Improving the Structure-Function Relationship in Glaucomatous Visual Fields by Using a Deep Learning-Based Noise Reduction Approach.

PURPOSE: To investigate whether processing visual field (VF) measurements using a variational autoencoder (VAE) improves the structure-function relationship in glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS: The training data consisted of 82 433 VF measurements from 16 836 eyes. The testing dataset consisted of 117 eyes of 75 patients with open-angle glaucoma. METHODS: A VAE model to reconstruct the threshold of VF was developed using the training dataset. OCT and VF (Humphrey Field Analyzer 24-2, Swedish interactive threshold algorithm standard) measurements were carried out for all eyes in the testing dataset. Visual fields in the testing dataset then were reconstructed using the trained VAE. The structure-function relationship between the circumpapillary retinal nerve fiber layer (cpRNFL) thickness and VF sensitivity was investigated in each of twelve 30° segments of the optic disc (3 nasal sectors were merged). Similarly, the structure-function relationship was investigated using the VAE-reconstructed VF. MAIN OUTCOME MEASURES: Structure-function relationship. RESULTS: The corrected Akaike information criterion values with threshold were found to be smaller than the threshold reconstructed with the VAE (thresholdVAE) in 9 of 10 sectors. A significant relationship was found between threshold and cpRNFL thickness in 6 of 10 sectors, whereas it was significant in 9 of 10 sectors with thresholdVAE. CONCLUSIONS: Applying VAE to VF data results in an improved structure-function relationship.

Comparing Structure-Function Relationships Based on Drasdo's and Sjöstrand's Retinal Ganglion Cell Displacement Models.

Purpose: To compare structure-function relationships based on the Drasdo and Sjöstrand retinal ganglion cell displacement models. Methods: Single eyes from 305 patients with glaucoma and 55 heathy participants were included in this multicenter, cross-sectional study. The ganglion cell and inner plexiform layer (GCIPL) thickness was measured using spectral domain optical coherence tomography. Visual field measurements were performed using the Humphrey 10-2 test. All A-scan pixels (128 × 512 pixels) were allocated to the closest 10-2 location with both displacement models using degree and millimeter scales. Structure-function relationships were investigated between GCIPL thickness and corresponding visual sensitivity in nonlong (160 eyes) and long (200 eyes) axial length (AL) groups. Results: In both the nonlong and long AL groups, compared with the no-displacement model, both the Drasdo and the Sjöstrand models showed that the structure-function relationship around the fovea improved (P < 0.05). The magnitude of improvement in the area was either comparable between the model or was larger for the Drasdo model than the Sjöstrand model (P < 0.05). Meanwhile, structure-function relationships outside the innermost retinal region that were based on the Drasdo and Sjöstrand models were comparable to or were even worse than (in the case of the Drasdo model) those obtained using the no-displacement model. Conclusions: Structure-function relationships evaluated based on both the Drasdo and Sjöstrand models significantly improved around the fovea, particularly when using the Drasdo model. This was not the case in other areas.

Relationship between novel intraocular pressure measurement from Corvis ST and central corneal thickness and corneal hysteresis.

AIMS: Corvis ST (CST) yields biomechanical corrected IOP (bIOP) which is purported to be less dependent on biomechanical properties. In our accompanied paper, it was suggested that the repeatability of bIOP is high. The purpose of the current study was to assess the relationship between intraocular pressure (IOP) measured with CST and central corneal thickness (CCT) and corneal hysteresis (CH), in comparison with IOP measured with Goldmann applanation tonometry (GAT) and the ocular response analyzer (ORA). METHODS: A total of 141 eyes from 141 subjects (35 healthy eyes and 106 glaucomatous eyes) underwent IOP measurements with GAT, CST and ORA. The relationships between IOP measurements (ORA-IOPg, ORA-IOPcc, CST-bIOP and GAT IOP) and biomechanical properties (CCT, CH and corneal resistance factor (CRF)) were analysed using the linear regression analysis. RESULTS: IOPg, IOPcc and GAT IOP were significantly associated with CCT (p<0.001), whereas bIOP was not significantly associated with CCT (p=0.19). IOPg, bIOP and GAT IOP were significantly associated with CH (IOPg: p<0.001; bIOP: p<0.001; GAT IOP: p=0.0054), whereas IOPcc was not significantly associated with CH (p=0.18). All of IOP records were associated with CRF (p<0.001). CONCLUSION: The bIOP measurement from CST is independent from CCT, but dependent on CH and CRF.

