Dietrich Bonhoeffer Klinikum

BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.

PURPOSE: The second International Consensus Conference on B3 lesions was held in Zurich, Switzerland, in March 2018, organized by the International Breast Ultrasound School to re-evaluate the consensus recommendations. METHODS: This study (1) evaluated how management recommendations of the first Zurich Consensus Conference of 2016 on B3 lesions had influenced daily practice and (2) reviewed current literature towards recommendations to biopsy. RESULTS: In 2018, the consensus recommendations for management of B3 lesions remained almost unchanged: For flat epithelial atypia (FEA), classical lobular neoplasia (LN), papillary lesions (PL) and radial scars (RS) diagnosed on core-needle biopsy (CNB) or vacuum-assisted biopsy (VAB), excision by VAB in preference to open surgery, and for atypical ductal hyperplasia (ADH) and phyllodes tumors (PT) diagnosed at VAB or CNB, first-line open surgical excision (OE) with follow-up surveillance imaging for 5 years. Analyzing the Database of the Swiss Minimally Invasive Breast Biopsies (MIBB) with more than 30,000 procedures recorded, there was a significant increase in recommending more frequent surveillance of LN [65% in 2018 vs. 51% in 2016 (p = 0.004)], FEA (72% in 2018 vs. 62% in 2016 (p = 0.005)), and PL [(76% in 2018 vs. 70% in 2016 (p = 0.04)] diagnosed on VAB. A trend to more frequent surveillance was also noted also for RS [77% in 2018 vs. 67% in 2016 (p = 0.07)]. CONCLUSIONS: Minimally invasive management of B3 lesions (except ADH and PT) with VAB continues to be appropriate as an alternative to first-line OE in most cases, but with more frequent surveillance, especially for LN.

The second International Consensus Conference on B3 lesions was held in Zurich, Switzerland, in March 2018, organized by the International Breast Ultrasound School to re-evaluate the consensus recommendations. This study (1) evaluated how management recommendations of the first Zurich Consensus Conference of 2016 on B3 lesions had influenced daily practice and (2) reviewed current literature towards recommendations to biopsy. In 2018, the consensus recommendations for management of B3 lesions remained almost unchanged: For flat epithelial atypia (FEA), classical lobular neoplasia (LN), papillary lesions (PL) and radial scars (RS) diagnosed on core-needle biopsy (CNB) or vacuum-assisted biopsy (VAB), excision by VAB in preference to open surgery, and for atypical ductal hyperplasia (ADH) and phyllodes tumors (PT) diagnosed at VAB or CNB, first-line open surgical excision (OE) with follow-up surveillance imaging for 5 years. Analyzing the Database of the Swiss Minimally Invasive Breast Biopsies (MIBB) with more than 30,000 procedures recorded, there was a significant increase in recommending more frequent surveillance of LN [65% in 2018 vs. 51% in 2016 (p = 0.004)], FEA (72% in 2018 vs. 62% in 2016 (p = 0.005)), and PL [(76% in 2018 vs. 70% in 2016 (p = 0.04)] diagnosed on VAB. A trend to more frequent surveillance was also noted also for RS [77% in 2018 vs. 67% in 2016 (p = 0.07)]. Minimally invasive management of B3 lesions (except ADH and PT) with VAB continues to be appropriate as an alternative to first-line OE in most cases, but with more frequent surveillance, especially for LN.

Lobular neoplasia (LN) is a term that encompasses both lobular carcinoma in situ and atypical lobular hyperplasia. These lesions have been shown to constitute both risk indicators and nonobligate precursors of invasive breast cancer, they are relatively uncommon, and are most often identified in specimens taken for other reasons. Their incidence has increased in the last 2 decades, and novel variants, including a pleomorphic type, have been described. Loss of E-cadherin expression is recognized as a hallmark diagnostic feature of LN and invasive lobular carcinomas, and immunohistochemical (IHC) analysis using anti-E-cadherin antibodies has been proven to be a useful method to differentiate between lobular and ductal lesions. The frequent use of E-cadherin IHC analysis in routine diagnostic histopathology, however, has resulted in confusion with regard to the actual value of IHC with antibodies against E-cadherin and other proteins of the cadherin-catenin complex. This review provides an update on recent clinicopathologic and molecular data on LN and invasive lobular carcinoma and a discussion about the use and limitations of IHC with E-cadherin in diagnostic breast pathology.

Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo-rosettes, small to medium-sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot-like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1-MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1-11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow-up, 4.84 years). In this to date, largest series of ependymomas with YAP1-MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.

Pathological analysis of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers. However, clinical utility of the immunohistochemical (IHC) assay for Ki67 immunohistochemistry has been hampered by unacceptable between-laboratory analytical variability. The International Ki67 Working Group has conducted a series of studies aiming to decrease this variability and improve the evaluation of Ki67. This study tries to assess whether acceptable performance can be achieved on prestained core-cut biopsies using a standardized scoring method. Sections from 30 primary ER+ breast cancer core biopsies were centrally stained for Ki67 and circulated among 22 laboratories in 11 countries. Each laboratory scored Ki67 using three methods: (1) global (4 fields of 100 cells each); (2) weighted global (same as global but weighted by estimated percentages of total area); and (3) hot-spot (single field of 500 cells). The intraclass correlation coefficient (ICC), a measure of interlaboratory agreement, for the unweighted global method (0.87; 95% credible interval (CI): 0.81-0.93) met the prespecified success criterion for scoring reproducibility, whereas that for the weighted global (0.87; 95% CI: 0.7999-0.93) and hot-spot methods (0.84; 95% CI: 0.77-0.92) marginally failed to do so. The unweighted global assessment of Ki67 IHC analysis on core biopsies met the prespecified criterion of success for scoring reproducibility. A few cases still showed large scoring discrepancies. Establishment of external quality assessment schemes is likely to improve the agreement between laboratories further. Additional evaluations are needed to assess staining variability and clinical validity in appropriate cohorts of samples.

Importance: After aneurysmal subarachnoid hemorrhage, the use of lumbar drains has been suggested to decrease the incidence of delayed cerebral ischemia and improve long-term outcome. Objective: To determine the effectiveness of early lumbar cerebrospinal fluid drainage added to standard of care in patients after aneurysmal subarachnoid hemorrhage. Design, Setting, and Participants: The EARLYDRAIN trial was a pragmatic, multicenter, parallel-group, open-label randomized clinical trial with blinded end point evaluation conducted at 19 centers in Germany, Switzerland, and Canada. The first patient entered January 31, 2011, and the last on January 24, 2016, after 307 randomizations. Follow-up was completed July 2016. Query and retrieval of data on missing items in the case report forms was completed in September 2020. A total of 20 randomizations were invalid, the main reason being lack of informed consent. No participants meeting all inclusion and exclusion criteria were excluded from the intention-to-treat analysis. Exclusion of patients was only performed in per-protocol sensitivity analysis. A total of 287 adult patients with acute aneurysmal subarachnoid hemorrhage of all clinical grades were analyzable. Aneurysm treatment with clipping or coiling was performed within 48 hours. Intervention: A total of 144 patients were randomized to receive an additional lumbar drain after aneurysm treatment and 143 patients to standard of care only. Early lumbar drainage with 5 mL per hour was started within 72 hours of the subarachnoid hemorrhage. Main Outcomes and Measures: Primary outcome was the rate of unfavorable outcome, defined as modified Rankin Scale score of 3 to 6 (range, 0 to 6), obtained by masked assessors 6 months after hemorrhage. Results: Of 287 included patients, 197 (68.6%) were female, and the median (IQR) age was 55 (48-63) years. Lumbar drainage started at a median (IQR) of day 2 (1-2) after aneurysmal subarachnoid hemorrhage. At 6 months, 47 patients (32.6%) in the lumbar drain group and 64 patients (44.8%) in the standard of care group had an unfavorable neurological outcome (risk ratio, 0.73; 95% CI, 0.52 to 0.98; absolute risk difference, -0.12; 95% CI, -0.23 to -0.01; P = .04). Patients treated with a lumbar drain had fewer secondary infarctions at discharge (41 patients [28.5%] vs 57 patients [39.9%]; risk ratio, 0.71; 95% CI, 0.49 to 0.99; absolute risk difference, -0.11; 95% CI, -0.22 to 0; P = .04). Conclusion and Relevance: In this trial, prophylactic lumbar drainage after aneurysmal subarachnoid hemorrhage lessened the burden of secondary infarction and decreased the rate of unfavorable outcome at 6 months. These findings support the use of lumbar drains after aneurysmal subarachnoid hemorrhage. Trial Registration: ClinicalTrials.gov Identifier: NCT01258257.

