Prognostic relevance of high atonal homolog-1 expression in Merkel cell carcinoma.

BACKGROUND: It has recently been reported that atonal homolog 1 (ATOH1) gene is down-regulated in Merkel cell carcinoma (MCC) and thus may represent a tumor suppressor gene. OBJECTIVES: We aimed to test for ATOH1 gene mutations and expression levels in MCC tissues and cell lines. METHODS: Genomic DNA isolation and amplification via PCR was successfully performed in 33 MCCs on formalin-fixed paraffin-embedded tissue and three MCC cell lines, followed by Sanger sequencing of the whole ATOH1 gene to detect genomic aberrations. ATOH1 mRNA levels were determined by RT-PCR. Immunohistochemistry of ATOH1 was performed to quantify protein expression in tumor samples and cell lines. RESULTS: Neither in any of the 33 MCC tissue samples nor in the three cell lines ATOH1 mutations were present. ATOH1 was expressed in all lesions, albeit at different expression levels. Univariate analysis revealed that the total immunohistology score significantly correlated with the occurrence of tumor relapse (r = 0.57; P = 0.0008). This notion was confirmed in multivariate analysis suggesting that ATOH1 expression is a potential independent predictor for tumor relapse in MCC patients (P = 0.028). MCC-related death also correlated with ATOH1 expression (r = 0.4; P = 0.025); however, ATOH1 expression did not retain its predictive value in the regression model. CONCLUSIONS: In contrast to anecdotal reports ATOH1 expression is not lost by genetic alterations in MCC. However, protein expression of ATOH1 is increased in advanced MCC indicating that ATOH1 is involved in MCC progression.

[Are there diurnal variations in choroidal thickness?]. / Unterliegt die Aderhautdicke zirkadianen Schwankungen?

PURPOSE: Measurement of diurnal choroidal thickness in healthy eyes to investigate thickness variations. METHODS: A total of 30 healthy eyes in 30 subjects were examined at 6 predefined times within 24 h. Choroidal thickness was visualized using the 7-line scan of spectral domain optical coherence tomography (OCT) with enhanced depth imaging (Spectralis, Heidelberg Engineering) and manually measured by two independent observers. For statistical analyses the mean value was calculated. RESULTS: The mean choroidal thickness was 270 ± 87 µm. Choroidal thickness changes from baseline ranged between - 47 µm and + 41 µm. There was a statistically significant negative correlation between baseline choroidal thickness and the thickness in examinations at 10:30 am, 1:30 pm and 4:30 pm with the Spearman correlation test. Due to the large diversity in the individual diurnal fluctuations, a significant diurnal variation of choroidal thickness was not observed. There was a significant negative correlation between age and choroidal thickness. CONCLUSIONS: In this study a significant diurnal variation of choroidal thickness was not observed. Patient age correlated negatively with choroidal thickness.

[Oculomotor system and multiple sclerosis]. / Okulomotorik und multiple Sklerose.

Disorders of ocular motility due to multiple sclerosis can cause significant symptoms, such as blurred vision, diplopia, oscillopsia and dizziness. The spectrum of ocular motor disorders is broad due to the multifocal nature of the disease. The most frequent disorders include dysmetric saccades, impaired smooth pursuit, internuclear ophthalmoplegia (INO), impaired vestibulo-ocular reflex, misalignment of visual axes, impaired vergence and gaze-evoked nystagmus. Patients with abnormal eye movements are more handicapped than patients without ocular motility disorders as eye movement disorders and gait disturbances are both caused by an extensive involvement of the brainstem and cerebellum.

[Bilateral diffuse uveal melanocytic proliferation in a patient with metastatic breast cancer]. / Bilaterale diffuse uveale melanozytäre Proliferation bei metastasierendem Mammakarzinom.

