Sorafenib dose escalation in treatment-naïve patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study.

OBJECTIVE: To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Intra-patient dose escalation may enhance the clinical benefit of targeted anticancer agents in metastatic disease. In this non-randomised, open-label, Phase 2b study, treatment-naïve patients with mRCC were initially treated with the standard oral sorafenib dose [400 mg twice daily (BID)]. Two dose escalations were planned, each 200 mg BID after 28 days at the prior level. Dose reductions, interruptions, or delayed escalations were used to manage adverse events (AEs). The primary endpoint was objective response rate (ORR) in the modified intent-to-treat (mITT) population, which comprised patients with ≥6 months of treatment including ≥4 months of therapy at their highest tolerated dose. Secondary endpoints included progression-free survival (PFS) and safety. RESULTS: In all, 83 patients received sorafenib. The dose received for the longest duration was 400, 600, and 800 mg BID in 48.2%, 15.7%, and 24.1% of patients, respectively. The ORR was 44.4% [n = 8/18; 95% confidence interval (CI) 21.5-69.2] and 17.9% (n = 12/67; 95% CI 9.6-29.2) in the mITT and ITT populations, respectively. The median (95% CI) PFS was 7.4 (6.0-11.7) months (ITT). The most common AEs of any grade were hand-foot skin reaction (66.3%) and diarrhoea (63.9%). CONCLUSION: Sorafenib demonstrated clinical benefit in treatment-naïve patients with mRCC. However, relatively few patients could sustain doses of >400 mg BID. There was evidence that, where tolerated, escalation from the standard sorafenib dose may have enhanced clinical benefit. However, this study does not support dose escalation for most patients with treatment-naïve mRCC. Alternative protocols for sorafenib dose escalation could be explored.

Longitudinal mode competition and mode clustering in (Al,In)GaN laser diodes.

Longitudinal mode competition in (Al,In)GaN laser diodes at λ = 445nm and 515 nm with mode competition frequencies from 10 MHz to 150 MHz is observed. Up to two dozen lasing modes oscillate with the lasing mode rolling from the short wavelength edge to the long wavelength edge of the gain profile. The experimental results can be described very well with a set of multi-mode rate equations including self-, symmetric and asymmetric cross gain saturation. By tuning essential parameters of the gain saturation terms, mode competition disappears and single mode operation as well as mode clustering is found. This proves that the mechanisms of gain saturation have not only a profound impact on the complex temporal-spectral behavior but also explains mode clustering in (Al,In)GaN laser diodes, both in pulsed and continuous wave (cw) operation as a natural nonlinear effect without the necessity to add noise.

Mode shaping in semiconductor broad area lasers by monolithically integrated phase structures.

By broadening the stripe width of the active waveguide region, it is possible to extract high optical powers from semiconductor broad area lasers. However, a weak output beam quality, optical filamentation, and high peak power densities will result, which are invoked by the amplification of higher order modes. We show an approach to influence the optical field inside the resonator by integrating optical phase structures directly into the waveguide. Those elements offer the possibility to enlarge the active gain area for the desired fundamental laser mode, while additional diffraction losses for higher order modes are generated, thus achieving an improved beam quality. We report on considerations in designing those elements and demonstrate a first experimental realization.

A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors.

INTRODUCTION: The research objective was to systematically review evidence on neurotrophic tyrosine receptor kinase (NTRK) gene fusion frequency in solid tumors. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review (SLR) was conducted of studies published from January 1987 to 2 January 2020. Selected studies were appraised for use in meta-analysis, with frequency reported as a point estimate with confidence intervals, to estimate NTRK gene fusion tumor incidence and prevalence. RESULTS: The SLR identified 222 studies from North America (n = 122), Europe (n = 33), Asia (n = 41), Brazil (n = 5), Australia (n = 2), and multi-continental (n = 19) reporting NTRK gene fusion frequencies across 101 histologies. Studies were prospective (n = 43) and retrospective (n = 179). Testing methods involved DNA (n = 93), RNA (n = 72), combined DNA/RNA (n = 48), protein [immunohistochemistry (IHC), n = 5], and unreported (n = 5). Sample sizes ranged from 1 to 66,871. Of the 222 studies, 107 were suitable for meta-analysis. Highest NTRK gene fusion frequencies were reported in rare cancers: infantile/congenital fibrosarcoma (90.56%, 95% CI 67.42-100.00), secretory breast cancer (92.87%, 95% CI 72.62-100.00), and congenital mesoblastic nephroma (21.52%, 95% CI 13.06-32.20). Lower frequencies were reported in non-small cell lung cancer (0.17%, 95% CI 0.09-0.25), colorectal adenocarcinoma (0.26%, 95% CI 0.15-0.36), cutaneous melanoma (0.31%, 95% CI 0.07-0.55), and non-secretory breast carcinoma (0.60%, 95% CI 0.00-1.50). Reported frequency was ~0% for some cancers: mesothelioma, renal cell carcinoma, prostate cancer, and bone sarcoma. Estimated global overall NTRK gene fusion tumour incidence and 5-year prevalence in 2018 was 0.52 and 1.52 per 100,000 persons, respectively. CONCLUSION: This research confirms the rarity and varying frequency of NTRK gene fusion across tumor types. Limitations included relatively low historic NTRK gene fusion testing and reporting, limited study samples for some cancers, and suboptimal molecular testing methods. In this rapidly developing area, gold-standard testing methods and companion diagnostics are needed to capture all NTRK gene fusions.