We report on the unexpected finding of a 46,XY karyotype in a 30 year-old woman with normal ovarian function and a former pregnancy at 17 years of age. Chromosome analysis was performed prior to intracyoplasmic sperm injection (ICSI), due to infertility of her husband. Repeated chromosome analysis in lymphocytes of the female resulted in a normal male karyotype. Fluorescence in-situ hybridization (FISH) analysis of cultured lymphocyte interphase nuclei detected in 99% of the cells one X and one Y chromosome-specific signal respectively, whereas two X chromosome-specific signals were observed in only 1% of the nuclei. Chromosome analysis of fibroblasts of ovarian and muscular tissues as well as of skin revealed a normal female karyotype (46,XX). Chimerism could be proven by variable number of tandem repeats (VNTR) analysis. Since the case history of the patient revealed that her twin brother died shortly after birth, it can be assumed that chimerism is caused by feto-fetal transfusion during pregnancy and delivery of the proposita.

BACKGROUND AND PURPOSE: In patients with ischemic stroke, randomized trials showed a better functional outcome after endovascular therapy with new-generation thrombectomy devices compared with medical treatment, including intravenous thrombolysis. However, effects on mortality and the generalizability of results to routine clinical practice are uncertain. METHODS: In a prospective observational register-based study patients with ischemic stroke treated either with thrombectomy, intravenous thrombolysis, or their combination were included. Primary outcome was the modified Rankin scale score (0 [no symptoms] to 6 [death]) at 3 months. Ordinal logistic regression was used to estimate the common odds ratio as treatment effects (shift analysis). Propensity score matching was applied to compare patients treated either with intravenous thrombolysis alone or with intravenous thrombolysis plus thrombectomy. RESULTS: Among 2650 recruited patients, 1543 received intravenous thrombolysis, 504 underwent thrombectomy, and 603 received intravenous thrombolysis in combination with thrombectomy. Later time-to-treatment was associated with worse outcomes among patients treated with thrombectomy plus thrombolysis. In 241 pairs of propensity score-matched patients with a proximal intracranial occlusion, thrombectomy plus thrombolysis was associated with improved functional outcome (common odds ratio, 1.84; 95% confidence interval, 1.32-2.57), and reduced mortality (15% versus 33%; P<0.0001) compared with intravenous thrombolysis alone. Results were similar in various sensitivity analyses accounting for missing outcome data and different analytic methods. CONCLUSIONS: Results from this large prospective registry show that also in routine clinical care thrombectomy plus thrombolysis compared with thrombolysis alone improved functional outcome and reduced mortality in patients with ischemic stroke. Earlier treatment was associated with better outcomes.

AIMS: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. METHODS AND RESULTS: breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799-0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74-0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively. CONCLUSIONS: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.

Triple-negative breast cancers (TNBC), as a group of tumours, have a worse prognosis than stage-matched non-TNBC and lack the benefits of routinely available targeted therapy. However, TNBC is a heterogeneous group of neoplasms, which includes some special type carcinomas with a relatively indolent course. This review on behalf of the European Working Group for Breast Screening Pathology reviews the literature on the special histological types of BC that are reported to have a triple negative phenotype and indolent behaviour. These include adenoid cystic carcinoma of classical type, low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, low-grade mucoepidermoid carcinoma, secretory carcinoma, acinic cell carcinoma, and tall cell carcinoma with reversed polarity. The pathological and known molecular features as well as clinical data including treatment and prognosis of these special TNBC subtypes are summarised and it is concluded that many patients with these rare TNBC pure subtypes are unlikely to benefit from systemic chemotherapy. A consensus statement of the working group relating to the multidisciplinary approach and treatment of these rare tumour types concludes the review.

