Early autologous and allogeneic peripheral blood stem cell transplantation for adult patients with acute B and T cell precursor neoplasms: a 12-year single center experience.

Adult acute lymphoblastic leukemia/lymphoma (ALL/LBL) is a rare and heterogeneous malignancy characterized by uncontrolled proliferation of B or T cell precursor cells. Here, we retrospectively analyzed the outcome of early autologous stem cell transplantation in standard-risk patients in first complete remission (n=24) and of allogeneic transplantation in high and highest risk, and relapsed/refractory patients (n=35). The 10-year overall survival after autologous transplantation was 45%. The 10-year overall survival after allogeneic transplantation was 58%. The cumulative incidence of relapse was 29% after allogeneic and 67% after autologous transplantation. The cumulative incidence of non-relapse mortality was 0% after autologous and 12% after allogeneic transplantation. This retrospective single center analysis in a limited number of standard-risk patients clearly demonstrates that early autologous transplantation in first complete remission leads to an acceptable long-term outcome with a short overall treatment duration of less than 6 months compared with more than 2 years with conventional chemotherapy. More sensitive and standardized methods to detect minimal residual disease (MRD) will further help to identify those patients more accurately who are most likely to benefit from such a short and intensive treatment strategy (i.e., MRD negative standard-risk patients) or those who require early targeted therapy (e.g., blinatumomab) in case of MRD positivity. Early allogeneic transplantation results in long-term survival/cure in nearly two-thirds of all high and highest risk, and relapsed/refractory patients.

HIV and SARS-CoV-2 co-infection: cross-sectional findings from a German 'hotspot'.

PURPOSE: This study aimed to determine the proportion of people living with HIV with anti-SARS-CoV-2 IgG antibodies in a sample from a large single HIV center in Munich, Germany, after the first phase of the coronavirus pandemic and to infer the prevalence of SARS-CoV-2 co-infection in people living with HIV. METHODS: Prospective sub-study of the ongoing ArcHIV cohort between May and July 2020. Anti-SARS-CoV-2 IgG antibodies were measured using the recomWell SARS-CoV-2 IgG ELISA (Mikrogen, Neuried, Germany); positive and borderline results were re-tested using the recomLine SARS-CoV-2 IgG immunoassay (Mikrogen, Neuried, Germany). Demographic and medical data were extracted from the electronic patient files. RESULTS: Overall, 500 people living with HIV were included in the study (83% male, median age 51 years). Three participants had been diagnosed with COVID-19 prior to study inclusion. Of those, nine were confirmed positive for SARS-CoV-2 IgG antibodies, resulting in an estimated seroprevalence (accounting for sensitivity and specificity of the test) of 1.5% (CI 95%: 0.69; 3.13) for the entire study sample, and 2.2% (CI 95%: 1.1; 3.9) for the subset of the Munich citizens. There were no marked differences for people living with HIV with and without SARS-CoV-2 co-infection. CONCLUSION: The seroprevalence of SARS-CoV-2 co-infection in people living with HIV as found in our study does not seem to exceed previous reports from general populations of 'hot-sport' areas; comparative data from the Munich population can be expected to be published soon. Our data also highlight, once more, the need to do confirmatory testing on positive samples to minimize the impact of false-positive results.

Comparing refractive outcomes of a standard industry toric IOL calculator using anterior corneal astigmatism and total corneal refractive power.

