Blood flow velocity vector field reconstruction from dual-beam bidirectional Doppler OCT measurements in retinal veins

In this paper, we demonstrate the possibility to reconstruct the actual blood flow velocity vector field in retinal microvessels from dual-beam bidirectional Doppler optical coherence tomography measurements. First, for a better understanding of measured phase patterns, several flow situations were simulated on the basis of the known dual beam measurement geometry. We were able to extract the vector field parameters that determine the measured phase pattern, allowing for the development of an algorithm to reconstruct the velocity vector field from measured phase data. In a next step, measurements were performed at a straight vessel section and at a venous convergence; the obtained phase data were evaluated by means of the new approach. For the straight vessel section, the reconstructed flow velocity vector field yielded a parabolic flow. For the venous convergence, however, the reconstructed vector field deviated from a parabolic profile, but was in very good accordance with the simulated vector field for the given vessel geometry. The proposed algorithm allows predictions of the velocity vector field. Moreover, the algorithm is also sensitive to directional changes of the flow velocity as small as <1°, thereby offering insight in the flow characteristics of the non-Newtonian fluid blood in microvessels.OCIS codes: (110.4500) Optical coherence tomography, (170.2655) Functional monitoring and imaging, (280.2490) Flow diagnostics     

Variability of the Diagnostic ECG Pattern in an ICD Patient Population with Brugada Syndrome

Introduction: The spontaneous presence of a coved-type ECG is considered as an important risk factor in Brugada syndrome. However, diagnosis making and risk stratification may be hampered by the dynamic nature of the ECG abnormalities. The objective of this study was to determine the variability and predictive value of the electrocardiogram in Brugada patients implanted with a cardioverter-defibrillator (ICD).
Methods and Results: We analyzed consecutive 12-lead ECGs from 89 ICD patients (44 ± 14 years, 69 males) with Brugada syndrome. A total of 1,161 ECGs were included for analysis (13 ± 8 ECGs/patient). Twenty-four percent of the ECGs/patient were coved-type I, 25% saddleback-type II or III, and 51% normal. Fifty-seven patients had a diagnostic coved-type ECG spontaneously (group A), 32 patients only after drug challenge (group B). In group A, 38% of the ECGs/patient were diagnostic, 25% saddleback-type, and 37% normal. Fifty-five group A patients (96%) had transient normalization and/or conversion to saddleback-type ECGs. During a mean follow-up of 48 ± 35 months, 16 patients (18%) experienced appropriate shocks. All patients with appropriate shocks had spontaneous diagnostic ECGs. They tended to have more coved-type ECGs (36 vs 22%, respectively, P = 0.05) than patients without appropriate shocks.
Conclusions: Analysis of serial ECG recordings in an ICD patient population shows that the Brugada-ECG pattern is highly variable over time. In patients with spontaneous coved-type ECG, only every third ECG is diagnostic and every third ECG normal. Patients with spontaneous coved-type ST-segment elevation have a high incidence of appropriate shocks. Spontaneous saddleback-type electrocardiograms are not helpful for risk stratification.     

Mesenchymal stem cells are resistant to carbon ion radiotherapy

Mesenchymal stem cells (MSCs) participate in regeneration of tissues damaged by ionizing radiation. However, radiation can damage MSCs themselves.Here we show that cellular morphology, adhesion and migration abilities were not measurably altered by photon or carbon ion irradiation. The potential for differentiation was unaffected by either form of radiation, and established MSC surface markers were found to be stably expressed irrespective of radiation treatment. MSCs were able to efficiently repair DNA double strand breaks induced by both high-dose photon and carbon ion radiation. We have shown for the first time that MSCs are relatively resistant to therapeutic carbon ion radiotherapy. Additionally, this form of radiation did not markedly alter the defining stem cell properties or the expression of established surface markers in MSCs.     

New insights into the genetics of glioblastoma multiforme by familial exome sequencing

Glioblastoma multiforme (GBM) is the most aggressive and malignant subtype of human brain tumors. While a family clustering of GBM has long been acknowledged, relevant hereditary factors still remained elusive. Exome sequencing of families offers the option to discover respective genetic factors.We sequenced blood samples of one of the rare affected families: while both parents were healthy, both children were diagnosed with GBM. We report 85 homozygous non-synonymous single nucleotide variations (SNVs) in both siblings that were heterozygous in the parents. Beyond known key players for GBM such as ERBB2, PMS2, or CHI3L1, we identified over 50 genes that have not been associated to GBM so far. We also discovered three accumulative effects potentially adding to the tumorigenesis in the siblings: a clustering of multiple variants in single genes (e.g. PTPRB, CROCC), the aggregation of affected genes on specific molecular pathways (e.g. Focal adhesion or ECM receptor interaction) and genomic proximity (e.g. chr22.q12.2, chr1.p36.33). We found a striking accumulation of SNVs in specific genes for the daughter, who developed not only a GBM at the age of 12 years but was subsequently diagnosed with a pilocytic astrocytoma, a common acute lymphatic leukemia and a diffuse pontine glioma.The reported variants underline the relevance of genetic predisposition and cancer development in this family and demonstrate that GBM has a complex and heterogeneous genetic background. Sequencing of other affected families will help to further narrow down the driving genetic causes for this disease.     

