjuvant study predominantly performed in this population.

Does Urinary Bisphenol-A Change after Bariatric Surgery?

BACKGROUND: One of the world's highest volume chemicals is bisphenol-A (BPA), an organic compound with a high solubility in fat. An emerging body of literature has suggested a link between BPA, obesity, and insulin resistance. The study aim was to determine if surgical weight loss is associated with changes in BPA levels. STUDY DESIGN: Demographic, preoperative, and 3-, 6-, and 12-month postoperative urine and laboratory data were prospectively collected on 22 bariatric surgery patients at a single academic institution. Laboratory values included hemoglobin A1C, fasting insulin, and fasting glucose. Demographic, preoperative and postoperative data, and urinary BPA levels were compared using Student's t-tests and simple regression analyses using GraphPad Prisim6 software. RESULTS: Patients were predominantly privately insured (86%), female (83%), and white (68%). Urinary BPA excretion was negatively correlated with weight at 6 months (r = -0.47, p = 0.029) and 12 months (r = -0.65, p = 0.006). The average weight before surgery was 274 pounds. Average preoperative BPA excretion was 2.4 ng/mL (SD = 1.0 ng/mL) in patients lighter than average weight and 1.3 ng/mL (SD = 0.7 ng/mL) in patients heavier than average weight (p = 0.006). Average BPA excretion at 12 months was 2.5 ng/mL (SD = 2.2 ng/mL) among lighter patients and 0.58 ng/mL (SD = 0.4 ng/mL) among heavier patients (p = 0.05). Follow-up included 18 patients at 3 months, 22 patients at 6 months, and 16 patients at 12 months. Higher urinary excretion of BPA preoperatively correlated with lower 6-month patient weight (r = -0.557, p = 0.025). Higher preoperative fasting insulin correlated significantly with reduced BPA excretion at 6 months postoperatively (r = -0.5366, p = 0.032). CONCLUSIONS: Excretion of BPA increases as bariatric surgery patients lose weight. Heavier patients with insulin resistance may store more BPA in adipose tissue and therefore excrete less BPA.

Ultrasound-Guided Percutaneous Vein Access for Placement of Broviac Catheters in Extremely Low Birth Weight Neonates: A Series of 3 Successful Cases.

As medical and surgical interventions to support premature infants have evolved, the need for long-term vascular access in extremely low birth weight infants has increased. The classic approach to Broviac(®) (C.R. Bard, Covington, GA) catheter placement in very small neonates has been through an open surgical cutdown technique. Ultrasound guidance has emerged as a potentially beneficial method for obtaining central venous access in children and is being applied to smaller and smaller infants. This case series reports the feasibility of using ultrasound-guided percutaneous vein access to obtain a long-term central venous line in three extremely low birth weight infants who all weighed less than 850 g at the time of line placement.

Obesity-Related Hormones and Metabolic Risk Factors: A Randomized Trial of Diet plus Either Strength or Aerobic Training versus Diet Alone in Overweight Participants.

There is debate about the additive effects of exercise in conjunction with diet to treat obesity, and not much is known about the differential effects of strength versus aerobic training. This randomized controlled trial examined the effects of diet plus strength training, diet plus aerobic training, or diet only on metabolic risk factors associated with obesity. Eighty-one overweight and obese participants completed the 8-week intervention. All participants received an energy-restrictive formula diet with an energy content based on 70% of measured resting metabolic rate (RMR). Participants assigned to an exercise group trained 3 days/week under supervision. Anthropometrics and fasting hormones were assessed pre- and post-intervention. Mean weight loss (8.5 ± 4.3kg SD) did not differ between groups nor did reductions in BMI or body fat, although the diet plus strength training group showed marginally greater lean mass retention. There were significant improvements in the values and number of metabolic syndrome risk factors, and decreases in insulin concentrations and insulin resistance, which did not vary between groups. For men, testosterone increased significantly more in the diet plus aerobic training as compared to the other groups. As compared to diet alone, the addition of strength or aerobic training did not improve changes in BMI, body fat or metabolic risk factors although the diet plus strength training group showed a trend toward preservation of lean mass, and the diet plus aerobic group in men resulted in increased testosterone concentrations.