A 64-year-old female patient with a history of metastatic breast cancer presented with bilateral deterioration of visual acuity over a period of several weeks. Examination revealed patchy fundus pigmentation, serous retinal detachment and cataract in both eyes. After diagnosis of a bilateral diffuse uveal melanocytic proliferation (BDUMP) and due to disease progression, a course of plasmapheresis three times a week over a period of 2 weeks was initiated. Apart from the occurrence of peripheral edemas the therapy was well-tolerated by the patient. Treatment success could not be evaluated because the patient died a short time later. This is the first reported case of BDUMP due to breast cancer.

[Effect of intravitreal bevacizumab on pigment epithelial detachment in occult choroidal neovascularization]. / Effekt von Bevacizumab auf die Abhebung des retinalen Pigmentepithels bei okkulter choroidaler Neovaskularisation.

PURPOSE: This study aimed to investigate the effect of bevacizumab on pigment epithelial detachment (PED) in occult choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD) and to determine predictive factors. METHODS: 73 eyes of patients with AMD and PED due to CNV with subretinal and/or intraretinal fluid were assessed. Patients were treated with 1.25 mg of intravitreal bevacizumab. RESULTS: After 30.6 weeks, the mean visual acuity (VA) increased from 0.53 to 0.49 logMAR (p=0.170). The mean PED height decreased from 354.4 µm to 277.4 µm (p=0.004). Although 53.4% of the eyes showed a reduction in PED, this did not correlate with a significant change in VA. Predictive factors were a high baseline PED and VA <0.32. CONCLUSION: Half of the patients showed PED flattening. Especially in patients with distinctive PED, a response to intravitreal bevacizumab may be expected. This therapy can stabilize VA, but PED flattening does not essentially correlate with an increase in VA.

[Endophthalmitis after repeated bevacizumab injections]. / Endophthalmitis nach mehrfachen Bevacizumab-Injektionen. Diagnose: Immunreaktion mit Pseudohypopyon nach mehrfachen Bevacizumab-Injektionen.

Symptoms resembling endophthalmitis developed 1 day after the seventh injection of bevacizumab in a 76-year-old woman with extrafoveal occult choroidal neovascularization in conjunction with age-related macular degeneration. The diagnosis reached was an immune reaction with pseudohypopyon after repeated bevacizumab injections. The condition resolved completely within 5 days under sole administration of corticosteroids. Treatment was then continued with pegaptanib and no further intraocular irritation occurred.

[OCT-based re-injections for anti-VEGF-treatment for neovascular ARMD]. / OCT-Befund als Reinjektionskriterium bei der Anti-VEGF-Therapie für neovaskuläre AMD.

BACKGROUND: We present an optical coherence tomography (OCT)-based individual reinjection procedure for bevacizumab treatment in neovascular age-related macular degeneration (ARMD). METHODS: Thirty-two patients with active subfoveal occult choroidal neovascularisation in ARMD received a single intravitreal injection of 1.25 mg bevacizumab and were reinjected based on new or persisting subretinal or intraretinal fluid on OCT. Patient visits were every 6-8 weeks. RESULTS: After a single injection, 74% of patients demonstrated complete retinal fluid absorption, with 44% of patients showing no relapse during a follow-up of 30+/-13 weeks. Fifty-six percent of patients required a second injection after a mean of 19+/-8 weeks, with 82% of patients showing absorption of macular fluid thereafter with regain of their previous achieved best-corrected visual acuity. Thirty-two percent did not require any further injection (follow-up 32+/-12 weeks). Of those patients not showing retinal fluid absorption after the first injection (26%), 44% demonstrated retinal fluid absorption after the second injection. All patients achieved stabilisation of visual acuity during follow-up, with 30% of patients showing a significant gain of >or=3 lines. CONCLUSIONS: OCT-based reinjections of bevacizumab in neovascular ARMD reduce the number of injections and lead to anatomic and functional retinal stabilisation.

[Intravitreal bevacizumab for choroidal neovascularization due to pathological myopia]. / Intravitreal Bevacizumab bei choroidaler Neovaskularisation infolge pathologischer Myopie.

