Selinexor for the treatment of recurrent or metastatic salivary gland tumors: Results from the GEMS-001 clinical trial.

OBJECTIVES: We aimed to evaluate the activity of selinexor, an oral selective inhibitor of nuclear export, in patients with recurrent or metastatic salivary gland tumors (SGT). METHODS: GEMS-001 is an open-label Phase 2 study for patients with recurrent or metastatic SGT with two parts. In Part 1 of the protocol, patients had tumor samples profiled with targeted next generation sequencing as well as immunohistochemistry for androgen receptor, HER-2 and ALK. For Part 2, patients with no targeted therapies available were eligible to receive selinexor 60 mg given twice weekly every 28 days. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS) and prevalence of druggable alterations across SGT. RESULTS: One hundred patients were enrolled in GEMS-001 and underwent genomic and immunohistochemistry profiling. A total of 21 patients who lacked available matched therapies were treated with selinexor. SGT subtypes (WHO classification) included adenoid cystic carcinoma (n = 10), salivary duct carcinoma (n = 3), acinic cell carcinoma (n = 2), myoepithelial carcinoma (n = 2), carcinoma ex pleomorphic adenoma (n = 2) and other (n = 2). Of 18 evaluable patients, stable disease (SD) was observed in 17 patients (94%) (SD ≥6 months in 7 patients (39%)). However, no objective responses were observed. The median PFS was 4.9 months (95% confidence interval, 3.4-10). The most common treatment-related Grade 1-2 adverse events were nausea [17 patients (81%)], fatigue [16 patients (76%)], and dysgeusia [12 patients (57%)]. Most common treatment-related Grade 3-4 adverse events were hyponatremia [3 patients (14%)], neutrophil count decrease [3 patients (14%)] and cataracts [2 patients (10%)]. No treatment-related deaths were observed. CONCLUSIONS: Although tumor reduction was observed across participants, single agent selinexor anti-tumor activity was limited.

Effectiveness of a hospital-based postnatal parent education intervention about pain management during infant vaccination: a randomized controlled trial.

BACKGROUND: Parents have reported that they want to learn how to reduce pain in infants during vaccinations. Our objective was to compare different levels of intensity of postnatal education about pain mitigation on parental self-reported use of interventions at future infant vaccinations. METHODS: We conducted a longitudinal, 3-group parallel, add-on, randomized controlled trial on the postnatal ward of a hospital. New mothers, unaware of the hypothesis, were randomly assigned to 1 of 3 intervention groups and 3 follow-up groups (i.e., 9 groups, 3 × 3). The 3 intervention groups were control (general immunization information), pain pamphlet (pain mitigation information), and pain pamphlet and pain video (pain mitigation information). Both pain mitigation education groups also received general immunization information. The 3 follow-up groups were 2-, 4- and 6-month infant vaccinations. Mothers reported use of breastfeeding, sucrose and topical anesthetics during infant vaccinations in a telephone survey. RESULTS: Of 3420 participants, follow-up was available for 2549 (75%): 36.1%, 34.2% and 29.7% reported on pain mitigation practices at 2-, 4- and 6-month vaccinations, respectively (p = 0.9). Maternal characteristics did not differ (p > 0.05): mean age, 33.6 years; 58% were primipara. Utilization of any intervention (breastfeeding, sucrose or topical anesthetics) was 53.2%, 61.4% and 63.0% for control, pain pamphlet, and pain pamphlet and pain video groups, respectively (p < 0.001); both pain education groups had higher utilization than the control group, but did not differ from one another. Uptake differed among intervention groups at 2 and 4 months but not at 6 months. INTERPRETATION: Hospital-based postnatal education increased parental use of pain interventions at infant vaccinations and can be added to existing education. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01937143.

Protective effects of ferulic acid and related polyphenols against glyoxal- or methylglyoxal-induced cytotoxicity and oxidative stress in isolated rat hepatocytes.

Glyoxal (GO) and methylglyoxal (MGO) cause protein and nucleic acid carbonylation and oxidative stress by forming reactive oxygen and carbonyl species which have been associated with toxic effects that may contribute to cardiovascular disease, complications associated with diabetes mellitus, Alzheimer's and Parkinson's disease. GO and MGO can be formed through oxidation of commonly used reducing sugars e.g., fructose under chronic hyperglycemic conditions. GO and MGO form advanced glycation end products which lead to an increased potential for developing inflammatory diseases. In the current study, we have investigated the protective effects of ferulic acid and related polyphenols e.g., caffeic acid, p-coumaric acid, methyl ferulate, ethyl ferulate, and ferulaldehyde on GO- or MGO-induced cytotoxicity and oxidative stress (ROS formation, protein carbonylation and mitochondrial membrane potential maintenance) in freshly isolated rat hepatocytes. To investigate and compare the protective effects of ferulic acid and related polyphenols against GO- or MGO-induced toxicity, five hepatocyte models were used: (a) control hepatocytes, (b) GSH-depleted hepatocytes, (c) catalase-inhibited hepatocytes, (d) aldehyde dehydrogenase (ALDH2)-inhibited hepatocytes, and (e) hepatocyte inflammation system (a non-toxic H2O2-generating system). All of the polyphenols tested significantly decreased GO- or MGO-induced cytotoxicity, ROS formation and improved mitochondrial membrane potential in these models. The rank order of their effectiveness was caffeic acid∼ferulaldehyde>ferulic acid>ethyl ferulate>methyl ferulate>p-coumaric acid. Ferulic acid was found to decrease protein carbonylation in GSH-depleted hepatocytes. This study suggests that ferulic acid and related polyphenols can be used therapeutically to inhibit or decrease GO- or MGO-induced hepatotoxicity.