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Highly malignant gliomas are characterized by pronounced intra‑ and intertumoral heterogeneity. On the genetic level, this heterogeneity may be caused by spontaneous mutation events, but recent studies have reported distinct mutational signatures that may be caused by an enzyme family with cytidine desaminase activity, the apolipoprotein B mRNA editing enzyme catalytic polypeptide‑like (APOBEC) proteins. Among these, APOBEC3B contributes to tumor progression in a variety of types of tumor, including breast cancer. In the present study, the expression of APOBEC3B was detected at the mRNA and protein levels in solid human glioma tissue and human glioma cell lines. In vitro, treatment with temozolomide, the most commonly used chemotherapeutic in glioma therapy, induced APOBEC3B expression. Furthermore, the knockdown of APOBEC3B by clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 resulted in reduced proliferation and enhanced chemosensitivity of glioma cells. Thus, APOBEC3B contributes to glioma progression and may be a future target for therapeutic intervention.

Accurate monitoring of the t(14;18) translocation is regarded as highly desirable in patients with follicular lymphoma (FL) as absence of bcl-2/IgH positive cells has been correlated with a reduced risk of recurrence and, more recently, pre-treatment t(14;18) load with response to rituximab (R; Blood 2004;103:4416-23). With the arrival of R clinical and molecular remission rates for various lymphoma entities improved significantly, creating the need to carefully review and reassess the role of PCR negativity for clinical outcome, specifically when considering the prolonged presence of the drug as compared to chemotherapy. To determine the rate of molecular clearance achieved by the addition of different doses of R 16 newly diagnosed, t(14;18) positive patients with FL (Ann Arbor stages III/IV) were investigated before, during and after primary chemotherapy with six cycles of CHOP combined with varying (1, 3 or 6) cycle numbers of R (varR1-, varR3- or varR6-CHOP, respectively) regarding molecular remission status. For this purpose classic nested PCR as well as a newly established RQ-PCR employing juxtaposed hybridisation probes were employed to assess molecular remission prior, during and post therapy. Interestingly, administering just a single cycle of R (varR1-CHOP) in combination with a standard regimen of CHOP resulted in rapid and effective clearance of t(14;18) carrying cells from the peripheral blood of 4/5 patients in this treatment group. 6/8 (6/8) varR1-/varR3-CHOP patients were fully cleared and 8/8 (7/8) var6-CHOP patients as assessed by RQ- (nested) PCR. This indicates the high clearance capacity of this combination therapy approach even when adding a very low cycle number of R (1 and 3, respectively) to CHOP in primary therapy of FL. In summary, the relationship established between molecular clearance and minimal residual disease/risk of recurrence may have to be redefined in the times of R. Upcoming large prospective trials will have to elucidate to what degree the clearance of peripheral blood from t(14;18) positive cells can still be regarded as informative regarding absence of minimal residual disease, remission status and/or risk of recurrence.

This study assessed prevalence, frequency, age and gender distribution and breakpoint locations, and detection method validity for the bcl-2/IgH rearrangement in 204 healthy individuals. For this purpose, both classic two-step, nested, semi-quantitative PCR as well as a newly established sequence-specific, hybridization probe-based real-time quantitative PCR (RQ-PCR) were employed and tested for their sensitivity and specificity for detecting t(14;18) positive cells in healthy blood donors. Interestingly, almost a quarter (24%; 39/204) of all healthy individuals carried the translocation, confirming data of one large prior report [Summers KE, Goff LK, Wilson AG, Gupta RK, Lister TA, Fitzgibbon J. Frequency of the Bcl-2/IgH rearrangement in normal individuals: implications for the monitoring of disease in patients with follicular lymphoma. J Clin Oncol 2001;19(2):420-4]. Regarding presence as well as frequency of the translocation, no correlation to age (mean frequency 2.0:10(4), with a median ofl:10(4), for40 years, and mean frequency 1.9:10(4), with a median ofl:10(4) for individualsor=40 years) nor gender was detected. Comparing the two PCR approaches, a 95.1% concordance (194/204) regarding t(14;18) detection was determined for nested and RQ-PCR, with nested PCR being slightly more sensitive (reproducible detection limit l:10(5) cells versus 1:10(4); maximum detection limit l:10(6) versus 1:10(5)). Sequence analysis confirmed individual breakpoints for all samples analyzed (29/29), indicating detection validity for both PCR approaches and ruling out contamination. The breakpoint location distribution pattern appeared to be comparable to the pattern seen with follicular lymphoma (FL) patient collectives. In conclusion, clonal bcl-2/IgH rearrangements are indeed a very frequent observation in healthy individuals, and appear to be independent of age and gender in regard to presence and frequency. This represents a conflicting finding in context of potential biological significance, and presents a potential disruptive factor for minimal residual disease (MRD) monitoring in FL patients. Prospective future trials will have to clarify the biological significance of this important observation.

