Minimally Invasive Breast Biopsy After Neoadjuvant Systemic Treatment to Identify Breast Cancer Patients with Residual Disease for Extended Neoadjuvant Treatment: A New Concept.

BACKGROUND: Breast cancer patients with residual disease after neoadjuvant systemic treatment (NAST) have a worse prognosis compared with those achieving a pathologic complete response (pCR). Earlier identification of these patients might allow timely, extended neoadjuvant treatment strategies. We explored the feasibility of a vacuum-assisted biopsy (VAB) after NAST to identify patients with residual disease (ypT+ or ypN+) prior to surgery. METHODS: We used data from a multicenter trial, collected at 21 study sites (NCT02948764). The trial included women with cT1-3, cN0/+ breast cancer undergoing routine post-neoadjuvant imaging (ultrasound, MRI, mammography) and VAB prior to surgery. We compared the findings of VAB and routine imaging with the histopathologic evaluation of the surgical specimen. RESULTS: Of 398 patients, 34 patients with missing ypN status and 127 patients with luminal tumors were excluded. Among the remaining 237 patients, tumor cells in the VAB indicated a surgical non-pCR in all patients (73/73, positive predictive value [PPV] 100%), whereas PPV of routine imaging after NAST was 56.0% (75/134). Sensitivity of the VAB was 72.3% (73/101), and 74.3% for sensitivity of imaging (75/101). CONCLUSION: Residual cancer found in a VAB specimen after NAST always corresponds to non-pCR. Residual cancer assumed on routine imaging after NAST corresponds to actual residual cancer in about half of patients. Response assessment by VAB is not safe for the exclusion of residual cancer. Response assessment by biopsies after NAST may allow studying the new concept of extended neoadjuvant treatment for patients with residual disease in future trials.

Thrombocytopenia With Absent Radii Syndrome With an Unusual Urological Pathology: A Case Report.

Thrombocytopenia with absent radii (TAR) syndrome is a rare congenital syndrome that follows an autosomal recessive pattern of inheritance. TAR syndrome is characterized by thrombocytopenia and bilateral absence (aplasia) of the radii of the forearms. This syndrome can be associated with defects within the skeletal, cardiac, renal, or gastrointestinal systems. It is important for clinicians treating patients with TAR syndrome to be aware of the myriad of complications that may arise in the other organ systems in order to promptly diagnose and treat any associated anomalies. We present a case of an African American infant diagnosed with TAR syndrome who was also found to have grade 5 vesicoureteral reflux and moderate right hydronephrosis, as well as cow's milk protein allergy.

ON-ICE trial: Investigation of the combined effects of oxytocin and naltrexone on stress-induced and alcohol cue-induced craving in alcohol use disorder-Study protocol of a phase II randomised double-blind placebo-controlled parallel-group trial.

INTRODUCTION: Although alcohol dependence (AD) is highly prevalent, only few medications are approved for its treatment. While currently approved medications, such as naltrexone (NTX), reduce craving and relapse risk to a certain extent, new approaches are needed to complement these pharmaca. One potential compound is oxytocin (OXY), which proved beneficial effects on alcohol craving and stress reactivity in preliminary clinical studies and synergism with NTX effects. METHODS AND ANALYSIS: This clinical phase II trial is a monocentre two-armed, placebo (PLC)-controlled, 1:1 randomised, double-blind, parallel-group study. 62 participants with AD will be randomised to receive either intranasal OXY spray (24 IU) or PLC spray plus oral NTX (50 mg) for 2 days, and alcohol craving will be assessed using a validated combined stress-exposure and cue-exposure experiments and MRI. The primary outcome will be the intensity of alcohol craving, assessed using the Alcohol Urge Questionnaire (AUQ), 60 min after OXY/PLC application, directly after the stress and cue exposures. Secondary outcomes include subjective stress, negative affect, cortisol and OXY plasma levels, and neural response to alcohol and emotional cues and natural rewards. Follow-up drinking data were collected over 90 days. The primary efficacy analysis will test the difference between the verum and the PLC group in the distribution of AUQ craving scores. Appropriate statistical analysis will be used for the evaluation of the secondary outcomes. ETHICS AND DISSEMINATION: This trial has been approved by the ethics committee of Heidelberg University and competent authority. All participants in the trial will provide written informed consent. The study will be conducted according to the principles of the Declaration of Helsinki and in accordance to the German Medicinal Products act. Results of this study will be disseminated in peer-reviewed scientific journals and deidentified data, and the statistical analysis plan will be made available via open-access online repositories. TRIAL REGISTRATION NUMBERS: EudraCT 2021-003610-40 and NCT05093296.

