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.

Possible presence of hydrophilic SO3H nanoclusters on the surface of dry ultrathin Nafion® films: a positron annihilation study.

Solutions of Nafion® with an ion exchange capacity (IEC) of 0.91 meq g(-1), which are on the verge of the formation of SO(3)H nanoclusters, were spin coated on silicon (Si), glassy carbon (GC) and platinum/silicon (Pt/Si) substrates to form films of up to 256 nm thickness. Nanostructure of the films was studied using Doppler broadening of annihilation radiation (DBAR), positron annihilation lifetime (PAL), X-ray photoelectron spectroscopy (XPS), an atomic force microscope (AFM) and contact angle measurements. Contact angles as low as 10 degrees indicate that the surface of dry ultrathin Nafion® films on Si is highly hydrophilic. XPS data of 10 nm thick, ultrathin film on Si show that oxygen concentration is enhanced and the SO(3)H group concentration, in other words, IEC on the surface is much higher than other films. The S parameter measured by DBAR of an ultrathin Nafion® film on Si is much higher than that of the films on the other substrates. We consider that a large number of hydrophilic, reversed micelle like SO(3)H groups are on the surface of the ultrathin Nafion® film on Si but not on the surface of other films. Positrons implanted into the film are trapped by the SO(3)H clusters, annihilating with the electrons of oxygen and exhibit the high S parameter. The SO(3)H concentration on the surface of thin Nafion® films on GC and Pt/Si substrates may not be so high as the threshold for the formation of a large number of SO(3)H clusters. Positrons implanted into the films annihilate mostly with fluorine atoms, resulting in a low S parameter. The film-substrate interaction plays an essential role in nanostructuring of Nafion® thin films, which may also be the case for Nafion® on the catalysts of polymer electrolyte fuel cells.

Positronium formation in aromatic polymer electrolytes for fuel cells.

We measured the yield of positronium (Ps) in sulfonated aromatic proton conducting membranes for the polymer electrolyte fuel cell (PEFC) with and without -SO(2)- in their chemical structures by positron annihilation lifetime spectroscopy (PALS). It was observed that Ps formation is almost totally inhibited in the polymers without -SO(2)- such as sulfonated poly(ether ether ketone) (SPEEK). On the other hand Ps favorably forms in those with -SO(2)- as sulfonated polyether sulfone (SPES), which is due to the anti-inhibition effect of -SO(2)-. The high probability of Ps formation in these polymers enables the study of the free volume and the mechanism of gas permeation by PALS.

Effects of ion exchange on the free volume and oxygen permeation in Nafion for fuel cells.

Variations of the free volume, O2 permeability, and structure of the Nafion membrane upon ion exchange of H+ with Na+ and K+ were studied. The free volume was quantified using the positron annihilation lifetime (PAL) technique, whereas the polymer structure was characterized by dynamic mechanical analysis (DMA), nanoindentation, and wide-angle X-ray diffraction (WAXD). It was found that the ion exchange significantly expands the free volume and at the same time decreases the O2 permeability. This is opposed to the simple free volume model in which the structure with less open volume is more amenable to lower permeability. Comparison of experimental data collected by different techniques revealed that not only the free volume but also the polymer stiffness plays an essential role in O2 permeation.

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.

Superoxide dismutase in senescence-accelerated mouse retina.

To examine the relationship between retinal ageing and superoxide dismutase, we studied the dismutase, with immunohistochemistry and immunoquantitative analysis, in the retina of senescence-accelerated mice P8/Ta (SAMP8/Ta) 3 and 12 months after birth. Accelerated senescence-resistant mice R1TA (SAMR1TA), which show no acceleration of senescence, were used as controls. In SAMP8/Ta, copper-zinc superoxide dismutase and manganese superoxide dismutase immunoreactivity in the photoreceptor inner segments, the outer nuclear layer and the inner nuclear layer increased earlier than in the controls. The increase in both superoxide dismutases with age occurred not only in SAMP8/Ta retinas but also in the controls. In conclusion, we propose the possibility that SAMP8/Ta undergo deterioration not only of learning and memory but also acceleration of senescence in the retina. The dismutases also appear to increase with normal ageing in the retina.

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.

Dilation and reduced distensibility of carotid artery in patients with abdominal aortic aneurysms.