PURPOSE: The aim of this study was to evaluate the safety and efficacy of intravitreal bevacizumab as a treatment for choroidal neovascularization (mCNV) due to pathological myopia. METHODS: A consecutive series of 23 patients with mCNV treated with 1.25 mg intravitreal bevacizumab after being thoroughly informed about the off-label character of the treatment. Of the patients 6 received additional photodynamic therapy at the time of first injection. Reinjections were given every 6 weeks if intraretinal or subretinal fluid persisted. RESULTS: The pre-injection mean visual acuity (VA) was 0.25 (0.58 logMAR+/-0.36). During a follow up of 16.6+/-13.7 weeks 1.4+/-0.8 injections were given. Complete resorption of subretinal or intraretinal fluid was achieved in all patients. VA improved by 2.3+/-3.5 lines on average, 9 patients (39.1%) had an increase of >or=3 lines, none lost more than 1 line. Patients with bevacizumab monotherapy (n=17) had an improvement of 2.59+/-3.9 lines, 7 patients (41.2%) had an increase of >or=3 lines. No intraocular or systemic side effects were observed. CONCLUSIONS: In this as yet largest series of patients with mCNV treated with intravitreal bevacizumab, the treatment seemed to be effective and safe.

[Exposure to light during vitreoretinal surgery. II: Characteristics of endoilluminators]. / Lichtexposition bei vitreoretinaler Chirurgie. II. Physikalische Charakteristika von Endoilluminationssystemen.

PURPOSE: Light can cause phototoxic retinal damage. The aim of this study was to evaluate the risk of retinal hazard by endoilluminators during vitreoretinal surgery. METHODS: The spectra, radiance, and irradiance of six light sources with different associated fibre optics (20 G, 23 G, standard collimated, wide-angle diffuse) were measured and compared with thresholds published by international standardisation committees. RESULTS: The spectra of the endoilluminators differed significantly in the short wavelength band. The maximum radiance ranged from 15 mW to 190 mW and the calculated irradiance from 36 mW/cm2 to 1,130 mW/cm2 (distance 5 mm) and from 9 mW/cm2 to 376 mW/cm2 (distance 10 mm). Compared with published thresholds for surgery, time limits ranging from 0.7 min to 264 min (distance 5 mm) and 2.7 min to 1,052 min (distance 10 mm) seem to be safe. CONCLUSIONS: Light systems used for vitreoretinal surgery differ considerably in spectra, radiance, and irradiance; these differences have an impact on the maximum tolerable exposure times during surgery.

[Light exposition in vitreoretinal surgery. I. Basics]. / Lichtexposition bei vitreoretinaler Chirurgie. I. Grundlagen.

Due to its function of light perception, the eye is exposed to high levels of radiation of the optical spectrum. Most of the ultraviolet and infrared radiation is absorbed in the cornea and lens, and mostly only radiation of the visible spectrum can reach the retina. Visible light can cause retinal damage by photomechanical, photothermal, and photochemical mechanisms. The most important mechanism of light damage to the retina under daily conditions or when using ophthalmologic light sources is the photochemical light toxicity caused by light-induced chemical reactions. The extent of damage depends on several factors, such as wavelength, exposure time, and irradiance. Particularly the shorter portion of the visible light spectrum (blue light) is responsible for photochemical damage to the retina.

[Surgical treatment of lamellar macular hole]. / Operative Therapie bei Makulaschichtforamen.

