Expanding the spectrum of low-grade sinonasal adenocarcinoma with biphasic seromucinous differentiation and activating HRAS/AKT1 mutations.

AIMS: Low-grade non-intestinal-type sinonasal adenocarcinoma (LGSNAC) is a rare heterogeneous and poorly characterised group of tumours, distinct from intestinal- and salivary-type neoplasms. Therefore, further characterisation is needed for clearer biological understanding and classification. METHODS AND RESULTS: Clinical, histological and molecular characterisation of four cases of biphasic, low-grade adenocarcinomas of the sinonasal tract was performed. All patients were male, aged between 48 and 78 years, who presented with polypoid masses in the nasal cavity. Microscopically, virtually all tumours were dominated by tubulo-glandular biphasic patterns, microcystic, focal (micro)papillary, oncocytic or basaloid features. Immunohistochemical staining confirmed biphasic differentiation with an outer layer of myoepithelial cells. Molecular profiling revealed HRAS (p.G13R, p.Q61R) mutations, and concomitant AKT1 (p.E17K, p.Q79R) mutations in two cases. Two cases showed potential in-situ/precursor lesions adjacent to the tumour. Follow-up periods ranged from 1 to 30 months, with one case relapsing locally after 12 and > 20 years. CONCLUSION: This study further corroborates a distinct biphasic low-grade neoplasm of the sinonasal tract with seromucinous differentiation. Although morphological and molecular features overlap with salivary gland epithelial-myoepithelial carcinoma, several arguments favour categorising these tumours within the spectrum of LGSNAC.

Surgical Treatment of Brooke-Spiegler Syndrome.

ABSTRACT: Brooke-Spiegler Syndrome (BSS) is a very rare autosomal dominant hereditary disease which arises from heterozygous mutations in the CYLD gene. Patients with BSS are predisposed to multiple skin appendage tumors such as cylindromas, which are benign tumors occurring mainly on the scalp. The tumors mostly appear around puberty and usually show slow growth throughout life. Malignant cylindroma formation in BSS patients has been reported. Apart from the skin, major and minor salivary glands have rarely been involved.We here report a case of a 46-year-old female patient with BSS presenting with multiple aesthetically and functionally unpleasing cylindromas covering almost her entire hair-bearing scalp with further tumors on her face. Interestingly, her parotid glands were enlarged and showed multiple lesions with a diameter up to 18 to 20 mm. She was successfully treated by total subgaleal scalp excision and coverage through a dermal substitute and split thickness skin graft. Constant follow-up imaging was initiated to prevent unhindered tumor growth of salivary glands.

No interacting influence of lavender oil preparation silexan on oral contraception using an ethinyl estradiol/levonorgestrel combination.

PURPOSE: Silexan is an oral Lavender oil preparation with proven anxiolytic efficacy. Given the high prevalence of anxiety and restlessness in younger women, oral contraceptives and Silexan will likely be co-administered. METHODS: A double-blind, randomised, 2-period crossover study was performed to investigate the effects of Silexan on the pharmacokinetics and pharmacodynamics of Microgynon(®), a combination oral contraceptive containing ethinyl estradiol 0.03 mg (EE) and levonorgestrel 0.15 mg (LNG) in healthy, fertile, adult females. During 2 consecutive cycles of 28 days, oral contraception was given for 21 days combined with 1 × 160 mg/day Silexan or placebo. Plasma concentration-time profiles of EE and LNG were obtained on day 18 ± 1 up to 24 h after dosing. The primary outcome measure was the area under the concentration-time curve over a dosing interval of τ = 24 h (AUCτ) for EE and LNG plasma levels. An interaction with Silexan was formally excluded if the 90 % confidence interval for the AUCτ ratio during co-administration with Silexan or placebo was included within the range of 0.80-1.25. Secondary outcomes included EE and LNG peak concentration (C max) and time to C max (t max), follicle size, endometrial thickness, the Hoogland score, and serum levels of estradiol, progesterone, and sex hormone-binding globulin. RESULTS: A total of 24 women (mean age 27.3 years; mean body mass index 22.2 kg/m(2)) participated. The confidence intervals for the EE and LNG AUCτ and C max ratios fell within the pre-specified limits, indicating no interaction (point estimates [Silexan/placebo] AUCτ EE 0.97, LNG 0.94; C max EE 0.99, LNG 0.96). For LNG, t max was slightly delayed. No secondary outcome indicated any impairment of contraceptive efficacy. CONCLUSIONS: Co-administration of Silexan did not affect the efficacy of a combination oral contraceptive containing EE and LNG and was well tolerated.