BACKGROUND: Although patients with abdominal aortic aneurysms (AAA) frequently have coexisting systemic atherosclerosis, the dilatative manifestation of AAA is the opposite of the occlusion characteristic of atherosclerotic disease. It has been suggested that this dilatative disease is caused by an alteration in connective tissue metabolism in systemic arterial wall. Such a condition might alter systemic arterial diameter and wall behavior. We investigated arterial characteristics in AAA patients, including morphologic changes and wall mechanics in the carotid artery. METHODS AND RESULTS: Atherosclerotic intimal changes such as intima-media thickness (IMT), plaque formation, diameter, and wall elasticity of the carotid artery were determined ultrasonographically in patients with AAA (n = 102) and compared with age-matched patients with the atherosclerotic diseases arteriosclerosis obliterans (ASO, n = 115) and coronary artery disease (CAD, n = 123) and with age-matched healthy control patients (CTL, n = 45). Intimal disease in AAA was significantly milder than in ASO, at the same level as CAD, and more severe than in CTL. Although end-diastolic luminal diameters (mm) in AAA (7.05 +/- 1.08), ASO (6.74 +/- 0.18), and CAD (6.66 +/- 0.83) were significantly higher than in CTL (5.97 +/- 0.93), they were also excessively increased compared with the equivalent diameters seen in ASO (P <.01) and CAD (P <.01). Luminal distensibility (x 10(-6) cm(2). dyne(-1)) in AAA (0.83 +/- 0.48) was excessively decreased compared not only with CTL (1.70 +/- 1.11, P <.01) but also with ASO (1.12 +/- 0.47, P <.01) and CAD (1.18 +/- 0.59, P <. 01). These relations remained true when adjusted for blood pressure and luminal diameter. Intra-AAA group analysis showed that distensibility in ruptured cases (n = 14) was significantly lower than in nonruptured cases (n = 88) (0.58 +/- 0.24 vs 0.88 +/- 0.50, P <.05). CONCLUSIONS: Excessive arterial dilation and reduced distensibility without severe intimal disease were found in the carotid arteries of patients with AAA. This suggests that these patients may be subject to systemic arterial alterations, including structural and functional abnormalities.

Circulating biochemical marker levels of collagen metabolism are abnormal in patients with abdominal aortic aneurysm.

Changes in extracellular matrix composition induced by abnormal collagen metabolism in the aortic wall may be an important factor in the progression of aortic structural changes. The authors have measured several types of biochemical marker for collagen metabolism in plasma: carboxyterminal propeptide of type Icollagen (PICP) for a pure collagen synthesis marker, matrix metalloproteinase-1 (MMP-1) for a degradation marker of collagen matrix, and tissue inhibitors of metalloproteinase-1 (TIMP-1) as a native inhibitor of MMP-1. Subjects of this study were 17 patients with abdominal aortic aneurysm (AAA), 14 patients with atherosclerosis obliterans (ASO), and 22 age/sex-matched healthy controls (HC). Blood samples were drawn from a forearm vein and measured by radioimmunoassay or enzyme-linked immunosorbent assay. Plasma concentrations of PICP in patients with AAA were significantly decreased compared to those in HC patients (82.0 +/- 16.4 vs 111.3 +/- 40.3 ng/mL; p < 0.01), but those in patients with ASO (105.4 +/- 55.4 ng/mL) were comparable to control concentrations. Although no differences in plasma concentrations of MMP-1 were observed among the three subject groups (HC, 20.0 +/- 5.6 ng/mL; ASO, 21.4 +/- 13.8 ng/mL; AAA, 24.5 +/- 11.7 ng/mL; NS), MMP-1/PICP ratio as an index of collagen degradation to collagen neosynthesis in AAA was significantly elevated compared to HC (0.32 +/- 0.18 vs 0.20 +/- 0.08; p < 0.01). Plasma concentrations of TIMP-1 in patients with AAA (293.8 +/- 61.2 ng/mL) or ASO (327.6 +/- 54.9 ng/mL) were significantly higher than in HC (227.3 +/- 60.2 ng/mL; both p < 0.01). In conclusion, these data suggest that although a compensatory mechanism such as increased TIMP-1 may be activated, collagen neosynthesis may decrease with relatively increased collagen degradation in patients with AAA.

Abnormal Peripheral Vasodilatory Reserve Without Endothelial Dysfunction in Patients With Aortic Dissection.