Intelligent Vacuum-Assisted Biopsy to Identify Breast Cancer Patients With Pathologic Complete Response (ypT0 and ypN0) After Neoadjuvant Systemic Treatment for Omission of Breast and Axillary Surgery.

PURPOSE: Neoadjuvant systemic treatment (NST) elicits a pathologic complete response in 40%-70% of women with breast cancer. These patients may not need surgery as all local tumor has already been eradicated by NST. However, nonsurgical approaches, including imaging or vacuum-assisted biopsy (VAB), were not able to accurately identify patients without residual cancer in the breast or axilla. We evaluated the feasibility of a machine learning algorithm (intelligent VAB) to identify exceptional responders to NST. METHODS: We trained, tested, and validated a machine learning algorithm using patient, imaging, tumor, and VAB variables to detect residual cancer after NST (ypT+ or in situ or ypN+) before surgery. We used data from 318 women with cT1-3, cN0 or +, human epidermal growth factor receptor 2-positive, triple-negative, or high-proliferative Luminal B-like breast cancer who underwent VAB before surgery (ClinicalTrials.gov identifier: NCT02948764, RESPONDER trial). We used 10-fold cross-validation to train and test the algorithm, which was then externally validated using data of an independent trial (ClinicalTrials.gov identifier: NCT02575612). We compared findings with the histopathologic evaluation of the surgical specimen. We considered false-negative rate (FNR) and specificity to be the main outcomes. RESULTS: In the development set (n = 318) and external validation set (n = 45), the intelligent VAB showed an FNR of 0.0%-5.2%, a specificity of 37.5%-40.0%, and an area under the receiver operating characteristic curve of 0.91-0.92 to detect residual cancer (ypT+ or in situ or ypN+) after NST. Spiegelhalter's Z confirmed a well-calibrated model (z score -0.746, P = .228). FNR of the intelligent VAB was lower compared with imaging after NST, VAB alone, or combinations of both. CONCLUSION: An intelligent VAB algorithm can reliably exclude residual cancer after NST. The omission of breast and axillary surgery for these exceptional responders may be evaluated in future trials.

Diagnosing Pathologic Complete Response in the Breast After Neoadjuvant Systemic Treatment of Breast Cancer Patients by Minimal Invasive Biopsy: Oral Presentation at the San Antonio Breast Cancer Symposium on Friday, December 13, 2019, Program Number GS5-03.

