Quantitative longitudinal natural history of 8 gangliosidoses-conceptual framework and baseline data of the German 8-in-1 disease registry. A cross-sectional analysis.

PURPOSE: Gangliosidoses are a group of inherited neurogenetic autosomal recessive lysosomal storage disorders usually presenting with progressive macrocephaly, developmental delay, and regression, leading to significant morbidity and premature death. A quantitative definition of the natural history would support and enable clinical development of specific therapies. METHODS: Single disease registry of 8 gangliosidoses (NCT04624789). Cross-sectional analysis of baseline data in N = 26 patients. Primary end point: disease severity assessed by the 8-in-1 score. Secondary end points: first neurologic sign or symptom observed (1) by parents and (2) by physicians, diagnostic delay, as well as phenotypical characterization. Tertiary end points: neurologic outcomes (development, ataxia, dexterity) and disability. RESULTS: The 8-in-1 score quantitatively captured severity of disease. Parents recognized initial manifestations (startle reactions) earlier than physicians (motor developmental delay and hypotonia). Median diagnostic delay was 3.16 (interquartile range 0.69-6.25) years. In total, 8 patients presented with late-infantile phenotypes. CONCLUSION: Data in this registry raise awareness of these rare and fatal conditions to accelerate diagnosis, inform counseling of afflicted families, define quantitative end points for clinical trials, and can serve as historical controls for future therapeutic studies. We provide further insight into the rare late-infantile phenotype for GM2-gangliosidosis. Longitudinal follow up is planned.

First Results from the Prospective German Registry for Childhood Glaucoma: Phenotype-Genotype Association.

Childhood glaucoma is a heterogeneous disease and can be associated with various genetic alterations. The aim of this study was to report first results of the phenotype-genotype relationship in a German childhood glaucoma cohort. Forty-nine eyes of 29 children diagnosed with childhood glaucoma were prospectively included in the registry. Besides medical history, non-genetic risk factor anamnesis and examination results, genetic examination report was obtained (23 cases). DNA from peripheral blood or buccal swab was used for molecular genetic analysis using a specific glaucoma gene panel. Primary endpoint was the distribution of causative genetic mutations and associated disorders. Median age was 1.8 (IQR 0.6; 3.8) years, 64% participants were female. Secondary childhood glaucoma (55%) was more common than primary childhood glaucoma (41%). In 14%, parental consanguinity was indicated. A mutation was found in all these cases, which makes consanguinity an important risk factor for genetic causes in childhood glaucoma. CYP1B1 (30%) and TEK (10%) mutations were found in primary childhood glaucoma patients. In secondary childhood glaucoma cases, alterations in CYP1B1 (25%), SOX11 (13%), FOXC1 (13%), GJA8 (13%) and LTBP2 (13%) were detected. Congenital cataract was associated with variants in FYCO1 and CRYBB3 (25% each), and one case of primary megalocornea with a CHRDL1 aberration. Novel variants of causative genetic mutations were found. Distribution of childhood glaucoma types and causative genes was comparable to previous investigated cohorts. This is the first prospective study using standardized forms to determine phenotypes and non-genetic factors in childhood glaucoma with the aim to evaluate their association with genotypes in childhood glaucoma.

Radiological Monitoring of Modern Immunotherapy: A Novel Challenge for Interdisciplinary Patient Care. / Radiologisches Monitoring von modernen Immuntherapien: Neue Herausforderung für die interdisziplinäre Zusammenarbeit.