Trastuzumab in combination with paclitaxel enhances antitumor activity by promoting apoptosis in human epidermal growth factor receptor 2-positive trastuzumab-resistant gastric cancer xenograft models.

Trastuzumab, a humanized anti-human epidermal growth factor receptor 2 antibody drug, is the first-line therapy for human epidermal growth factor receptor 2-positive breast and gastric cancer. For breast cancer, the benefit of continuous treatment with trastuzumab after it becomes refractory to first-line therapy has been demonstrated. However, it is unclear whether trastuzumab can show similar efficacy as a second-line treatment for gastric cancer. Here, we report that trastuzumab in combination with paclitaxel exhibits increased antitumor efficacy even for trastuzumab-resistant xenografted tumors. We derived the trastuzumab-resistant models from previously established human epidermal growth factor receptor 2-positive gastric cancer patient-derived cells. Human epidermal growth factor receptor 2 expression, PIK3CA mutation, and phosphatase and tensin homolog expression in these resistant models was equivalent to those in the trastuzumab-sensitive parental model, whereas cyclin-dependent kinase inhibitors, such as p16, p15, and p21, were downregulated. Trastuzumab in combination with paclitaxel enhanced antitumor activity in both the sensitive and resistant models. In the trastuzumab-sensitive model, the combination of trastuzumab and paclitaxel resulted in suppression of the AKT-p27-retinoblastoma protein pathway and induction of apoptosis. Although this combination did not suppress retinoblastoma protein phosphorylation in the trastuzumab-resistant model, it did markedly decrease epidermal growth factor receptor and human epidermal growth factor receptor 2 phosphorylation and further enhance paclitaxel-mediated apoptosis. These results suggested that trastuzumab in combination with paclitaxel can still exert more potent antitumor efficacy than each agent alone in trastuzumab-resistant models, providing evidence that trastuzumab remains beneficial in the treatment of trastuzumab-resistant tumors.

Investigating the structure-function relationship using Goldmann V standard automated perimetry where glaucomatous damage is advanced.

PURPOSE: To investigate if the structure-function relationship between circumpapillary retinal nerve fibre layer (cpRNFL) thickness and visual field (VF) thresholds is stronger when using the Goldmann V target rather than the Goldman III target where glaucomatous damage is advanced. METHODS: Optical coherence tomography (OCT) and VF (Humphrey Field Analyzer 24-2 or 30-2) measurements with Goldmann III (SITA standard) and V (full-threshold) targets were carried out in 51 eyes of 51 patients with primary open angle glaucoma. The relationship between cpRNFL thicknesses in supero- and infero-temporal sectors, and VF sensitivity with the Goldmann III or V target was investigated. RESULT: Visual field sensitivities (dB) both with the Goldmann III target and Goldmann V target showed a floor effect in the structure-function relationship against cpRNFL thickness, at approximately 60 µm. There was no significant relationship between visual field sensitivity measured with the Goldmann V target (dB scale: p = 0.12, 1/Lambert scale: p = 0.40; linear mixed models) and cpRNFL thickness, when corresponding visual field sensitivity, measured with the Goldmann III target, was <20 dB. CONCLUSION: There was no improvement in the structure-function relationship using the Goldmann V target (full-threshold), compared to using the Goldmann III target (SITA standard), where glaucomatous damage was advanced.

Repeatability of the Novel Intraocular Pressure Measurement From Corvis ST.