Pharmacokinetics, safety and tolerability of mipomersen in healthy Japanese volunteers and comparison with Western subjects.

OBJECTIVES: To characterize the safety, tolerability, pharmacokinetics (PK) and dose proportionality of mipomersen after single subcutaneous (SC) administration to Japanese healthy subjects; and to compare the PK profiles of Japanese and Western subjects. METHODS: 20 healthy first-generation Japanese male subjects were enrolled into one of three treatment cohorts (50, 100 and 200 mg SC) in a dose-escalation design. Within each cohort, subjects were randomized in a 4 : 1 ratio to receive mipomersen or placebo. RESULTS: Mipomersen was absorbed rapidly after SC administration; median tmax varied between 2 and 3 hours. After reaching peak levels, plasma concentrations of mipomersen decayed multiphasically with an initial distribution t1/2 in several hours and a terminal t1/2 of 261 - 393 hours. Mean Cmax increased in a dose-linear manner while all mean AUC from time 0 to different cut points increased slightly more than dose proportionally. Although mean terminal t1/2 varied in the dose range tested, it did not show dose-dependence. The PK profiles of mipomersen in Japanese subjects are similar to those observed in Western subjects. A single SC dose of 50 mg, 100 mg and 200 mg mipomersen was well tolerated by male Japanese subjects. CONCLUSION: Single SC doses of 50 - 200 mg were safe and well tolerated when administered to Japanese subjects. Comparison of PK between Japanese and Western subjects does not support any need for dose adjustment in Japanese population in future clinical development.

Tympanoplasty in chronic otitis media patients with an intact, but severely retracted malleus: a treatment challenge.

OBJECTIVE: To analyze the outcome of patients with chronic otitis media (COM) with an intact, but markedly medialized ossicular chain, treated by removing the malleus head and interposing an autologous incus and then an underlay myringoplasty. STUDY DESIGN: Retrospective clinical study. SETTING: Tertiary referral center. PATIENTS: The search criteria within the prospective surgical database was COM with a central perforation (without cholesteatoma) with a markedly medialized malleus handle (the umbo adherent to the promontory) with an intact ossicular chain (study, n = 15) or an incus necrosis at the lenticular process (incus, n = 23). Only primary surgeries performed at our otorhinolaryngology department were included. INTERVENTION: All patients underwent the same surgical procedure consisting of an autologous incus interposition and underlay myringoplasty with temporalis fascia. MAIN OUTCOME MEASURE: The patients' audiological and follow-up data were retrieved from the database. The postoperative audiogram (0.5-3 kHz) with the longest follow-up was used. RESULTS: The preoperative air-conduction thresholds were less impaired in the study group than in the incus group. After their surgery, all, except 3 patients, improved their hearing, and 97% had an intact tympanic membrane at a mean follow-up of 2 years. The air-bone gap was closed within 20 dB in 80% (study) and in 87% (incus), in one third of all patients even within 10 dB. Although the largest improvement was seen in the lower frequencies, closure of the air-bone gap at 4 kHz was difficult to achieve. CONCLUSION: Patients presenting with COM, a (central) perforation, a medially rotated malleus and intact ossicular chain are a treatment challenge. Lateralizing the malleus handle may require disconnection of the ossicular chain and an autologous incus interposition to bring back the reconstructed tympanic membrane in its original position and improve the hearing.

Otoplasty using a modified anterior scoring technique: standardized measurements of long-term results.