The aim of this study was to investigate the role of NBS1 in the pathogenesis of malignant melanoma of the skin. To exclude the common 657del5 founder mutation, a total of 376 melanoma patients from Southern Germany were analyzed for sequence alterations in exon 6 of NBS1 by direct sequencing. Analyses revealed one 657del5 mutation and three nonsynonymous sequence variations in exon 6 of NBS1 (V210F, R215W, and F222L). Analysis of an additional sample of 629 melanoma patients and 604 controls revealed no F222L mutation, indicating that this newly identified sequence alteration is not a common polymorphism. In a case-control association study including 632 melanoma patients and 615 cancer-free control participants from Southern Germany, three publicly known single nucleotide polymorphisms located in the NBS1 gene region were analyzed. No significant associations between single nucleotide polymorphisms (rs9995, rs867185 and rs1063045) or referring calculated haplotypes and melanoma risk were identified. These results suggest that NBS1 does not play a major role in predisposition to melanoma in the Southern German population but that alterations of this gene might contribute to the risk of this cancer.

There is strong evidence to suggest that the peroxisome proliferator-activated receptor (PPAR)-gamma, a member of the nuclear receptor family of transcriptional regulators, mediates tumor suppressive activities in a variety of human cancers. Recently, PPARgamma agonists were found to inhibit growth of melanoma cell lines. Here, we tested the possibility that variations in the gene encoding PPARgamma (PPARG) influence melanoma risk. Two variations of PPARG (P12A[rs1801282] and C161T [rs3856806]) were investigated in two independent case-control studies with a total of 832 melanoma patients and 790 control individuals. In the first study, homozygous carriers of the rare *T allele of the C161T polymorphism in exon 6 of PPARG were significantly more common among patients with melanoma than among healthy subjects (6.0 vs. 2.0%; P=0.0096) and this association was independent of clinical risk factors such as skin type and nevus count (odds ratio 5.18; 95% confidence interval 1.68-15.96; P=0.0041). This finding, however, could not be replicated in the second case-control study. We therefore conclude that the investigated PPARG polymorphisms are not likely to constitute a significant risk factor for the development of melanoma among German Caucasians.

Fludarabine in combination with cyclophosphamide is an effective treatment for newly diagnosed as well as relapsed follicular lymphoma. The anti-CD20 antibody rituximab has been employed successfully for the same indications. No such data were available on a combined use of these agents. Therefore, we conducted a phase II study to evaluate the safety and efficacy of a combination of rituximab (375 mg/m2), fludarabine (4 x 25 mg/m2) and cyclophosphamide (1 x 750 mg/m2), for the treatment of relapsed follicular lymphoma. An unexpected, severe hematologic toxicity with significant, prolonged thrombocytopenias WHO grade III/IV in 6 (35%) of 17 patients treated in total occurred, leading to early termination of the trial. Cytologic and serologic analyses point toward a direct toxic effect. Older patients (mean age 64.7 vs. 56.5 yr) were significantly (P = 0.02) more likely to suffer from this toxicity, whereas no other clinical or hematologic parameter differed statistically between the patients suffering from thrombocytopenia and those who did not. The addition of rituximab to fludarabine/cyclophosphamide employed at doses given above in relapsed follicular lymphoma may have led to this increase in thrombocytopenias. Therefore, caution should be exercised when combining these drugs for the treatment of patients with relapsed follicular lymphoma, especially when treating older patients.

Ocular prevalence is defined as an unequal weighting of the eyes in the directional perception of stereo objects. Opinions differ as to the cause and relevance of ocular prevalence. Hans-Joachim Haase suggested that ocular prevalence is due to fixation disparity, brought about by incomplete compensation of heterophoria. He further suggested that prismatic spectacles determined by his "measuring and correcting methodology" (MKH) could restore bicentral fixation and thus establish a perceptual balance between both eyes.We examined 10 non-strabismic subjects with a visual acuity ofor = 1.0 in both eyes. It turned out that all 10 had a "fixation disparity type II", characterised according to Haase by a "disparate retinal correspondence". All subjects underwent the automatic Freiburg Ocular Prevalence Test, without and with MKH prisms. In addition we examined ocular prevalence under forced vergence and compared ocular prevalence with stereoacuity.Spontaneous ocular prevalence ranged between 1 and 69 %. Averaged over all 10 subjects, ocular prevalence without and with the MKH prisms were not significantly different. Statistical evaluation of single subjects revealed only in one of the 10 a significant difference (Bonferroni-corrected p = 0.001). In the subgroup of 5 subjects who underwent forced vergence, ocular prevalence remained unaltered between 0 and 18 Delta base out. The stereoscopic threshold of all 10 subjects ranged between 1.5 and 14.5 arcsec. There was no correlation between ocular prevalence and stereoscopic threshold (r = - 0.2, p = 0.5).Our results indicate that ocular prevalence is largely independent of phoria correction and vergence stress. The excellent stereoacuity of all subjects suggests that ocular prevalence is abandoned for the sake of optimal resolution when very small differences in depth have to be judged.