PURPOSE: To assess the repeatability of intraocular pressure (IOP) measured with the Corvis ST (CST) and the Ocular Response Analyzer (ORA). METHODS: A total of 141 eyes from 141 subjects were studied, including 35 healthy eyes and 106 glaucomatous eyes. All subjects underwent IOP evaluations with Goldmann applanation tonometer, CST, and ORA. With CST, biomechanical corrected IOP (bIOP) was calculated; bIOP is purported to be less dependent on biomechanical properties. For ORA, corneal-compensated intraocular pressure (IOPcc) and Goldmann-correlated IOP (IOPg) were derived. The repeatability of the various IOP values was assessed using the coefficient of variance (CV) and the intraclass correlation coefficient (ICC). RESULTS: The CV with bIOP (5.5 ± 3.1: mean ± standard deviation) was significantly smaller than the CVs measured with IOPg (7.3 ± 4.3) and IOPcc (7.2 ± 4.4). ICC values were 0.90, 0.80, and 0.86 with IOPg, IOPcc, and bIOP, respectively. CONCLUSIONS: The bIOP showed a better prevision and repeatability for IOP measurement. TRANSLATIONAL RELEVANCE: The bIOP measurement from CST had a better reproducible than IOPcc measurement from ORA.

Sustained effect of continuous treatment with bevacizumab following bevacizumab in combination with chemotherapy in a human ovarian clear cell carcinoma xenograft model.

Although bevacizumab maintenance following bevacizumab in combination with chemotherapy has demonstrated significant prolongation of progression-free survival in clinical studies in patients with ovarian cancer, the majority of the cancer cases in the study were of the serous histotype; therefore, data regarding clear cell carcinoma is limited. Furthermore, the efficacy of bevacizumab beyond progression has not yet been demonstrated in ovarian cancer. A xenograft model using the human ovarian clear cell carcinoma cell line RMG-I was used to investigate the antitumor effects and the mechanisms of bevacizumab in maintenance treatment and bevacizumab when administered beyond disease progression. In the RMG-I model, bevacizumab maintenance following bevacizumab in combination with paclitaxel exhibited increased tumor suppression, compared with its absence, and inhibited the increase of microvessel density (MVD) in tumors. Following disease progression during bevacizumab maintenance, continued bevacizumab treatment in combination with PEGylated liposomal doxorubicin as a secondary chemotherapeutic agent had increased efficacy, compared with PEGylated liposomal doxorubicin alone, and resulted in lower MVD accompanied with lower levels of insulin-like growth factor binding protein-3, which is reported to have angiogenic activity. Continuous suppression of angiogenesis by bevacizumab may contribute to the superior efficacy of bevacizumab maintenance and bevacizumab beyond progression in ovarian cancer.

Molecular targeting of HER2-overexpressing biliary tract cancer cells with trastuzumab emtansine, an antibody-cytotoxic drug conjugate.

PURPOSE: Trastuzumab emtansine (T-DM1) provides clinical benefit in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2). However, its efficacy against biliary tract cancers (BTC) has not been evaluated. In this study, the effectiveness of T-DM1 in various BTC cell lines and xenograft models with different levels of HER2 expression was investigated. METHODS: HER2 expression status in xenografts and patient tissue microarrays was assessed by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). Cell-surface HER2 expression levels and cell growth inhibition in response to T-DM1 were examined in 17 BTC cell lines. The antitumor activity of T-DM1 was evaluated in four xenograft mouse models with different levels of HER2 expression. The effects of T-DM1 on HER2 signaling, antibody-dependent cell-mediated cytotoxicity (ADCC), cell cycle, and apoptosis were assessed in vitro. RESULTS: Cell-surface expression of HER2 was observed in both gallbladder carcinoma and cholangiocarcinoma tissues. The anti-proliferative activity of T-DM1 was higher in BTC cell lines and breast cancer cell lines with higher levels of HER2 expression. The HER2 status (IHC score|HER2-to-CEP17 ratio by FISH testing) of each BTC xenograft was 3 +|8.3 for KMCH-1, 2 +|4.7 for Mz-ChA-1, 1 +/0|1.4 for OCUG-1, and 0|1.1 for KKU-100, and T-DM1 showed antitumor activity in proportion to the HER2 status. T-DM1 inhibited HER2 signaling and induced ADCC, mitotic arrest, and apoptosis in KMCH-1 cells. CONCLUSIONS: T-DM1 exhibited preclinical activity in HER2-overexpressing BTC. Further evaluation in clinical studies is warranted.

Relationship between the Vertical Asymmetry of the Posterior Pole of the Eye and the Visual Field Damage in Glaucomatous Eyes.

