The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer.

Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients. Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval for clinical use, primarily due to issues such as induction of the heat shock response (HSR), off-target effects, and unfavorable toxicity profiles. We sought to examine the effects of HVH-2930, a novel C-terminal HSP90 inhibitor, in overcoming trastuzumab resistance. Methods: The effect of HVH-2930 on trastuzumab-sensitive and -resistant cell lines in vitro was evaluated in terms of cell viability, expression of HSP90 client proteins, and impact on cancer stem cells. An in vivo model with trastuzumab-resistant JIMT-1 cells was used to examine the efficacy and toxicity of HVH-2930. Results: HVH-2930 was rationally designed to fit into the ATP-binding pocket interface cavity of the hHSP90 homodimer in the C-terminal domain of HSP90, stabilizing its open conformation and hindering ATP binding. HVH-2930 induces apoptosis without inducing the HSR but by specifically suppressing the HER2 signaling pathway. This occurs with the downregulation of HER2/p95HER2 and disruption of HER2 family member heterodimerization. Attenuation of cancer stem cell (CSC)-like properties was associated with the downregulation of stemness factors such as ALDH1, CD44, Nanog and Oct4. Furthermore, HVH-2930 administration inhibited angiogenesis and tumor growth in trastuzumab-resistant xenograft mice. A synergistic effect was observed when combining HVH-2930 and paclitaxel in JIMT-1 xenografts. Conclusion: Our findings highlight the potent efficacy of HVH-2930 in overcoming trastuzumab resistance in HER2-positive breast cancer. Further investigation is warranted to fully establish its therapeutic potential.

Case report: Management of recurrent pupillary optic capture with sutureless surgical technique using 7-0 polypropylene flange.

Background: To report a novel surgical technique for recurrent pupillary optic capture after flanged intraocular lens (IOL) fixation. Methods: In this retrospective case series, we detail our use of two parallel 7-0 polypropylene sutures passed between the iris plane and the optic of scleral-fixated IOL to address pupillary optic capture. Flanges were created using ophthalmic cautery to secure it to the sclera without suture. Results: Two eyes with pupillary optic capture underwent a sutureless surgical technique using 7-0 polypropylene flanges. No recurrences of pupillary optic capture were observed during the 1-year follow-up. Conclusion: Our sutureless surgical technique using a 7-0 polypropylene flange was an effective, efficient, and less invasive approach for treating recurrent pupillary optic capture.

Repositioned versus exchanged flanged intraocular lens fixation for intraocular lens dislocation.

This study aimed to compare the outcomes of flanged intraocular lens (IOL) fixation with new IOL exchange after dislocated IOL removal and repositioned dislocated IOL in patients with IOL dislocation. Eighty-nine eyes that underwent flanged IOL fixation were retrospectively included, with 51 eyes in the exchanged IOL group and 38 eyes in the repositioned IOL group. In both groups, best-corrected visual acuity (BCVA) improved at 1, 3, 6, and 12 months postoperatively and did not differ between the two groups at any of these time points. However, at 1 week postoperatively, BCVA in the repositioned IOL group improved compared with baseline, whereas that in the exchanged IOL group did not. Moreover, there were lesser changes in the corneal endothelial cell density (ECD) and corneal astigmatism in the repositioned IOL group than in the exchanged IOL group. The IOL positions, including IOL tilt and IOL decentration, were not different between the groups. Flanged IOL fixation with new IOL exchange and with repositioned dislocated IOL for patients with IOL dislocation had similar visual outcomes and IOL position. However, the latter had a smaller corneal ECD decrease and astigmatic change. This technique was effective in treating IOL dislocation while minimizing corneal injury.

Effect of external subretinal fluid drainage on persistent subretinal fluid after scleral buckle surgery in macula-involving rhegmatogenous retinal detachment.

This study aimed to analyze the duration and causes of persistent subretinal fluid (PSF) after scleral buckle (SB) surgery in patients with macula-involving rhegmatogenous retinal detachment (RRD). Sixty-one eyes of 61 patients with macula-involving RRD who underwent SB surgery between 2016 and 2022 were reviewed retrospectively. PSF was confirmed on optical coherence tomography. The PSF duration after surgery and the analysis of relevant ocular and systemic factors were conducted according to the PSF duration. The mean duration of PSF was 5.9 ± 4.6 months in all eyes and 8.1 ± 5.0 months in eyes not treated with external subretinal fluid (SRF) drainage, which was significantly longer than 4.5 ± 3.7 months in those subjected to external SRF drainage. The mean best-corrected visual acuity improved significantly 3 months after surgery. There were significant visual improvements in the external SRF drainage group compared to the non-drainage group during all follow-up periods. Longstanding shallow RRD was significantly associated with longer PSF duration after SB surgery. External SRF drainage during SB surgery can effectively reduce SRF, shorten the duration of PSF, and accelerate visual improvement.

