Molecular profiling of Asian patients with advanced melanoma receiving check-point inhibitor treatment.

OBJECTIVE: Melanoma is major medical challenge and being able to monitor treatment response is critical. This study aimed to use molecular profiling of Asian patients with advanced melanoma who were receiving treatment with check-point inhibitors (CPIs) to identify novel biomarkers of tumor response. METHODS: Next-generation sequencing (NGS) was performed using tumor specimens collected from 178 Asian patients with metastatic melanoma receiving CPIs. The NGS data and clinical-pathological factors were analyzed for potential genetic biomarkers of tumor response to CPI treatment. RESULTS: The most common melanoma subtype was acral melanoma (40%), followed by cutaneous melanoma (32%), mucosal melanoma (26%), and others (2%). For calculation of treatment efficacy, 164 of the patients could be evaluated. The overall response rate was 45.7%, of which 41 cases exhibited complete responses (25.0%) and 34 showed partial responses (20.7%). There were no significant differences in tumor responses based on melanoma subtype (P = 0.295). Genetically, NRAS mutations, TP53 mutations, and NF2 deletions were significantly associated with resistance to CPIs (P < 0.05). In contrast, MYC and RPS6KB1 amplifications were associated with responsiveness to CPIs (P < 0.05). Median progression-free survival (PFS) for patients treated with CPIs was 5.9 months (95% CI, 3.8-8.05 months). Univariate analysis identified TP53 and BRAF mutations, NF2 deletions, and BIRC2 amplifications as poor prognostic factors for PFS (P < 0.05). CONCLUSIONS: This study determined the integrated genomic profiles of Asian patients with metastatic melanoma receiving CPIs and identified candidate biomarkers that reflected treatment outcomes.

Retinal vessel structure measurement using spectral-domain optical coherence tomography.

PURPOSE: To assess the reliability and validity of spectral-domain optical coherence tomography (SD-OCT) measurements of retinal vessel lumen diameters and wall thicknesses. METHODS: SD-OCT was used to characterize the circular region around the optic disc of 40 eyes (20 subjects). The inner and outer sides (vitreal and choroidal sides) of the vessel wall and the luminal diameter were measured using intensity graphs. RESULTS: Mean arterial and venous luminal diameters were 95.1±16.1 and 132.6±17.8 µm, respectively. The wall thicknesses of inner and outer sides of the artery were 23.9±4.9 and 21.2±3.5 µm, respectively. The wall thicknesses of the inner and outer sides of the vein were 20.7±4.2 and 16.3±4.3 µm, respectively. There were significant differences between the inner and outer wall thicknesses in both the artery and vein (P<0.01). Intra- and interobserver intraclass correlation coefficients (ICCs) for lumen measurements were >0.95, and for wall thicknesses were >0.85, except for the outer wall thickness measurements. The mean value of outer and inner wall thicknesses showed good reproducibility, with ICCs of >0.85. CONCLUSION: Intensity graph-assisted measurements using SD-OCT provided more objective information in finding boundaries of vessels. Luminal diameters and wall thicknesses obtained with OCT showed good overall reproducibility, with inner wall thicknesses being thicker, and with better reproducibility compared with outer wall thicknesses, where ICC values were the lowest among the inner wall thicknesses, mean thicknesses of inner and outer walls, and luminal diameters. When using SD-OCT measurements, caution is therefore advised when using only the outer wall as representative of the wall thicknesses.

Determination of macular hole size in relation to individual variabilities of fovea morphology.

PURPOSE: To determine the preoperative anatomic factors in macular holes and their correlation to hole closure. METHODS: Forty-six eyes with consecutive unilateral macular hole who had undergone surgery and followed up for at least 6 months were enrolled. Optical coherence tomography images and best-corrected visual acuity (BCVA) within 2 weeks prior to operation and 6 months after surgery were analyzed. The maximal hole dimension, foveal degeneration factors (inner nuclear layer cysts, outer segment (OS) shortening) and the widest foveolar floor size of the fellow eyes were measured. For overcoming preoperative individual variability of foveal morphology, an 'adjusted' hole size parameter (the ratio between the hole size and the fellow eye foveolar floor size) was used based on the fact that both eyes were morphologically symmetrical. RESULTS: Mean preoperative BCVA (logMAR) was 1.03±0.43 and the mean postoperative BCVA was 0.50±0.38 at 6 months. Preoperative BCVA is significantly associated with postoperative BCVA (P=0.0002). The average hole diameter was 448.9±196.8 µm and the average fellow eye foveolar floor size was 461.3±128.4 µm. There was a correlation between hole diameter and the size of the fellow eye foveolar floor (Pearson's coefficient=0.608, P<0.0001). The adjusted hole size parameter was 0.979±0.358 (0.761-2.336), which was a strong predictor for both anatomic (P=0.0281) and visual (P=0.0016) outcome. CONCLUSION: When determining the extent of preoperative hole size, we have to take into consideration the foveal morphologic variations among individuals. Hole size may be related to the original foveal shape, especially in relation to the centrifugal retraction of the foveal tissues.

