The efficacy of eribulin mesylate for patients with cutaneous angiosarcoma previously treated with taxane: a multicentre prospective observational study.

BACKGROUND: Taxanes are the current first-line treatment for advanced cutaneous angiosarcoma (CAS) for patients who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. However, no effective second-line therapy for such patients has been established. METHODS: We designed a single-arm prospective observational study of eribulin mesylate (ERB) administered at a dose of 1·4 mg m-2 on days 1 and 8 in a 21-day cycle. Patients with advanced CAS who were previously treated with a taxane and were scheduled to begin ERB treatment were enrolled. The primary endpoint was overall survival (OS) and the secondary endpoints were response rate (RR), progression-free survival (PFS) and toxicity assessment. RESULTS: We enrolled a total of 25 patients. The median OS and PFS were 8·6 months and 3·0 months, respectively. The best overall RR was 20% (five of 25). In total, 16 grade 3/4 severe adverse events (SAEs) occurred; however, all patients recovered. Patients who achieved partial response or stable disease as best response had longer OS than those with progressive disease (median OS not reached and 3·3 months, respectively; P < 0·001). Patients who did not experience SAEs showed longer OS than those who did (median OS 18·8 months and 7·5 months, respectively; P < 0·05). Patients with distant metastasis had shorter median OS than those with locoregional disease, but without statistically significant difference. CONCLUSIONS: ERB showed a promising RR and is a potential candidate for second-line treatment for patients with CAS, after treatment with taxanes. However, owing to the occurrence of SAEs in over half of the participants, caution should be exercised regarding ERB use in elderly patients. What is already known about this topic? Taxanes are the current first-line treatment for patients with advanced cutaneous angiosarcoma (CAS) who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. No effective therapy for taxane-resistant CAS has been established thus far. Eribulin suppresses microtubule polymerization and elicits an antitumour effect similar to that of taxanes. What does this study add? In our single-arm prospective observational study to evaluate the efficacy of eribulin for treating patients with advanced CAS who previously received taxanes, the median overall survival and progression-free survival were 8·6 and 3·0 months, respectively. Response rates at weeks 7, 13 and 25 were 20%, 17% and 14%, respectively. Although 16 grade 3/4 severe adverse events occurred, all patients recovered. Eribulin showed a promising response rate and is a potential candidate for second-line treatment in CAS after taxane treatment. Linked Comment: Smrke and Benson. Br J Dermatol 2020; 183:797-798.

Long-term effect on optic nerve of silicone oil tamponade in rabbits: histological and EDXA findings.

PURPOSE: Side-effects after intravitreal use of silicone oil (SO) are not well defined and elucidated. The object of this study was to examine the influence and toxicity of SO on the optic nerve after vitrectomy with SO tamponade. METHODS: We injected medical grade SO and emulsified SO into rabbit eyes after gas-mediated vitreous compression and examined the eyes by light microscopy (LM), transmission electron microscopy (TEM) and energy dispersive X-ray analysis (EDXA) (point analysis and area analysis) 6 months after injection. We compared the findings in the non-treated eyes and eyes with only gas-mediated vitreous compression with those in SO-injected eyes. RESULTS: Vacuole-like structures were seen in the optic nerve posterior to the lamina cribrosa. In the group treated with only gas-mediated vitreous compression, the myelin structures were shown by TEM to be destroyed and replaced by glial tissue, while in groups injected with medical grade or emulsified SO severe destruction of the myelin sheath (myelinolysis) was observed. Silicone was identified at the electron-dense edges of the vacuoles by EDXA point analysis, but not in the vacuoles without electron-dense deposits. Dots of Si K alpha were not seen in the control groups, and dense dots were observed in SO-injected groups, by EDXA area analysis. CONCLUSIONS: Some of the vacuoles might be artefacts caused by insufficient fixation or the operative procedure, but TEM showed almost no artefacts in the control optic nerve. Thus, most vacuoles may be SO storage sites. SO uptake into the optic nerve might play a role in the pathogenesis of optic nerve atrophy after SO injection.

Surgical outcome of combined trabeculotomy and cataract surgery.