PURPOSE: This study investigated the relationship between the shape of the posterior pole of the eye and the vertical asymmetry of visual field (VF) damage in glaucomatous eyes. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 83 eyes of 43 patients with open-angle glaucoma. METHODS: The VF was measured using the Humphrey 24-2 or 30-2 Swedish Interactive Thresholding Algorithm (SITA) standard. The vertical asymmetry of VF damage was defined as the difference between the mean total deviation (mTD) values of the superior and inferior hemi-retinas. This difference was calculated for the hemifield, central, middle, and peripheral areas. A vertical cross-sectional image of the macula was obtained, and the magnitudes of superior and inferior retinal tilt (RT) were calculated as the difference between the lower margins of the retinal pigment epithelium (RPE) at the fovea and at a location 2 mm superior or inferior to the RPE. The RT asymmetry was defined as the difference between the inferior and superior RT. Data were analyzed using a multivariate linear mixed model. MAIN OUTCOME MEASURES: The relationship between mTD asymmetry (hemifield, central, middle, and peripheral) and both RT asymmetry and other factors (intraocular pressure, axial length, corneal radius, age, gender, mean deviation, refraction, and visual acuity) was assessed. RESULTS: The inferior RT was significantly larger than the superior RT (P < 0.001). Hemifield mTD asymmetry was related to RT asymmetry (P = 0.017). These relationships were significant in the middle (P = 0.029) and peripheral areas (P = 0.023), but not in the central area (P = 0.40). Other factors were not related to mTD asymmetry. CONCLUSIONS: Vertical asymmetry of the posterior pole was related to the vertical asymmetry of glaucomatous VF damage.

Comparison of Esterman disability scores obtained using Goldmann perimetry and the Humphrey field analyzer in Japanese low-vision patients.

PURPOSE: To compare the Esterman Disability Score (EDS) obtained with Goldmann perimetry (GP) testing and the Humphrey field analyzer (HFA) in low vision Japanese subjects. Subjects were also divided into groups by diagnosis to examine how disease influences EDS measurements. METHODS: The EDS was obtained using GP (GP-EDS) and the built-in testing program of the HFA (HFA-EDS). Tests were performed within 3 months of each other. Regression analyses were used to examine the relationship between GP-EDS and HFA-EDS. RESULTS: A total of 128 visually impaired subjects were included in this study. Subjects had low vision because of glaucoma (57 subjects), age-related macular degeneration (AMD, 17 subjects), retinitis pigmentosa (RP, 17 subjects), and other causes (37 subjects). The GP-EDS obtained was well-correlated with HFA-EDS (r = 0.87, P < 0.001) and it was possible to estimate HFA-EDS from GP-EDS. The GP-EDS was significantly lower than the HFA-EDS in eyes with glaucoma and RP. There was no significant difference between EDS values in eyes with AMD or other disease. CONCLUSION: The GP-EDS correlated well with the HFA-EDS. However, the relationship between the EDS measured with the two different testing modalities varies by disease.

Improving the structure-function relationship in glaucomatous and normative eyes by incorporating photoreceptor layer thickness.

The purpose of the study was to investigate whether the structure-function relationship in glaucomatous and normative eyes is improved by considering photoreceptor layer thickness. Humphrey 10-2 visual fields (VF) and optical coherence tomography were carried out in 615 eyes of 391 subjects, including 100 eyes of 53 healthy controls and 515 eyes of 338 glaucoma patients. The relationship between mean VF sensitivity and the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell layer and inner plexiform layer (GCL + IPL) was analyzed using linear mixed models, by glaucoma status and degree of myopia. The structure-function relationship was also analyzed by supplementing the RNFL and GCL + IPL thickness with the thicknesses of: (i) the inner nuclear layer and outer plexiform layer (INL + OPL); (ii) the outer nuclear layer and inner segment of photoreceptor layer (ONL + ISL); (iii) the outer segment layer of photoreceptor and retinal pigment epithelium (OSL + RPE). The model included total thickness of RNFL, GCL + IPL and OSL + RPE was highly more optimal than the model that only included the total thickness of RNFL and GCL + IPL, in all subsets of eyes by glaucoma status and degree of myopia.