PURPOSE: To evaluate refractive outcomes for a standard industry calculator using anterior corneal astigmatism or total corneal refractive power. METHODS: This prospective interventional study evaluated the refractive outcomes of 56 eyes using a standard industry calculator (Zeiss ZCalc) and a digital IOL alignment software. After A-constant optimisation the ZCalc was recalculated with two different keratometry values using appropriate refractive indices: anterior corneal astigmatism (ACA) by IOLMaster 700 and total corneal refractive power (TCRP) by Pentacam. The Barrett toric calculator was used as a reference. RESULTS: Undercorrection of 0.04 ± 0.42 D after 1 week and 0.13 ± 0.48 D after 3 months was achieved for the spherical equivalent by using a standard industry calculator. IOL misalignment was 2.8° ± 3.4° using a digital alignment system. For the ZCalc, the mean absolute error could be reduced from 0.19 ± 0.40 D using ACA to 0.04 ± 0.48 D when considering total corneal refractive power (p = 0.06). The Barrett calculator delivered better refractive outcomes than using a standard industry calculator with ACA measurements only (- 0.06 ± 0.43 D; p < 0.01). CONCLUSION: Reliable and accurate refractive outcomes in toric IOL calculation were achieved by using the ZCalc calculator. The prediction error for a widely used standard industry toric IOL calculator could be reduced by using measured total corneal refractive power.

[Retinal OCT: Vitreoretinal Interface]. / Netzhaut-OCT: vitreoretinale Grenzfläche.

The gold standard for the assessment of the vitreoretinal interface (VRI) is high resolution OCT. It is therefore essential to select the appropriate scan modalities to detect all morphological changes in different diseases, not only at the VRI, but also in all layers of the retina and in the foveal and parafoveal areas. These can be raster scans, radial scans or "en face" scans. Morphological changes at the VRI and especially in the outer retinal layers are good prognostic factors in high resolution OCT for the success of surgery for vitreomacular interface disorders. The following article gives an overview of current OCT procedures as well as correlations between morphological and functional findings.

[Comparison of Intravitreal Dexamethasone Implant versus Intravitreal Ranibizumab as a First-Line Treatment of Macular Oedema due to Retinal Vein Occlusion]. / Vergleich von intravitrealem Dexamethason-Implantat mit intravitrealem Ranibizumab als Erstbehandlung des Makulaödems bei retinalen venösen Gefäßverschlüssen.

PURPOSE: The present study investigated the treatment effect of dexamethasone implant (Ozurdex®, group 1) and anti-VEGF injection (Lucentis®, group 2) in course of macular oedema due to retinal vein occlusion in a retrospective, non-randomised case series. MATERIAL AND METHODS: Group 1 comprised 60 patients (31 with CRVO and 29 with BRVO) and group 2 included 52 patients, 27 with CRVO and 25 with BRVO) and both groups were further treated in case of recurrence. Preoperative and in monthly intervals best corrected visual acuity (BCVA), central retinal thickness using SD-OCT (Spectralis, Heidelberg Engineering), intraocular pressure, biomicroscopy status and a fundus photo documentation (Optomap) were evaluated. The primary clinical endpoint was visual acuity 12 months after the first intravitreal therapy, while secondary endpoints included the central retinal thickness change and safety of therapy. RESULTS: In group 1, an increase of BCVA (± standard deviation) of 8.4 (± 1.9) letters was observed in CRVO patients and a gain of 10.7 (± 3.8) letters in BRVO patients after 12 months, while in group 2, an increase of BCVA of 6.9 (± 1.9) letters (CRVO) compared to 12.5 (± 3.7) letters (BRVO) was observed after the same time span. In both groups a significant reduction in retinal thickness was achieved. An increase of intraocular pressure above 5 mmHg was observed in nearly half of the cases In group 1, but was well controlled by conservative antiglaucomatous therapy. We observed a progression of lens opacity in approximately 50 % of the cases in group 1. CONCLUSION: The treatment with Ozurdex compared to Lucentis appears to provide a trend towards a better although not significant visual acuity increase after 12 months in CRVO patients. A similar trend favouring anti-VEGF treatment with Lucentis was seen in patients with BRVO. However, the lens status and age of the patient should be taken into account when considering a treatment with Ozurdex.

Spironolactone in the treatment of central serous chorioretinopathy - a case series.