PURPOSE: To evaluate the efficacy of combined trabeculotomy and cataract surgery in lowering intraocular pressure and improving visual acuity in adults with primary open-angle glaucoma. PATIENTS AND METHODS: A consecutive series of 141 eyes with primary open-angle glaucoma or ocular hypertension was prospectively recruited. One hundred five eyes with visual field defects were treated by trabeculotomy combined with phacoemulsification and intraocular lens implantation (TPI group), and 36 eyes without visual field defects underwent cataract surgery (PI group). Patients in the TPI and PI groups were followed for more than 6 months after surgery (578.1 +/- 35.8 days and 616.0 +/- 58.5 days, respectively). The intraocular pressure reductions after surgery were compared between the groups to evaluate the effect of combined trabeculotomy and cataract surgery. Visual acuity and the complication rate in the two groups were secondary outcomes. The success probabilities of both groups were evaluated by Kaplan-Meier life table analysis with log rank test. RESULTS: A significant intraocular pressure reduction was observed in the TPI and PI groups up to 3 years and up to 1 year and 6 months after surgery, respectively; the magnitude of the reduction was significantly larger in the TPI group up to 3 years after surgery. The success probabilities of TPI group for intraocular pressure control under 21, 17, and 15 mm Hg were 95.8%, 58.7%, and 30.0%, respectively, 1 year after surgery, and 84.9%, 29.5%, and 13.5%, respectively, 3 years after surgery; the success probabilities were significantly higher than those of the PI group. Of 105 eyes, 104 (99.0%) had visual acuity equal to or better than the baseline acuity 3 months after combined trabeculotomy and cataract surgery. CONCLUSION: Combined trabeculotomy and cataract surgery normalizes intraocular pressure and improves visual acuity in adults with glaucoma and coexisting cataract.

Immunohistochemical study of p53, p21 and PCNA in pterygium.

Since mutated p53 is one of the most frequent gene abnormalities in human cancer, we hypothesized that mutation of p53 may play an important role in growth and recurrence of pterygia, a dysplasia of the conjunctiva. Therefore, we compared pterygia of Japanese and Tunisian patients using antibodies against p53, p21 and proliferating cell nuclear antigen (PCNA). In Nagasaki, 21 pterygia of Japanese individuals were removed and in Gabes, 19 primary pterygia of Tunisian individuals. Positive staining of wild type p53 was not found in the Japanese pterygia, whereas 38.1% were positive for mutant p53, none were positive for p21 and 76.2% were positive for PCNA. The incidence of mutant p53-positive staining was 50.0% in males and 22.2% in females, which was statistically significant. In the 19 Tunisian patients, positive staining of wild type p53 was not found, whereas 36.8% were positive for mutant p53, 0% for p21 and 63.1% for PCNA. Differences between Japanese patients and Tunisian patients were not significant. There were 2 types of pterygium. One type did not show mutant p53 and the other showed mutant p53 caused by ultraviolet light. However, damage caused by p53-dependent programmed cell death of pterygium cells may lead to mutations in other genes which may allow the progressive multistep development of limbal tumors. It is possible that mutant p53-positive pterygia can develop into limbal tumors.

Failure of exclusion of internal iliac artery aneurysms.

PURPOSE: We investigated in detail the state of internal iliac artery (IIA) aneurysms over the midterm after the exclusion procedure. METHODS: From January 1990 to December 1998, 29 patients underwent the exclusion procedure for IIA aneurysms. The medical records of 27 survivors were retrospectively reviewed, and 30 excluded aneurysms of these patients were followed up with computed tomography scanning over the midterm. RESULTS: In the immediate postoperative period, 26 aneurysms were completely thrombosed, and four were incompletely thrombosed. In the midterm, 24 aneurysms were completely thrombosed (complete group), and six were incompletely thrombosed (incomplete group). No aneurysms expanded or ruptured during the follow-up period from 6 to 98 months (mean, 26 months). The size of the excluded aneurysm decreased in 22 of 24 aneurysms in the complete group, but no change in size was noted in the six aneurysms in the incomplete group. The preoperative size of the IIA aneurysm in the incomplete group was significantly larger than that in the complete group (P =.0047). The size of two aneurysms in the incomplete group was smaller than 3.0 cm. The aneurysms in the incomplete group extended significantly deep into the pelvis as compared with those in the complete group (P =.0008). CONCLUSIONS: The exclusion of IIA aneurysm did not reliably result in thrombosis of the aneurysm. For IIA aneurysms extending deeply into the pelvis, even if the size of the aneurysm is smaller than 3.0 cm, the exclusion procedure should not be performed.