Clinical characteristics of responders to intravitreal bevacizumab in central serous chorioretinopathy patients.

PURPOSE: To investigate factors associated with good response to intravitreal bevacizumab (IVB) in central serous chorioretinopathy (CSC) patients. METHODS: We retrospectively reviewed 42 eyes of CSC patients of symptom duration more than 3 months who received a single or multiple successive IVBs on an as-needed basis (0.05 ml, 1.25 mg). High responders (HRs) were defined as complete resolution of subretinal fluid (SRF) on spectral domain optical coherence tomography (SD-OCT). Moderate responders (MRs) were defined as SRF resolution of 50-99% of pretreatment volume and poor responders (PRs) as SRF resolution <50%. Clinical, SD-OCT, fluorescein, and indocyanine green angiography findings were analyzed to find factors associated with HR. Descriptive statistics for all demographic and clinical variables were calculated, and comparisons were made using Wilcoxon's matched-pairs signed-rank test, the Mann-Whitney U-test for means with continuous data, Pearson's χ(2) test, and Fisher's exact test for categorical data. RESULTS: The mean number of IVB was 1.9. At postoperative 1 month, there were 10 (24%) HRs, 18 (43%) MRs, and 14 (33%) PRs. At the last follow-up (the mean 8.6 months), there were 25 HRs (60%), 9 MRs (21%), and 8 PRs (19%). Thicker subfoveal choroid (P=0.036), smaller lesion diameter (P=0.019), and better baseline best-corrected visual acuity (P=0.002) predicted HRs at postoperative 1 month. HR at the last follow-up was associated with classic pattern fluorescein angiography finding. CONCLUSIONS: Suboptimal effects of IVB on persistent CSC suggest primary IVB on selective cases with better vision, smaller lesion, and thicker choroid at baseline.

Aloe barbadensis extracts reduce the production of interleukin-10 after exposure to ultraviolet radiation.

Cutaneous exposure to ultraviolet radiation suppresses the induction of T cell mediated responses such as contact and delayed type hypersensitivity (DTH) by altering the function of immune cells in the skin and causing the release of immunoregulatory cytokines. Extracts of crude Aloe barbadensis gel prevent this photosuppression. Because the regulation of contact hypersensitivity and DTH responses differ, we investigated whether protection was afforded by a single or multiple agents in Aloe and the mechanism by which this material prevents suppression of DTH immunity. The ability of Aloe gel to prevent suppression of contact hypersensitivity responses to hapten decayed rapidly after manufacture. In contrast, agents that protected against systemic suppression of DTH responses to Candida albicans were stable over time. Oligosaccharides prepared from purified Aloe polysaccharide prevented suppression of DTH responses in vivo and reduced the amount of IL-10 observed in ultraviolet irradiated murine epidermis. To assess the effect of Aloe extracts on keratinocytes, Pam 212 cells were exposed in vitro to ultraviolet radiation and treated for 1 h with Aloe oligosaccharides. Culture supernatants were collected 24 h later and injected into mice. Supernatants from ultraviolet irradiated keratinocytes suppressed the induction of DTH responses, whereas Aloe oligosaccharide treatment reduced IL-10 and blocked the suppressive activity of the supernatants. These results indicate that Aloe contains multiple immunoprotective factors and that Aloe oligosaccharides may prevent ultraviolet induced suppression of DTH by reducing keratinocyte derived immunosuppressive cytokines.

Evaluation of an activated carbon felt passive sampler in monitoring organic vapors.

Using an activated carbon felt (ACF, KF-1600), the applicability of an ACF passive sampler in monitoring organic vapors was evaluated. The evaluated results of the ACF passive sampler were compared with those of a 3 M (Model 3500) passive sampler. At low-humidity condition (8 +/- 3% RH), the sampling rates of the ACF passive sampler for volatile organic vapors were within the range of +/-25% from the results of a charcoal tube, which was the reference method recommended by NIOSH. However, at high humidity condition (90 +/- 5% RH), even though the sampling rates for toluene, MIBK, and PCE were within the range of +/-25%, the sampling rates of ACF sampler for n-hexane and MEK decreased steeply with time after being high at the beginning of the exposure time. Under this condition, the sampling rate of the 3 M passive sampler for MEK was also high at the beginning of the exposure time. In case of the ACF passive sampler, the sampling rates of the relatively strong adsorbates such as toluene, MIBK, and PCE were much less affected by humidity than those of n-hexane and MEK which were weak adsorbates.

Axial length and intraoperative posterior vitreous detachment as predictive factors for surgical outcomes of diabetic vitrectomy.