Suppression of TNBC metastasis by doxazosin, a novel dual inhibitor of c-MET/EGFR.

BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and EGFR in TNBC is associated with worse clinicopathological features and unfavorable outcomes. Although the development of new c-MET inhibitors and the emergence of 3rd-generation EGFR inhibitors represent promising treatment options, the high costs involved limit the accessibility of these drugs. In the present study, we sought to investigate the therapeutic potential of doxazosin (DOXA), a generic drug for benign prostate hyperplasia, in targeting TNBC. METHODS: The effect of DOXA on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis, c-MET/EGFR signaling pathway, molecular docking studies and impact on cancer stem cell (CSC)-like properties. An in vivo metastatic model with CSCs was used to evaluate the efficacy of DOXA. RESULTS: DOXA exhibits notable anti-proliferative effects on TNBC cells by inducing apoptosis via caspase activation. Molecular docking studies revealed the direct interaction of DOXA with the tyrosine kinase domains of c-MET and EGFR. Consequently, DOXA disrupts important survival pathways including AKT, MEK/ERK, and JAK/STAT3, while suppressing CSC-like characteristics including CD44high/CD24low subpopulations, aldehyde dehydrogenase 1 (ALDH1) activity and formation of mammospheres. DOXA administration was found to suppress tumor growth, intra- and peri-tumoral angiogenesis and distant metastasis in an orthotopic allograft model with CSC-enriched populations. Furthermore, no toxic effects of DOXA were observed in hepatic or renal function. CONCLUSIONS: Our findings highlight the potential of DOXA as a therapeutic option for metastatic TNBC, warranting further investigation.

Primary and additional treatment preference in aggressive retinopathy of prematurity and type 1 retinopathy of prematurity.

OBJECTIVE: This study aimed to evaluate the preference for antivascular endothelial growth factor (anti-VEGF) versus laser ablation therapy as primary and additional treatment in aggressive retinopathy of prematurity (ROP) and type 1 ROP. METHODS: This multicentre retrospective study was conducted at nine medical centres across South Korea. A total of 94 preterm infants with ROP who underwent primary treatment between January 2020 and December 2021 were enrolled. All eyes were classified as having type 1 ROP or aggressive ROP. Data on the zone, primary treatment chosen, injection dose, presence of reactivation and additional treatment were collected and analysed. RESULTS: Seventy infants (131 eyes) with type 1 ROP and 24 infants (45 eyes) with aggressive ROP were included. Anti-VEGF injection was selected as the primary treatment in 74.05% of the infants with type 1 ROP and 88.89% with aggressive ROP. Anti-VEGF injection was selected as the ROP was located in zone I or posterior zone II, and laser ablation was selected when it was located in zone II. The anti-VEGF injection doses varied and tended to be higher in the aggressive ROP group. Infants with aggressive ROP were 2.08 times more likely to require additional treatment than those with type 1 ROP. When ROP reactivation occurred, laser therapy was preferred as an additional treatment. CONCLUSION: In Korea, the preference for anti-VEGF therapy or laser therapy differed according to ROP subtype, zone and primary or secondary treatment. These findings suggest that ROP treatment are considered according to ROP subtype, location and reactivation.

Management of Steroid-Induced Glaucoma in a Patient with Pyoderma Gangrenosum.

Pyoderma gangrenosum (PG) is an uncommon inflammatory skin disorder typically presenting as painful skin ulcers, which may also exhibit extracutaneous findings. PG can occur at the site of trauma or surgery, which is known as the pathergic phenomenon. A 36-year-old man developed bilateral steroid-induced glaucoma after prolonged systemic immunosuppressive treatment for cutaneous pyoderma gangrenosum. After successful Ahmed glaucoma valve implantation surgery with donor scleral patch graft in the right eye, the same surgery failed repeatedly in the left eye and complicated with the prolonged conjunctival necrosis and the exposure of the donor scleral patch graft. Under the impression of ocular involvement of PG, microinvasive glaucoma surgery (MIGS) with XEN® Gel Stent was performed in the left eye; the conjunctival bleb was successfully formed without conjunctival necrosis, and intraocular pressure was well maintained. Ophthalmic surgery can be complicated in patients with PG, and the surgical option should be selected prudently to minimize surgical trauma. MIGS, as a minimally invasive surgical technique, could offer an advantage for patients with PG.