Diagnostic implications of elevated levels of smooth-muscle myosin heavy-chain protein in acute aortic dissection. The smooth muscle myosin heavy chain study.

BACKGROUND: A rapid 30-minute assay of circulating smooth-muscle myosin heavy-chain protein has been developed as a biochemical diagnostic tool for aortic dissection. OBJECTIVE: To determine the sensitivity and specificity of this assay. DESIGN: Cross-sectional study. SETTING: 8 major cardiovascular centers in Japan. PATIENTS: 95 patients with acute aortic dissection, 48 patients with acute myocardial infarction, and 131 healthy volunteers. MEASUREMENTS: Levels of circulating smooth-muscle myosin heavy-chain protein. RESULTS: Patients with acute aortic dissection who presented within 3 hours after onset had elevated levels of circulating smooth-muscle myosin heavy-chain protein. In these patients, the assay had a sensitivity of 90.9%, a specificity of 98% compared with healthy volunteers, and a specificity of 83% compared with patients who had acute myocardial infarction; the clinical decision limit was 2.5 microgram/L. All patients with proximal lesions had elevated levels of smooth-muscle myosin heavy-chain protein, and only patients with distal lesions had decreased levels (<2.5 microgram/L). CONCLUSIONS: Levels of smooth-muscle myosin heavy-chain protein can be used to diagnose aortic dissection soon after symptom onset. The assay had the greatest diagnostic value in patients with proximal lesions.

Markedly increased unilateral intraocular pressure during hemodialysis in a patient with ipsilateral exfoliative glaucoma.

PURPOSE: To report a man with markedly increased intraocular pressure in a unilateral exfoliated eye during hemodialysis. METHOD: Case report. RESULTS: A 75-year-old man with unilateral exfoliative glaucoma complained of blurred vision in his right eye during hemodialysis. The blurred vision always occurred during hemodialysis, and the intraocular pressure was increased during hemodialysis. The average increase in intraocular pressure during hemodialysis in the right eye was 22.5 mm Hg, and the intraocular pressure in the left eye remained in the normal range during hemodialysis. Argon laser trabeculoplasty was performed on the right eye, and a decrease in intraocular pressure was attained. CONCLUSION: Physicians must be alert to intraocular pressure increases in these eyes during hemodialysis.

Growth factors in cultured pterygium fibroblasts: immunohistochemical and ELISA analysis.

BACKGROUND: In order to study growth factors in the pathogenesis and recurrence of pterygium, we grew pterygium tissues in culture and compared fibroblasts from primary and from recurrent pterygia with reference to the fibroangiogenic growth factors basic fibroblast growth factor (b-FGF), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha). METHODS: We used indirect immunohistochemical procedures against human b-FGF, PDGF, TGF-beta and TNF-alpha. As controls, we used cultured normal human conjunctival fibroblasts. A serum-free conditioned medium (CM) from confluent fibroblasts derived from primary and recurrent explants was assessed by enzyme-linked immunosorbent assay to determine the level of the above-mentioned growth factors. RESULTS: Immunoreactivity of b-FGF was stronger in recurrent than in primary pterygium fibroblasts. PDGF immunolabeling was stronger in primary than in recurrent pterygium fibroblasts. TGF-beta and TNF-alpha immunolabeling was weak in both pterygia. All these growth factors were very sparse in normal conjunctival fibroblasts. Basic-FGF and TGF-beta 1 were found in the CM from both primary and recurrent pterygium, while PDGF and TNF-alpha were not detectable. CONCLUSION: The strong immunoreactivity and the release of b-FGF in cultured fibroblasts of recurrent pterygia suggest that fibroblasts may play an important role in the recurrence of pterygium.

TNP-470 (a fungus-derived inhibitor of angiogenesis) reduces proliferation of cultured fibroblasts isolated from primary pterygia: a possible drug therapy for pterygia.

