Long-term prognosis after endoscopic submucosal dissection for esophageal cancer in older adult patients.

BACKGROUND: The validity of endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) in older individuals with comorbidities remains unclear. Therefore, this study evaluated the safety and efficacy of ESD and additional treatment for ESCC in older adult patients. METHODS: The clinicopathological characteristics and clinical outcomes of 398 consecutive older adult patients (≥ 65 years) with 505 lesions who underwent ESD for ESCC at the Hiroshima University Hospital between September 2007 and December 2019 were retrospectively evaluated. Additionally, the prognoses of 381 patients who were followed up for > 3 years were assessed. RESULTS: The mean patient age and procedure time were 73.1 ± 5.8 years and 77.1 ± 43.5 min, respectively. The histological en bloc resection rate was 98% (496/505). Postoperative stenosis, perforation, pneumonia, and delayed bleeding were conservatively treated in 82 (16%), 19 (4%), 15 (3%), and 5 (1%) patients, respectively. The 5-year overall and disease-specific survival rates were 78.9% and 98.0%, respectively (mean follow-up time: 71.1 ± 37.3 months). Multivariate analysis showed that age and the American Society of Anesthesiologists classification of physical status class ≥III (hazard ratio: 1.27; 95% confidence interval: 1.01-1.59, p = 0.0392) were independently associated with overall survival. A significantly lower overall survival rate was observed in the high-risk follow-up group than in the low-risk follow-up and high-risk additional treatment groups (p < 0.01). However, no significant difference in disease-specific survival was observed among the three groups. CONCLUSIONS: ESD is safe for ESCC treatment in patients aged ≥ 65 years. However, additional treatments should be considered based on the patient's general condition.

Clinicopathological and genomic features of superficial esophageal squamous cell carcinomas in nondrinker, nonsmoker females.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is sometimes detected in non-drinker and non-smoker females who are considered to have very low risk of ESCC development in daily practice. This study examined the clinicopathological and genomic characteristics of ESCCs in females with no history of drinking and smoking. METHODS: The sample comprised 118 ESCC lesions occurring in 95 female patients who underwent endoscopic submucosal dissection at our department between January 2008 and December 2019. The patients were categorized into two groups: 51 lesions in 49 patients with no history of drinking and smoking (nondrinker/nonsmoker [NDNS] group) and 69 lesions in 45 patients with a history of drinking or smoking (drinker/smoker [DS] group). We analyzed the differences in clinicopathological and cancerous genomic characteristics between the groups. Significant genomic alterations were validated using immunohistochemistry. RESULTS: Multiple logistic regression revealed that older age, fewer multiple Lugol-voiding lesions (LVLs), and reflux esophagitis (RE) were independently associated with the occurrence of ESCCs in the NDNS group. ESCC lesions in the NDNS group were predominantly located in the mid-thoracic esophagus, posterior wall side, with 0-IIa, the aspect ratio of the lesion >2 (vertical/horizontal), and endoscopic keratinization. Genetic analysis showed that CDKN2A driver alterations were significantly more frequent and KMT2D alterations were significantly less frequent in the NDNS group than in the DS group. KMT2D alterations were strongly correlated with immunostaining. CONCLUSION: Older nondrinker, nonsmoker females with RE and fewer multiple LVLs may develop longitudinal 0-IIa ESCC with keratinization of the posterior wall of the mid-thoracic esophagus. ESCCs in nondrinker, nonsmoker females had fewer KMT2D alterations and more CDKN2A alterations, which may be a biomarker for treatment.

Predictive factors for esophageal stenosis in patients receiving prophylactic steroid therapy after endoscopic submucosal dissection for esophageal squamous cell carcinoma.

BACKGROUND: Methods to prevent esophageal stenosis (ES) after endoscopic submucosal dissection (ESD) for superficial esophageal squamous cell carcinoma (ESCC) have received increasing attention. Although steroid administration is a prophylactic treatment, the risk factors for ES during prophylactic steroid therapy remain unknown. Therefore, this study aimed to retrospectively evaluate the risk factors for refractory ES in patients administered prophylactic steroids after ESD for ESCC. METHODS: Among 795 patients with ESCC (854 lesions), 180 patients (211 lesions) administered local triamcinolone acetonide (TrA) and/or oral prednisolone were recruited for this study. We compared the total number of endoscopic balloon dilatation (EBD) procedures performed for post-ESD ES and clinical findings (tumor size, ESD history or chemoradiation therapy [CRT], entire circumferential resection, muscle layer damage, supplemental oral prednisolone administration, EBD with TrA injection, and additional CRT) between patients with refractory and non-refractory ES. EBD was continued until dysphagia resolved. We categorized cases requiring ≥ 8 EBD procedures as refractory postoperative stenosis and divided the lesions into two groups. RESULTS: Multivariate logistic regression analysis revealed that factors such as ESD history, CRT history, tumor size, and entire circumferential resection were independently associated with the development of refractory ES. The withdrawal rates of EBD at 3 years were 96.1% (52/53) and 58.5% (39/59) in the non-refractory and refractory groups, respectively. CONCLUSIONS: Our data suggest that entire circumferential resection and CRT history are risk factors for refractory post-ESD ES in ESCC, even with prophylactic steroid administration.