MULTIPLE-SESSION SUBTHRESHOLD MICROPULSE LASER THERAPY FOR EXUDATIVE PERIFOVEAL VASCULAR ANOMALOUS COMPLEX: A CASE REPORT.

PURPOSE: To report a case of exudative perifoveal vascular anomalous complex treated with a 532-nm subthreshold micropulse laser unresponsive to intravitreal injections. METHODS: A case report. RESULTS: A 65-year-old woman presented with blurred vision in the left eye for 1 month. An isolated perifoveal aneurysm surrounded by retinal hemorrhages and hard exudates was revealed in fundus examination, and optical coherent tomography showed a round lesion with a hyperreflective wall, subretinal fluid, and an intraretinal cyst. She was diagnosed with exudative perifoveal vascular anomalous complex and received four intravitreal injections. However, her best-corrected visual acuity decreased, and an aneurysmal lesion with macular edema persisted for approximately 6 months. Three sessions of 532-nm subthreshold micropulse laser therapy around the aneurysm were applied because the intravitreal injection treatment was ineffective. Since the last session, macular edema disappeared, the involuted lesion remained substantially stable without recurrence, and her best-corrected visual acuity improved without visual field defect. CONCLUSION: To our knowledge, this is the first report of a successful subthreshold micropulse laser treatment for an exudative perifoveal vascular anomalous complex lesion, and it could be a safe and effective method for the patient unresponsive to intravitreal injections.

Long-term surgical outcomes of Ahmed valve implantation in refractory glaucoma according to the type of glaucoma.

BACKGROUND: We evaluated the long-term efficacy and surgical outcomes of Ahmed glaucoma valve (AGV) implantation in patients with refractory glaucoma by glaucoma type. METHODS: In total, 135 eyes of 135 patients diagnosed with refractory glaucoma and underwent AGV implantation between 2002 and 2018 were reviewed retrospectively. The best-corrected visual acuity (BCVA), intraocular pressure (IOP), and number of antiglaucoma medications were investigated at baseline and follow-up. The cumulative probability of qualified success according to the glaucoma type was evaluated at 12, 24, 36, and 60 months postoperatively. RESULTS: The mean IOP of all patients was 35.7 ± 11.7 mmHg, which was significantly reduced 12.7 ± 7.0 mmHg at 1 week, 16.2 ± 7.5 mmHg at 2 weeks, 17.6 ± 6.8 mmHg at 1 month, 17.5 ± 6.4 mmHg at 3 months, 16.1 ± 6.0 mmHg at 6 months, 16.7 ± 8.0 mmHg at 12 months, 16.4 ± 6.6 mmHg at 24 months, 15.6 ± 5.0 mmHg at 36 months, and 15.6 ± 5.6 mmHg at 60 months after surgery (p < 0.001, respectively). The mean number of antiglaucoma medications was 3.7 ± 1.3, which significantly decreased to 0.4 ± 0.9 at 1 week, 0.3 ± 0.8 at 2 weeks, 0.7 ± 0.9 at 1 month, 1.1 ± 1.1 at 3 months, 1.4 ± 1.0 at 6 months, 1.5 ± 1.1 at 12 months, 1.6 ± 1.2 at 24 months, 1.7 ± 1.2 at 36 months, and 1.8 ± 1.3 at 60 months after surgery (p < 0.001, respectively). The mean BCVA significantly improved from postoperative 2 weeks. Although 71 (52.6%) eyes had postoperative complications, the cumulative probability of surgical success was 72.6% at 12 months, 66.7% at 24 months, and 63.7% at 36 and 60 months. According to the glaucoma type, the success rate of AGV implantation was more than 50% even after 60 months follow-up, except subgroup of neovascular glaucoma (NVG) due to retinal vein occlusion (RVO). CONCLUSIONS: AGV implantation in patients with refractory glaucoma was, after long-term follow-up, successful overall. Therefore, AGV implantation can be an effective surgical option to reduce the IOP and number of antiglaucoma medications and to improve visual acuity for various glaucoma types.