PURPOSE: To study drug therapy for pterygium, especially the effect of a fumagillin analog, TNP-470, a potent anti-angiogenic compound, on the growth of cultured fibroblasts obtained from primary pterygia and normal human conjunctiva. METHODS: Cultured pterygium fibroblasts (PF) were exposed to different concentrations of TNP-470 every other day for 7 days (Treatment A) and to a single dose before 4 days of culture (Treatment B). Human normal conjunctival fibroblasts (HCF) were treated with TNP-470 every other day for 7 days. The cells were observed daily by phase contrast microscopy. Cell proliferation was assessed by counting cells with a hemocytometer. Trypan blue uptake was used to determine cell viability at harvest. RESULTS: TNP-470 induced a significant inhibition of PF and HCF proliferation in a dose-dependent manner (P < .0001). At the lowest dose of TNP-470 (100 pg/ml), the cumulative inhibitory effect of TNP-470 was more potent than the sustained inhibitory effect observed by treatment B in one high dose. Nevertheless, the cytotoxic effect was dose-dependent and more marked after treatment A than after treatment B. After washing out of the drug, partial reversibility was observed at doses lower than 5 mg/ml with a significant increase of viability. HCF were less sensitive to TNP-470 and doses less than 5 mg/ml were not cytotoxic. CONCLUSIONS: TNP-470 appears to have a marked inhibitory effect on PF proliferation, and it may be of considerable value in the prevention of pterygium growth and recurrence.

Analysis of localization of adult T-cell leukemia-derived factor in the transient ischemic rat retina after treatment with OP-1206 alpha-CD, a prostaglandin E1 analogue.

Prostaglandin E1 (PGE1) is commonly used in therapy for obstructive diseases, including ischemic retinopathy, in which pathogenetic reactive oxygen intermediates are responsible. However, the mechanism(s) of PGE1 in reducing tissue damage is still unclear. Adult T-cell leukemia-derived factor/human thioredoxin (ADF) is induced by oxidative stresses and has protective activity against oxidative cellular injury. To evaluate the possible involvement of ADF in the tissue-protective effect of PGE1, we analyzed ADF expression immunohistochemically using a rat transient retinal ischemia model. Rats were treated orally with 300 micrograms/kg/day OP-1206 alpha-cyclodextrin clathrate (OP-1206), a stable PGE1 analogue, for 14 days after photodynamic retinal vascular thrombosis by rose Bengal. Rats without any OP-1206 treatment were used as controls. In the OP-1206-treated rats, minimal retinal atrophy due to ischemia/reperfusion was observed histologically up to 14 days, whereas in the non-treated rats the inner layer of the retina became markedly atrophic. In parallel with the histological change, after 14 days following thrombosis ADF immunoreactivity was preserved on retinal pigment epithelial cells in the OP-1206-treated rats, whereas it was diminished in the non-treated rats. These findings suggest an important role for ADF in the OP-1206-dependent suppression of retinal tissue damage caused by oxidative insult.

Detached retina affects morphologic and biochemical changes in the retina adjacent to bullous retinal detachment in rabbits.

PURPOSE: Long-term results, more than 10 years after successful retinal detachment surgery, have shown gradually decreasing visual acuity in some cases. It is unclear if reduced functional recovery postoperatively is caused by anatomic changes or biochemical disorders. To determine the etiology of the reduced visual acuity, we cytochemically examined the changes in the cellular responses of the edges of retinal detachments. METHODS: We histochemically studied the glucose-6-phosphatase (G6P) and 5'-nucleotidase (5'-Nase) activity in the rabbit retina. Experimental rhegmatogenous retinal detachment was produced in a rabbit model after partial vitrectomy, followed by retinal tear formation. RESULTS: Although 5'-Nase activity gradually decreased during the period of detachment, activity was still detectable after 24 weeks. G6P activity increased in the region of the detached neural retina. Around the border of the detached retina, the decrease in 5'-Nase activity extended approximately 140 micrometers into the adjacent attached retina at 2 weeks after detachment and 270 micrometers at 24 weeks. CONCLUSIONS: These observations suggest that some anatomical and biochemical damages may occur in the retina adjacent to bullous retinal detachment and may explain the reduction in postoperative vision in some clinical cases.