OBJECTIVE: We evaluated the ability of minimally invasive, image-guided vacuum-assisted biopsy (VAB) to reliably diagnose a pathologic complete response in the breast (pCR-B). SUMMARY BACKGROUND DATA: Neoadjuvant systemic treatment (NST) elicits a pathologic complete response in up to 80% of women with breast cancer. In such cases, breast surgery, the gold standard for confirming pCR-B, may be considered overtreatment. METHODS: This multicenter, prospective trial enrolled 452 women presenting with initial stage 1-3 breast cancer of all biological subtypes. Fifty-four women dropped out; 398 were included in the full analysis. All participants had an imaging-confirmed partial or complete response to NST and underwent study-specific image-guided VAB before guideline-adherent breast surgery. The primary endpoint was the false-negative rate (FNR) of VAB-confirmed pCR-B. RESULTS: Image-guided VAB alone did not detect surgically confirmed residual tumor in 37 of 208 women [FNR, 17.8%; 95% confidence interval (CI), 12.8-23.7%]. Of these 37 women, 12 (32.4%) had residual DCIS only, 20 (54.1%) had minimal residual tumor (<5 mm), and 19 of 25 (76.0%) exhibited invasive cancer cellularity of ≤10%. In 19 of the 37 cases (51.4%), the false-negative result was potentially avoidable. Exploratory analysis showed that performing VAB with the largest needle by volume (7-gauge) resulted in no false-negative results and that combining imaging and image-guided VAB into a single diagnostic test lowered the FNR to 6.2% (95% CI, 3.4%-10.5%). CONCLUSIONS: Image-guided VAB missed residual disease more often than expected. Refinements in procedure and patient selection seem possible and necessary before omitting breast surgery.

Bilateral Implantation of a New Refractive Multi-Segmented Multifocal Intraocular Lens in Cataract or Refractive Lens Exchange Patients.

PURPOSE: To evaluate the safety and efficacy of a new multi-segmented refractive multifocal intraocular lens (IOL) after phacoemulsification and refractive lens exchange (RLE). PATIENTS AND METHODS: In this prospective, multicenter clinical trial, 63 presbyopic subjects who had cataract or where RLE candidates were bilaterally implanted with the Precizon Presbyopia IOL (Ophtec BV, Groningen, the Netherlands) after phacoemulsification. The study was conducted at 6 clinical centers in Germany, the Netherlands, Belgium, Turkey and Spain. Subjects were evaluated at baseline and at 1 day, 1 week, 1 and 3 months postoperatively for monocular and binocular uncorrected (UDVA) and corrected distance visual acuity (CDVA), uncorrected (UIVA) and distance-corrected intermediate visual acuity (DCIVA), uncorrected (UNVA), corrected (CNVA) and distance-corrected near visual acuity (DCNVA), contrast sensitivity and quality of vision. RESULTS: Three months postoperatively, binocular UDVA and CDVA of ≥20/40 was achieved in 98.4% (60/61) and 100%, respectively. Binocular UIVA and DCIVA of ≥20/40 was achieved in 96.7% (59/61) and 93.4% (57/61) respectively. Binocular UNVA, CNVA and DCNVA of ≥20/40 was achieved in 93.4% (57/61), 98.4% (60/61) and 95% (57/60) subjects, respectively. Complete spectacle independence was achieved in 80% (49/61) patients; 93% of patients reported that they were quite or very satisfied with the outcomes of the procedure. CONCLUSION: Precizon Presbyopia IOL implantation is a safe and effective method to provide good visual acuity at all distances in presbyopic and cataract patients.

Rhabdomyolysis as the Initial Presentation of SARS-CoV-2 in an Adolescent.

The novel coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2, has created a global pandemic, with many cases affecting the elderly. However, children have been affected as well, with ∼2.4% to 3.7% of cases reported. This case is the first published case of an adolescent presenting with rhabdomyolysis as the first sign of novel coronavirus disease 2019, with extremely elevated creatinine kinase levels, approaching almost 400 000 U/L. This case adds to the growing body of literature of a variety of life-threatening manifestations associated with severe acute respiratory syndrome coronavirus 2 infection and highlights the importance of how prompt recognition of these unique presentations of the disease is important to mitigate complications.