Spectral dynamics of 405 nm (Al,In)GaN laser diodes grown on GaN and SiC substrate.

We investigate the spectral properties of violet 405 nm (Al,In)GaN laser diodes (LDs). Depending on the substrate the LDs are grown on, the lasing spectra show significant differences. LDs grown on low dislocation GaN substrate have a broad spectrum with several longitudinal modes, while LDs grown on SiC substrate are lasing on a single longitudinal mode.With increasing current, the laser emission of LDs grown on SiC substrate jumps from one longitudinal mode to another (mode hopping), whereas GaN substrate LDs show a smooth but asymmetric mode comb. The different envelopes of these spectra can be understood by assuming a variation of the gain for each individual longitudinal mode. With a high spectral resolution setup, we measure the gain of each longitudinal mode, employing the Hakki-Paoli method. Measurements show a slightly fluctuating gain for the modes of GaN substrate LDs, but much larger fluctuations for LDs on SiC substrate. We carry out simulations of the longitudinal mode spectrum of (Al,In)GaN laser diodes using a rate equation model with nonlinear gain (self saturation, symmetric and asymmetric cross saturation) and including gain fluctuations. With a set of parameters which is largely identical for LDs on either substrate, the simulated spectra truly resemble those typical for LDs on GaN or SiC substrate.

Measurement and simulation of filamentation in (Al,In)GaN laser diodes.

(Al,In)GaN-based laser diodes with ridge widths broader than a few micrometer tend to show filamentation effects in the lateral direction. By time-resolved scanning near-field optical microscopy, we find different kinds of filaments depending on ridge width and lateral position. We investigate these effects systematically and compare them to the results of corresponding simulations, which are based on a simple rate equation model including the lateral dimension. By this comparison we find a consistent and reasonable set of material parameters that can describe the laser diode. Furthermore, we discuss several reasons for filamentation dynamics like ridge asymmetry or spatial hole-burning, as well as critical temperatures that induce filamentation.

Nail penetration of sertaconazole with a sertaconazole-containing nail patch formulation.

BACKGROUND AND OBJECTIVE: Sertaconazole, an imidazole antifungal drug, has been proven to have broad and potent antifungal activity. In the present study, the pharmacokinetics of sertaconazole nail patches, developed for treatment of onychodystrophy and onychomycosis, were investigated in healthy volunteers. The objective of the study was to investigate the penetration of sertaconazole into the nail and plasma and the residual sertaconazole concentration in patches after 1 week of application onto the nails. METHODS: In a double-blind study, 16 healthy adults were treated with a 2.2 cm2 nail patch containing sertaconazole 3.63 mg and another patch containing no antifungal agent, which were placed on the left and right thumbnail of each subject, respectively (or vice versa), in a randomized order. The treatment period was 6 weeks and the patches were replaced weekly. Nail clippings, used nail patches, and blood samples were investigated to determine sertaconazole concentrations. RESULTS: Sertaconazole was detected in all sertaconazole-treated nail samples with mean concentrations of >100 microg/g, which exceeds the minimum inhibitory concentrations (MICs) for all relevant fungi in this context. Measurements of the residual dose in the patches suggested that 16-71% of the active ingredient had penetrated into the nail. No plasma sertaconazole concentrations could be detected. CONCLUSION: By virtue of their positive influence (occlusion) on water and lipid metabolism in dystrophic nails, nail patches should have beneficial therapeutic effects in onychodystrophic conditions. Addition of the antifungal agent sertaconazole adds broad-spectrum antimicrobial activity. In this study, the concentrations of sertaconazole in the nails were shown to be well above the MIC values for pathogenic fungi relevant to onychomycosis. No systemic absorption of the active ingredient was detectable, which should exclude unwanted systemic effects of the drug.

Dermatomycoses of the glabrous skin : a double-blind, randomised, comparative trial of sertaconazole 2% cream once daily versus vehicle.