Mapping the Central 10° Visual Field to the Optic Nerve Head Using the Structure-Function Relationship.

Purpose: To investigate the structure-function mapping in the central 10° by relating Humphrey field analyzer (HFA) 10-2 visual field (VF) and circumpapillary retinal nerve fiber layer (cpRNFL) thickness from spectral-domain optical coherence tomography (SD-OCT). We also compared the obtained results with a previously reported mapping between 10-2 VF and the optic disc. Methods: In 151 eyes of 151 POAG patients and 35 eyes from 35 healthy participants, cpRNFL thickness measurements were obtained using SD-OCT and the 10-2 VF was measured with the HFA. The relationship between visual sensitivity and cpRNL thickness values in the temporal 180° was analyzed using least absolute shrinkage and selection operator (LASSO) regression. The optic disc angle corresponding to each VF test point was then derived using the coefficients from the optimal LASSO regression. Results: The structure-function map obtained was largely consistent with the mapping reported previously; superior central VF test points correspond to a more vulnerable area of the optic disc, more distant toward the inferior pole from the center of the temporal quadrant (9:00 o'clock for the right eye) while inferior VF test points correspond closer to the center of the temporal quadrant. The prediction error tended to be large in the 'more vulnerable area' in the map reported previously. Conclusions: The structure-function map obtained largely confirms the previously reported map; however, some important differences were observed.

Changes in Axial Length and Progression of Visual Field Damage in Glaucoma.

Purpose: To investigate the relationship between axial length (AL) elongation and progression of primary open-angle glaucoma (POAG). Methods: AL was measured twice over a 5.1 ± 0.76 (mean ± standard deviation: SD) year period in 125 eyes of 72 patients with POAG. The eyes were divided into not long (AL < 26 mm, 80 eyes) and long (>26 mm, 45 eyes) groups. During this period, patients' visual fields (VFs) were measured with the Humphrey Field Analyzer 12.4 ± 7.5 times and intraocular pressure (IOP) was measured with Goldmann applanation tonometry 27.0 ± 7.5 times. The relationship between the mean total deviation (mTD) progression rates in the whole field and superior and inferior hemifield, as well as in 10 VF sectors, and the variables of age, mean IOP, SD of IOP, AL, difference in AL (△AL), and mTD value at baseline was examined. Results: There was a significant difference between AL at baseline and AL at repeat measurement (P < 0.0001). △AL was 0.035 ± 0.10 mm. An increase in △AL was significantly related to AL at baseline (P = 0.027), but not to age, mean IOP, and SD of IOP. △AL was related to the progression of mTD in the inferior hemifield (slower mTD progression was associated with increased △AL), but not in the whole field or superior hemifield. Increased △AL was related to slower progression rates in 2 of 10 sectors, both in the inferior hemifield. Conclusions: The main finding was that an increase in AL was significantly related to slower VF progression in the inferior hemifield.

Evaluating the Usefulness of MP-3 Microperimetry in Glaucoma Patients.

PURPOSE: The purpose of the current study was to evaluate the test-retest reproducibility and structure-function relationship of the MP-3 microperimeter, compared against the Humphrey Field Analyzer (HFA). METHODS: Design: Reliability and validity study. SETTING: Institutional, or clinical practice. STUDY POPULATION: Thirty eyes of 30 primary open-angle glaucoma patients were enrolled. OBSERVATION PROCEDURES: Visual fields (VF) were measured twice with the MP-3 and HFA instruments, using the 10-2 test grid pattern in both perimeters. Ganglion cell complex (GCC) thickness was measured using optical coherence tomography (OCT). Test-retest reproducibility was assessed using the mean absolute deviation (MAD) measure at all 68 VF test points, and also the intraclass correlation coefficient (ICC) of the repeated VF sensitivities. The structure-function relationship between VF sensitivities (measured with MP-3 or HFA) and GCC thickness (adjusted for the retinal ganglion cell displacement) was analyzed using linear mixed modeling. MAIN OUTCOME MEASURE: Reproducibility and structure-function relationship. RESULTS: The average measurement duration with the HFA 10-2 was 7 minutes and 6 seconds (7m06s) ± 0m49s (mean ± standard deviation). A significantly (P < .001, paired Wilcoxon test) longer measurement duration was observed for the MP-3 test: 10m29s ± 2m55s. There were no significant differences in MAD and ICC values between HFA (MAD; 0.83 ± 0.69 dB and ICC: 0.89 ± 0.69, mean ± standard deviation) and MP-3 (MAD: 0.65 ± 0.67 dB and ICC: 0.89 ± 0.69). MP-3 VF sensitivities had a stronger structure-function relationship with GCC thickness compared to HFA. CONCLUSIONS: The MP-3 microperimeter has a similar test-retest reproducibility to the HFA but a better structure-function relationship.