PURPOSE: To evaluate the safety of a new suprachoroidal device, the Cypass micro-stent, for the surgical treatment of open-angle glaucoma (OAG) implanted in conjunction with cataract surgery. SETTING: Multicenter clinical study. DESIGN: Prospective interventional case series. METHODS: This is an interim report of an ongoing safety study. Patients with OAG glaucoma (Shaffer grade 3 and 4) who were also candidates for cataract surgery in the affected eye had standard phacoemulsification followed by micro-stent implantation in the supraciliary space. Included were patients with uncontrolled (≥ 21 mm Hg, Cohort 1) or controlled (<21 mm Hg, Cohort 2) medicated intraocular pressure (IOP) at baseline. Glaucoma medications were discontinued at surgery and resumed at the discretion of each investigator. Measures included adverse events/complications and postoperative changes in IOP or medication. RESULTS: The mean baseline medicated IOP was 21.1 mm Hg ± 5.91 (SD); the mean number of IOP-lowering medications was 2.1 ± 1.1 (N = 184). There were no major events such as retinal or choroidal detachment or endophthalmitis. The most common complications were transient early hypotony (13.8%) and transient IOP increase (10.5%). Uncontrolled patients (n = 57) had a 37% IOP reduction (P<.001), with more than a 50% reduction in glaucoma medications at 6 months (P<.001). Intraocular pressure-controlled patients (n = 41) had a 71.4% reduction in glaucoma medications (P<.001). CONCLUSION: Initial clinical experience with the new micro-stent showed a low rate of surgical complications with concomitant decreases in IOP and/or glaucoma medications.

PURPOSE: To evaluate safety and clinical outcomes of a novel supraciliary device, the CyPass Micro-Stent, for surgical treatment of open-angle glaucoma when implanted in conjunction with cataract surgery. PATIENTS AND METHODS: Subjects (n=142) with open-angle glaucoma and cataract underwent combined phacoemulsification, with intraocular lens insertion, and microstent implantation into the supraciliary space of study eyes (n=167). Two analysis cohorts were prespecified based upon medicated baseline intraocular pressure (IOP): ≥21 mm Hg (cohort 1, n=65) or <21 mm Hg (cohort 2, n=102). Glaucoma medications were discontinued or tapered at surgery, and restarted at investigator discretion. The main postoperative outcome measures were adverse events, IOP changes, and number of IOP-lowering medications. RESULTS: Mean±SD follow-up was 294±121 days. No major intraoperative or postoperative complications occurred. Preoperative baseline mean IOP was 20.2±6.0 mm Hg and mean number of IOP-lowering medications was 2.0±1.1. Cohort 1 showed a 35% decrease in mean IOP and a 49% reduction in mean glaucoma medication usage; cohort 2 demonstrated a 75% reduction in mean medication usage while maintaining mean IOP<21 mm Hg. For all eyes, mean IOP at 12 months was 15.9±3.1 mm Hg (14% reduction from baseline). Early and late postoperative IOP elevation occurred in 1.2% and 1.8% of eyes, respectively. Two subjects developed mild transient hyphema, and none exhibited prolonged inflammation, persistent hypotony, or hypotony maculopathy. CONCLUSIONS: CyPass Micro-Stent implantation, combined with cataract surgery, resulted in minimal complications and reduced IOP and IOP-lowering medication use at 12 months postoperatively.

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. Results One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0–3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. Conclusion Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

<h3>Objective</h3> The aim of this study was to assess the efficacy of adalimumab in patients with active non-infectious uveitis in three different centres. <h3>Methods</h3> In a retrospective study we identified patients from our databases who were treated with adalimumab. The composite outcome measure for efficacy included reduction of macular oedema by optic coherence tomography, visual acuity, anterior chamber cells, reduction of frequency of flares and reduction of prednisone dose during the treatment. At least one of the criteria had to be improved and none worsened to declare treatment as effective. <h3>Results</h3> 60 patients with an average age of 37.3 years (range 4–71 years) were treated with adalimumab over an average follow-up period of 87.9 weeks (range 12–222 weeks). The indication for treatment was in 41 (68.3%) patients the activity of both uveitis and systemic disease and in 19 (31.7%) patients uveitis activity only. 15 (25%) patients were treated before with etanercept and 10 (16.7%) patients with infliximab. 49 out of 60 (81.7%) patients improved, while the other 11 (18.3%) patients did not meet improvement criteria and were given additional or alternative immunosuppressive treatment. At the last follow-up, 47 (78.3%) patients were still on adalimumab treatment. 13 (21.6%) patients stopped adalimumab treatment, due to inefficacy in eight, another three patients due to side effects (liver enzyme elevation and furunculosis), one patient due to pregnancy and one patient died. <h3>Conclusions</h3> This large retrospective case series showed that adalimumab is effective in up to 80% of patients with uveitis.