BACKGROUND: The pathogenesis of central serous chorioretinopathy (CSC) is still poorly understood. An animal model of CSC proved that the mineralocorticoid receptor [1] of the choroid also plays a role in CSC. Since there is still no evidence-based therapy for non-self-limiting CSC, this case series evaluates the effect of oral spironolactone in CSC patients. METHODS: In this interventional, uncontrolled, prospective case series, we present 18 consecutive CSC patients. Patients were treated with spironolactone 25 mg twice daily (Spironolacton AL® 50 mg, ALIUD PHARMA) for up to 12 weeks. Follow-up examinations with BCVA, OCT, and EDI-OCT were performed at 1, 2, and 3 months after starting the treatment. Main outcome measure was a change of subretinal fluid (SRF) (in micrometers) measured by optical coherence tomography. Secondary outcome was a change in central retinal thickness (CRT) (in micrometers) measured by OCT and a change in BCVA. RESULTS: The subretinal fluid (SRF; mean) decreased from 219 µm (baseline) to 100 µm (visit 3) (difference 119 µm). Total central retinal thickness (CRT; mean) decreased from 405 µm before treatment (baseline) to 287 µm after treatment (difference 118 µm). The BCVA (in logMAR; mean) increased from 0.32 at baseline to 0.20 at visit 3. CONCLUSION: Our case series could confirm a positive influence of spironolactone on the course CSC. Longer follow-up with a larger number of cases could provide more data about the long-term efficiency, recurrences, and safety of this well-tolerated and non-invasive treatment option of CSC.

[Functional and morphological correlations in macular hole surgery]. / Funktionelle und morphologische Korrelationen in der Makulaforamen-Chirurgie.

BACKGROUND: The purpose of this study is to establish the correlation between functional and morphological aspects before and 12 months after macular hole surgery. METHODS: In this prospective, interventional, consecutive study 16 eyes of 16 patients were included. All eyes received a successful transconjunctival 23-gauge vitrectomy with ILM peeling after initial diagnosis and maximum duration of symptoms of two months. Preoperatively and 3, 6 and 12 months postoperatively determinations of best-corrected visual acuity (logMAR), a 10° microperimetry (MP-1) and a spectral-domain based optical coherence tomography (SD-OCT) examination were performed. The photoreceptor layer (inner and outer segment, IS/OS) was evaluated based on SD-OCT images and correlated with data assessed by microperimetry analysis in the foveal and parafoveal region. RESULTS: After three months a stabilisation of BCVA with regeneration of the IS/OS line, an improvement of the fixation behaviour and the macular sensitivity could be observed. A significant restitution of the IS/OS line was observed after 12 months. Best corrected visual acuity, mean overall macular sensitivity and fixation improved significantly within the twelve month observation period (p < 0.05). Comparison of patients with at least two lines of visual acuity gain with patients having less than two lines of visual acuity gain 12 months after surgery showed no statistically significant difference in regeneration of the IS/OS integrity in the fovea (p = 0.433), but a difference was seen in the parafoveal region. A postoperative visual acuity gain of at least two lines was significantly more often seen in eyes with postoperative continuous IS/OS line in the parafoveal sectors compared to eyes with persistent IS/OS defects (p < 0.02). CONCLUSION: Correlations of morphological and functional improvements can be observed after successful micro-invasive macular hole surgery. The extent of the preoperative IS/OS defect, particularly in the parafoveal region, is a good predictive parameter for the postoperatively obtained macular sensitivity. The prediction of the postoperative visual acuity should not be made on the basis of a single clinical, anatomic finding.

A corticoid-sensitive cytokine release assay for monitoring stress-mediated immune modulation.