Investigating the Usefulness of Fundus Autofluorescence in Retinitis Pigmentosa.

PURPOSE: To investigate the relationship between visual field (VF) loss and the rings of the ellipsoid zone (EZ) and autofluorescence (AF) in patients with retinitis pigmentosa (RP). DESIGN: Cross-sectional study. PARTICIPANTS: A total of 28 eyes of 15 patients with a clinical diagnosis of RP. METHODS: The VF was measured at a 1-degree interval on the horizontal or vertical lines, within the central 10 degrees from fixation, using MP-3 microperimetry (Nidek Co. Ltd., Aichi, Japan), and the sensitivity deviation from the normative database was calculated. OCT was performed, and the EZ was identified. Fundus AF was also measured, and the AF ring was identified. The VF test points were categorized according to their relationship with the EZ line and AF ring. The relationship between mean retinal sensitivity deviations on both the horizontal and vertical lines and the diameters of the EZ line and the AF ring in the corresponding directions was analyzed. The relationship between visual sensitivity deviation and the locations against EZ line and AF rings was also investigated. MAIN OUTCOME MEASURES: The relationship between the visual sensitivity deviation and the locations against EZ line and AF rings. RESULTS: The diameter of the AF ring had a significantly stronger relationship with mean retinal sensitivity deviation compared with the diameter of the EZ line in both the horizontal and vertical directions. Test point location inside/on/outside the AF ring was significantly related to retinal sensitivity deviation independent of the location inside/outside the EZ line (P < 0.001, linear mixed model). CONCLUSIONS: Visual sensitivity damage is significantly associated with the EZ lines and AF rings. The development of the AF ring is related to the decrease of visual function independent of and stronger than the EZ line.

The structure-function relationship measured with optical coherence tomography and a microperimeter with auto-tracking: the MP-3, in patients with retinitis pigmentosa.

The purpose of the current study was to investigate the structure-function relationship in patients with retinitis pigmentosa (RP) using optical coherence tomography and the MP-3 microperimeter. Visual field (VF) measurements were carried out using MP-3 microperimetry and the Humphrey Field Analyzer (HFA, Carl-Zeiss, CA), 22 eyes of 11 patients with a clinical diagnosis of RP, both with the 10-2 test grid pattern. Optical coherence tomography (OCT, Spectralis, Heidelberg, Germany) was also performed and the ellipsoid zone (EZ) was identified in the OCT image. The mean (±SD) number of test points located within the EZ edge was 11.6 (±5.9). There was a significant relationship between mean retinal sensitivity measured with MP-3 and the area surrounded by the EZ circular line: AEZ (p < 0.05), but this was not the case with HFA (p > 0.05). The difference between retinal sensitivity inside and outside the EZ edge was significantly larger with MP-3 than with HFA (p < 0.001). Our findings suggest that retinal sensitivity measured with MP-3 better reflects the magnitude of structural damage observed with OCT, compared with HFA. Further, the difference in retinal sensitivity between the inside and outside EZ edge is significantly larger for the MP-3 test, compared with the HFA.

Goldmann V Standard Automated Perimetry Underestimates Central Visual Sensitivity in Glaucomatous Eyes with Increased Axial Length.