PURPOSE: Vitrectomy and peeling in patients with lamellar macular hole was evaluated with regard to anatomical and functional outcome. PATIENTS AND METHODS: In a retrospective study, 10 patients with lamellar macular hole underwent vitrectomy, membrane-peeling (epiretinal membrane [ERM] and internal limiting membrane [ILM]) and gas (n=9) or silicone oil (n=1) endotamponade. In most patients (n=9), cataract surgery was also performed. Pre- and postoperative ocular coherence tomography (OCT) findings, visual acuity (ETDRS), and Birkhäuser near visual acuity were evaluated. RESULTS: Mean follow-up was 15+/-11 months after surgery with a minimum follow-up of 6 months. Best corrected visual acuity (BCVA) improved in all patients; the average BCVA gain was 3+/-2 lines. Preoperative mean BCVA was 0.35 (0.45+/-0.23logMAR), and postoperative BCVA was 0.64 (0.19+/-0.21logMAR). Eight of ten patients had a postoperative BCVA > or =20/40, and six patients had a postoperative BCVA > or =20/25. Mean near visual acuity was 0.5+/-0.26 (range 0.2-0.9). Postoperative OCT revealed a closed lamellar macular hole in six patients, with restored foveal contour in three of them. The other four patients showed a persistent inner retinal defect with an intact photoreceptor layer. CONCLUSION: Surgical treatment including vitrectomy, ERM-ILM-peeling and endotamponade appears to benefit patients with lamellar macular hole. All patients improved functionally. Surgical treatment can close the lamellar macular hole and restore foveal architecture.

[OCT-guided reinjection of 2.5 mg bevacizumab for treating macular edema due to retinal vein occlusion]. / OCT-Befund als Reinjektionskriterium für die 2,5-mg-Bevacizumab-Therapie bei venösen retinalen Verschlüssen.

BACKGROUND: Macular edema (ME) due to retinal vein occlusion can be successfully treated with intravitreal bevacizumab therapy. There is no common recommendation concerning time intervals and criteria for reinjection. METHOD: Sixty-three patients (follow-up 30+/-18 weeks) received intravitreal injections of 2.5 mg bevacizumab. Reinjection was performed only if optical coherence tomography (OCT) showed persistent or recurrent ME. Check-ups were performed every 6-8 weeks. RESULTS: There was complete resolution of macular edema in 31 patients after the first injection (improvement in visual acuity 3.7+/-3.7 lines); 65.2% of these patients developed recurrence of ME within 13.3+/-4.4 weeks, which completely resolved again after a second injection. Visual acuity gained the same level as after the first injection. Another relapse of ME in this group occurred in 69% of patients after another 13.4+/-5.4 weeks. Patients with persistent ME after the first injection (n=32) received a second injection, initially leading to resolution of ME in 33.3%, but all of these patients had a relapse within 13.9+/-4.1 weeks. CONCLUSION: OCT-guided reinjection leads to anatomic and functional stabilization or improvement even if transient recurrence of ME occurs.

[Central and branch retinal vein occlusion. Current strategies for treatment in Germany, Austria and Switzerland]. / Retinale Zentralvenen- und Venenastverschlüsse: Aktueller Therapiestand in Deutschland, Osterreich und der Schweiz.

BACKGROUND: The main object of this study was to find out what treatment methods are currently preferred for central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) in Germany, Austria and Switzerland. METHODS: A questionnaire concerning the different medicamentous, surgical and laser treatments available for CRVO and BRVO was developed and sent out to the members of the German Retina Society. RESULTS: This analysis is based on 124 returned questionnaires. We found that 64% of our colleagues recommend isovolemic hemodilution in patients with CRVO. Pentoxyfyllin infusions are endorsed by 32% and 27%, respectively, for CRVO and BRVO. Panretinal photocoagulation is applied only if neovascularization is present by 39% of those responding, whereas 61% perform prophylactic photocoagulation when there is no visible neovascularization, depending on the degree of ischemia. In the case of macular edema due to BRVO 52% recommend macular grid photocoagulation. Sheathotomy is recommended by 51% for BRVO suggest, and 43% advise radial optic neurotomy (RON) for CRVO. Intravitreal injection of triamcinolone is performed for CRVO or BRVO by 58% and 56%, respectively, and para-bulbar injection of triamcinolone by 2% and 3%. Intravitreal anti-VEGF treatment is applied by 72% of respondents, the majority (94%) using bevacizumab for this purpose. CONCLUSION: Members of the German Retina Society apply widely differing treatments in patients with CRVO and BRVO. Further clinical studies to evaluate the different therapeutic options seem necessary in order to set up guidelines for the treatment of venous retinal occlusions.

