Clinicopathological features of in situ follicular neoplasm and relations with follicular lymphoma in Japan.

This study aims to investigate the clinicopathological features of in situ follicular neoplasm (ISFN) in Japan. ISFN is a rare condition formerly considered as an early precursor of follicular lymphoma (FL). This is a first original report of ISFN from Asian country. We reviewed 19 biopsy samples of ISFN. ISFNs were categorized into two groups: (1) ISFN, consisting of ISFN with strong positivity for BCL-2 immunohistochemical staining (IHC), and obvious translocation of BCL-2; and (2) ISFN-like FL, featuring cases without obvious translocation but having morphological features and characteristic IHC findings of ISFN. As control, we adopted obvious FL. For some cases showing coexisting ISFN and FL lesions in the same lymph node, we could conduct further clonality analysis for each lesion. Nine of the 19 cases of ISFN coexisted with FL or had a history of overt B- or T-cell lymphoma including FL. Statistical comparison among ISFN-like FL and FL showed no significant differences in pathological features. Molecular analysis suggested that ISFN lesion and FL lesion in the same lymph node each have a different clonality. ISFN coexists or associates with other overt lymphomas frequently.

Clinical and biological relevance of CREB3L1 in Philadelphia chromosome-negative myeloproliferative neoplasms.

Cyclic AMP-response element-binding protein 3-like 1 (CREB3L1) is a gene involved in the unfolded protein response (UPR). Recently, we demonstrated that CREB3L1 is specifically overexpressed in the platelets of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). In this study, we aimed to show the clinical and biological relevance of CREB3L1 in these hematological diseases. Overexpression of CREB3L1 was specific to platelets in MPNs and associated with a higher risk of thrombosis and fibrotic transformation in essential thrombocythemia (ET) and polycythemia vera (PV) cases, respectively. Furthermore, we found that UPR genes were downregulated in platelets of patients with ET and PV, which were more pronounced in patients harboring the JAK2 V617F mutation. However, CREB3L1 overexpression does not alter UPR gene expression or cell proliferation in UT-7/TPO/CALRm cells exogenously expressing mutated calreticulin and HEL cells harboring endogenous JAK2 V617F. Furthermore, CREB3L1 overexpression did not modulate sensitivity to endoplasmic reticulum stress in these cell lines. Taken together, our data show 1) a potential role of CREB3L1 expression in platelets as a new marker of high-risk MPNs and 2) an association between CREB3L1 overexpression and UPR gene downregulation in these patients' platelets, with CREB3L1 not altering UPR in our in vitro models and possibly further in vivo mechanisms being involved.

Deep Learning Approach for Automated Detection of Myopic Maculopathy and Pathologic Myopia in Fundus Images.

PURPOSE: To determine whether eyes with pathologic myopia can be identified and whether each type of myopic maculopathy lesion on fundus photographs can be diagnosed by deep learning (DL) algorithms. DESIGN: A DL algorithm was developed to recognize myopic maculopathy features and to categorize the myopic maculopathy automatically. PARTICIPANTS: We examined 7020 fundus images from 4432 highly myopic eyes obtained from the Advanced Clinical Center for Myopia. METHODS: Deep learning (DL) algorithms were developed to recognize the key features of myopic maculopathy with 5176 fundus images. These algorithms were also used to develop a Meta-analysis for Pathologic Myopia (META-PM) study categorizing system (CS) by adding a specific processing layer. Models and the system were evaluated by 1844 fundus image. The area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to determine the performance of each DL algorithm. The rate of correct predictions was used to determine the performance of the META-PM study CS. MAIN OUTCOME MEASURES: Four trained DL models were able to recognize the lesions of myopic maculopathy accurately with high sensitivity and specificity. The META-PM study CS also showed a high accuracy and was qualified to be used in a semiautomated way during screening for myopic maculopathy in highly myopic eyes. RESULTS: The sensitivity of the DL models was 84.44% for diffuse atrophy, 87.22% for patchy atrophy, 85.10% for macular atrophy, and 37.07% for choroidal neovascularization, and the AUC values were 0.970, 0.978, 0.982, and 0.881, respectively. The rate of total correct predictions from the META-PM study CS was 87.53%, with rates of 90.18%, 95.28%, 97.50%, and 91.14%, respectively, for each type of lesion. The META-PM study CS showed an overall rate of 92.08% in detecting pathologic myopia correctly, which was defined as having myopic maculopathy equal to or more serious than diffuse atrophy. CONCLUSIONS: The novel DL models and system can achieve high sensitivity and specificity in identifying the different types of lesions of myopic maculopathy. These results will assist in the screening for pathologic myopia and subsequent protection of patients against low vision and blindness caused by myopic maculopathy.