CDKN2a mutation‐negative melanoma families have increased risk exclusively for skin cancers but not for other malignancies

Germline CDKN2A mutations are found in 5–20% of melanoma families. Numerous studies have shown that carriers of CDKN2A mutations have increased risks of non‐melanoma cancers, but so far there have been no studies investigating cancer risks in CDKN2A wild type (wt) melanoma families. In this prospective cohort study, index melanoma cases (n = 224) and their first‐degree relatives (n = 944) were identified from 154 confirmed CDKN2A wt melanoma families. Cancer diagnoses in family members and matched controls were obtained from the Swedish Cancer Registry. Relative risks (RR), odds ratios (OR) and two‐sided 95% confidence intervals (95% CI) were calculated. In index cases and first‐degree relatives, the prospective RR for melanoma was 56.9 (95% CI 31.4–102.1) and 7.0 (95% CI 4.2–11.4), respectively, and for squamous cell skin cancers 9.1 (95% CI 6.0–13.7) and 3.4 (95% CI 2.2–5.2), respectively. In neither group, elevated risks were seen for non‐skin cancers. In a subgroup analysis, CDKN2A wt melanoma families with young (<40 years) melanoma cases were found to have increased risk of non‐skin cancers (RR 1.5, 95% CI 1.0–1.5). Further, MC1R gene variants were increased in familial melanoma cases compared to controls (OR 2.4, 95% CI 1.6–3.4). Our findings suggest that in the majority of CDKN2A wt melanoma families, a segregation of variants in low‐risk melanoma genes such as MC1R causes increased skin cancer susceptibility, rather than mutations in high‐risk cancer predisposing genes, such mutations are more probable to be found in melanoma families with young melanoma cases. This study further supports an implication of CDKN2A mutation screening as a clinical test that determines counseling and follows up routines of melanoma families.     

Genomic profile of pseudomyxoma peritonei analyzed using next‐generation sequencing and immunohistochemistry

Pseudomyxoma peritonei (PMP) is a relatively rare clinical syndrome characterized by neoplastic epithelial cells growing in the peritoneal cavity and secreting mucinous ascites. Our aim was to explore the molecular events behind this fatal but under‐investigated disease. We extracted DNA from 19 appendix‐derived PMP tumors and nine corresponding normal tissues, and analyzed the mutational hotspot areas of 48 cancer‐related genes by amplicon‐based next‐generation sequencing (NGS). Further, we analyzed the protein expression of V600E mutated BRAF, MLH1, MSH2, MSH6 and p53 from a larger set of PMP tumors (n = 74) using immunohistochemistry. With NGS, we detected activating somatic KRAS mutations in all of the tumors studied. GNAS was mutated in 63% of the tumors with no marked difference between low‐grade and high‐grade tumors. Only one (5.3%) tumor showed oncogenic PIK3CA mutation, one showed oncogenic AKT1 mutation, three (15.8%) showed SMAD4 mutations and none showed an APC mutation. P53 protein was aberrantly expressed in higher proportion of high‐grade tumors as compared with low‐grade ones (31.3 vs. 7.1%, respectively; p = 0.012) and aberrant expression was an independent factor for reduced overall survival (p = 0.002). BRAF V600E mutation was only found in one (1.4%) high‐grade tumor by immunohistochemistry (n = 74). All the studied tumors expressed mismatch repair proteins MLH1, MSH2 and MSH6. Our results indicate that KRAS mutations are evident in all and GNAS mutations in most of the PMPs, but BRAF V600E, PIK3CA and APC mutations are rare. Aberrantly expressed p53 is associated with high‐grade histology and reduced survival.     

Is further screening of men with baseline PSA < 1 ng ml−1 worthwhile? The discussion continues—Results of the Swiss ERSPC (Aarau)

Recent studies indicate frequent early PSA retesting unrelated of men's baseline PSA, which increases the harms of early detection especially among men with low PSA. The current study investigates the PCa incidence among men with baseline PSA <1.0 ng ml^?1 in order to adjust retest intervals for more targeted early detection. Between 1998 and 2012, 2,416 men with baseline PSA <1.0 ng ml^?1 were prospectively observed. Primary endpoint was PCa diagnosis. Negative predictive value (NPV) and number needed to screen (NNS) to detect one PCa were calculated. During a median follow‐up time of 12.1 years, 54 (2.2%) PCa were diagnosed with n = 26 (48.1%) among men with baseline PSA of 0.75 ≤ 1.0 ng ml^?1 (upper baseline PSA quartile). The 10‐year probability of being diagnosed with PCa increased significantly from 0.19% (baseline PSA < 0.40 ng ml^?1) to 2.0% (baseline PSA 0.40 ≤ 0.56 ng ml^?1), 2.5% (baseline PSA 0.56 ≤ 0.75 ng ml^?1) over 4.4% (baseline PSA 0.75 ≤ 1.0 ng ml^?1) (all p values <0.0001), respectively. The frequency of Gleason ≥7 PCa increased from 1 (0.17%) to 8 (1.4%), 5 (0.8) over 11 (1.8%) in these groups. The 8‐year NPV for Gleason ≥ 7 PCa were 99.8 (baseline PSA < 0.40 ng ml^?1), 99.8 (baseline PSA 0.40 ≤ 0.56 ng ml^?1), 100 (baseline PSA 0.56 ≤ 0.75 ng ml^?1) and 99.5 (baseline PSA 0.75 ≤ 1.0 ng ml^?1), respectively. During 12 years, the numbers were 99.8, 98.6, 99.2, and 98.2, respectively. Therefore, due to the very low rate of Gleason ≥ 7 PCa, further screening might be omitted in men with baseline PSA < 0.4 ng ml^?1. Between 0.4 and 1.0 ng ml^?1, an 8‐year interval can be discussed.