OBJECTIVE: The aim of this multicentre, double-blind, vehicle-controlled study was to investigate the safety and efficacy of once-daily topical application of sertaconazole 2% cream compared with corresponding vehicle cream in the treatment of patients with tinea of glabrous skin. PATIENTS AND METHODS: A total of 400 patients were recruited at seven investigational sites; 144 patients in the intent-to-treat (ITT) population and 127 in the per-protocol (PP) population were treated for 3 weeks with either sertaconazole 2% once daily or corresponding vehicle cream. To evaluate therapeutic efficacy and safety, microscopic examination of native preparations, mycological cultures, and clinical assessment of the state of the lesion (objective and subjective monitoring of symptoms) were analysed after 3 weeks of treatment. RESULTS: Based on these parameters, in both the PP and ITT populations, sertaconazole cream 2% once daily induced a higher cure rate than the vehicle cream: 82% of the PP population (vehicle cream control 61%; p = 0.014) and 83% of the ITT population (vehicle cream control 59%; p = 0.003) randomised to sertaconazole with a previously positive mycological culture showed negative culture results after sertaconazole treatment. No statistically significant differences were observed regarding frequency and severity of adverse effects. CONCLUSION: These data indicate that treatment of superficial dermatomycoses with sertaconazole 2% cream for 3 weeks is efficient and safe. The once-daily application regimen may improve patient compliance, which has been shown to be of exceptional importance for successful treatment of dermatomycoses of the glabrous skin.

Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer.

PURPOSE: This trial evaluated the efficacy and safety of sorafenib plus gemcitabine/cisplatin in chemotherapy-naive patients with unresectable stage IIIB to IV nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between February 2007 and March 2009, 904 patients were randomly assigned to daily sorafenib (400 mg twice a day) or matching placebo plus gemcitabine (1,250 mg/m(2) per day on days 1 and 8) and cisplatin (75 mg/m(2) on day 1) for up to six 21-day cycles. Because of safety findings from the Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC (ESCAPE) trial, patients with squamous cell histology were withdrawn from the trial in February 2008 and excluded from analysis. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS) and time-to-progression (TTP). RESULTS: The primary analysis population consisted of 772 patients (sorafenib, 385; placebo, 387); the two groups had similar demographic and baseline characteristics. Median OS was similar in the sorafenib and placebo groups (12.4 v 12.5 months; hazard ratio [HR], 0.98; P = .401). By investigator assessment, sorafenib improved median PFS (6.0 v 5.5 months; HR, 0.83; P = .008) and TTP (6.1 v 5.5 months; HR, 0.73; P < .001). Grade 3 to 4 drug-related adverse events more than two-fold higher in the sorafenib group included hand-foot skin reaction (8.6% v 0.3%), fatigue (7.3% v 3.6%), rash (5.7% v 0.5%), and hypertension (4.2% v 1.8%). No unexpected toxicities were observed. CONCLUSION: This study did not meet its primary end point of improved OS when sorafenib was added to first-line gemcitabine/cisplatin in patients with advanced nonsquamous NSCLC. Identification of predictive biomarkers is warranted in future trials of sorafenib.

Rate and extent of percutaneous absorption of sertaconazole nitrate after topical administration.

The purpose of this open study was to evaluate the rate and extent of the penetration of sertaconazole nitrate (CAS 99592-32-2, Zalaïn) penetration into the stratum corneum/lucidum of the human skin. Selected areas of 9 cm2 each of the back skin of 12 healthy volunteers were exposed over 8 different time intervals (between 0 and 48 h) to 100 mg of a 2% cream preparation of the compound or to placebo. Using a HPLC-assay the relative amounts of the applied dose of sertaconazole nitrate were determined in the residual cream of the skin surface as well as in 3 layers of the epidermis obtained by the stripping technique. Sertaconazole nitrate was shown to penetrate into the stratum corneum shortly after application, disappearing from the application areas with a mean apparent half-life of approximately 60 h. Immediately after topical application the residual amount of the applied mean dose of 2103 +/- 146.3 microg on the skin's surface was 88.9 +/- 2.3%, decreasing steadily to 52.4 +/- 8.5% after 48 h. A relevant amount of the applied dose (5.3 +/- 3.0%) was recovered from the stratum corneum already 30 min after application, and 3 h after administration a plateau was reached (6.9 +/- 3.2) which could be maintained until 48 h. A gradient from the site of application to the epidermis was apparent since the amounts recovered in The estimated average level of sertaconazole nitrate for a volume of 1 mL of stratum corneum after application of 100 mg cream was 1409 microg immediately after application and reached a plateau at 3 h with 9029 microg. Although not directly measured, the results also gave information about the mean amount of sertaconazole nitrate that penetrated through the stratum corneum and deeper layers allowing an estimate of the total mean amount of compound penetrating into the skin. The relative portion of this amount steadily increased from 1.1% of the applied dose at 0 h to 24.1% at 12 h, 34.2% at 24 h and finally to 37.6% of dose after 48 h of exposure. In view of the high target organ levels of the compound maintained over days, its rapid appearance in the stratum corneum after application and the earlier finding that Sertaconazole nitrate is not distributed into blood in substantial quantities the pharmacokinetic properties of this antifungal preparation therapy can be regarded as favourable.