INTRODUCTION: The Retro-IDEAL (ILUVIEN Implant for chronic DiabEtic MAcuLar edema) study is a retrospective study designed to assess real-world outcomes achieved with the ILUVIEN® (0.19 mg fluocinolone acetonide (FAc)) in patients with chronic diabetic macular edema (DME) in clinical practices in Germany. METHODS: This study was conducted across 16 sites in Germany and involved 81 eyes (63 patients) with persistent or recurrent DME and a prior suboptimal response to a first-line intravitreal therapy (primarily anti-VEGF intravitreal therapies). RESULTS: Patients were followed-up for 30.8 ± 11.3 months (mean ± standard deviation) and had a mean age of 68.0 ± 10.4 years. Best-recorded visual acuity (BRVA) improved by +5.5 letters at month 9 (P ⩽ 0.005, n=56; from a baseline of 49 letters) and this was maintained through to month 30 (P ⩽ 0.05, n = 42). There was a concurrent improvement in central macular thickness with a reduction from 502 µm at baseline to 338 µm at year 1 (P ⩽ 0.0001, n = 43). This effect was sustained to year 3 (i.e. 318 µm; P ⩽ 0.0001, n = 29). Mean intraocular pressure (IOP) remained constant between baseline and year 3 with a peak change of 1.9 mm Hg occurring at year 1. Elevated IOP was observed in a similar percentage of patients prior to (22.2% of cases) and following (27.2%) treatment with the FAc implant. In the majority of cases, these elevations were managed effectively with IOP medications. CONCLUSIONS: Despite substantial amounts of prior intravitreal treatments - primarily with anti-vascular endothelial growth factor (VEGF) drugs - this real-world study showed that sustained structural and functional improvements can last for up to 3 years with a single FAc implant.

OBJECTIVE: Fabry disease is a rare X-linked inherited lysosomal storage disorder affecting multiple organ systems. It includes central nervous system involvement via micro- and macroangiopathic cerebral changes. Due to its clinical symptoms and frequent MRI lesions, Fabry disease is commonly misdiagnosed as multiple sclerosis. We present an overview of cases from Fabry centres in Germany initially misdiagnosed with multiple sclerosis and report the clinical, MR-tomographical, and laboratory findings. METHODS: Eleven Fabry patients (one male, ten females) initially diagnosed with multiple sclerosis were identified from 187 patient records (5.9%) and analyzed for presenting symptoms, results of the initial diagnostic workup, and the clinical course of the disease. RESULTS: Four patients were identified as having a "possible" history of MS, and 7 patients as "definite" cases of multiple sclerosis (revised McDonald criteria). On average, Fabry disease was diagnosed 8.2 years (±9.8 years) after the MS diagnosis, and 12.8 years after onset of first symptoms (±10.3 years). All patients revealed white matter lesions on MRI. The lesion pattern and results of cerebrospinal fluid examination were inconsistent and non-specific. White matter lesion volumes ranged from 8.9 mL to 34.8 mL (mean 17.8 mL±11.4 mL). There was no association between extra-neurological manifestations or enzyme activity and lesion load. CONCLUSION: There are several anamnestic and clinical hints indicating when Fabry disease should be considered a relevant differential diagnosis of multiple sclerosis, e.g. female patients with asymmetric, confluent white matter lesions on MRI, normal spinal MR imaging, ectatic vertebrobasilar arteries, proteinuria, or lack of intrathecally derived immunoglobulin synthesis.