Induction of human thioredoxin in cultured human retinal pigment epithelial cells through cyclic AMP-dependent pathway; involvement in the cytoprotective activity of prostaglandin E1.

Human thioredoxin is one of the oxidative stress-inducible proteins and has a protective function against oxidant-induced injury. To evaluate the possible involvement of thioredoxin in the cytoprotective function of prostaglandin E1, we analysed the effect of prostaglandin E1 on cellular injury by hydrogen peroxide and intracellular thioredoxin induction. Cellular survival of human retinal pigment epithelial cell line, established from normal retinal pigment epithelial cells, following exposure to hydrogen peroxide was markedly improved by pretreatment of 1 microm prostaglandin E1. Thioredoxin expression was augmented in a dose-dependent manner when retinal pigment epithelial cells were pretreated with 10 nm-1 microm prostaglandin E1 1 hr before the exposure to hydrogen peroxide. Intracellular cyclic AMP level was elevated by Prostaglandin E1 when the cells were simultaneously exposed to hydrogen peroxide. Forskolin, an activator of adenylate cyclase, and dibutylyl cAMP, a cyclic AMP analog, could also induce thioredoxin and extend survival of retinal pigment epithelial cells. On the other hand, thioredoxin induction and cellular protection by prostaglandin E1 was blocked by Rp diastereoisomer of cyclic adenosine 3', 5', monophosphorothioate, a competitive inhibitor of cyclic AMP dependent protein kinase. Thioredoxin induction was augmented significantly by pretreatment with prostaglandin I2, a stimulator of cyclic AMP dependent signal pathway, while treatment with prostaglandin F2alpha, a stimulator of inositol phosphate-dependent signal pathway, failed to enhance thioredoxin. These findings indicate that prostaglandin E1 has a cytoprotective activity against oxidative injury, partly through thioredoxin induction via cyclic AMP dependent pathway.

Immunohistochemical localization of basic fibroblast growth factor, platelet derived growth factor, transforming growth factor-beta and tumor necrosis factor-alpha in the pterygium.

Some fibroangiogenic factors have recently been shown to play potential roles in fibrovascular diseases. The aim of this study was to examine whether there is any relationship between growth factors and pterygium genesis. Twenty-three primary pterygia and 4 normal conjunctiva specimens were analyzed by indirect immunohistochemistry using specific antibodies against basic fibroblast growth factor (b-FGF), platelet derived growth factor (PDGF), transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha). Positive immunostaining of these growth factors was located in the epithelial cells, endothelial cells of vessels, basement membranes of vessels and epithelium, fibroblasts and infiltrating inflammatory cells in the pterygium. In the normal conjunctiva, positive immunolabeling for TGF-beta and PDGF was much weaker than in the pterygium. We conclude that growth factors may interact directly or indirectly in the pathogenesis of pterygium although proof of this awaits further studies.

Glial-, neuronal- and photoreceptor-specific cell markers in rosettes of retinoblastoma and retinal dysplasia.

Previous studies have shown that a rosette formation represents an attempt to form embryonic retinal tissue, primarily rods and cones. To test the theories as to the origin and characteristics of retinoblastoma cells, we compared the characteristics of tumor rosettes with those of dysplastic rosettes seen in retinal dysplasia using the glial, neuronal and photoreceptor markers. Forty-four retinoblastoma and one retinal dysplasia specimens were analyzed by indirect immunohistochemistry, using specific antibodies against glial fibrillary acidic protein, S-100 protein, myelin basic protein, neuron-specific enolase, neurofilament, retinal S-antigen and retinal pigment epithelial antigen. In human retinoblastoma, all the glial, neuronal, retinal pigment epithelial, and photoreceptor cell markers, except for the neurofilament, were present in parts of rosette-forming tumor cells. However, their localization was different for each antigen and it was not clear whether each tumor cell possesses several antigens. These immuno-positive tumor cells were cytologically indistinguishable from other rosette-forming cells at the light microscopic level. In retinal dysplasia, neuron specific enolase and retinal S-antigen were diffusely expressed in the dysplastic rosettes, however, other antigen were not seen in those rosettes. The staining pattern by immunocytochemistry is totally different in tumor rosettes from dysplastic ones. We found varying localizations of different immunoreactivities within tumor rosettes. These results led us to suggest that tumor cells in the rosettes of retinoblastoma may have the ability to differentiate into neural and glial cells. To prove the theory that retinoblastoma cells may have originated from a primitive neuroectodermal cell capable of multipotentiality, further investigation is needed.