PURPOSE: To investigate the effect of axial length (AL) on the structure-function relationship between retinal nerve fiber layer (RNFL) thickness measurements and visual field (VF) sensitivity measured with Goldmann III and V. METHOD: There were 85 eyes of 85 patients with primary open angle glaucoma included in the current study. Optical coherence tomography and VF (Humphrey Field Analyzer 24-2 or 30-2) measurements with Goldmann III and V targets were carried out in all patients. The optic disc and the VF were divided into six clusters and the relationship between circumpapillary RNFL (cpRNFL) thickness and VF sensitivity (with Goldmann III or V), age, and AL were investigated in each cluster. RESULT: Visual sensitivity with Goldmann III (19.3 ± 11.7 dB, mean ± standard deviation) was significantly lower than that with Goldmann V (24.6 ± 11.0 dB, P < 0.001, linear mixed model). Visual sensitivities with both Goldmann III and V were significantly correlated with cpRNFL thickness in all clusters. Visual sensitivity decreased with increasing AL in the nasal retinal area for both targets, however, this phenomenon was only observed with the Goldmann V target in the temporal area. CONCLUSION: Visual sensitivity measured with the size V target decreases with increasing AL in the temporal area, which corresponds to the papillomacular bundle. In the nasal retinal area, visual sensitivity decreases with the increase of AL for both Goldmann III and Goldmann V. TRANSLATIONAL RELEVANCE: Careful consideration is needed when measuring visual sensitivity using Goldmann V target in glaucomatous eyes with increased AL.

The association between photoreceptor layer thickness measured by optical coherence tomography and visual sensitivity in glaucomatous eyes.

PURPOSE: To assess the thickness of the photoreceptor layer in the macular region in glaucomatous eyes. METHOD: Humphrey 10-2 visual field (VF) testing was carried out and mean threshold (mTH) was calculated in 118 eyes from 118 patients with open angle glaucoma. Macular optical coherence tomography (OCT) measurements (RS 3000, Nidek Co.ltd., Aichi, Japan) were also carried out in all eyes. Thickness measurements were recorded in the outer segment and retinal pigment epithelium (OS+RPE), the nerve fiber layer (NFL), the ganglion cell layer and inner plexiform layer (GCL+IPL), the inner nuclear layer and outer plexiform layer (INL+OPL) and the outer nuclear layer and inner segment (ONL+IS). The relationship between mTH and the thickness of these five different layers was investigated. Additionally, the influence of OS+RPE on mTH was investigated using partial correlation eliminating the effect of other variables of NFL, GCL+IPL, INL+OPL, ONL+IS, age, gender and axial length. RESULTS: The thickness of the OS+RPE layer was significantly decreased with the decrease of mTH (coefficient = 0.63 p <0.001). Partial correlation analysis suggested OS+RPE thickness is significantly (coefficient = 0.31, p <0.001) related to mTH, independent from NFL, GCL+IPL, INL+OPL, ONL+IS, age, gender and axial length. CONCLUSIONS: The thickness of the RPE+OS layer appears to be related to visual sensitivity in glaucoma.

Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model.

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), shows superior efficacy in patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations (EGFR Mut+). However, almost all tumors eventually develop resistance to erlotinib. Recently, the Phase II JO25567 study reported significant prolongation of progression-free survival (PFS) by erlotinib plus bevacizumab combination compared with erlotinib in EGFR Mut+ NSCLC. Herein, we established a preclinical model which became refractory to erlotinib after long-term administration and elucidated the mode of action of this combination. In this model, tumor regrowth occurred after remarkable shrinkage by erlotinib; regrowth was successfully inhibited by erlotinib plus bevacizumab. Tumor vascular endothelial growth factor (VEGF) was greatly reduced by erlotinib in the erlotinib-sensitive phase but significantly increased in the erlotinib-refractory phase despite continued treatment with erlotinib. Although EGFR phosphorylation remained suppressed in the erlotinib-refractory phase, phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated AKT, and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) were markedly higher than in the erlotinib-sensitive phase; among these, pERK was suppressed by erlotinib plus bevacizumab. MVD was decreased significantly more with erlotinib plus bevacizumab than with each drug alone. In conclusion, the erlotinib plus bevacizumab combination demonstrated promising efficacy in the B901L xenograft model of EGFR Mut+ NSCLC. Re-induction of VEGF and subsequent direct or indirect VEGF-dependent tumor growth was suggested as a major mechanism of erlotinib resistance, and erlotinib plus bevacizumab achieved remarkably prolonged antitumor activity in this model.