OBJECTIVE: To evaluate long-term results of otoplasty using standardized measurements. METHODS: We performed a retrospective study of patients who underwent otoplasty using a modified anterior scoring technique combined with postauricular fixation sutures. Two hundred twenty-two consecutive patients (421 primary otoplasties) were included. Each auricle was examined before surgery, after surgery, and at a long-term follow-up visit, and the distance between the lateral helical rim and the mastoid surface was measured at 3 points. In addition, patient satisfaction was evaluated using a questionnaire. RESULTS: Seventy-two percent of 222 patients were examined at a long-term follow-up visit. Follow-up of 301 auricles was on average 6.25 years (range, 44-106 months). The mean preoperative measurements among all auricles were 23.3 mm at the uppermost point of the helix, 28.6 mm at the middle, and 25.9 mm at the lobule; these values were 14.2, 14.0, and 16.1 mm, respectively, at the end of the operation and 16.0, 17.5, and 17.4 mm, respectively, 6 years later. Long-term data revealed a median 2-mm lateralization of the auricle. The aesthetic result of otoplasty was rated as "very good" by 71.8% of patients and as "good" by 19.4% of patients; 6.9% of patients thought the result was "satisfactory" and 1.9% "unsatisfactory." Complete recurrence of the protrusion was seen in 7 ears (2.3%) and partial recurrence within the upper third of the pinna in 26 ears (8.6%). CONCLUSIONS: Otoplasty using a modified anterior scoring technique combined with postauricular fixation sutures provides long-term improved results in 91.2% of cases. Complications and sequelae are few, and rates are comparable to those of other long-term studies. A 2-mm lateralization of the auricle may be expected. Standardized measurements of the auricle are important because they supplement the overall aesthetic evaluation of the corrected ear and provide an objective baseline for long-term follow-up.

Hydroxyethyl starch (HES) [130/0.4], a new HES specification: pharmacokinetics and safety after multiple infusions of 10% solution in healthy volunteers.

OBJECTIVE: To investigate the pharmacokinetics and safety of a daily infusion of 500 mL of hydroxyethyl starch (HES) [130/0.4] 10% solution on 10 consecutive days. STUDY DESIGN AND PARTICIPANTS: An open, one-way, multiple-dose study was performed in 12 healthy male volunteers. Daily infusions over 30 minutes of 500 mL of HES (130/0.4) 10% solution were performed on 10 consecutive days. Plasma and urine HES concentrations were determined repeatedly during the study until 72 hours after the last infusion. RESULTS: Maximum plasma HES concentrations, assessed with geometric means of 7.7 and 7.4 mg/mL, respectively, as well as the time courses of the plasma concentrations were similar on days 1 and 10 of treatment. Plasma HES concentrations 24 hours after the last infusion were 0.48 mg/mL (mean). Total plasma clearance was calculated as 23.7 and 21.8 mL/min on days 1 and 10, respectively. Urinary recoveries of 69% on day 1 and of 70% on day 10 were in good agreement. CONCLUSION: The results clearly demonstrated that there is no relevant accumulation in plasma after repetitive infusion of the medium-molecular weight HES (130/0.4) solution, which exhibits a high renal excretion rate over 10 days. Local as well as systemic tolerability of 10 repeated doses was good.

Pharmacokinetics of anti-D IgG in pregnant RhD-negative women.

OBJECTIVE: To assess the pharmacokinetics of anti-D IgG in pregnant Rhesus D-negative women after intramuscular and intravenous administration of 300 microg of Rhophylac. DESIGN: An open, randomised, multicentre study. SETTING: Seven gynaecological practices in Germany. SAMPLE: Fourteen RhD-negative pregnant women at risk of becoming Rhesus D immunised received study drug at 28th week of pregnancy either by intramuscular or intravenous route. MAIN OUTCOME MEASURES: Anti-D IgG concentrations of serum samples obtained up to 11 weeks following antenatal Rhesus D prophylaxis were quantified by flow cytometry. RESULTS: Mean anti-D IgG concentrations after intravenous and intramuscular administration differed up to seven days post-injection, from two weeks onwards they were comparable to each other. Irrespective of the administration route, anti-D IgG in serum was detectable in all women up to at least nine weeks post-administration. CONCLUSIONS: The serum concentrations of anti-D IgG measured after administration of Rhophylac were very similar to those obtained with 300 microg of a different anti-D immunoglobulin product.