GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma.

BACKGROUND: GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. OBJECTIVES: To characterize these tumours in terms of clinical behaviour and genetic characteristics. METHODS: Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. RESULTS: We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). CONCLUSIONS: Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented. GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma. What does this study add? GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma. GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma. What is the translational message? Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma. As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed. Linked Comment: Rafei-Shamsabadi. Br J Dermatol 2020; 183:806-807.

Oral transmucosal midazolam premedication for preschool children.

PURPOSE: To evaluate the acceptance and effectiveness of 0.2 mg x kg(-1) of oral transmucosal midazolam as a premedicant in infants and preschool children. METHOD: In a randomized, prospective double-blind placebo controlled study, 44 healthy children, between the ages of eight months to six years, presenting for elective surgery were divided in two groups. The medicated group received 0.2 mg x kg(-1) of injectable midazolam mixed with an equal volume of strawberry syrup and the placebo group received plain syrup 0.08 ml x kg(-1). Medications were placed on the anterosuperior aspect of the child's tongue in 3-5 aliquots of 0.2-0.4 ml. A blinded observer assessed the acceptance of the medication by willingness to open the mouth for the next aliquot and the efficacy of the medication was assessed by ease of separation from the parent. RESULTS: Ninety-six percent of the children in the placebo group and 95% in the midazolam group willingly accepted the medication. Separation of children from parents was successful in 95% of the medicated children compared with 59% in the placebo group (P = 0.006). CONCLUSION: Oral midazolam in thick strawberry syrup, administered in small aliquots via the oral transmucosal route was well accepted and proved to be an effective premedicant in infants and preschool children.

False alarms and sensitivity of conventional pulse oximetry versus the Masimo SET technology in the pediatric postanesthesia care unit.

UNLABELLED: We compared the incidence and duration of false alarms (FA)and the sensitivity of conventional pulse oximetry (CPO) with Masimo Signal Extraction Technology (Masimo SET; Masimo Corporation, Irvine, CA) in children in the postanesthesia care unit. Disposable oximeter sensors were placed on separate digits of one extremity. Computerized acquisition of synchronous data included electrocardiograph heart rate, SpO(2), and pulse rate via CPO and Masimo SET. Patient motion, respiratory, and other events were simultaneously documented. SpO(2) tracings conflicting with clinical observations and/or documented events were considered false. These were defined as 1) Data dropout, complete interruption in SpO(2) data; 2) False negative, failure to detect SpO(2)

A comparison of continuous epidural infusion and intermittent intravenous bolus doses of morphine in children undergoing selective dorsal rhizotomy.

BACKGROUND AND OBJECTIVES: Selective dorsal rhizotomy (SDR) is associated with moderale to severe postoperative pain. Although the efficacy of epidural analgesia in this population has been demonstrated, it has not been compared with conventional intravenous (i.v.) analgesia. This prospective study compared the effects of epidural and i.v. morphine regarding postoperative analgesia, side effects, and outcomes in children following SDR. METHODS: Twenty-seven children were randomized to receive either epidural or i.v. analgesia. Children in the epidural group had a catheter placed by the neurosurgeon and received preservative-free morphine (Duramorph) 30 microg/kg, followed by an infusion of 3 microg/kg/h for 3 days. Children in the i.v. group received morphine 0.05-0.1 mg/kg intraoperatively, followed by 0.02 mg/kg doses postoperatively administered by nurses via a patient-controlled analgesia device. RESULTS: The epidural group experienced lower pain scores (P = .04) and fewer muscle spasms (P < or = .04), and tolerated activity better (P < or = .02) during the early postoperative period than the i.v. group. Side effects were similar between groups, with no respiratory depression in either group. Parents of children in both groups perceived an adequate level of comfort and were very satisfied with the analgesic technique. Additionally, parents believed that their child's postoperative pain was less than anticipated (P < or = .01). CONCLUSIONS: Both techniques provided effective postoperative analgesia with a similar incidence of side effects; however, our findings suggest that continuous infusions of epidural morphine improved overall comfort with lower pain scores, fewer muscle spasms, and improved tolerance of activity during the initial postoperative period.

Prolonged recovery stay and unplanned admission of the pediatric surgical outpatient: an observational study.

