Effect of the Duration of Intraretinal or Subretinal Fluid on the Response to Treatment in Undertreated Age-Related Macular Degeneration.

We investigated the association between the duration of intraretinal fluid (IRF) or subretinal fluid (SRF) and the response to antivascular endothelial growth factor injection in patients with undertreated age-related macular degeneration (ARMD). The Ethics Committee of Toho University Sakura Medical Center approved this study (no. S18030). Eighty eyes of ARMD patients with VA ≤20/100 were retrospectively assessed. Each injection's efficacy was classified, and the fluid accumulation prior to each injection was evaluated. The effect changes following to accumulated IRF, SRF, the longest persistent IRF period (≥10 months), and their determining factors were evaluated. Throughout observation, acquired refractoriness was rarely associated with increased accumulation of IRF or SRF. The injection span had a tendency to be short, and the polypoidal choroidal vasculopathy and occult choroidal neovasculopathy (CNV) proportions had a tendency to be higher among patients with diminished effects than among those with maintained effects. VA differed significantly with continuous IRF duration, but not with accumulated fluid. The diminishing effect of injections during long-standing IRF was rarely associated with undertreatment. The mechanism underlying acquired refractoriness remains unknown; the effect change demonstrated various patterns, including diminished and improved responses. The longest continuous IRF duration was associated with VA decline. Shortening the duration of continuous IRF may be necessary.

Postoperative Refractive Prediction Error Measured by Optical and Acoustic Biometry after Phacovitrectomy for Rhegmatogenous Retinal Detachment without Macular Involvement.

INTRODUCTION: The aim of this study was to investigate the postoperative prediction error measured by optical biometry and acoustic biometry in eyes after phacovitrectomy for rhegmatogenous retinal detachment (RRD) with no macular involvement. METHODS: Forty-nine eyes of 49 patients (32 male, 17 female; mean age 62.6 ± 7.5 years) with RRD without macular involvement who underwent phacovitrectomy (RRD group) and 49 eyes of 33 patients (21 male, 12 female; mean age 74.1 ± 7.1 years) without macular disease who underwent cataract surgery (control group) were included in this retrospective comparative study. The difference between the preoperative predictive value and the postoperative refractive value was measured both by optical and acoustic biometry and compared in each group. RESULTS: The postoperative refractive error calculated by acoustic biometry was -0.81 ± 0.75D and that calculated by optic biometry was -0.44 ± 0.77D in the RRD group. The postoperative refractive error calculated by acoustic biometry was -0.21 ± 0.64D and that calculated by optic biometry was 0.27 ± 0.71D in the control group. Significant myopic shifts were observed in the RRD group using both acoustic biometry and optic biometry but not in the control group. CONCLUSION: Phacovitrectomy for RRD with no macular involvement resulted in a significant myopic shift when compared with cataract surgery alone in patients without macular disease when calculated by both acoustic biometry and optic biometry.

Changes in choroidal blood flow and choroidal thickness after treatment in two cases of pediatric anisohypermetropic amblyopia.

PURPOSE: We aimed to examine the changes in choroidal blood flow (CBF) and central choroidal thickness (CCT) in children with anisohypermetropic amblyopia using laser speckle flowgraphy (LSFG) and enhanced depth imaging optical coherence tomography (EDI-OCT). OBSERVATIONS: The patients were both 6-year-old Japanese male children with complaints of worsening right visual acuity and were diagnosed with anisohypermetropic amblyopia. The decimal best-corrected visual acuities (BCVAs) in cases 1 and 2 were both 0.5. In both cases, LSFG results demonstrated CBF impairment in amblyopic eyes compared with fellow eyes. EDI-OCT results also showed that the CCTs of amblyopic eyes were greater than those of fellow eyes at the initial visit. Several months after the first visit, the decimal BCVAs in both cases had improved to 1.0 because of treatment. Further, the CBF gradually increased along with a decrease in the CCT of the amblyopic eye. The axial lengths and spherical powers of the amblyopic eyes in the two cases were not different during follow-up. CONCLUSIONS AND IMPORTANCE: We have determined the changes in CBF and CCT in two children with anisohypermetropic amblyopia for the first time. CBF impairments may be involved in the pathogenesis of anisohypermetropic amblyopia, and LSFG may be useful in examining CBF in pediatric anisohypermetropic amblyopia.

Detection of EGFR T790M Mutation in Pericardial Effusion from a Non-Small Cell Lung Cancer Patient with Erlotinib Therapy.

We report the case of a Japanese male with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)-sensitive lung adenocarcinoma, who had an EGFR mutation and presented in the emergency department with acute cardiac tamponade as the recurrence during EGFR-TKI therapy. We could detect a second mutation, T790M in exon 20 in the pericardial effusion. This is the first report to detect the resistant mutation T790M in pericardial effusion. We suggest that the pericardial effusion may therefore be useful as surrogate tissue for detecting EGFR mutation.

MET increases the sensitivity of gefitinib-resistant cells to SN-38, an active metabolite of irinotecan, by up-regulating the topoisomerase I activity.