RESPONDER - diagnosis of pathological complete response by vacuum-assisted biopsy after neoadjuvant chemotherapy in breast Cancer - a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is a standard approach of the multidisciplinary treatment of breast cancer. Depending on the biological subtype a pathological complete response in the breast (bpCR) can be achieved in up to 60% of the patients. However, only limited accuracy can be reached when using imaging for prediction of bpCR prior to surgery. Due to this diagnostic uncertainty, surgery after NACT is considered to be obligatory for all patients in order to either completely remove residual disease or to diagnose a bpCR histologically. The purpose of this trial is to evaluate the accuracy of a vacuum-assisted biopsy (VAB) to diagnose a bpCR after NACT prior to surgery. METHODS: This study is a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial. The study will take place at 21 trial sites in Germany. Six hundred female patients with breast cancer after completed NACT showing at least a partial response to NACT treatment will be enrolled. A vacuum-assisted biopsy (VAB) guided either by ultrasound or mammography will be performed followed by histopathological evaluation of the VAB specimen before standard, guideline-adherent breast surgery. The study is designed to prove that the false negative rate of the VAB is below 10%. DISCUSSION: As a bpCR is becoming a more frequent result after NACT, the question arises whether breast surgery is therapeutically necessary in such cases. To study this subject further, it will be crucial to develop a reliable test to diagnose a bpCR without surgery. During the study we anticipate possible problems in patient recruitment as the VAB intervention does not provide participating patients with any personal benefit. Hence, a proficient informed consent discussion with the patient and a detailed explanation of the study aim will be crucial for patient recruitment. Another critical issue is the histopathological VAB evaluation of a non-tumorous specimen as this may have been taken either from the former tumor region (bpCR) or outside of the (former) tumor region (non-representative VAB, sampling error). TRIAL REGISTRATION: The trial has been registered at clinicaltrials.gov with the identifier NCT02948764 on October 28, 2016 and at the German Clinical Trials Register ( DRKS00011761 ) on February 20, 2017. The date of enrolment of the first participant to the trial was on March 8, 2017.

Clinical outcomes after implantation of a toric intraocular lens with a transitional conic toric surface.

PURPOSE: To evaluate the postoperative outcomes after implantation of a hydrophilic toric intraocular lens (tIOL) with a transitional conic toric surface in patients with astigmatism undergoing refractive lens exchange (RLE) or cataract surgery. METHODS: In this monocentric study, clinical outcomes following implantation of the hydrophilic Precizon toric IOL model 565 (Ophtec) were analysed. For intraoperative axis alignment, the Verion Image Guided System was used. Intended versus achieved refraction, IOL position, visual acuity outcomes and power vector analyses were evaluated 3 months postoperatively. RESULTS: Forty-three eyes of 28 patients (40 eyes cataract, 3 eyes RLE) received a Precizon toric IOL with a cylindrical power between 1.0 and 7.5 D. Target refraction was emmetropia except for four eyes that had a myopic target. The median postoperative IOL rotation at slit lamp was 3° with a range from 0° to 16°. Uncorrected distance visual acuity (UDVA) increased from median 0.5 logMAR preoperatively to median 0.06 logMAR at 3 months postoperatively. Corrected distance visual acuity increased from 0.20 to -0.02 logMAR. Median preoperative subjective cylinder was 1.5 D and 3 months postoperatively 0.25 D. CONCLUSION: Preoperative diagnostics, IOL selection and correct intraoperative positioning of tIOLs are essential for good outcomes and postoperative spectacle independence following cataract or RLE surgery. Visual acuities and rotational stability of the Precizon toric IOL showed very good outcomes and the subjective postoperative astigmatism could be reduced significantly.

Influence on intraocular lens power calculation of corneal radii measurement using an image-guided system.