STUDY OBJECTIVE: To determine the incidence of and reasons for prolonged length of stay in the postanesthesia care unit and unplanned hospital admissions of children scheduled for outpatient surgery. DESIGN: Prospective, observational cohort study. SETTING: C. S. Mott Children's Hospital, a tertiary care setting. PATIENTS: 168 ASA physical status I, II, and III children (birth to 18 years), 130 of whom experienced a prolonged length of stay and 61 who had an unplanned hospital admissions. MEASUREMENTS AND MAIN RESULTS: 3.9% of annual outpatient population experienced a prolonged length of stay, and 1.9% had an unplanned outpatient admission. Prolonged length of stay was most commonly due to postoperative nausea and vomiting (19%) or respiratory complications (16%), whereas unplanned hospital admissions were primarily for respiratory or surgical reasons (32% and 30%, respectively). Higher ASA status had a significant direct relationship with the incidence of unplanned outpatient admission and respiratory complications. Although most families were satisfied with the length of their child's care, 28% of parents whose children were sent home after a prolonged length of stay would have preferred a short hospital admission, and 16% of parents of children with an unplanned hospital admission would have preferred a longer stay in recovery and discharge home. CONCLUSION: Prolonged length of stay and unplanned hospital admissions were uncommon outcomes following pediatric outpatient surgery. However, the impact of such outcomes on hospital staffing and family convenience may have implications related to cost containment and patient satisfaction.

The relationship between extracorporeal circuit prime, albumin, and postoperative weight gain in children.

OBJECTIVES: This study evaluated postoperative weight gain in children who received albumin versus crystalloid prime for cardiopulmonary bypass (CPB). DESIGN: A retrospective case-controlled study. Children whose extracorporeal (EC) circuit prime contained albumin (group 1) were matched with those whose prime contained only crystalloid (group 2) on the basis of age, weight, and surgical repair. SETTING: A university-based medical center. PARTICIPANTS: Seventy-six children (newborn to 4 years of age) who underwent CPB for correction of a congenital heart anomaly from 1993 to 1995. Group 1 underwent surgery from October 1994 to September 1995, and group 2 from February 1993 to September 1994. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Group 1 had less weight gain on postoperative days (PODs) 1, 2 and 3 compared with group 2 (p = 0.04 on POD 1). Albumin (grams per milliliter) prime and prime volume in milliliters per kilogram were the best predictors of weight gain (p < 0.004), with prime volume being the more important. Children who weighed less than 7.5 kg received more prime volume and had greater weight gain than children who weighed 7.5 kg or greater on PODs 1, 2, and 3 (p < 0.02). CONCLUSION: Data suggest that adding albumin to the EC circuit prime and minimizing the prime volume will result in less postoperative weight gain. Further prospective study with a larger sample is warranted to determine whether albumin prime offers other clinical benefits.

Evaluation of simethicone for the treatment of postoperative abdominal discomfort in infants.

STUDY OBJECTIVE: To determine whether abdominal discomfort is a cause for distress symptoms in infants following administration of inhalational anesthesia, and to evaluate the effectiveness of simethicone in treating this discomfort. DESIGN: Randomized, double-blinded study. SETTING: Large tertiary care, university-based medical center. PATIENTS: 175 ASA physical status I and II infants under 28 months of age who underwent an inhalational anesthetic for a variety of procedures that were expected to cause relatively little pain. INTERVENTIONS: Children were assessed for the presence of postoperative abdominal discomfort, and, if evident, were randomly given either simethicone or placebo in a double-blinded fashion. MEASUREMENTS AND MAIN RESULTS: Abdominal discomfort was measured using the Faces Legs Activity Cry and Consolability (FLACC) Behavioral Pain Scale. Scores were recorded pre-drug; at 10, 20, and 30 minutes following drug administration; and at discharge. If discomfort had not resolved within 15 minutes after the drug was given, routine analgesics or other medications were administered. Abdominal girth was measured preoperatively, on admission into the postanesthesia care unit (PACU), and at discharge. 21% of infants exhibited symptoms of abdominal discomfort postoperatively. Younger infants were at greater risk for this condition. 36 infants were given either placebo or simethicone, and of these, infants who received simethicone were comfortable earlier and required fewer rescue medications compared with placebo. There were no differences in ability to tolerate oral fluids prior to discharge or in the length of stay in the PACU. CONCLUSIONS: Simethicone is a safe and inexpensive medication that may provide anesthesiologists with an effective treatment choice for suspected postoperative abdominal discomfort in infants.

Factors that influence parents' decisions to consent to their child's participation in clinical anesthesia research.

UNLABELLED: There is concern that the environment in which consent for anesthesia research is sought may be coercive. We therefore designed this study to determine the factors that parents consider in consenting to their child's participation in clinical anesthesia research. The study sample consisted of 246 parents who had been approached for permission to allow their child to participate in a clinical anesthesia study. Parents were asked to complete a questionnaire detailing the reasons for their decision to consent or decline their child's participation. There were no differences in the demographics of the consenters (n = 168) and nonconsenters (n = 78). Perceived risk and the importance of the study were the primary factors in the parents' decisions to consent or decline. Only 2.8% of nonconsenters strongly considered a lack of privacy as a deciding factor; 15.3% stated that they had insufficient time in which to make a decision, and 0% reported having felt pressured. Furthermore, only 3.1% of consenters strongly considered an obligation to consent. Results of this survey highlight factors that influence parents' decisions to consent to their child's participation in clinical anesthesia research. We hope that this information will be important to researchers in providing an appropriate environment for obtaining consent for clinical anesthesia research studies. IMPLICATIONS: Parents who are approached for permission for their child to participate in a research study must be fully informed and under no pressure to consent. This study describes factors that influence parents' decisions to consent to their child's participation in clinical anesthesia research.