BACKGROUND: Immunotherapy represents an effective therapeutic approach for many malignant diseases that were previously difficult to treat. However, since immunotherapy can lead to atypical therapy response patterns in the form of pseudo-progression or mixed responses and comprise an altered spectrum of adverse reactions, they present a new challenge for oncologic imaging. Detailed knowledge in this area is essential for oncologic clinical radiologists, since the radiological report is a cornerstone of response assessment, and increasingly influences therapy regimens and coverage by health insurances. METHOD: This white paper is based on an expert meeting in Frankfurt am Main and subsequent discussions between the authors. Based on the iRECIST criteria, it is intended to provide orientation for a response assessment of oncologic patients undergoing immunotherapy that can be applied in the clinical routine. RESULTS: Radiological therapy monitoring outside clinical studies is subject to inherent limitations, but should be performed based on iRECIST criteria, according to the opinion of the expert panel. It should be taken into account that immunotherapies can in principle lead to pseudo-progression and autoimmunological side effects. Since radiological follow-up is currently the only method to accurately distinguish real progressive disease from pseudo-progression, clinically stable patients with disease progression under immunotherapy should undergo additional short-term follow-up imaging according to the suspected diagnosis. Biopsy should be used cautiously and predominately in curative settings. CONCLUSION: For response assessment of immunotherapy in clinical studies, the new iRECIST criteria were published in 2017. Outside studies, the application of iRECIST criteria in the clinical routine is subject to several limitations. The recommendations implied in these criteria can, however, be used in conjunction with the current literature as a guideline in clinical practice and outside studies. KEY POINTS: · Novel immunotherapies can cause atypical response patterns like pseudo-progression. · Compared to real progressive disease, pseudo-progression occurs rather rarely, yet can influence therapy. · Short-term follow-up according to iRECIST can help to distinguish pseudo-progression from real progression. · Hence, radiological follow-up outside clinical studies should be oriented towards iRECIST criteria. CITATION FORMAT: · Lennartz S, Diederich S, Doehn C et al. Radiological Monitoring of Modern Immunotherapy: A Novel Challenge for Interdisciplinary Patient Care. Fortschr Röntgenstr 2020; 192: 235 - 244.

The Clinical and Molecular Spectrum of GM1 Gangliosidosis.

OBJECTIVE: To evaluate the clinical presentation of patients with GM1 gangliosidosis and to determine whether specific clinical or biochemical signs could lead to a prompt diagnosis. STUDY DESIGN: We retrospectively analyzed clinical, biochemical, and genetic data of 22 patients with GM1 gangliosidosis from 5 metabolic centers in Germany and Austria. RESULTS: Eight patients were classified as infantile, 11 as late-infantile, and 3 as juvenile form. Delay of diagnosis was 6 ± 2.6 months in the infantile, 2.6 ± 3.79 years in the late-infantile, and 14 ± 3.48 years in the juvenile form. Coarse facial features, cherry red spots, and visceromegaly occurred only in patients with the infantile form. Patients with the late-infantile and juvenile forms presented with variable neurologic symptoms. Seventeen patients presented with dystonia and 14 with dysphagia. Laboratory analysis revealed an increased ASAT concentration (13/20), chitotriosidase activity (12/15), and pathologic urinary oligosaccharides (10/19). Genotype analyses revealed 23 causative or likely causative mutations in 19 patients, 7 of them being novel variants. In the majority, a clear genotype-phenotype correlation was found. CONCLUSIONS: Diagnosis of GM1 gangliosidosis often is delayed, especially in patients with milder forms of the disease. GM1 gangliosidosis should be considered in patients with progressive neurodegeneration and spastic-dystonic movement disorders, even in the absence of visceral symptoms or cherry red spots. ASAT serum concentrations and chitotriosidase activity may be of value in screening for GM1 gangliosidosis.

The DNA methylation profile of human spermatogonia at single-cell- and single-allele-resolution refutes its role in spermatogonial stem cell function and germ cell differentiation.

Human spermatogonial stem cells (hSSCs) have potential in fertility preservation of prepubertal boys or in treatment of male adults suffering from meiotic arrest. Prior to therapeutic application, in vitro propagation of rare hSSCs is mandatory. As the published data points to epigenetic alterations in long-term cell culture of spermatogonia (SPG), an initial characterisation of their DNA methylation state is important. Testicular biopsies from five adult normogonadotropic patients were converted into aggregate-free cell suspensions. FGFR3-positive (FGFR3+) SPG, resembling a very early stem cell state, were labelled with magnetic beads and isolated in addition to unlabelled SPG (FGFR3-). DNA methylation was assessed by limiting dilution bisulfite pyrosequencing for paternally imprinted (H19 and MEG3), maternally imprinted (KCNQ1OT1, PEG3, and SNRPN), pluripotency (POU5F1/OCT4 and NANOG), and spermatogonial/hSSC marker (FGFR3, GFRA1, PLZF, and L1TD1) genes on either single cells or pools of 10 cells. Both spermatogonial subpopulations exhibited a methylation pattern largely equivalent to sperm, with hypomethylation of hSSC marker and maternally imprinted genes and hypermethylation of pluripotency and paternally imprinted genes. Interestingly, we detected fine differences between the two spermatogonial subpopulations, which were reflected by an inverse methylation pattern of imprinted genes, i.e. decreasing methylation in hypomethylated genes and increasing methylation in hypermethylated genes, from FGFR3+ through FGFR3- SPG to sperm. Limitations of this study are due to it not being performed on a genome-wide level and being based on previously published regulatory gene regions. However, the concordance of DNA methylation between SPG and sperm implies that hSSC regulation and germ cell differentiation do not occur at the DNA methylation level.