PURPOSE: To analyze the influence on intraocular lens (IOL) power calculation of corneal radii measured by the Verion Image-Guided System in comparison with those measured by partial coherence interferometry (PCI) (IOLMaster) and optical low-coherence reflectometry (OLCR) (Lenstar) systems. SETTING: International Vision Correction Research Centre, Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany. DESIGN: Prospective case series. METHODS: One eye of ophthalmologically healthy volunteers was examined with the image-guided, PCI, and OLCR systems. Corneal radii could be measured with all 3 devices; axial length (AL) and anterior chamber depth (ACD) could be measured with PCI and OLCR only. The IOL power calculations for the Acrysof SN60WF IOL using 4 formulas were compared between the image-guided system and both the PCI device and OLCR device. For IOL calculation with the image-guided system, the AL and ACD of the device used for comparison were applied. RESULTS: Of the 150 volunteers, 136 (mean age 39.60 years ± 17.31 [SD]) had valid measurements with all 3 devices and were included in the analysis. Compared with PCI, the image-guided system measured statistically significant larger values for corneal radii and IOL power calculations for all 4 formulas. There were no statistically significant differences between the image-guided system and the OLCR device. In both groups, the surgeon would have chosen the same IOL power in approximately 60% to 65% of cases and a ±0.5 diopter different IOL power in approximately 30% to 35% of cases when using the image-guided system. CONCLUSIONS: The IOL power calculation using the image-guided system showed statistically significant differences compared with the PCI device but not when compared with the OLCR device. The clinical relevance of this theoretical approach remains to be evaluated. FINANCIAL DISCLOSURE: Drs. Auffarth and Holzer received travel grants and lecture fees from Alcon Pharma GmbH and Carl Zeiss Meditec AG.

Comparison of a new image-guided system versus partial coherence interferometry, Scheimpflug imaging, and optical low-coherence reflectometry devices: Keratometry and repeatability.

PURPOSE: To determine the repeatability of keratometry of the Verion image-guided system and to compare the keratometry (K) values with those of established biometric devices. SETTING: International Vision Correction Research Centre, Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany. DESIGN: Prospective case series. METHODS: One randomly chosen eye of volunteers was examined with partial coherence interferometry (PCI) (IOLMaster 500), optical low-coherence reflectometry (OLCR) (Lenstar LS 900), a Scheimpflug device (Pentacam HR), and the new image-guided system by the same examiner. None of the eyes had ocular pathology. Three consecutive measurements were performed with the image-guided system and 1 with the other devices. The flat, steep, and average corneal radii; steep axis; and white-to-white (WTW) distance were analyzed and compared. RESULTS: One hundred twenty-three eyes of 123 volunteers (mean age 37.9 years ± 16.2 [SD]) had valid measurements for all examinations and were available for analysis. The image-guided system measured statistically significant smaller flat, steep, and average corneal radii than the Scheimpflug device, statistically significant larger flat and average corneal radii than the PCI device, and no statistically significant different values than the OLCR device. The measured steep axis did not differ significantly in any comparison. The WTW measurements were significantly higher than those of all other devices. The analysis of repeatability of the image-guided system showed high intraclass correlation coefficients (range 0.919 to 0.997). CONCLUSIONS: The new image-guided system had high repeatability for K, steep axis, and WTW measurements. The WTW measurements with the image-guided system were significantly higher than those using the other devices. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned.

Long-term outcomes of intrastromal femtosecond laser presbyopia correction: 3-year results.

BACKGROUND/AIMS: To analyse visual outcomes and corneal changes 3 years after intrastromal femtosecond laser presbyopia treatment. METHODS: In a prospective, unicentric clinical trial, 25 presbyopic patients received INTRACOR treatment (Technolas femtosecond laser) on their non-dominant eye. Examinations were performed preoperatively as well as 1, 24 and 36 months postoperatively and included refraction, near, intermediate and distance visual acuity tests, reading speed, corneal topography, stray light measurement, endothelial cell count and slit-lamp examination. RESULTS: Comparison of preoperative versus 36 months postoperative values showed in median an improvement of uncorrected near visual acuity (UNVA) from 0.70 logMAR to 0.10 logMAR (p<0.001). Corrected distance visual acuity (CDVA) was reduced from -0.10 logMAR to 0.00 logMAR (p<0.001). The spherical equivalent preoperatively was 0.625 D and after an initial myopic shift after 1 month (0.125 D) and 24 months (0.25 D), the 36 months value (0.50 D) returned to resemble the preoperative value in statistical terms (p=0.123). A significant corneal steepening of 1.50 D in the treated area was measured. Pachymetry (thinnest point) revealed a statistically significant, but clinically insignificant corneal thickening from 535 to 549 µm (p=0.033). Endothelial cell count did not change. 92.86% of patients felt comfortable with the surgery result. CONCLUSION: INTRACOR treatment after 36 months improved UNVA to varying degrees. The effect can be explained by a corneal steepening. An initial myopic shift was reversible. Reductions especially in CDVA have to be taken into account and therefore careful patient selection and information is obligatory. TRIAL REGISTRATION NUMBER: NCT01164358 and NCT01025050, Results.