Clinical Analysis of Persistent Subretinal Fluid after Pars Plana Vitrectomy in Macula with Diabetic Tractional Retinal Detachment.

(1) Background: We analyzed the duration of persistent subretinal fluid (PSF) and the contributing factors of PSF after pars plana vitrectomy in patients who had a macula with diabetic tractional retinal detachment (TRD). (2) Methods: Forty eyes of 40 patients who had pars plana vitrectomy due to a macula with diabetic TRD, between 2014 and 2020, were retrospectively reviewed. The duration of PSF, as well as relevant ocular and systemic factors, was analyzed. (3) Results: The mean duration of PSF was 4.4 ± 4.7 months. The prevalence of PSF was 75.0% at 1 month, 50.0% at 3 months, 30.0% at 6 months and 10.0% at 12 months after surgery. Blood urea nitrogen, creatinine, and estimated glomerular filtration rate (eGFR) were significantly associated with the duration of PSF in the univariate analysis. In the multivariate analysis, only eGFR was significantly associated with the duration of PSF (ß = -0.089, p = 0.030). (4) Conclusion: PSF may persist for more than 12 months in a macula with diabetic TRD after vitrectomy. Moreover, patients with impaired kidney function tended to have a delayed subretinal fluid absorption. Therefore, careful investigation of preoperative systemic conditions, especially kidney function, should be considered before TRD surgery in diabetic patients.

Long-Term Effect of Silicone Oil Tamponade for Postoperative and Posttraumatic Bacterial Endophthalmitis.

PURPOSE: To compare clinical features and microbial profiles, treatment outcomes, and prognostic factors of the eyes between postoperative and posttraumatic bacterial endophthalmitis after pars plana vitrectomy (PPV) with silicone oil (SO) tamponade. METHODS: Overall, 57 eyes of 57 patients who diagnosed exogenous bacterial endophthalmitis and underwent PPV with SO tamponade between 2000 and 2019 were reviewed. Causative microorganisms, culture positivity, change of mean best-corrected visual acuity (BCVA), and course of treatment were investigated between postoperative and posttraumatic groups, and relevant factors were analyzed according to the final BCVA. RESULTS: The mean BCVA change was not significantly different between groups. The positive rate of microorganisms was significantly higher in the postoperative group. The mean time to surgery over 48 hours, initial BCVA worse than hand motion, and additional surgery after initial vitrectomy were correlated with poor final BCVA worse than 20/200. There was significantly achieved final BCVA 20/200 or better in the Staphylococcus and Streptococcus group than the Enterococcus and Pseudomonas group. CONCLUSION: PPV with SO tamponade may be an effective surgical treatment strategy for exogenous bacterial endophthalmitis. Final visual outcomes were not significantly different between postoperative and posttraumatic groups, and the mean time to surgery, initial visual acuity, additional surgery, and type of microorganism are significantly related to visual prognosis.

Germline Mutations for Novel Candidate Predisposition Genes in Sporadic Schwannomatosis.

