The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing.

To decipher the mutational pattern of primary CNS lymphoma (PCNSL), we performed whole-exome sequencing to a median coverage of 103 × followed by mutation verification in 9 PCNSL and validation using Sanger sequencing in 22 PCNSL. We identified a median of 202 (range: 139-251) potentially somatic single nucleotide variants (SNV) and 14 small indels (range: 7-22) with potentially protein-changing features per PCNSL. Mutations affected the B-cell receptor, toll-like receptor, and NF-κB and genes involved in chromatin structure and modifications, cell-cycle regulation, and immune recognition. A median of 22.2% (range: 20.0-24.7%) of somatic SNVs in 9 PCNSL overlaps with the RGYW motif targeted by somatic hypermutation (SHM); a median of 7.9% (range: 6.2-12.6%) affects its hotspot position suggesting a major impact of SHM on PCNSL pathogenesis. In addition to the well-known targets of aberrant SHM (aSHM) (PIM1), our data suggest new targets of aSHM (KLHL14, OSBPL10, and SUSD2). Among the four most frequently mutated genes was ODZ4 showing protein-changing mutations in 4/9 PCNSL. Together with mutations affecting CSMD2, CSMD3, and PTPRD, these findings may suggest that alterations in genes having a role in CNS development may facilitate diffuse large B-cell lymphoma manifestation in the CNS. This may point to intriguing mechanisms of CNS tropism in PCNSL.

[Structure and process quality of quality-assured mamma diagnostics in Schleswig-Holstein]. / Struktur- und Prozessqualität in der qualitätsgesicherten Mammadiagnostik in Schleswig-Holstein.

PURPOSE: To demonstrate the structure and process quality of quality-assured mamma diagnostics (QuaMaDi) by means of quality indicators as defined in the European Guidelines for Quality Assurance in Breast Cancer Screening and Diagnosis and in the National Guideline on Early Detection of Cancer in Germany. Furthermore, spatial differences and changes in the chronological sequence were analyzed. MATERIALS AND METHODS: We used administrative data as documented in the time period 2006 - 2009 in QuaMaDi in Schleswig-Holstein (SH), Germany, and analyzed quality indicators as defined in the abovementioned guidelines (absolute and relative frequencies, 95 % confidence intervals). RESULTS: Each year approximately 6 % of all women age 20 or older living in SH are examined using QuaMaDi. Only minor differences regarding age and clinical data were seen between the patients in the four regions of SH. Reference values for the quality indicators are largely reached (i. e., proportion of women with breast density ACR 3 or 4 plus additional ultrasound = 96.2 %; proportion with repeated mammography = 0.2 %). Spatial differences are only minor. In the chronological sequence, quality indicators improve, if they did not reach the reference values in the beginning, or indicate a high and constant quality. CONCLUSION: With regard to those quality indicators that were computable, reference values as defined in the guidelines were reached in 9 of 12 cases. In one case the difference between the observed value and the reference values is system-immanent and in another case the difference is less than four percentage points (reference value 90 %).

An in vitro study to evaluate the accuracy of stereotactic localization using magnetic resonance imaging by means of the Leksell stereotactic system.

The advantages of using magnetic resonance imaging (MRI) as opposed to computed tomographic (CT) scans or ventriculography in stereotactic surgery include the increased tissue contrast of the lesion or target, direct non-reformatted multiplanar imaging and target coordinate determination as well as reduced imaging artefacts produced by the stereotactic frame. One disadvantage of MR stereotaxis, however, is the potential for anatomic inaccuracy due to equipment-induced inhomogeneities of the magnetic field. The authors present an experimental study on an in vitro model to examine the accuracy of target localization using the Leksell stereotactic frame and MR imaging. Ten formalin-fixed brains taken from patients who had died of non-neurological diseases were sealed in a properly modelled plaster-cast shell simulating the skull bone. These models were fixed in the Leksell stereotactic frame and high-field MR images were performed (Siemens Magnetom SP 1.5 Tesla, T1-weighted spin echo sequences, TR/TE 600/15 ms, slice thickness 2 mm, FOV 300 mm). Following electrocoagulation of different targets on both lentiforme nuclei, the localization and extension of the lesions were controlled by MRI. A gross-/histopathological verification was performed. This model allows a good representation of the anatomic structures without any artefacts. The postoperative MRI control and the pathological examination of the lesions matched well with the preoperatively defined targets. The correlation of coordinates and measurements obtained with the pathological studies were within a +/- 2 mm range in all cases.

Juvenile Huntington chorea: clinical, ultrastructural, and biochemical studies.

A brain biopsy from a 20-year-old patient whose clinical course was marked by progressive dementia and chorea since age 10 years showed increased amounts of lipofuscin, abnormal mitochondria, and other organelles in cortical neurons, neurites, and astrocytes. Juvenile Huntington chorea was confirmed at autopsy. High levels of three histone-like proteins (molecular weight 10,000 to 16,000) in the microsomal fraction of purified neurons were found by SDS-polyacrylamide gel electrophoresis. Fatty acids were abnormal in white matter sphingomyelin. These ultrastructural and biochemical findings conformed to those established in adult Huntington chorea, thus strengthening the concept of a uniform pathologic process in adult and juvenile Huntington diseases in spite of some clinical and histologic differences.

Mucolipidosis IV. Clinical, ultrastructural, histochemical, and chemical studies of a case, including a brain biopsy.

A 7-year-old Ashkenazi Jewish boy with normal early development started to regress at 8 months of age and made no further developmental progress. Corneal clouding was noted at age 10 months. Corneal and conjunctival biopsy at 14 months, cerebral biopsy at 24 months, and fibroblast cultures at 32 months showed lysosomal inclusions, suggesting the storage of lipid-like and mucopolysaccharide-like material. In the brain, dense fluorescent inclusions resembled those in ceroid-lipofuscinosis. Total ganglioside content of white matter was raised, but the pattern was normal. The level of nonlipid hexosamine in the brain was normal. The cornea and conjunctiva contained electronlucent vacuoles resembling those in the mucopolysaccharidoses. Cornea, brain, and lymphocytes contained concentric membranous lamellar structures reminiscent of those in the gangliosidoses. The clinical picture and ultrastructural findings support the impression that this case belongs to a new variant of the mucolipidoses, mucolipidosis IV.