Targeted next-generation sequencing analysis in couples at increased risk for autosomal recessive disorders.

BACKGROUND: Many of the genetic childhood disorders leading to death in the pre- or neonatal period or during early childhood follow autosomal recessive modes of inheritance and bear specific challenges for genetic counseling and prenatal diagnostics. Parents are carriers but clinically unaffected, and diseases are rare but have recurrence risks of 25% in the same family. Often, affected children (or fetuses) die before a genetic diagnosis can be established, post-mortem analysis and phenotypic descriptions are insufficient and DNA from affected fetuses or children is not available for later analysis. A genetic diagnosis showing biallelic causative mutations is, however, the requirement for targeted carrier testing in parents and prenatal and preimplantation genetic diagnosis in further pregnancies. METHODS: We undertook targeted next-generation sequencing (NGS) for carrier screening of autosomal recessive lethal disorders in 8 consanguineous and 5 non-consanguineous couples with one or more affected children. We searched for heterozygous variants (non-synonymous coding or splice variants) in parents' DNA, using a set of 430 genes known to be causative for rare autosomal recessive diseases with poor prognosis, and then filtering for variants present in genes overlapping in both partners. Putative pathogenic variants were tested for cosegregation in affected fetuses or children where material was available. RESULTS: The diagnosis for the premature death in children was established in 5 of the 13 couples. Out of the 8 couples in which no causative diagnosis could be established 4 consented to undergo further analysis, in two of those a potentially causative variant in a novel candidate gene was identified. CONCLUSIONS: For the families in whom causative variants could be identified, these may now be used for prenatal and preimplantation genetic diagnostics. Our data show that NGS based gene panel sequencing of selected genes involved in lethal autosomal recessive disorders is an effective tool for carrier screening in parents and for the identification of recessive gene defects and offers the possibility of prenatal and preimplantation genetic diagnosis in further pregnancies in families that have experienced deaths in early childhood and /or multiple abortions.

Isolated Splenic Metastasis from Non-Small-Cell Lung Cancer: A Case Report and Review of the Literature.

Metastases to the spleen are rare but have been reported for different tumor entities, including breast cancer, lung cancer, colorectal cancer, ovarian cancer, and melanoma. As an isolated event, splenic metastasis from non-small-cell lung cancer (NSCLC) is exceedingly rare. Until now, only 28 cases have been reported in the medical literature. We report the case of a 66-year-old woman with NSCLC (adenocarcinoma) who presented with a synchronous, isolated splenic metastasis. Operative removal of both primary tumor and metastasis was not possible due to multiple comorbidities. Therefore, treatment was limited to combined systemic chemotherapy and simultaneous radiation of the primary tumor, which led to partial remission of the disease. Isolated metastasis to the spleen in NSCLC has been reported only 28 times in the medical literature, most often in male patients with right-sided lung tumors, most of which were adenocarcinomas. The majority of patients were asymptomatic with respect to splenic metastasis. About half of the reported cases were isolated metachronous splenic metastases. Splenectomy seems to confer a survival advantage. We review the pertinent medical literature.

Chest CT for suspected pulmonary complications of oncologic therapies: how I review and report.

In cancer patient during or following oncologic therapies with respiratory symptoms and pulmonary pathology at chest CT the differential diagnosis includes infection, therapy-induced disease and tumour progression.Although CT morphology may be typical or even pathognomonic in some conditions the diagnosis is usually made by a synopsis of imaging, clinical and laboratory features.Close communication with referring colleagues and a good knowledge of potential side effects of therapeutic concepts, their time course and CT morphology is crucial in the differential diagnosis.This review describes a personal approach to the radiological diagnosis of therapy-induced pulmonary abnormalities in cancer patients.