[Bevacizumab for the treatment of macular edema secondary to retinal vein occlusion]. / Bevacizumab zur Therapie des Makulaödems infolge venöser retinaler Gefässverschlüsse.

BACKGROUND: Retinal vein occlusion often leads to macular edema as a result of an elevated level of intravitreal VEGF. We report on the anatomic and functional results after intravitreal bevacizumab injections in patients with retinal vein occlusion. METHODS: In a prospective study, 18 patients with central, and 22 patients with branch retinal vein occlusion, all of whom had persistent macular edema (>300 microm) received 2.5 mg intravitreal bevacizumab. ETDRS visual acuity, ophthalmic examination and stratus OCT were performed at baseline, 1 week after injection and then monthly. Further injections were given every 6 weeks in patients with persistent or recurring macular edema. RESULTS: The findings did not deteriorate in any of the 40 patients. The injections (mean of 2.6+/-1.4 injections/patient) were very well tolerated in all cases during a mean follow-up of 23+/-13 weeks. On the last visit, 73.3% of patients with central retinal vein occlusion and 76.5% of those with branch retinal vein occlusion were found to have significantly improved visual acuity (by at least 3 lines). Mean central retinal thickness had decreased from 921+/-264 to 239+/-66.2 microm in patients with central retinal vein occlusion, and from 678+/-221 to 236+/-78 microm in patients with branch retinal vein occlusion. CONCLUSIONS: Neither intraocular nor systemic side-effects were observed in this study after repeated intravitreal injections of 2.5 mg bevacizumab. Current results suggest that intravitreal anti-VEGF therapy is a promising option in macular edema secondary to retinal vein occlusion.

Penetration of teicoplanin into heart valves and subcutaneous and muscle tissues of patients undergoing open-heart surgery.

Penetration of teicoplanin into serum, heart valves, and subcutaneous and muscle tissues was determined in 22 patients undergoing open-heart surgery. Each patient received 12 mg of teicoplanin per kg of body weight as a 30-min intravenous infusion preoperatively. Within 10 h, serum concentrations of teicoplanin declined from 43.1 to 2.8 microg/ml. Teicoplanin concentrations in subcutaneous tissues reached their peak of 9.2 microg/g after 2 to 3 h and decreased slowly to 2.3 microg/g after 9 to 10 h. Concentrations in muscle decreased from 8.7 microg/g to nondetectable levels. Teicoplanin concentrations in cardiac valvular tissue reached their peak of 6.1 microg/g and decreased thereafter to 1.7 microg/g. Teicoplanin concentrations in heart valves were high enough to inhibit methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci, which are known to cause postoperative wound infections and infective endocarditis.

5-HT1A receptor-effector system responsivity in panic disorder.

To explore 5-HT1A receptor responsivity in panic disorder (PD), hypothermic, neuroendocrine and behavioral responses to the selective partial 5-HT1A receptor agonist ipsapirone (IPS) were investigated in patients with primary PD and healthy controls. Fourteen patients and matched controls received a single oral dose of 0.3 mg/kg IPS or placebo under double-blind, random-assignment conditions. IPS induced hypothermia and corticotropin (ACTH)/cortisol release but had only minimal effects on behavior. Compared with controls, the patients with PD exhibited significantly attenuated thermoregulatory and neuroendocrine responses to IPS. Although the healthy subjects reported increased drowsiness and the PD patients rated themselves more nervous and less calm following administration of IPS, no consistent changes in ratings of anxiety or panic symptoms were recorded. The impaired hypothermic and ACTH/cortisol responses following 5-HT1A receptor activation reflects subsensitivity of both the pre- and post-synaptic 5-HT1A receptor-effector system, thus supporting the hypothesis that a 5-HT1A receptor-related serotonergic dysfunction may be linked to the pathophysiology of PD. Future studies of 5-HT1A receptor-effector complex function in conjunction with assessment of the responsivity of other subtypes (e.g. 5-HT2, 5-HT3) should promote the evaluation of 5-HT system integrity in anxiety disorders and its involvement in anxiolytic drug effects.