Intrastromal femtosecond laser surgical compensation of presbyopia with six intrastromal ring cuts: 3-year results.

BACKGROUND/AIMS: To assess over a 36-month period functional results of the modified INTRACOR femtosecond laser-based intrastromal procedure to treat presbyopia. METHODS: 20 eyes of 20 presbyopic patients with mild hyperopia were included. The INTRACOR procedure with a modified pattern (six concentric intrastromal ring cuts) was performed using the FEMTEC femtosecond laser (Bausch+Lomb/Technolas Perfect Vision, Munich, Germany). Patients were also randomly divided into three subgroups to compare the effect of three different small inner ring diameters (1.8/2.0/2.2 mm (Groups A/B/C)). Follow-up examinations were performed at 1, 3, 6, 12, 24 and 36 months, and included near and distance visual acuity tests, slit-lamp examinations and corneal topography. RESULTS: Median uncorrected near visual acuity (UNVA) increased from 0.7/0.7/0.7 logMAR (Groups A/B/C) to -0.1/0.1/0.1 logMAR 36 months after surgery. Uncorrected distance visual acuity changed slightly from 0.1/0.2/0.1 logMAR to 0.2/0.3/0.1 logMAR. Losses of two lines of binocular corrected distance visual acuity (CDVA) were noted in 0/25/0% of eyes. Median spherical equivalent changed from 0.75/0.75/0.75 dioptres to -0.19/0.13/-0.19 dioptres. Overall patient satisfaction with the procedure was 80%. CONCLUSIONS: INTRACOR with a modified pattern improved UNVA in all patients over a 36-month follow-up period. The possibility of reduced CDVA underlines the need for careful patient selection. TRIAL REGISTRATION NUMBER: NCT00928122.

Implantation of three-piece silicone toric additive IOLs in challenging clinical cases with high astigmatism.

PURPOSE: To analyze the refractive outcomes and safety of three-piece silicone toric sulcus-fixated add-on intraocular lenses (IOLs) (HumanOptics/Dr.Schmidt Intraocularlinsen, Erlangen, Germany) in complex clinical cases with high astigmatism such as in cases with previous penetrating keratoplasty. METHODS: Interventional case series of 21 eyes of 20 patients enrolled at two German centers. Functional results including power vector analysis, accuracy of IOL power calculation, rotational stability, and postoperative complications were evaluated from 2 months to 6 years postoperatively. RESULTS: The preoperative subjective cylinder exceeded or was equal to -6.00 diopters (D) in 81% of eyes (range: -2.00 to -17.00 D). The median follow-up period was 7.6 months (range: 57 days to 6 years). The efficacy analysis focused on the 2 to 6 months follow-up visit. Postoperatively, there was a median reduction of astigmatism by 70.59% (subjective cylinder range: 0.00 to -5.00 D), improvement of uncorrected distance visual acuity, and unchanged median corrected distance visual acuity. The attempted spherical equivalent was achieved within ± 0.50 D in 45% and within ± 1.00 D in 65% of cases. Five eyes received secondary surgical alignment of axis. Other complications related to the surgical procedure were mainly transient shortly after implantation, such as intraocular pressure elevation (2 of 21 eyes) or corneal edema (2 of 21 eyes). Persisting changes were seen only in rare cases and included pigment dispersion (1 of 21 eyes) or corneal edema requiring a second keratoplasty within 9 months after surgery (2 of 21 eyes). CONCLUSIONS: Toric add-on IOLs may be useful in reducing high astigmatism and anisometropia and increasing spectacle independence even in complex clinical conditions with high refractive errors.