PURPOSE: The aim of this study was to evaluate through 2 postoperative years the clinical outcomes associated with a novel supraciliary micro-stent for the surgical treatment of open-angle glaucoma (OAG) when implanted in conjunction with cataract surgery. PATIENTS AND METHOD: In a multicenter, prospective, consecutive case series, 136 subjects (136 eyes) with OAG and requiring cataract surgery with 24-month postoperative data were included. A combined phacoemulsification procedure, with intraocular lens insertion and CyPass Micro-Stent implantation into the supraciliary space of the study eye, was performed. At baseline, all subjects were on glaucoma medication with either uncontrolled intraocular pressure (IOP; ≥ 21 mmHg, Cohort 1, n=51) or controlled IOP (<21 mmHg, Cohort 2, n=85). Glaucoma medications were stopped postoperatively, but could be restarted if needed, at the investigator's discretion. Device-related adverse events, postoperative IOP, best corrected distance visual acuity (BCDVA), and number of IOP-lowering medications were recorded. RESULTS: The micro-stent was successfully implanted in all eyes. At 24 months, 82 subjects remained in the study. No sight-threatening adverse events occurred. The most common adverse events were transient hypotony (15.4%) and micro-stent obstruction (8.8%), typically due to iris tissue overgrowth. Fifteen subjects (11%) required secondary incisional glaucoma surgery. For Cohort 1 (n=23), mean ± SD IOP was 15.8 ± 3.8 mmHg after 24 months (change, -37% ± 19%). Mean IOP decrease from baseline was statistically significant (p<0.0001) at months 6, 12, and 24. For Cohort 2 (n=59), mean ± SD IOP at 24 months was 16.1 ± 3.2 mmHg (change, 0% ± 28%). Mean decrease from baseline was statistically significant at months 6 (p=0.0188) and 12 (p=0.0356). At 24 months, the mean ± SD number of medications was 1.0 ± 1.1 in Cohort 1 and 1.1 ± 1.1 in Cohort 2. Mean decrease from baseline medication use was statistically significant at months 6 (p<0.001), 12 (p<0.001), and 24 (p=0.0265) in Cohort 1, and at months 6, 12, and 24 (all p<0.0001) in Cohort 2. CONCLUSIONS: CyPass Micro-Stent implantation, in combination with cataract surgery, was associated with minimal complications while substantially lowering IOP and/or use of IOP-lowering medications.

The Ki67 labelling index (LI - proportion of staining cells) is widely used to reflect proliferation in breast carcinomas. Several cut-off values have been suggested to distinguish between tumours with low and high proliferative activity. The aim of the current study was to evaluate the distribution of Ki67 LIs in breast carcinomas diagnosed at different institutions by different pathologists using the method reflecting their daily practice. Pathologists using Ki67 were asked to provide data (including the LI, type of the specimen, receptor status, grade) on 100 consecutively stained cases, as well as details of their evaluation. A full dataset of 1709 carcinomas was collected from 19 departments. The median Ki67 LI was 17% for all tumours and 14% for oestrogen receptor-positive and HER2-negative carcinomas. Tumours with higher mitotic counts were associated with higher Ki67 LIs. Ki67 LIs tended to cluster around values ending with 5 or 0 both in cases where the values were obtained by counting the proportion of stained tumour cell nuclei and those where the values were obtained by estimation. On the basis of the distribution pattern described, some currently used Ki67 LI cut off values are not realistic, and it is proposed to select more realistic values ending with 0 or 5.

Syringocystadenocarcinoma papilliferum is an extremely rare cutaneous adnexal neoplasm. The purpose of our investigation was to study a series of syringocystadenocarcinoma papilliferum to document morphologic variations of the neoplasm. This is a light-microscopic study of 6 cases of syringocystadenocarcinoma papilliferum obtained from the combined archival, institutional, and consultations files of the authors over 60 years, complemented by a literature review. Syringocystadenocarcinoma papilliferum invariably occurred in association with syringocystadenoma papilliferum and presented as an in situ adenocarcinoma and/or invasive adenocarcinoma. Additionally, an invasive component was represented by squamous cell carcinoma. Variable present features included pagetoid migration of the neoplastic cells, dirty necrosis, mucinous ductal metaplasia, and ductal changes analogous to those seen in the breast. The ductal changes included patterns identical to columnar cell change (flat epithelial atypia), usual ductal hyperplasia, atypical ductal hyperplasia, and ductal carcinoma in situ. A combination of the above patterns in a single lesion was noted. It is concluded that morphologic diversity of syringocystadenocarcinoma papilliferum is substantial. Its association with the benign counterpart and ductal changes suggests a transformation that may involve usual ductal hyperplasia-atypical ductal hyperplasia-(ductal) adenocarcinoma in situ-invasive adenocarcinoma pathway.