Endoscopic findings suggestive of a high risk of non-radical cure after definitive chemoradiotherapy for cT1bN0M0 esophageal squamous cell carcinoma.

BACKGROUND: Definitive chemoradiotherapy (DCRT) is a curative treatment option for cT1bN0M0 esophageal squamous cell carcinoma (ESCC); however, local residual disease and recurrence after complete remission may occur. We aimed to identify endoscopic findings associated with the risk of non-radical cure (local remnant or recurrence) after DCRT for cT1bN0M0 ESCC. METHODS: We retrospectively analyzed 40 consecutive patients with cT1bN0M0 ESCC who had undergone DCRT between January 2007 and December 2017. We examined the endoscopic findings in patients with residual or recurrent (RR) disease (RR group) and those without RR disease [non-RR (NRR) group] after DCRT. We also evaluated outcomes after DCRT for each endoscopic finding. RESULTS: There were 10 patients in the RR group and 30 patients in the NRR group. The RR group had a significantly larger tumor size and a higher proportion of lesions with type 0-I. The 5-year relapse-free survival rate was significantly lower in type 0-I and in the presence of B3 vessels. Endoscopic findings in 15 patients with cT1bN0M0 ESCC, type 0-I, who underwent DCRT revealed significantly more reddish lesions in the RR group compared to the NRR group. CONCLUSIONS: cT1bN0M0 ESCC large size, with B3 vessels, and type 0-I has a high risk of non-radical cure after DCRT, especially the reddish type 0-I, which may need to be considered for treatment similar to advanced cancer, including surgery with preoperative DCRT.

Elastin gene polymorphisms in neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

PURPOSE: To study and reveal genetic variation in the elastin gene (ELN) that may be associated with neovascular age-related macular degeneration (AMD) and/or polypoidal choroidal vasculopathy (PCV). Eyes with neovascular AMD and PCV exhibit substantially different structural alterations of the elastic layer in the Bruch's membrane. The hypothesis for the present study was that ELN polymorphisms may play a role in the development of neovascular AMD and PCV and that genetic differences in ELN between these two phenotypes may be a reason for the histopathologic differences. To test these hypotheses, ELN was screened for genetic variation in a Japanese case-control dataset. METHODS: Two hundred eighty-five subjects were enrolled: 78 with neovascular AMD, 103 with PCV, and 104 control. We genotyped five tagged single nucleotide polymorphisms (SNPs) in ELN, and allele, genotype, and haplotype frequency distributions among neovascular AMD, PCV, and control subjects were compared by chi(2) tests. RESULTS: A common ELN variant was significantly associated with susceptibility to PCV. The age- and sex-adjusted odds ratio was 7.56 for individuals homozygous for the risk allele compared with those carrying no more than one copy of the risk allele. Significantly different distributions were found in allele and haplotype frequencies between neovascular AMD and PCV in this region, but no particular ELN SNPs or haplotypes were significantly associated with neovascular AMD. CONCLUSIONS: The findings implicate ELN as a susceptibility gene for PCV, and suggest that a different pathogenic process may be involved in the phenotypic expression of neovascular AMD and PCV.

The upregulation of angiogenic gene expression in cultured retinal pigment epithelial cells grown on type I collagen.

PURPOSE: Increases in matrix proteins, such as type I collagen and fibronectin, are observed with aging in the retinal pigment epithelium (RPE) basement membrane. However, little is known about altered gene expression profiles of RPE associated with increases in matrix proteins. We investigated changes in gene expression profiles of a human RPE cell line (ARPE-19) cultured on type I collagen. METHODS: Visually confluent ARPE-19 cells were grown on either Matrigel (M group) or type I collagen (C group) without serum over 3 days. Total RNA was extracted and reverse transcribed. Gene expression profiles in both groups were compared using microarray analyses. Several angiogenic genes including integrin alpha V, integrin alpha 2, integrin beta 1, integrin beta 3, VEGF-A, VEGF-B, and VEGF-C were subjected to quantitative analyses using real-time PCR. RESULTS: Out of 192 genes examined, angiogenesis-related genes (17.7%) and extracellular matrix-related genes (30.2%) were expressed highly (with more than 1.5-fold difference) in the C group when compared with the M group. In real-time PCR analyses, all VEGF and integrin family genes examined were expressed more in the C group than in the M group. CONCLUSIONS: Type I collagen likely causes an upregulation in a number of angiogenic gene expression patterns as seen in RPE in vitro experiments.