Effects of anesthetic technique on side effects associated with fentanyl Oralet premedication.

STUDY OBJECTIVES: To evaluate the efficacy of 5 to 10 micrograms/kg of oral transmucosal fentanyl citrate (OTFC) as an anesthetic premedication, and to determine whether propofol induction reduces postoperative nausea and vomiting (PONV) in pediatric patients premedicated with OTFC undergoing outpatient surgery. DESIGN: Prospective, randomized, double-blinded study. SETTINGS: University of Michigan Health Care Systems and University of Arizona. PARTICIPANTS: 62 ASA physical status I and II children aged 4 to 14 years (8.9 +/- 0.5 years). INTERVENTIONS: Subjects were randomly assigned to one of four groups: (1) OTFC premedication and halothane induction; (2) OTFC premedication and propofol induction; (3) placebo premedication and halothane induction; and (4) placebo premedication and propofol induction. OTFC or placebo was administered 30 minutes prior to induction, and activity (sedation), apprehension, and cooperation scores were recorded before, at 15 and 30 minutes after study drug, and on induction. All perioperative adverse events were recorded. MEASUREMENTS AND MAIN RESULTS: Children who received OTFC became drowsier and had a significant change from baseline in combined activity, apprehension, and cooperation scores, whereas those who received placebo became less cooperative at induction. Patients who received OTFC experienced more adverse events overall (p < 0.001) than patients who received placebo. Additionally, OTFC patients experienced more vomiting (p < 0.001) and pruritus (p = 0.049) than controls. The incidence of PONV in patients who received OTFC and halothane induction was 50%, compared to 30% in patients receiving OTFC and a propofol induction (p = NS). CONCLUSIONS: OTFC in doses of 5 to 10 micrograms/kg was effective in producing sedation and facilitating cooperation with induction; however, it was associated with significant PONV in our study. Although propofol induction did not significantly reduce PONV in our study, further study with a larger sample, and with propofol as the sole anesthetic, may be warranted.

Quality control of peptide drugs. Chiral amino acid analysis versus standard for icatibant acetate.

A method of chiral amino acid analysis versus standard is presented. By treating the peptide sample and a chiral standard whose intrinsic chiral composition is known in the same way, i.e. simultaneous hydrolysation and analysis, exact corrections can be made for the sequence-related and many hydrolysation-related racemisations. The accuracy obtained in this way permits use of the results for quality control of the chiral purity of peptide drugs. Using the bradykinin antagonist Icatibant acetate (INNM) the method was validated with respect to its precision, accuracy, specificity, limit of detection, and robustness.

Plasma concentrations of S-verapamil after single doses of two different galenic formulations of racemic verapamil.

The results of enantioselective analysis of verapamil (CAS 52-53-9) in plasma samples obtained at tmax after single dose applications of a 80 mg fast dissoluting (IR) tablet, a controlled release (CR) formulation (240 mg) and an intravenous injection of 5 mg verapamil are reported. The mean fraction of S-verapamil obtained in samples containing the Cmax of racemic verapamil was somewhat smaller after application of the IR-form than observed with the CR formulation. (IR = 15.8 +/- 3.8%; CR = 18.8 +/- 2.0%; p < 0.01), after the intravenous application the mean S-fraction was 32.8 +/- 1.4%. In vitro dissolution tests of the two oral preparations prove that the isomers were released as racemate.

Perspectives of in vitro dissolution tests in establishing in vivo/in vitro correlations.

Perspectives of in vitro dissolution tests in establishing an in vivo/in vitro correlation are considered at three different levels. The first involves the selection of a drug product, or suitable batch(es), for the correlation study. This requires evaluation of the biopharmaceutical properties of the proposed drug from a profile compiled from a set of dissolution tests under different experimental conditions. These characteristics are needed for properly designing the in vivo study and are also referred to when only a poor correlation is obtained. The second is to define the specific in vitro test system either prospectively, by assessing plausibility of in vitro results, or retrospectively, after interpretation of in vivo data. This distinct test system has to be validated both physically and analytically. The third aspect of dissolution testing for correlations is to provide sound data and derived parameters in consideration of statistical aspects (variability) and of a sufficient number of suitable sampling intervals. In vitro models proposed for the special study of the simulation of food effects on bioavailability are discussed but concluded to be as yet not satisfactory for general application.