The human immune system is orchestrated in a complex manner and protects the host against invading organisms and controls adequate immune responses to different antigen challenges in an endo-, auto- and paracrine-regulated fashion. The variety and intensity of immune responses are known to be dependent on stress-sensitive neural, humoral and metabolic pathways. The delayed-type hypersensitivity (DTH) skin test was a validated and standardized measure applied in clinical studies to monitor the integral function of cellular immune responses in vivo. The DTH skin test was, however, phased out in 2002. To obtain insight into the mechanisms of stress-sensitive immune reactions, we have developed an alternative in-vitro assay which allows the evaluation of antigen-dependent cellular immune responses triggered by T lymphocytes. The change in the concentration of proinflammatory cytokines in supernatant of the blood-antigen mixture is of particular interest to mirror the degree and adequacy of cellular immune responses. In this study we report that the proinflammatory cytokines interleukin (IL)-2, interferon (IFN)-γ and tumour necrosis factor (TNF)-α show a time-dependent increase upon ex-vivo bacterial, viral and fungal antigen stimulations. Furthermore, evidence is provided that this assay is sensitive to mirror stress hormone-mediated immune modulation in humans as shown either after hydrocortisone injection or after acute stress exposure during free fall in parabolic flight. This in-vitro test appears to be a suitable assay to sensitively mirror stress hormone-dependent inhibition of cellular immune responses in the human. Because of its standardization and relatively simple technical handling, it may also serve as an appropriate research tool in the field of psychoneuroendocrinology in clinical as in field studies.

EGF receptor inhibitor erlotinib as a potential pharmacological prophylaxis for posterior capsule opacification.

BACKGROUND: Posterior capsule opacification (PCO) is the most frequent complication after cataract surgery, leading to a loss of sight if untreated. Erlotinib might be of therapeutic interest as an effective target agent (selective EGF-tyrosin-kinase-1 inhibitor). In this in-vitro study, erlotinib was evaluated for ocular biocompatibility and its effect on cell proliferation, migration, 3D matrix contraction and spreading of human lens epithelial cells. METHODS: To exclude toxic concentrations, erlotinib was assessed for its biocompatibility on five different human ocular cell types in vitro by the tetrazolium dye-reduction assay (MTT) and the Live-Dead assay. To determine its effect on human lens epithelial cell (HLE-B3) proliferation, the MTT test was performed after incubation with different concentrations of erlotinib. Chemotactic migration was analyzed with the Boyden chamber assay and chemokinetic migration was assessed by time lapse microscopy. Contraction was measured by a 3D collagen type 1 matrix contraction assay, and cell spreading was determined by measuring the cell diameter on a fibronectin coated surface. RESULTS: The maximum non-toxic concentration of erlotinib was determined to be 100 µM in cell culture. Erlotinib potently inhibits human lens epithelial cell proliferation, with an IC50 of about 10 µM (8.8 µM ± 0.9 µM SD; r (2) =0.94). Chemotactic migration (p=0.004) and chemokinetic migration (p=0.001) were reduced significantly in a concentration-based manner. Erlotinib prevented human lens epithelial cells from matrix contraction (p=0.001) and cell-spreading (p=0.001). CONCLUSIONS: Erlotinib might become of clinical relevance for PCO prophylaxis in the future since it displayed good biocompatibility on ocular cells and mitigated human lens epithelial cell proliferation, migration, contraction, and spreading in vitro. Further studies are warranted to evaluate its potential for clinical application.

Dilatative uropathy as a manifestation of neurohypophyseal diabetes insipidus due to a novel mutation in the arginine vasopressin-neurophysin-II gene.

Polydypsia and polyuria are frequent symptoms in patients with sellar masses caused by neurohypophyseal diabetes insipidus. Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a disorder caused by mutations in the arginine vasopressin (AVP) -neurophysin II (NPII) gene, should be considered as a rare differential diagnosis. A delayed diagnosis bears the risk of life-threatening electrolyte imbalances and permanent urinary tract damage, leading to impaired quality of life.We present a Caucasian kindred of at least 4 generations with FNDI.Clinical histories, endocrine para-meters, and results of molecular analyses of the AVP gene are presented with a review of the literature on diabetes insipidus (DI) related urinary tract dilatation.Polyuria and polydipsia were only reported based on explicit and thorough interrogation after more than 4 years of clinical follow-up. A novel heterozygous mutation in the AVP gene was found in all examined symptomatic subjects (c.1-33_c.4del37nt). A literature review revealed that non-obstructive hydronephrosis (NOH) is a rare but known complication of DI.Since increased fluid intake is often a typical familial pattern in adFNDI, it is frequently missed as being pathologic in affected patients, therefore a detailed clinical history of drinking volumes is of critical importance. AVP gene testing is an important component in the confirmation of the diagnosis. Otherwise unexplainable NOH should lead to further investigations and evaluation of rare diseases like FNDI.