LOC387715/HTRA1 variants in polypoidal choroidal vasculopathy and age-related macular degeneration in a Japanese population.

PURPOSE: To investigate whether variants in the LOC387715 locus and the HtrA serine peptidase 1 (HTRA1) gene within the 10q26 locus are associated with polypoidal choroidal vasculopathy (PCV) and wet age-related macular degeneration (AMD) in a Japanese population, and whether genetic diversity exists between PCV and wet AMD in this locus. DESIGN: Cross-sectional study. METHODS: We genotyped 243 Japanese individuals, including 76 PCV cases, 73 wet AMD cases, and 94 controls using two single nucleotide polymorphisms (SNPs) that are located in the LOC387715 locus (rs10490924) or the HTRA1 gene (rs11200638). Genotyping was performed using TaqMan assays (Applied Biosystems, Foster City, California, USA). RESULTS: Two SNPs generated highly significant allelic associations with PCV (rs10490924, P = 5.7 x 10(-6); rs11200638, P = 5.2 x 10(-6)) and AMD (rs10490924, P = 1.4 x 10(-6); rs11200638, P = 3.4 x 10(-7)). The odds ratios and population attributable risks were higher for the AMD cases than for the PCV cases. Homozygotes for the risk allele at rs11200638 had a 6.33-fold increased risk of PCV and a 13.77-fold increased risk of wet AMD when compared with homozygotes for the wild-type allele. There were no significant differences in either allelic or genotypic frequencies between PCV and AMD cases. CONCLUSIONS: The LOC387715/HTRA1 variants are associated with PCV and wet AMD in the Japanese population. The associations are stronger in AMD than in PCV. PCV and AMD share common genetic factors, which suggests that PCV and wet AMD are similar in some pathophysiologic aspects.

Different effects of angiopoietin-2 in different vascular beds: new vessels are most sensitive.

In this study, we used double transgenic mice with inducible expression of angiopoietin-2 (Ang2) to investigate the role of Ang2 in the retinal and choroidal circulations and in three models of ocular neovascularization (NV). Mice with induced expression of Ang2 ubiquitously, or specifically in the retina, survived and appeared grossly normal. They also had normal-appearing retinal and choroidal circulations, demonstrating that high levels of Ang2 did not induce regression of mature retinal or choroidal vessels. When Ang2 expression was induced soon after birth, there was increased density of the deep capillary bed on postnatal day (P) 11 that returned to normal by P18, the time that retinal vascular development is usually completed. In mice with ischemic retinopathy, induction of Ang2 during the ischemic period resulted in a significant increase in retinal NV, but induction of Ang2 at a later time point when ischemia (and vascular endothelial growth factor [VEGF]) was less, hastened regression of NV. In triple transgenic mice that coexpressed VEGF and Ang2, the increased expression of Ang2 inhibited VEGF-induced NV in the retina. Increased expression of Ang2 also resulted in regression of choroidal neovascularization. These data suggest that ocular neovascularization, but not mature retinal or choroidal vessels, is sensitive to Ang2; a high Ang2/VEGF ratio promotes regression, while high Ang2 in the setting of hypoxia and/or concomitantly high Ang2 and VEGF stimulate neovascularization.

Analysis of cytokine mRNAs in murine herpes simplex virus type 1 retinitis.

PURPOSE: To investigate cytokine mRNA expression during the inflammatory process induced in the contralateral eyes by uniocular inoculation of herpes simplex virus type 1 (HSV-1) via the anterior chamber. METHODS: BALB/c mice were inoculated in the anterior chamber with 5 x 10(4) plaque-forming units of HSV-1 (KOS). mRNA was extracted from the inflamed posterior segments of the uninoculated eyes at 0 (control), 9, 11, 14, and 21 days postinoculation (p.i.). Reverse transcription-polymerase chain reaction was performed for semiquantitative analysis of mRNA expression of interleukin (IL)-1beta, IL-2, IL-4, IL-10, IL-12p35, IL-12p40, interferon (IFN)gamma, tumor necrosis factor (TNF)alpha, transforming growth factor (TGF)beta2 and induced nitric oxide synthase (iNOS). RESULTS: Peak mRNA expression of iNOS was observed at day 14 p.i. The time profiles of mRNA expression for IL-1beta, IL-2, IL-4, IL-10, IFN-gamma, TNFalpha were similar to that of iNOS, while TGFbeta2, IL-12p35, and IL-12p40 demonstrated a reverse pattern. CONCLUSIONS: The kinetics of the analyzed cytokines synchronized with the clinicopathological activity of the experimental murine HSV-1 retinitis. The immunosuppressive cytokines TGFbeta2 and IL-10 demonstrated different peaks of mRNA expressions suggesting that the down-regulation phase of the inflammatory process was controlled by several factors working at different phases.