NDST1 missense mutations in autosomal recessive intellectual disability.

NDST1 was recently proposed as a candidate gene for autosomal recessive intellectual disability in two families. It encodes a bifunctional GlcNAc N-deacetylase/N-sulfotransferase with important functions in heparan sulfate biosynthesis. In mice, Ndst1 is crucial for embryonic development and homozygous null mutations are perinatally lethal. We now report on two additional unrelated families with homozygous missense NDST1 mutations. All mutations described to date predict the substitution of conserved amino acids in the sulfotransferase domain, and mutation modeling predicts drastic alterations in the local protein conformation. Comparing the four families, we noticed significant overlap in the clinical features, including both demonstrated and apparent intellectual disability, muscular hypotonia, epilepsy, and postnatal growth deficiency. Furthermore, in Drosophila, knockdown of sulfateless, the NDST ortholog, impairs long-term memory, highlighting its function in cognition. Our data confirm NDST1 mutations as a cause of autosomal recessive intellectual disability with a distinctive phenotype, and support an important function of NDST1 in human development.

A boy with homozygous microdeletion of NEUROG1 presents with a congenital cranial dysinnervation disorder [Moebius syndrome variant].

BACKGROUND: We report on a 6-year-old Turkish boy with profound sensorineural deafness, balance disorder, severe disorder of oral motor function, and mild developmental delay. Further findings included scaphocephaly, plagiocephaly, long palpebral fissures, high narrow palate, low-set posteriorly rotated ears, torticollis, hypoplastic genitalia and faulty foot posture. Parents were consanguineous. METHODS AND RESULTS: Computed tomography and magnetic resonance imaging showed bilateral single widened cochlear turn, narrowing of the internal auditory canal, and bilateral truncation of the vestibulo-cochlear nerve. Microarray analysis and next generation sequencing showed a homozygous deletion of chromosome 5q31.1 spanning 115.3 kb and including three genes: NEUROG1 (encoding neurogenin 1), DCNP1 (dendritic cell nuclear protein 1, C5ORF20) and TIFAB (TIFA-related protein). The inability to chew and swallow, deafness and balance disorder represented congenital palsies of cranial nerves V (trigeminal nerve) and VIII (vestibulo-cochlear nerve) and thus a congenital cranial dysinnervation disorder. CONCLUSIONS: Based on reported phenotypes of neurog1 null mutant mice and other vertebrates, we strongly propose NEUROG1 as the causative gene in this boy. The human NEUROG1 resides within the DFNB60 locus for non-syndromic autosomal recessive deafness on chromosome 5q22-q31, but linkage data have excluded it from being causative in the DFNB60 patients. Given its large size (35 Mb, >100 genes), the 5q22-q31 area could harbor more than one deafness gene. We propose NEUROG1 as a new gene for syndromic autosomal recessive hearing loss and congenital cranial dysinnervation disorder including cranial nerves V and VIII.

Imaging beyond RECIST: CT and MRI in molecular therapies.

Until recently, almost all systemic antineoplastic therapies in cancer patients aimed at destruction of tumor cells, i.e. they were cytotoxic. The effect of therapy was assessed by measuring the tumor size with a decrease in size suggesting response to therapy and an increase suggesting progression. Modern molecular therapies, however, are mostly not cytotoxic but aim to reduce tumor perfusion or metabolism by blocking specific cell functions without causing cell death. Assessment of tumor size alone may, therefore, not be appropriate in this setting and can even lead to false conclusions. This presentation gives examples of changes at computed tomography (CT) and magnetic resonance imaging (MRI) of tumors undergoing therapy with molecular therapies, highlights potential pitfalls und suggests criteria for response assessment. The presentation focuses on CT and MRI of chest and abdominal tumors and specifically excludes positron emission tomography/CT and brain tumors.

Consensus report on the radiological management of patients with gastrointestinal stromal tumours (GIST): recommendations of the German GIST Imaging Working Group.