INTRODUCTION: Most non-small-cell lung cancer tumors with epidermal growth factor receptor mutations are responsive to EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, but almost all such tumors ultimately acquire resistance. We previously found that a gefitinib-resistant cell line, PC-9/Met in which MET (MNNG-HOS transforming gene) is amplified, was more sensitive than its parent cell line (PC-9) to 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan. The purpose of this study was to investigate the mechanisms responsible for the increased sensitivity of the gefitinib-resistant cell line to SN-38. METHODS: The sensitivity of PC-9 and PC-9/Met to SN-38 was assessed by performing water soluble tetrazolium salt (WST-1) assays. Topoisomerase I (topo I) activities were determined for the cell lines cultured in the presence of hepatocyte growth factor and for those of which MET expression was knocked down by introducing a MET-specific small interfering RNA. RESULTS: PC-9/Met exhibited higher topo I activities, and higher topo I gene and protein expression levels than PC-9 did. Suppression of MET expression by a MET-specific small interfering RNA led to a decrease in the topo I protein expression in the PC-9/Met cells. The stimulation of PC-9 with hepatocyte growth factor caused an increase in the topo I protein level via the activation of MET. CONCLUSIONS: The increased sensitivity of PC-9/Met cells to SN-38 compared with that of PC-9 cells was partially because of topo I activities resulting from increased topo I mRNA and protein expression caused by MET signaling.

Serum heparan sulfate concentration is correlated with the failure of epidermal growth factor receptor tyrosine kinase inhibitor treatment in patients with lung adenocarcinoma.

INTRODUCTION: The epidermal growth factor receptor (EGFR) mutation status is a validated biomarker for the stratification of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatment in patients with non-small cell lung cancer (NSCLC); however, its use is limited in patients with wild-type EGFR, and new biomarkers are needed. We hypothesized that the serum concentration of heparan sulfate (HS), which activates oncogenic growth factor receptor signaling through EGFR and non-EGFR signaling pathways, may be a novel glycobiological biomarker for EGFR-TKIs treatment in NSCLC. METHODS: The pretreatment serum HS concentrations were determined using enzyme-linked immunosorbent assay in 83 patients with stage IV non-small cell lung adenocarcinoma who received EGFR-TKIs treatment. The relationship between the serum HS concentrations and patient characteristics, tumor response, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: Patient sex, performance status, smoking history, and EGFR mutation status were associated with tumor response. The serum HS concentrations were significantly higher among patients with progressive disease than among those without progressive disease (p = 0.003). Furthermore, the serum HS concentrations were strongly associated with a poor PFS and OS in a univariate Cox analysis (p = 0.0022 and p = 0.0003, respectively). A stratified multivariate Cox model according to the EGFR mutation status showed that higher HS concentrations were significantly associated with a shorter PFS and OS (p = 0.0012 and p = 0.0003). CONCLUSION: We concluded that a high-serum HS concentration was strongly related to a poor treatment outcome of EGFR-TKIs and may be a promising noninvasive and repeatable glycobiological biomarker in cancer treatment.

Impact of serum hepatocyte growth factor on treatment response to epidermal growth factor receptor tyrosine kinase inhibitors in patients with non-small cell lung adenocarcinoma.

PURPOSE: The epidermal growth factor receptor (EGFR) mutation status has emerged as a validated biomarker for predicting the response to treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI) in patients with non-small cell lung cancer. However, the responses to EGFR-TKIs vary even among patients with EGFR mutations. We studied several other independently active biomarkers for EGFR-TKI treatment. EXPERIMENTAL DESIGN: We retrospectively analyzed the serum concentrations of 13 molecules in a cohort of 95 patients with non-small cell lung adenocarcinoma who received EGFR-TKI treatment at three centers. The pretreatment serum concentrations of amphiregulin, ß-cellulin, EGF, EGFR, epiregulin, fibroblast growth factor-basic, heparin-binding EGF-like growth factor, hepatocyte growth factor (HGF), platelet-derived growth factor ß polypeptide, placental growth factor, tenascin C, transforming growth factor-α, and vascular endothelial growth factor (VEGF) were measured using enzyme-linked immunosorbent assay and a multiplex immunoassay system. The associations between clinical outcomes and these molecules were evaluated. RESULTS: The concentrations of HGF and VEGF were significantly higher among patients with progressive disease than among those without progressive disease (P < 0.0001). HGF and VEGF were strongly associated with progression-free survival (PFS) and overall survival (OS) in a univariate Cox analysis (all tests for hazard ratio showed P < 0.0001). A stratified multivariate Cox model according to EGFR mutation status (mutant, n = 20; wild-type, n = 23; unknown, n = 52) showed that higher HGF levels were significantly associated with a shorter PFS and OS (P < 0.0001 for both PFS and OS). These observations were also consistent in the subset analyses. CONCLUSIONS: Serum HGF was strongly related to the outcome of EGFR-TKI treatment. Our results suggest that the serum HGF level could be used to refine the selection of patients expected to respond to EGFR-TKI treatment, warranting further prospective study.

[A case of severe asthma exacerbation complicated with cerebral edema and diffuse multiple cerebral micro-bleeds].

A 36-year-old woman was admitted to the Intensive Care Unit for the treatment of severe asthma exacerbation. Her condition of asthma improved with systemic glucocorticosteroids, inhaled beta2-agonist, intravenous theophylline and inhaled anesthesia (isoflurane) under mechanical ventilation. Her consciousness was disturbed even after terminating isoflurane. Brain CT and MRI scan showed cerebral edema and diffuse multiple cerebral micro-bleeds. Glyceol, a hyperosmotic diuretic solution consisting of 10% glycerol and 5% fructose in saline, was administered to decrease cerebral edema. Her consciousness disturbance gradually recovered. Cerebral edema and hemorrhage improved. On the 69th hospital day, she was discharged from hospital without sequelae. This case is a rare one in which severe asthma exacerbation was complicated with cerebral edema and diffuse multiple cerebral hemorrhage. Inhaled anesthesia for asthma exacerbation should be used carefully to avoid delay of diagnosis of central nervous system complications.