Prognostic Factors for Axial Length Elongation and Posterior Staphyloma in Adults With High Myopia: A Japanese Observational Study.

PURPOSE: To identify prognostic factors for axial length (AL) elongation and incidence of posterior staphyloma (PS) in adult Japanese patients with high myopia. DESIGN: Retrospective, observational cohort study. METHODS: Six-year follow-up data for 345 patients (620 eyes with AL ≥ 26.5 mm and spherical equivalent [SE] ≤- 8.00 diopters) admitted to the Tokyo Medical and Dental University Hospital from 2007 to 2017 were analyzed retrospectively. Main outcome measures were change in AL from baseline, factors associated with AL, categorization of eyes with high myopia, factors associated with incidence of PS, and impact of PS on myopic maculopathy and visual function. RESULTS: The mean annual increase in AL was 0.03 mm. Presence of optic nerve disc conus (P = .025), steeper corneal curvature, lower SE, and decreased choroidal thickness (CT) (all P < .001) were associated with increased AL in univariate and multivariate analyses. Younger age (P = .003) and no use of intraocular pressure-lowering medications (P = .046) were associated with increased AL. Eyes with high myopia were categorized using factor analysis as associated with glaucoma, severe pathologic myopia, and mild-to-moderate pathologic myopia. Older age, increased AL, glaucoma, and choroidal thinning (all P ≤ .001) were identified as significant risk factors for the incidence of PS in univariate and/or multivariate analyses. Incidence of PS was a precursor for myopic maculopathy and visual field defects. CONCLUSIONS: Optic nerve disc conus, steeper corneal curvature, lower SE, decreased CT, and no use of intraocular pressure-lowering medications were prognostic factors for increased AL. Older age, increased AL, glaucoma, and decreased CT were prognostic factors for PS.

Detection of posterior vortex veins in eyes with pathologic myopia by ultra-widefield indocyanine green angiography.

AIMS: To analyse the characteristics of posterior vortex veins detected in highly myopic eyes by wide-field indocyanine green angiography (ICGA). METHODS: One hundred and fifty-eight consecutive patients (302 eyes) with high myopia (myopic refractive error >8.0 dioptres (D) or axial length ≥26.5 mm) were studied. Wide-field ICGA was performed with the Spectralis HRA module. RESULTS: Posterior vortex veins were found in 80 eyes (26%). The prevalence of posterior staphyloma was significantly higher in eyes in which posterior vortex vein was detected than in eyes without posterior vortex vein. The posterior vortex veins were classified into five types according to the site of exit from the eye; around the optic nerve in 28%, in the macular area in 17%, along the border of staphyloma in 6%, along the margin of macular atrophy or large peripapillary conus in 21%, and elsewhere in 28%. In one eye, two posterior vortex veins collected the choroidal venous blood from the entire fundus. CONCLUSIONS: Wide-field ICGA can analyse the characteristic features of choroidal blood outflow system through posterior vortex veins in highly myopic eyes. They may play an important role as routes of choroidal outflow in highly myopic eyes.

High-level in vivo gene marking after gene-modified autologous hematopoietic stem cell transplantation without marrow conditioning in nonhuman primates.

The successful engraftment of genetically modified hematopoietic stem cells (HSCs) without toxic conditioning is a desired goal for HSC gene therapy. To this end, we have examined the combination of intrabone marrow transplantation (iBMT) and in vivo expansion by a selective amplifier gene (SAG) in a nonhuman primate model. The SAG is a chimeric gene consisting of the erythropoietin (EPO) receptor gene (as a molecular switch) and c-Mpl gene (as a signal generator). Cynomolgus CD34+ cells were retrovirally transduced with or without SAG and returned into the femur and humerus following irrigation with saline without prior conditioning. After iBMT without SAG, 2-30% of colony-forming cells were gene marked over 1 year. The marking levels in the peripheral blood, however, remained low (<0.1%). These results indicate that transplanted cells can engraft without conditioning after iBMT, but in vivo expansion is limited. On the other hand, after iBMT with SAG, the peripheral marking levels increased more than 20-fold (up to 8-9%) in response to EPO even at 1 year posttransplant. The increase was EPO-dependent, multilineage, polyclonal, and repeatable. Our results suggest that the combination of iBMT and SAG allows efficient in vivo gene transduction without marrow conditioning.