The "Measuring and Correcting Methodology" after H.-J. Haase (MKH) aims at converting "fixation disparity" into bicentral fixation, using prismatic spectacles. In the context of the MKH, fixation disparity is diagnosed by a series of subjective tests. According to H.-J. Haase, a long-standing fixation disparity can lead to "disparate correspondence" between the central areas of both retinae, which consolidates the fixation disparity and gradually converts a "young" into an "old fixation disparity". In "old fixation disparity" it is thought that bicentral fixation does not occur anymore, so that stereoacuity is impaired. However, prismatic spectacles can, according to H.-J. Haase, restitute bicentral fixation and consequently improve stereoacuity, even in some cases of "old fixation disparity".Ten non-strabismic subjects with a visual acuity of/= 1.0 in both eyes were examined. It turned out that all ten had, according to MKH, a "disparate correspondence", 5 subjects with a "young" and 5 with an "old fixation disparity". According to the MKH, a correcting prism was determined. All 10 subjects underwent the automatic Freiburg Stereoacuity Test, without and with the MKH-prism.Without the MKH-prism, the stereoscopic threshold ranged between 1.5 and 14.5 arcsec. With the MKH-prism, the values were not significantly different.Stereoacuity ranged between good and excellent in the 5 subjects with "young" as well as in the 5 subjects with "old fixation disparity". The MKH-prism did not improve the stereoacuity in any of the subjects. These results cast doubt on Haase's assertion that an "old fixation disparity" implies a reduced stereoacuity. Hence, the premise for a benefit of the MKH-prism with respect of stereoacuity is not substantiated. In the 5 subjects with a "young fixation disparity", the good stereoacuity is consistent with Haase's theory, so that a benefit of the MKH-prism for stereoacuity was not expected. In previous studies, stereoacuity was found to be better with the MKH-prism than without it. These studies are questionable since learning with repeated testing was not taken into account. We conclude that there is no sound evidence for the assumption that the MKH-prism can improve stereoacuity.

Neuronal activation leads to an increase in the local cortical perfusion. The exact regulatory mechanisms leading to these changes are still unknown. To elucidate the role of oxygen in the initial hemodynamic regulation, a disactivation paradigm was performed with fMRI. A stimulus was applied following a previous extended activation in order to evoke physiological variations of the local oxygen concentration. The results demonstrate that the initial hemodynamic response time is independent of the local blood oxygen concentration.

Background: There is a need for a stereotest with the following properties: (1) Natural viewing conditions, i.e. stimulus contours visible for each eye alone, but no or hardly any cue for monocular detection, and (2) suitability for threshold determination over a wide range of disparities. To comply with these requirements, we developed the Freiburg Stereoacuity Test. Method: The stimulus configuration is shown on a visual display unit (VDU) using phase-difference haploscopy with ferromagnetic liquid crystal shutters. The stereo target consists of a vertical bar that can be presented "in front of" or "behind" a frame. The sizes of the bar and the frame are kept constant relative to the stereo disparity. Anti-aliasing allows for disparities finer than the pixel raster. To mask monocular cues the bar is displaced randomly to the right or left. The stereo threshold was determined in two observers with normal eyes, using first the method of constant stimuli and then the best PEST. Both procedures were repeated with observers wearing scatter transparencies that reduced their visual acuity to about 1/10. In addition, the two observers with insight into the test design and two strabismic patients performed the best PEST procedure with one eye only. Results: With constant stimuli both observers achieved a stereoacuity of 2.6 arcsec and 3.1 arcsec, respectively, taking a hit rate of 75% as the threshold. The best PEST revealed a stereoacuity of 2.5 arcsec and 3.0 arcsec, respectively. The scatter transparencies raised the threshold to 261 and 257, respectively. With one eye only, the two observers with insight into the test design exploited the subtle position cue and reached a coarse pseudostereopsis. The two strabismic patients did not utilise the position cue. Conclusion: The Freiburg Stereoacuity Test allows determination of stereoacuity over a wide range of disparities (1–1000 arcsec). Although the stimuli can be seen with each eye alone, monocular depth cues are sufficiently masked. The Freiburg Stereoacuity Test is available at http://www.ukl.uni-freiburg.de/aug/bach/fst/.

Variants in the tumor suppressor gene ARLTS1 (ADP-ribosylation factor-like tumor-suppressor gene 1) have been shown to influence familial cancer risk. Both Cys148Arg and Trp149Stop were associated with an increased risk of familial or high-risk familial breast cancer, respectively. We studied the impact of these gene variants on melanoma risk, investigating 351 melanoma patients and 804 control subjects. While ARLTS1 Trp149Stop did not influence melanoma risk (OR = 0.83, 95% CI = 0.37-1.88, p = 0.65), Cys148Arg revealed a statistically significant association with an increased risk for heterozygous carriers (OR = 1.43, 95% CI = 1.05-1.95, p = 0.02). An additional risk enhancement, though statistically non-significant, was observed in individuals with multiple melanomas (OR = 2.33, 95% CI = 0.87-6.26, p = 0.08).