The aim was to reach consensus in imaging for staging and follow-up as well as for therapy response assessment in patients with gastrointestinal stromal tumours (GIST). The German GIST Imaging Working Group was formed by 9 radiologists engaged in assessing patients with GIST treated with targeted therapy. The following topics were discussed: indication and optimal acquisition techniques of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET)/CT; tumour response assessment considering response criteria and measurement techniques on CT, MRI and PET/CT; result interpretation; staging interval and pitfalls. Contrast-enhanced CT is the standard method for GIST imaging. MRI is the method of choice in case of liver-specific questions or contraindications to CT. PET/CT should be used for early response assessment or inconclusive results on morphologic imaging. All imaging techniques should be standardized allowing a reliable response assessment. Response has to be assessed with respect to lesion size, lesion density and appearance of new lesions. A critical issue is pseudoprogression due to myxoid degeneration or intratumoural haemorrhage. The management of patients with GIST receiving a targeted therapy requires a standardized algorithm for imaging and an appropriate response assessment with respect to changes in lesion size and density.

[Response judgement - conventional versus new methods]. / Beurteilung des Therapieerfolgs - konventionelle versus neue Methoden.

New ways of evaluating treatment success among thoracic tumour patients are increasingly being used alongside more conventional methods. These new approaches include tumour regression grading, CAD volumetry (computer-assisted volumetry), determination of the tumour density and tumour perfusion as well as the use of positron emission tomography (PET) using 18F-FDG (fluorodeoxyglucose) or other tracers. Increasingly, endpoints that impact directly on the patient's quality of life and tumour-related symptoms are becoming more relevant factors together with the objectively measurable parameters used for assessing treatment response. This contribution describes the potential value of new methods and end-points from the point of view of a pathologist, radiologist, nuclear medicine specialist, radiotherapist, thoracic surgeon, medical and pneumology oncologist, and general practitioner.

CT screening for lung cancer.

Please include a few sentences as an abstract of the paper so that it will have a presence in the online databases.

Staging of oesophageal cancer.

Diagnosis of oesophageal cancer is usually made at endoscopic biopsy. Imaging is used to stage the tumour, assess response to therapy, and detect complications of therapy and recurrence. For therapy planning, differentiation of resectable (T1-T3, N0, localised N1) versus irresectable disease (T4, extensive N1, M1) is important. Endoscopic ultrasound (EUS) is the method of choice for diagnosing T1-T3 stages, and N0 versus N1, including endoscopic ultrasound (EUS)-guided fine-needle aspiration. Computed tomography (CT) or magnetic resonance imaging (MRI) are used to demonstrate infiltration of adjacent structures, distant lymphadenopathy and distant metastases, however, positron emission tomography (PET) and PET-CT are superior in this respect. If imaging suggests irresectable disease, histologic confirmation may be required in order not to prevent curative resection in false positive findings.

Accuracy of automated volumetry of pulmonary nodules across different multislice CT scanners.

The purpose of this study was to compare the accuracy of an automated volumetry software for phantom pulmonary nodules across various 16-slice multislice spiral CT (MSCT) scanners from different vendors. A lung phantom containing five different nodule categories (intraparenchymal, around a vessel, vessel attached, pleural, and attached to the pleura), with each category comprised of 7-9 nodules (total, n = 40) of varying sizes (diameter 3-10 mm; volume 6.62 mm(3)-525 mm(3)), was scanned with four different 16-slice MSCT scanners (Siemens, GE, Philips, Toshiba). Routine and low-dose chest protocols with thin and thick collimations were applied. The data from all scanners were used for further analysis using a dedicated prototype volumetry software. Absolute percentage volume errors (APE) were calculated and compared. The mean APE for all nodules was 8.4% (+/-7.7%) for data acquired with the 16-slice Siemens scanner, 14.3% (+/-11.1%) for the GE scanner, 9.7% (+/-9.6%) for the Philips scanner and 7.5% (+/-7.2%) for the Toshiba scanner, respectively. The lowest APEs were found within the diameter size range of 5-10 mm and volumes >66 mm(3). Nodule volumetry is accurate with a reasonable volume error in data from different scanner vendors. This may have an important impact for intraindividual follow-up studies.

Detection of pulmonary nodules at multirow-detector CT: effectiveness of double reading to improve sensitivity at standard-dose and low-dose chest CT.