Egress route of emulsified 20 centistokes silicone oil from anterior chamber of rabbit.

Silicone oil is used in recent clinical practice, however, it may cause adverse reactions in the eyes. When the high viscosity silicone oil is contaminated with low molecular weight silicone oil, the contamination may cause ocular toxicity or elevation of the intraocular pressure. To obtain information on the distribution of this preparation, emulsified 20 centistokes silicone oil was injected into the anterior chamber of rabbit eyes. The silicone oil droplets were visualized by light and electron microscopy by using oil soluble phthalocyanine blue. This copper containing dye remains in the tissue after removal of the silicone oil by organic solvents. Two and 4 weeks after an injection, the silicone emulsion was observed as numerous small vacuoles with blue precipitate at the margin of vacuoles within elongated trabecular endothelial cells, fibroblasts along the route of uveoscleral outflow and cells of the iris. Three hours after the injection, only a few vacuoles were present in these cells. These results demonstrated that the emulsified silicone oil leaves the anterior chamber through the conventional and unconventional routes. Phagocytosis by the trabecular endothelial cells and fibroblasts along the uveoscleral route caused an accumulation of the emulsified silicone oil in these cells. With chronic exposure to emulsified silicone oil, changes in the trabecular meshwork may lead to a reduction in the outflow of aqueous humor and cause glaucoma.

Mitochondrial induction of adult T cell leukemia derived factor (ADF/hTx) after oxidative stresses in retinal pigment epithelial cells.

PURPOSE: Adult T cell leukemia derived factor (ADF) is a human homologue of thioredoxin (hTx), which exhibits scavenging activity with reactive oxygen intermediates. In their previous study, the authors found that after transient retinal ischemia, the expression of thioredoxin in rat retinal pigment epithelium (RPE) layer increased markedly. The present investigation is to determine intracellular ADF localization in RPE after transient ischemia and in cultured human RPE cells after oxidative insult by H2O2. METHODS: The authors employed immunoelectron microscopy to examine ADF localization in RPE. Labeling density analysis was performed to supplement the main observation in the experiment of transient retinal ischemia. 3-(4,5-dimethylthiazol-2yl)-2-5-diphenyltetrazolium bromide (MTT) assay was performed to verify the protective role of recombinant ADF (rADF) against H2O2. RESULTS: In immunogold electron microscopy, sparse ADF-positive labeling was seen in the cytosol and mitochondria in normal rat RPE and in untreated cultured RPE cells. After oxidative stress, it was concentrated in mitochondria in both groups. MTT assay proved that rADF protected cultured RPE from the toxicity of H2O2. CONCLUSIONS: This study shows the induction of ADF/hTx in mitochondria of RPE after oxidative stresses and its protective effect on cultured RPE exposed to H2O2. The data indicate the possibly important role of ADF/hTx in the protection of retinal cells from the oxidative stresses associated with retinal ischemic disease and probably with regular visual activity.

[Sympathetic ophthalmia in an elderly man].

A 78-years-old man suffered from sympathetic ophthalmia. He had been treated with 5-fluorouracil (5-FU) for metastasis of colon cancer in the liver. He received a perforating eye injury in the left eye thereafter the eye became phthisic. Two months after the injury, he noticed visual disturbance in the right eye. He was treated with large doses of systemic corticosteroid after a diagnosis of uveitis of the right eye, but the visual acuity of the right eye became worse. The eye showed non-specific diffuse uveitis. A diagnosis of sympathetic ophthalmia was made from previous history and ocular findings. We enucleated the injured eye and continued the systemic corticosteroid. Then the right eye improved. Histopathological examination of the enucleated eye revealed the choroid was infiltrated with a granulomatous lesion of lymphocytes and epithelioid cells. HLA typing showed DR4, DR8, DR52, DR53, and DQ1, and we made a final diagnosis of sympathetic ophthalmia. It is probable that the clinical findings were modified by the 5-FU treatment and the patient's advanced age.