Femtosecond laser correction of presbyopia (INTRACOR) in emmetropes using a modified pattern.

PURPOSE: To evaluate functional results and corneal changes after femtosecond laser correction of presbyopia (INTRACOR, Technolas Perfect Vision GmbH) in emmetropes using a modified treatment pattern over a 12-month period. METHODS: Twenty eyes from 20 emmetropic patients were treated with a modified intrastromal INTRACOR pattern consisting of 5 central rings and 8 radial cuts in a prospective, nonrandomized, uncontrolled, open, single-center, clinical study. Refraction, visual acuity, endothelial cell density, corneal pachymetry, total corneal power, and stray light were evaluated preoperatively and 1 (except endothelial cell density and stray light), 3, 6, and 12 months postoperatively. Patients filled out a subjective questionnaire at 12 months postoperatively. RESULTS: Comparison of preoperative versus 12-month postoperative median values revealed a significant improvement in uncorrected near visual acuity (UNVA) from 0.60 (20/80) to 0.10 logMAR (20/25) (P<.0001) and a significant decrease in corrected distance visual acuity (CDVA) from -0.10 (20/16) to 0.00 logMAR (20/20), which equals a median loss of one line (P=.0005). Fifteen percent of patients lost two lines of CDVA in the treated eye. Subjective spherical equivalent refraction remained unchanged at 0.00 diopters (D) (P=.194). After INTRACOR treatment, significant corneal steepening of 1.40 D and midperipheral flattening of 0.50 D occurred (both P<.0001). Corneal pachymetry at the thinnest point and endothelial cell density did not change significantly (P=.829 and P=.058, respectively). CONCLUSIONS: After 12 months, the modified INTRACOR pattern improved UNVA in emmetropic patients without inducing a myopic shift or significant changes in endothelial cell density or pachymetry.

Ocular outcome and frequency of neurological manifestations in patients with acute posterior multifocal placoid pigment epitheliopathy (APMPPE).

PURPOSE: The purpose of this study was to describe the visual prognosis as well as the frequency and clinical severity of central nervous system involvement in all acute posterior multifocal placoid pigment epitheliopathy (APMPPE) patients of one centre. METHODS: A retrospective database review of all patients and a prospective clinical, ophthalmological and neurological follow-up, if possible, were conducted. RESULTS: Eighteen patients with APMPPE were included with a mean follow-up of 17.1 months. Thirteen patients participated in a follow-up exam. Visual acuity improved in 9 of 18 patients to a mean of 0.17 log minimum angle of resolution (MAR) in the worse eye and remained stable in eight patients (mean, 0.03 logMAR). In the majority of patients, the 30° static perimetry improved at follow-up compared to the initial exams. Still, in up to 50 to 60 %, small visual field defects persisted. Overall, 11 patients (61 %) showed neurologic symptoms of varying severity. The most common neurological symptom was headache in nine (50 %) patients. Other symptoms included paraesthesias, psychosis, vertigo, and, as the most severe complication, stroke due to cerebral vasculitis. Fifteen patients were treated with systemic corticosteroids. CONCLUSIONS: Visual prognosis is good in patients with APMPPE, but visual field defects may remain. Neurological signs and symptoms, especially headaches, are frequent in APMPPE and should be taken seriously. Adequate investigations including MRI and CSF examination should be initiated in these patients.

Severe Arthrographis kalrae keratomycosis in an immunocompetent patient.