The purpose of this study was to assess the effectiveness of double reading to increase the sensitivity of lung nodule detection at standard-dose (SDCT) and low-dose multirow-detector CT (LDCT). SDCT (100 mAs effective tube current) and LDCT (20 mAs) of nine patients with pulmonary metastases were obtained within 5 min using four-row detector CT. Softcopy images reconstructed with 5-mm slice thickness were read by three radiologists independently. Images with 1.25-mm slice thickness served as the gold standard. Sensitivity was assessed for single readers and combinations. The effectiveness of double reading was expressed as the increase of sensitivity. Average sensitivity for detection of 390 nodules (size 3.9+/-3.2 mm) for single readers was 0.63 (SDCT) and 0.64 (LDCT). Double reading significantly increased sensitivity to 0.74 and 0.79, respectively. No significant difference between sensitivity at SDCT and LDCT was observed. The percentage of nodules detected by all three readers concordantly was 52% for SDCT and 47% for LDCT. Although double reading increased the detection rate of pulmonary nodules from 63% to 74-79%, a considerable proportion of nodules remained undetected. No difference between sensitivities at LDCT and SDCT for detection of small nodules was observed.

Impact of low-dose CT on lung cancer screening.

Despite advances in therapy, the prognosis of lung cancer remains dismal due to the fact that most cases of lung cancer are diagnosed at advanced stages, when the chance of cure is poor. In cases detected at early stages prognosis is better. Unfortunately, early lung cancer usually causes no symptoms and is, consequently, rarely diagnosed. Therefore, screening for early asymptomatic lung cancer with diagnostic procedures appears promising particularly as risk factors for lung cancer are well known (cigarette smoking, occupational asbestos exposure and others) and screening could, therefore, focus on these risk groups. In the past, screening trials using analysis of sputum cytology and to some extent chest radiography have failed to demonstrate a reduction in lung-cancer mortality with screening, probably due to insufficient sensitivity of these tests for early lung cancer. During the last decade the introduction of spiral computed tomography (CT) has provided a technique with a much higher sensitivity for small lung cancers. Feasibility studies using low-radiation-dose CT demonstrated a high proportion of non-small-cell lung cancer at the initial examination (prevalence) with decreasing numbers of detected cancers at follow-up (incidence). The proportion of early-stage tumors was high both at prevalence and incidence examinations. The rate of invasive procedures for benign lesions was low; most indeterminate lesions could be classified with non-invasive diagnostic approaches. The proportion of interval cancers (cancers diagnosed by symptoms between two screening CT scans) was low. As, however, these one-arm feasibility trials are not appropriate to assess a potential mortality reduction through CT screening, prospective randomised multicenter trials were recently initiated in several countries to analyse the effect of CT screening on lung-cancer mortality.

Low-voltage digital selenium radiography: detection of simulated interstitial lung disease, nodules, and catheters--a phantom study.

PURPOSE: To compare three tube voltages in digital selenium radiography for the detection of simulated interstitial lung disease, nodules, and catheters. MATERIALS AND METHODS: Simulated catheters, nodules, and ground-glass, linear, miliary, and reticular patterns were superimposed over an anthropomorphic chest phantom. Digital selenium radiography was performed with different tube voltages (70, 90, and 150 kVp). Hard-copy images were generated. Detection performance of five radiologists was compared by using receiver operating characteristic (ROC) analysis involving 54,000 observations. RESULTS: The detection of ground-glass, linear, miliary, and reticular patterns over lucent lung and of nodules equal to, smaller than, and larger than 10 mm increased when 70 kVp and/or 90 kVp was used. However, only the reticular pattern was significantly better detected at lower peak voltage (P <.05). Simulated catheters and nodules over the mediastinum showed smaller areas under the ROC curve at lower peak voltage. These results were not statistically significant (P >.05). CONCLUSION: The diagnostic performance of digital selenium radiography at lower peak voltage is at least as good as that at higher peak voltage for interstitial lung disease over lucent lung. Performance is equivalent for nodules and catheters over obscured chest regions at lower peak voltages compared with that at 150 kVp. Our results implicate that the use of high-voltage technique in digital selenium radiography should be reassessed.