BACKGROUND: Schwannomatosis is a late-onset tumor predisposition syndrome associated with the development of many different types of malignancies. A relevant genetic mechanism can be explained by three mutational events. The first-hit mutation is a germline mutation, and the SMARCB1 mutation on chromosome 22 is the most well-known genetic abnormality in patients with schwannomatosis. LZTR1 is another major predisposing gene in 22q-related schwannomatosis that lacks SMARCB1 variants. Although these two variants account for the occurrence of most familiar schwannomatoses, the genetic causes of sporadic schwannomatosis for the most part remain unknown. Therefore, current molecular diagnostic criteria cannot completely explain the basis of this disease. The common genetic background between schwannomatosis and other related malignant tumors is also unclear. Moreover, it is not easy to explain various clinical manifestations by only two known mutations. QUESTION/PURPOSES: (1) Are there important sequences outside the SMARCB1 or LZTR1 region on chromosome 22 that might carry a first-hit mutational predisposition to sporadic schwannomatosis? Or are there alternative evolutionarily conserved loci that might carry a first-hit mutational predisposition? (2) Is the age of disease onset associated to such genetic variants? METHODS: This study was a retrospective chart review and prospective genetic study on patients with schwannomatosis who were treated surgically. The clinical criteria to diagnose schwannomatosis were as follows: (1) histologically proven nonvestibular schwannomas; (2) no evidence of vestibular schwannomas on 3-mm brain MRI. A total of 21 patients were treated between March 2006 and June 2015. Since nine patients did not visit the outpatient clinic during the recruitment period, we obtained blood samples from 12 patients with schwannomatosis for a genetic analysis. After two patients were excluded because of their family history of schwannomatosis, genetic analyses were finally performed on 10 patients. Then, those with NF2, SMARCB1 or LZTR1 variants were screened by whole exome sequencing. All 10 patients passed our screening strategy. There were eight men and two women, with a median (range) age of 43 years (24 to 66) at the time of diagnosis. To select candidate genes, common ethnic variants and frequent mutations in in-house exome sequencing data were removed to exclude the population-specific polymorphisms not found in other population and to generalize the findings. Frameshift, nonsense, and splice-site variants were deemed pathogenic. Missense variants were classified as potentially pathogenic, variants of uncertain significance, or benign using in silico (via computer simulation) prediction algorithms, Sorting Intolerant From Tolerant (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2), and Combined Annotation Dependent Depletion (CADD). A variant was considered potentially pathogenic if two or more algorithms predicted the variant to be damaging and benign if none considered it damaging. Then, potentially pathogenic variants only in the genes associated with cancer-predisposition or DNA damage repair were classified as the pathogenic candidate variants of sporadic schwannomatosis. The predictions for pathogenic candidate variants were checked again on Clinical Interpretation of Genetic Variants (InterVar) based on the American College of Medical Genetics guidelines and validated against Mendelian clinically applicable pathogenicity scores (M-CAP scores). RESULTS: We detected 26 variants; 13 variants across 10 genes were predicted to be pathogenic and found in seven patients, two each in ARID1A, PTCH2, and NOTCH2 and one each in MSH6, ALPK2, MGMT, NOTCH1, CIC, TSC2, and CDKN2A. One frameshift deletion in PTCH2 met the criteria for pathogenic or likely pathogenic classification, as recommended by the American College of Medical Genetics guidelines. Six missense mutations were classified as possibly pathogenic variants based on M-CAP scores. Four predicted pathogenic missense variants were detected in DNA damage repair (DDR) genes. Three DDR genes were affected: ARID1A, MGMT, and MSH6. Among the nine predicted pathogenic mutations detected in known cancer-predisposing genes, one was a frameshift deletion and the others were missense mutations. Seven tumor suppressor genes were involved: PTCH2, ALPK2, CIC, NOTCH1, NOTCH2, TSC2, and CDKN2A. One patient with multiple pathogenic variants in two DDR genes, ARID1A and MSH6, received a schwannomatosis diagnosis at 33 years old. Each of the other patients who had single variants in the DDR gene received their diagnoses at 41 years of age. The age at diagnosis was 40 years or older in patients with variants in cancer-predisposing genes, except for one patient who had multiple variants in TSC2 and CDKN2A. The carrier of those variants received the diagnosis at 24 years old. CONCLUSIONS: This study identified first-hit candidate mutations predisposing patients to schwannomatosis that were not related to SMARCB1 or LZTR1 variations in a cohort of patients with sporadic schwannomatosis. Patients with sporadic schwannomatosis without SMARCB1 or LZTR1 genetic variation may have developed the disease because of genomic variants related to cancer initiation in areas other than chromosome 22. Seven of 10 patients had predicted pathogenic germline mutations in DDR and cancer predisposition genes. We detected multiple cancer-related mutations in each patient. The age at the time schwannomatosis was diagnosed might be associated with a combination of variants and characteristics of the genes containing the variants; however, we did not have enough patients to confirm this association. CLINICAL RELEVANCE: The germline mutations identified in this study and the ideas related to the age of disease onset may provide potential candidate variants for future research on sporadic schwannomatosis and help to revise the current clinical and molecular diagnostic criteria. Further in vivo and in vitro studies are needed for these variants.

Incidence and treatment outcomes of secondary epiretinal membrane following intravitreal injection for diabetic macular edema.