PURPOSE: To describe a severe case of keratomycosis caused by Arthrographis kalrae requiring repeated keratoplasty. METHODS: A 42-year-old otherwise healthy soft contact lens wearer developed a unilateral central corneal ulcer. Treatment with topical and systemic voriconazole is described. RESULTS: Repeated microbiological testing of ocular swabs (culture) initially yielded Candida albicans. Under treatment with topical clotrimazole, the ulcer progressed, and a corneal perforation required a keratoplasty à chaud. For prophylaxis, the patient received fluconazole systemically and continuous topical clotrimazole. However, in 2 weeks time, the mycotic infiltrates penetrated the corneal transplant and led to a second keratoplasty only 1 month after the first one. In the meantime, the microbiological analysis of the first keratoplasty revealed A. kalrae, which was sensitive to voriconazole. High-dose serum level-controlled systemic voriconazole and topical voriconazole were able to stabilize, but not eliminate the infection. About 1 year after the start of the voriconazole therapy, treatment had to be discontinued because of side effects. Mycotic infiltrates increased, and even an intracameral voriconazole injection could not prevent a third and a fourth keratoplasty. CONCLUSIONS: Ocular infection with A. kalrae is very rare. The microbiological differentiation of A. kalrae can be difficult. Because a broad spectrum of fungi is sensitive to voriconazole, the early topical and possibly systemic treatment is a reasonable therapeutic option when a mycotic infection of the eye is suspected, even before the causative fungus is identified.

An intact connexin N-terminus is required for function but not gap junction formation.

The cytoplasmic N-termini of connexins have been implicated in protein trafficking, oligomerization and channel gating. To elucidate the role of the N-terminus in connexin37 (CX37), we studied mutant constructs containing partial deletions of its 23 N-terminal amino acids and a construct with a complete N-terminus in which residues 2-8 were replaced with alanines. All mutants containing nine or more N-terminal amino acids form gap junction plaques in transiently transfected HeLa cells, whereas most of the longer deletions do not. Although wild-type CX37 allowed intercellular transfer of microinjected neurobiotin in HeLa cells and formed conducting hemichannels in Xenopus oocytes, none of the mutant constructs tested show evidence of channel function. However, in coexpression experiments, N-terminal mutants that formed gap junction plaques potently inhibit hemichannel conductance of wild-type CX37 suggesting their co-oligomerization. We conclude that as much as half the length of the connexin N-terminus can be deleted without affecting formation of gap junction plaques, but an intact N-terminus is required for hemichannel gating and intercellular communication.

Cataracts are caused by alterations of a critical N-terminal positive charge in connexin50.

PURPOSE: To elucidate the basis of the autosomal dominant congenital nuclear cataracts caused by the connexin50 mutant, CX50R23T, by determining its cellular distribution and functional behavior and the consequences of substituting other amino acids for arginine-23. METHODS: Connexin50 (CX50) mutants were generated by PCR and transfected into HeLa or N2a cells. Expressed CX50 protein was detected by immunoblot analysis and localized by immunofluorescence. Intercellular communication was assessed by microinjection of neurobiotin or by double whole-cell patch-clamp recording. RESULTS: HeLa cells stably transfected with CX50R23T or wild-type CX50 produced immunoreactive CX50 bands of identical electrophoretic mobility. Whereas HeLa cells stably expressing CX50 contained abundant gap junction plaques, CX50R23T localized predominantly in the cytoplasm. HeLa cells expressing wild-type CX50 showed large gap junctional conductances and extensive transfer of neurobiotin, but those expressing CX50R23T did not show significant intercellular communication by either assay. Moreover, CX50R23T inhibited the function of coexpressed wild-type CX50. Three CX50R23 substitution mutants (CX50R23K, CX50R23L, and CX50R23W) formed gap junction plaques, whereas two mutant substitutions with negatively charged residues (CX50R23D, CX50R23E) did not form detectable plaques. Only the mutant with a positive charge substitution (CX50R23K) allowed neurobiotin transfer at levels similar to those of wild-type CX50; none of the other mutants induced transfer. CONCLUSIONS: These results suggest that replacement of amino acid 23 in CX50 by any residue that is not positively charged would lead to cataract formation.