AIMS: To evaluate the relationship of axial length (AXL), intraoperatively assessed posterior vitreous detachment (PVD) status, and surgical outcomes of diabetic vitrectomy. METHODS: Retrospective, consecutive case series. Clinical records were reviewed for 115 eyes (50 males, 65 females) with more than a 6-month follow-up who underwent diabetic vitrectomy from a single surgeon. Thirty-three eyes had vitreous haemorrhage, 37 had tractional retinal detachment (TRD) threatening the macula, 43 had TRD involving the macula, and two had neovascular glaucoma. AXL was measured preoperatively by ultrasonography, and PVD status was classified intraoperatively: broad vitreo-retinal adhesion as no PVD, PVD at the macular area with attachment at the disc as incomplete PVD, and complete PVD. RESULTS: Forty-four eyes had no PVD, 23 had incomplete PVD, and 48 had complete PVD. A majority of the no PVD group had macula off TRD (97.7%), whereas vitreous haemorrhage (68.7%) predominated in the complete PVD group. Longer AXLs were noted in the complete PVD group compared with the no PVD and incomplete PVD groups (ANOVA in three groups P=0.0001). Univariate analysis showed that AXL had an influence on anatomical success (P=0.02). Multiple logistic regression analysis yielded that PVD status is a significant predictor of the final best corrected visual acuity (BCVA)>20/100, and BCVA>20/40 (P=0.01, P=0.02). CONCLUSIONS: Intraoperatively assessed PVD status is a prognostic factor for functional outcomes of diabetic vitrectomy. Shorter AXL was associated with lesser PVD. In eyes with a lack of PVD, careful timing and decision of surgery are mandatory.

Inhibition of choroidal neovascularisation in mice by systemic administration of the multikinase inhibitor, sorafenib.

BACKGROUND: To investigate the effect of orally administered sorafenib, a multikinase inhibitor, in a mouse model of choroidal neovascularisation (CNV). METHODS: Sorafenib or vehicle was administered orally to female C57BL/6 mice at the onset (day 0) of experiments. CNV was induced by laser photocoagulation the following day. After 14 days, mice were perfused with fluorescein-labelled dextran, and the area of CNV was measured on choroidal flat mounts by image analysis. In some groups of mice, treatments were started 7 days after the laser photocoagulation to determine the effect of the agent on established CNV. Expression of phosphorylated extracellular signal-regulated kinase (p-ERK) in choroidal tissues was measured by Western blot analysis to demonstrate the kinase-inhibitory effect of sorafenib in intracellular signalling pathways involved in CNV formation. RESULTS: Sorafenib significantly reduced the extent of CNV in a dose-dependent manner. The area of CNV was reduced by 43% in the 30 mg/kg/day group and by 61% in the 60 mg/kg/day group compared with vehicle-treated controls (both p<0.0001). Oral administration of sorafenib also caused significant regression of established CNV. The area of CNV was reduced by 59% in the 30 mg/kg/day group and by 66% in the 60 mg/kg/day group compared with both baseline and control measurements (p<0.0001). The expression of p-ERK in choroidal tissues was increased within 1 day of laser photocoagulation and remained elevated for 2 weeks. The expression of p-ERK was suppressed by sorafenib. CONCLUSIONS: Sorafenib demonstrated antiangiogenic properties in a mouse model of CNV and may be useful in the treatment of CNV.

XANES study on Ruddlesden-Popper phase, La(n+1)Ni(n)O(3n+1) (n=1,2 and infinity).

Ruddlesden-Popper phase, La(n+1)Ni(n)O(3n+1 (n=1, 2, and infinity) compounds were prepared by citrate sol-gel method. We revealed the origin of the variation of the electrical conductivities in La(n+1)Ni(n)O(3n+1 (n=1, 2, and infinity) using resistivity measurements, Rietveld analysis, and X-ray absorption spectroscopy. According to the XANES spectra, it is found that the degree of 4p(pi) - 4psigma energy splitting between 8345 eV and 8350 eV is qualitatively proportional to the elongation of the out-of-plane Ni-O bond length. With the decrease of 4p(pi) - 4psigma splitting, the strong hybridization of the sigma-bonding between Ni-3d and O-2p orbitals creates narrow antibonding sigma* bands, which finally results in the lower electrical resistivity.

Selective oxidation of allylic sulfides by hydrogen peroxide with the trirutile-type solid oxide catalyst LiNbMoO(6).

Chemoselective sulfur oxidation of allylic sulfides containing double bonds of high electron density due to multiple alkyl substituents or extended conjugation was developed using the composite metal oxide catalyst, LiNbMoO(6), without any epoxidation of the electron-rich double bond(s). Selective oxidation to either the corresponding sulfoxides or the sulfones was realized by controlling the stoichiometry of the quantitative oxidant, H(2)O(2). This new oxidant system had general applicability for chemoselective oxidation of various allylic, benzylic, or propargylic sulfides containing unsaturated carbon-carbon bonds with different electron properties. Various functional groups including hydroxy, formyl, and ethers of THP or TBDMS are compatible under this mild oxidation reaction condition.