Structural changes in the aortic wall have been reported to be present in aortic dissection (AD), while there have been no investigations concerning peripheral vasomotion characteristics. Peripheral arterial stiffness is an important factor in the regulation of the central aortic pressure because it produces excessive wave reflection. The present study investigated in AD patients endothelium-dependent peripheral vasodilation and the reactive hyperemic response which is considered to be altered by the structural abnormality of the peripheral resistance artery. Forearm blood flow (FBF) changes induced by intra-arterial infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and by occlusion-induced reactive hyperemia (RH) were measured plethysmographically in 10 AD patients, 7 healthy volunteers, and 7 patients with uncomplicated hypertension (UHT). There were no significant differences in the peak FBF response to ACh and SNP infusion for the three groups (ACh, 14.2 +/- 1.8 vs 17.2 +/- 4.5 vs 15.7 +/- 2.3 ml/min/dl tissue, NS; SNP 9.5 +/- 1.3 vs 10.6 +/- 1.7 vs 11.9 +/- 0.8 vs ml/min/dl tissue, NS). In the case of RH, however, peak FBF and maximum conductance were significantly lower in AD patients than in healthy volunteers and UHT patients (21.1 +/- 2.6 vs 36.1 +/- 4.7 and 32.4 +/- 2.6 ml/min/dl tissue volume, p < 0.01, and 0.25 +/- 0.03 vs 0.46 +/- 0.06 and 0.37 +/- 0.03 ml/min/dl per mmHg, p < 0.05, respectively). Peripheral vasodilatory function depending on the endothelium and smooth muscle in AD patients was not significantly different from that in healthy volunteers and UHT patients. However, reactive hyperemic vasodilatory reserve, which is a well-established, noninvasive measure of arterial structure, was significantly impaired in AD. These findings indicate that arterial structural abnormalities rather than systemic atherosclerotic changes represented by endothelial dysfunction may be present. We speculated that this aspect of peripheral resistance artery might possibly have an unfavorable effect on the postonset aortic conditions in AD patients.

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.

Peripheral resistance vessel dysfunction in Marfan syndrome.

BACKGROUND: Patients with Marfan syndrome show a hereditary abnormality of elastin metabolism that may cause aortic enlargement and dissection. We have hypothesized that abnormal elastin may alter peripheral vascular structure and function. METHODS: Forearm blood flow (FBF) (in milliliters per minute per 100 mL) response to the endothelium-dependent dilator acetylcholine (0.75 to 4.5 microg/min per 100 mL), the endothelium-independent dilator sodium nitroprusside (0.05 to 0.3 microg/min per 100 mL), and structure-related maximum dilator response (10-minute occlusion-induced reactive hyperemia) were measured by plethysmograph in 10 patients with Marfan syndrome (mean age 44 years) and 10 healthy age- and sex-matched controls. Patients with the complications of hypercholesterolemia, diabetes mellitus, or heart failure were excluded from the study. RESULTS: Basal FBF (mean +/- SE) did not differ between the 2 groups (2.7 +/- 0.3 vs 2.3 +/- 0.4). Maximum FBF response to acetylcholine in patients with Marfan syndrome was significantly lower than that of healthy controls (8.5 +/- 2.1 vs 15.4 +/- 1.7 mL/min per 100 mL; P <.05). Reactive hyperemia was also lower in patients with Marfan syndrome (at peak 23.0 +/- 2.5 vs 29.5 +/- 2.3 mL/min per 100 mL; P <.05), but sodium nitroprusside-induced FBF changes did not differ between the 2 groups (10.3 +/- 1.1 vs 10.2 +/- 1.5 mL/min per 100 mL; P = not significant). CONCLUSION: These observations suggest that endothelium-dependent dilation and maximum dilator reserve capacity are both abnormal in peripheral resistance vessels of patients with Marfan syndrome. These peripheral vasomotion abnormalities may have a detrimental impact on the cardiovascular system in this disorder.

Changes in manganese superoxide dismutase expression after exposure of the retina to intense light.

Manganese superoxide dismutase (Mn-SOD) is a naturally-occurring scavenger of superoxide, one of several reactive oxygen intermediates. To determine if Mn-SOD expression is enhanced as a defensive mechanism against oxidative challenges, such as intense light exposure, rats were exposed to cyclic light (80 lux) for 2 weeks, intense light (1,800 lux) for 24 h, and then again to cyclic light. Experimental and control (exposed to cyclic light only) eyes were enucleated 3 h, 1, 3, 7, and 14 days after light challenge. Protein expression was examined immunohistochemically using rabbit antisera against rat Mn-SOD. There was no significant difference between the light-exposed and the control groups in the thickness of the outer nuclear layers. Both retinal pigment epithelial cells and photoreceptor inner segments in the normal retina were labeled for Mn-SOD. Mn-SOD labeling was lost 3 h and day 1 after light challenge. It was re-expressed in the retinal pigment epithelial cells 3, 7, and 14 days after the light challenge, and in the photoreceptor inner segments after day 14. These results suggest that the retina might have a protective potential against light damage, in which Mn-SOD may play an important role.