A Pilot Implementation-Effectiveness Trial of a Single-Session Telehealth Workshop and Smartphone-Based Cognitive Behavioral Intervention for Managing Emotions Among College Students.

The number of college students who need mental health treatment outpaces the resources available to counseling centers to provide these needed services, presenting a need for low-cost, scalable interventions for college populations. We conducted a pilot implementation-effectiveness trial of a scalable treatment package that consisted of a single (telehealth) workshop plus a companion app that provided ecological momentary intervention. Participants (n = 177) received a workshop provided by counseling center staff and trainees. We were interested in (1) engagement with the app, (2) acceptability of the treatment package, and (3) initial effectiveness of the treatment package. Regarding engagement with the app, we found that participants preferred two reminder prompts per day and identified two key breakpoints when engagement declined significantly: at day 15, when just over half of the sample practiced a skill on the app at least once during the day and at day 41, when just over one third of people practiced a skill on the app each day. Regarding acceptability of the treatment package, students generally reported positive attitudes about the single-session workshop and app, but also noted that the content and assessments in the app needed to be more dynamic to improve how engaging it is. Regarding effectiveness, we found that about 75% of the sample experienced a significant reduction in negative affect from pre- to post-ecological momentary intervention. Moreover, there were significant pre- to post-study decreases in experiential avoidance and symptoms of anxiety and depression and increases in self-efficacy for managing negative emotions. The results of this study are promising in terms of providing initial support for this novel treatment package and provide useful information for researchers planning to develop and test similar interventions.

Spatial separation of parental genomes in preimplantation mouse embryos.

We have used two different experimental approaches to demonstrate topological separation of parental genomes in preimplantation mouse embryos: mouse eggs fertilized with 5-bromodeoxyuridine (BrdU)-labeled sperm followed by detection of BrdU in early diploid embryos, and differential heterochromatin staining in mouse interspecific hybrid embryos. Separation of chromatin according to parental origin was preserved up to the four-cell embryo stage and then gradually disappeared. In F1 hybrid animals, genome separation was also observed in a proportion of somatic cells. Separate nuclear compartments during preimplantation development, when extreme chromatin remodelling occurs, and possibly in some differentiated cell types, may be associated with epigenetic reprogramming.

Synchronous metastatic renal cell carcinoma to the genitourinary tract: two rare case reports and a review of the literature.

Synchronous metastasis of renal cell carcinoma (RCC) to the ureter or the bladder represents an extremely rare event. We report one case of synchronous metastasis of RCC to the ipsilateral ureter and one case of solitary synchronous metastasis of RCC to the urinary bladder. We review the literature and discuss possible mechanisms of dissemination. We discuss the surgical management of metastases from RCC as well as the surgical options in the treatment of these rare occurrences.

[Corneal dystrophies in optical coherence tomography]. / Hornhautdystrophien in der optischen Kohärenztomographie.

BACKGROUND: Corneal optical coherence tomography (anterior segment OCT, AS-OCT) is described in the current IC3D classification of corneal dystrophies to be a method for improvement of clinical diagnostics and treatment. OBJECTIVE: In this case series AS-OCT images of corneal dystrophies were analyzed with respect to morphological changes. MATERIAL AND METHODS: This was a retrospective imaging and morphological case series with 38 eyes. For image acquisition the corneal module of the high-resolution spectral-domain OCT Zeiss Cirrus HD-5000 platform (Oberkochen, Germany) was employed. The following corneal dystrophies were analyzed: epithelial basement membrane dystrophy, Meesmann corneal dystrophy, Reis-Bücklers corneal dystrophy, granular corneal dystrophy type 1, granular corneal dystrophy type 2 and macular corneal dystrophy. RESULTS: The AS-OCT images showed the typical changes of the dystrophies through hyperreflectivity and hyporeflectivity in the individual corneal layers. The findings in the AS-OCT images correlated well with the histological descriptions in the literature and provided additional information to the slit lamp examination, especially with respect to the exact location of the alterations. CONCLUSION: Corneal AS-OCT imaging seems to be a helpful tool for determination of morphological changes in patients with corneal dystrophies and can facilitate both the diagnostics and surgical treatment decisions.