The purpose of this study was to investigate the incidence of secondary epiretinal membrane (ERM) after intravitreal injection and the effect of ERM on visual acuity and central macular thickness (CMT) in patients with diabetic macular edema (DME). We included 147 eyes of 95 patients over 18 years old who were diagnosed with DME from 2012 to 2016, treated with intravitreal injection, and followed-up more than 24 months. Mean CMT in the ERM group was significantly thicker than in the non-ERM group after 9, 12, 18, and 24 months. Secondary ERM developed in 9.5% of patients during follow-up. Compared to other agents, the incidence of secondary ERM was significantly higher after intravitreal injection of dexamethasone implant. Among patients in the ERM group, the mean decrease of CMT between pre-injection and 2 weeks post-injection was significantly less after secondary ERM formation than before ERM formation. Secondary ERM formation was significantly associated with the number of intravitreal injections and the use of dexamethasone implant. Therefore, secondary ERM develops more frequently as the number of intravitreal injections increases and after intravitreal dexamethasone implant injection. The therapeutic effects of intravitreal injections for DME patients decrease after secondary ERM formation.

Angiographic features of drug-induced bilateral angle closure and transient myopia with Ciliochoroidal effusion.

BACKGROUND: To report five cases of acute drug-induced angle closure and transient myopia with ciliochoroidal effusion and to analyze angiographic findings of these cases. METHODS: This study is an observational case series. Five patients with acute drug-induced angle closure and transient myopia with ciliochoroidal effusion were examined by fluorescein angiography, indocyanine green angiography (ICGA) and ultrasound biomicroscopy (UBM). RESULTS: Five patients presented with bilateral visual loss and ocular pain after intake of topiramate, methazolamide, phendimetrazine tartrate or mefenamic acid. All patients showed elevated intraocular pressure (IOP) with shallow anterior chamber and myopic shift from - 0.5 to - 17.0 diopters (D). UBM showed ciliochoroidal effusions with diffuse thickening of the ciliary body in all cases. Rapid normalization of IOP and decrease of myopic shift occurred in all patients after discontinuing the suspected drugs. We classified the ICGA findings into 2 major signs (hypofluorescent dark spots, hyperfluorescent pinpoints) and 3 minor signs (diffuse choroidal hyperfluorescence, early hyperfluorescence of choroidal stromal vessel, and leakage and dilated retinal vessels). CONCLUSIONS: The pathogenesis of acute drug-induced angle closure and transient myopia with ciliochoroidal effusion may be idiosyncratic reaction of uveal tissue to systemic drugs. Accumulation of extravascular fluid in the ciliochoroidal layer had a major role in the pathogenesis. ICGA could be a useful method to examine the pathophysiology of this condition by imaging of the choroidal layer.

Weakly supervised lesion localization for age-related macular degeneration detection using optical coherence tomography images.

Age-related macular degeneration (AMD) is the main cause of irreversible blindness among the elderly and require early diagnosis to prevent vision loss, and careful treatment is essential. Optical coherence tomography (OCT), the most commonly used imaging method in the retinal area for the diagnosis of AMD, is usually interpreted by a clinician, and OCT can help diagnose disease on the basis of the relevant diagnostic criteria, but these judgments can be somewhat subjective. We propose an algorithm for the detection of AMD based on a weakly supervised convolutional neural network (CNN) model to support computer-aided diagnosis (CAD) system. Our main contributions are the following three things. (1) We propose a concise CNN model for OCT images, which outperforms the existing large CNN models using VGG16 and GoogLeNet architectures. (2) We propose an algorithm called Expressive Gradients (EG) that extends the existing Integrated Gradients (IG) algorithm so as to exploit not only the input-level attribution map, but also the high-level attribution maps. Due to enriched gradients, EG can highlight suspicious regions for diagnosis of AMD better than the guided-backpropagation method and IG. (3) Our method provides two visualization options: overlay and top-k bounding boxes, which would be useful for CAD. Through experimental evaluation using 10,100 clinical OCT images from AMD patients, we demonstrate that our EG algorithm outperforms the IG algorithm in terms of localization accuracy and also outperforms the existing object detection methods in terms of class accuracy.

Post-radiation sarcoma: A study by the Eastern Asian Musculoskeletal Oncology Group.