Concentration/effect relationship and enantioselective analysis of verapamil in hypertensive patients.

The concentration/effect relationship of verapamil was analyzed in 9 hypertensive patients using concentrations of racemic verapamil and the corresponding decrease in mean arterial blood pressure (MBP) in a sigmoidal Emax model. Concentration/effect data were obtained after a first dose (240 mg sustained release preparation) and at steady state after stepwise dose adjustment to obtain satisfactory BP control (less than 90/150 mm Hg). Emax (MBP) ranged from 15 to 40 mm Hg, and EC50 averaged 81 +/- 40 ng/ml (mean +/- SD). The fraction of S-verapamil in the overall racemic verapamil concentrations was measured in two patients by chiral high-performance liquid chromatography (HPLC) and showed a slight increase at steady state from 12.2 +/- 1.5 to 14.4 +/- 1.4% and from 14.0 +/- 1.3 to 16.3 +/- 0.6%. Concentration/effect curves for S-verapamil concentrations were similar to those obtained with racemic verapamil concentrations.

[Bioavailability and bioequivalence of organic nitrates. Isosorbide dinitrate--a study of sustained-release preparations]. / Bioverfügbarkeit und Bioäquivalenz von organischen Nitraten. Isosorbiddinitrat-Untersuchungen zu Fertigarzneimitteln mit retardierter Wirkstoff-Freisetzung.

Assessment of Bioavailability of Organic Nitrates/Comparative bioavailability study of sustained-release isosorbide dinitrate preparations. Relative bioavailabilities of isosorbide dinitrate (ISDN, CAS 87-33-2) and the metabolite isosorbide-5-mononitrate (IS-5-MN, CAS 16051-77-7) were studied after application of Maycor retard 40 (sustained-release capsules, multiple unit formulation, test preparation) in comparison to sustained-release tablets (single unit formulation, reference preparation) with 16 healthy male volunteers in a two-way crossover design. Test and reference formulations were previously characterised in vitro by dissolution tests. ISDN, IS-5-MN (IS-2-MN) plasma concentrations were determined using a selective and sensitive GLC-method with ECD-detection. As pharmacokinetic parameters AUC, Cmax and half value duration (HVD) were evaluated. Bioequivalence was assessed by calculating 90%-confidence intervals (ANOVA, ANOVAlog, Mann-Whitney-test) for ISDN and IS-5-MN. Bioequivalence was accepted if due to the inclusion rule one of the calculated intervals fulfill the requirements of 80 and 120% (AUC) or 70 and 130% (Cmax, HVD), respectively. Relative bioavailability of the test formulation was calculated as 94% (ISDN) and 96% (IS-5-MN). Maximum plasma concentrations of ISDN (IS-5-MN) were determined for the test preparation as 14.3 +/- 3.1 ng/ml (265 +/- 45 45 ng/ml) and as 22.8 +/- 12.6 ng/ml (287 +/- 59 ng/ml) for the reference product. HVD-values were for the test preparation 4.5 +/- 1.3 h (ISDN) and 8.5 +/- 1.3 h (IS-5-MN) and for the reference formulation 3.1 +/- 1.2 h (ISDN) and 8.1 +/- 1.4 (IS-5-MN).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamic profile of verapamil in relation to absolute bioavailability: investigations with a conventional and a controlled-release formulation.

The absolute bioavailability F and response (prolongation of the PR interval) of verapamil after single doses of the same oral formulation administered on two different days were investigated in 16 male subjects with an 80 mg fast dissolving and a 240 mg controlled-release preparation and compared with a bolus injection of 5 mg of verapamil. The absolute bioavailability was 23% in both investigations for the 80 mg preparation and 32% in both investigations for the 240 mg dosage form. The individual values obtained for tmax, cmax, F, and AUC0-alpha showed a wide intersubject variability; therefore, no significant differences could be observed between the two trials for each dosage, but significant differences existed between the investigations of the two preparations. After intravenous administration, concentration-effect curves were about twofold left shifted when compared with the 80 mg tablet and about threefold left shifted when compared with the 240 mg tablet. Estimation of the drug input rate showed significantly (p less than 0.05) smaller values when the controlled-release tablet was given (80 mg tablet: 95.1 and 107.7 mg/h; 240 mg tablet; 55.8 and 46.3 mg/h). Thus, the effect and bioavailability of verapamil show sufficient intersubject reproducibility if the same formulation is given. The differences between the responses and the bioavailability after administration of different preparations may be related as well to the drug absorption rate and the stereoselective first pass of verapamil as to saturation of first-pass metabolism.