Comparison of Two Toric IOL Calculation Methods.

PURPOSE: To compare two calculators for toric intraocular lens (IOL) calculation and to evaluate the prediction of refractive outcome. METHODS: Sixty-four eyes of forty-five patients underwent cataract surgery followed by implantation of a toric intraocular lens (Zeiss Torbi 709 M) calculated by a standard industry calculator using front keratometry values. Prediction error, median absolute error, and refractive astigmatism error were evaluated for the standard calculator. The predicted postoperative refraction and toric lens power values were evaluated and compared after postoperative recalculation using the Barrett calculator. RESULTS: We observed a significant undercorrection in the spherical equivalent (0.19 D) by using a standard calculator (p ≤ 0.05). According to the Baylor nomogram and the refractive influence of posterior corneal astigmatism (PCA), undercorrection of the cylinder was lower for patients with WTR astigmatism, because of the tendency of overcorrection. An advantage of less residual postoperative SE, sphere, and cylinder for the Barrett calculator was observed when retrospectively comparing the calculated predicted postoperative refraction between calculators (p ≤ 0.01). CONCLUSION: Consideration of only corneal front keratometric values for toric lens calculation may lead to postoperative undercorrection of astigmatism. The prediction of postoperative refractive outcome can be improved by using appropriate methods of adjustment in order to take PCA into account.

Modern Corneal Eye-Banking Using a Software-Based IT Management Solution.

BACKGROUND: Increasing government legislation and regulations in manufacturing have led to additional documentation regarding the pharmaceutical product requirements of corneal grafts in the European Union. The aim of this project was to develop a software within a hospital information system (HIS) to support the documentation process, to improve the management of the patient waiting list and to increase informational flow between the clinic and eye bank. MATERIALS AND METHODS: After an analysis of the current documentation process, a new workflow and software were implemented in our electronic health record (EHR) system. RESULTS: The software takes over most of the documentation and reduces the time required for record keeping. It guarantees real-time tracing of all steps during human corneal tissue processing from the start of production until allocation during surgery and includes follow-up within the HIS. Moreover, listing of the patient for surgery as well as waiting list management takes place in the same system. CONCLUSION: The new software for corneal eye banking supports the whole process chain by taking over both most of the required documentation and the management of the transplant waiting list. It may provide a standardized IT-based solution for German eye banks working within the same HIS.

Active demethylation of the paternal genome in the mouse zygote.

DNA methylation is essential for the control of a number of biological mechanisms in mammals [1]. Mammalian development is accompanied by two major waves of genome-wide demethylation and remethylation: one during germ-cell development and the other after fertilisation [2] [3] [4] [5] [6] [7]. Most previous studies have suggested that the genome-wide demethylation observed after fertilisation occurs passively, that is, by the lack of maintenance methylation following DNA replication and cell division [6] [7], although one other study has reported that replication-independent demethylation may also occur during early embryogenesis [8]. Here, we report that genes that are highly methylated in sperm are rapidly demethylated in the zygote only hours after fertilisation, before the first round of DNA replication commences. By contrast, the oocyte-derived maternal alleles are unaffected by this reprogramming. They either remain methylated after fertilisation or become further methylated de novo. These results provide the first direct evidence for active demethylation of single-copy genes in the mammalian zygote and, moreover, reveal a striking asymmetry in epigenetic methylation reprogramming. Whereas paternally (sperm)-derived sequences are exposed to putative active demethylases in the oocyte cytoplasm, maternally (oocyte)-derived sequences are protected from this reaction. These results, whose generality is supported by findings of Mayer et al. [9], have important implications for the establishment of biparental genetic totipotency after fertilisation, the establishment and maintenance of genomic imprinting, and the reprogramming of somatic cells during cloning.