5-Hydroxytryptamine1A receptor responsivity in obsessive-compulsive disorder. Comparison of patients and controls.

To evaluate 5-hydroxytryptamine1A receptor responsivity in obsessive-compulsive disorder, we examined hypothermic, neuroendocrine, and behavioral responses to the selective 5-hydroxytryptamine1A receptor ligand ipsapirone in patients with primary obsessive-compulsive disorder and healthy controls. Twelve patients and 22 controls received a single dose of ipsapirone, 0.3 mg/kg, or placebo under double-blind, random assignment conditions. Ipsapirone induced hypothermia and release of corticotropin and cortisol but had no effect on behavior, including obsessive or compulsive symptoms. Thermoregulatory and neuroendocrine responses to ipsapirone were not consistently different between healthy controls and patients with obsessive-compulsive disorder. These results provide no direct support for the hypothesis that a serotonergic dysfunction related to 5-hydroxytryptamine1A receptors may be linked to the pathophysiologic characteristics of obsessive-compulsive disorder and point to the need for the evaluation of other 5-hydroxytryptamine receptor subtypes. Future studies of the responsivity of 5-hydroxytryptamine1A receptors to direct-acting ligands, such as ipsapirone, should facilitate assessment of the integrity of the 5-hydroxytryptamine system and its involvement in antiobsessional drug effects.

Long-term fluoxetine treatment decreases 5-HT1A receptor responsivity in obsessive-compulsive disorder.

Fluoxetine (FLX) is a selective serotonin (5-HT) reuptake inhibitor with therapeutic benefit in patients with obsessive-compulsive disorder (OCD). To evaluate the effect of chronic FLX treatment on 5-HT1A receptor responsivity, hypothermic, neuroendocrine, and behavioral responses to the selective 5-HT1A receptor ligand ipsapirone (IPS) were examined in patients with primary OCD. A single dose of 0.3 mg/kg of IPS or placebo were given under double-blind, random-assignment conditions to ten patients before and during FLX treatment. The ability of IPS to induce hypothermia and ACTH/cortisol release was significantly attenuated during chronic FLX as compared to the pretreatment IPS challenge. The behavioral effects of IPS, though minimal, were less pronounced during FLX treatment. While FLX was effective in reducing the severity of OC symptoms, no significant correlation between attenuation of 5-HT1A receptor-mediated functional measures and FLX-induced improvement in OC symptoms was detected. These findings are consistent with the development of adaptive hyporesponsivity of the 5-HT1A receptor-effector system complex possibly involving subsensitivity of the 5-HT1A receptor itself and/or decreased functional activity of the postreceptor signal transduction. Modulation of 5-HT1A receptor-effector system function may be critical to the antidepressant/anti-OC efficacy of 5-HT reuptake inhibitors.

5-HT1A receptor responsivity in unipolar depression. Evaluation of ipsapirone-induced ACTH and cortisol secretion in patients and controls.

The selective 5-HT1A receptor ligand ipsapirone (IPS) induces corticotropin (ACTH) and cortisol secretion in humans. To explore 5-HT1A receptor-mediated hypothalamic-pituitary-adrenal (HPA) system activation in depression, 24 subjects (12 patients with unipolar depression and 12 individually matched controls) were given 0.3 mg/kg IPS or placebo in random order. Compared with controls, the depressed patients exhibited significantly decreased ACTH and cortisol responses to IPS in association with increased basal cortisol secretion. The impaired HPA response following 5-HT1A receptor challenge in unipolar depression could have resulted from glucocorticoid-dependent subsensitivity of the (post-synaptic) 5-HT1A receptor itself and/or from a defective postreceptor signaling pathway [inhibitory guanine nucleotide-binding protein (Gi)-adenylate cyclase complex function], thus supporting the hypothesis that a disintegrated 5-HT and HPA system interaction may be present in depression. Future studies of the HPA response to direct-acting 5-HT1A ligands, such as IPS, should facilitate the assessment of 5-HT/HPA system integrity in various affective disorders and its involvement in psychotropic drug effects.