The oncologic risk of ionizing radiation is widely known. Sarcomas developing after radiotherapy have been reported, and they are a growing problem because rapid advancements in cancer management and screening have increased the number of long-term survivors. Although many patients have undergone radiation treatment in Asian countries, scarce reports on post-radiation sarcomas (PRSs) have been published. We investigated the feature and prognostic factors of PRSs in an Asian population. The Eastern Asian Musculoskeletal Oncology Group participated in this project. Cases obtained from 10 centers were retrospectively reviewed. Patients with genetic malignancy predisposition syndrome, or who had more than one type of malignancy before the development of secondary sarcoma were excluded. Forty-two high-grade sarcomas among a total of 43 PRSs were analyzed. There were 29 females and 13 males, with a median age of 58.5 years; 23 patients had bone tumors and 19 had soft tissue tumors. The most common primary lesion was breast cancer. The median latency period was 192 months. There were no differences in radiation dose, latency time, and survival rates between bone and soft tissue PRSs. The most common site and diagnosis were the pelvic area and osteosarcoma and malignant fibrous histiocytoma for bone and soft tissue PRSs. The median follow-up period was 25.5 months. Five-year metastasis-free and overall survival rates were 14.5% and 16.6%, and 39.1% and 49.6% for bone and soft tissue PRSs. Survival differences depending on initial metastasis and surgery were significant in soft tissue sarcomas. Although this study failed to find ethnic differences, it is the largest review on PRS in an Asian population. As early recognition through long-term surveillance is a key to optimal management, clinicians should take efforts to understand the real status of PRS.

Origin of Satellite Ganglion Cysts with Effusion in the Flexor Hallucis Longus Tendon Sheath around the Hallux.

BACKGROUND: To describe the clinical and magnetic resonance imaging findings of ganglion cysts with effusion in the flexor hallucis longus tendon sheath around the hallux to evaluate their origin. METHODS: Patients with recurrent or painful ganglion cysts around the hallux with effusion in the flexor hallucis longus tendon sheath who underwent surgical treatment at St. Vincent's Hospital from February 2007 to August 2016 were investigated. Surgical indication was a painful or recurrent mass caused by the cystic lesions. Those without effusion of the flexor hallucis longus tendon sheath were excluded. We assessed the clinical and magnetic resonance imaging findings. RESULTS: Magnetic resonance imaging findings in all patients showed several ganglion cysts around the hallux and large fluid accumulations within the flexor hallucis longus tendon sheath. Regarding the location, six ganglion cysts were on the dorsomedial aspect, one on the plantar medial aspect, seven on the plantar lateral aspect, and one in the toe pulp. Ten patients showed joint effusions in both the metatarsophalangeal and interphalangeal joints, two in the metatarsophalangeal joints, and three in the interphalangeal joints. There were communication stalks with a tail shape or abutment between ganglion cysts with surrounding joint effusions. Intraoperatively, connections between ganglion cysts, the synovial cyst of the flexor hallucis longus tendon sheath, and surrounding joints were seen. CONCLUSIONS: Synovial fluid accumulation in the metatarsophalangeal or interphalangeal joint supplies the synovial cyst of the flexor hallucis longus tendon sheath and subsequently ganglion cysts in the hallux. In clinical practice, the surgeon should carefully check surrounding joints with tendon sheaths to prevent recurrence of the ganglion cysts around the hallux.

Effect of a Fibroin Enzymatic Hydrolysate on Memory Improvement: A Placebo-Controlled, Double-Blind Study.

The consumption of a specifically prepared silk fibroin protein enzymatic hydrolysate (FPEH) has been reported to improve cognitive function in healthy humans. The objective of the current study is to evaluate the dose-dependent effects of the FPEH on memory. Healthy adults with an average age of approximately 55 years were administered doses of 0, 280, 400 and 600 mg of FPEH per day in two divided doses for 3 weeks. The Rey-Kim Auditory Verbal Learning Test and the Rey-Kim Complex Figure Test of the Rey-Kim Memory Test were used to evaluate memory at baseline and after 3 weeks. The scores for each test were combined into the memory quotient score (MQ). Learning gradient, memory maintenance, retrieval efficacy, and drawing/recall scores were also compared. After 3 weeks of FPEH, dose-dependent increases were observed for the MQ, the learning gradient, the numbers of words remembered, the retrieval efficiency, and drawing/recall. The optimal dose for FPEH was 400 or 600 mg, depending on the end point measured. No adverse effects were reported. FPEH significantly improved measurements of memory in healthy adults by 3 weeks at doses over 280 mg daily, with an apparent plateau effect at 400-600 mg daily.