Complex patterns of ETS gene alteration arise during cancer development in the human prostate

An ERG gene 'break-apart' fluorescence in situ hybridization (FISH) assay has been used to screen whole-mount prostatectomy specimens for rearrangements at the ERG locus. In cancers containing ERG alterations the observed pattern of changes was often complex. Different categories of ERG gene alteration were found either together in a single cancerous region or within separate foci of cancer in the same prostate slice. In some cases the juxtaposition of particular patterns of ERG alterations suggested possible mechanisms of tumour progression. Prostates harbouring ERG alterations commonly also contained cancer that lacked rearrangements of the ERG gene. A single trans-urethral resection of the prostate specimen examined harboured both ERG and ETV1 gene rearrangements demonstrating that the observed complexity may, at least in part, be explained by multiple ETS gene alterations arising independently in a single prostate. In a search for possible precursor lesions clonal ERG rearrangements were found both in high grade prostatic intraepithelial neoplasia (PIN) and in atypical in situ epithelial lesions consistent with the diagnosis of low grade PIN. Our observations support the view that ERG gene alterations represent an initiating event that promotes clonal expansion initially to form regions of epithelial atypia. The complex patterns of ERG alteration found in prostatectomy specimens have important implications for the design of experiments investigating the clinical significance and mechanism of development of individual prostate cancers.     

The number of positive nodes and the ratio of positive to excised nodes are significant predictors of survival in women with micrometastatic node-positive breast cancer

BackgroundTo evaluate the prognostic impact of the number of positive nodes and the lymph node ratio (LNR) of positive to excised nodes on survival in women diagnosed with nodal micrometastatic breast cancer before the era of widespread sentinel lymph node biopsy.MethodsSubjects were 62,551 women identified by the Surveillance Epidemiology and End Results database, diagnosed with pT1–2pN0-1 breast cancer between 1988 and 1997. Kaplan–Meier breast cancer-specific survival (BCSS) and overall survival (OS) were compared between three cohorts: node-negative (pN0, n = 57,980) nodal micrometastasis all ⩽2 mm (pNmic, N = 1818), and macroscopic nodal metastasis >2 mm but <2 cm (pNmac, n = 2753). Nodal subgroups were examined by the number of positive nodes (1–3 versus ⩾4) and the LNR (⩽0.25 versus >0.25).ResultsMedian follow-up was 7.3 yr. Ten-year BCSS and OS in pNmic breast cancer were significantly lower compared to pN0 disease (BCSS 82.3% versus 91.9%, p < 0.001 and OS 68.1% versus 75.7%, p < 0.001). BCSS and OS with pNmic disease progressively declined with increasing number of positive nodes and increasing LNR. OS with pNmic was similar to pNmac disease when matched by the number of positive nodes and by the LNR. Both pN-based and LNR-based classifications were significantly prognostic of BCSS and OS on Cox regression multivariate analysis.ConclusionNodal micrometastasis is associated with poorer survival compared to pN0 disease. Mortality hazards with nodal micrometastasis increased with increasing number of positive nodes and increasing LNR. The number of positive nodes and the LNR should be considered in risk estimates for patients with nodal micrometastatic breast cancer.     

Amygdalohippocampal involvement in tinnitus and auditory memory

CONCLUSION: The preliminary results suggest that in chronic unilateral tinnitus the contralateral amygdalohippocampal complex does seem to be involved in tinnitus perception of pure tones. OBJECTIVES: Functional neuroimaging studies have revealed that the hippocampus and amygdala are involved in tinnitus perception. The amygdala and hippocampus are supplied by the anterior choroidal artery. Selective amobarbital injections in the anterior choroidal artery result in a non-functional amygdalohippocampal area for 10 min. The aim of this study was to assess the influence of this procedure on tinnitus perception. PATIENTS AND METHODS: Amobarbital (80 mg in total) was injected selectively in two sessions in the left and right anterior choroidal artery in six male patients with tinnitus: four with unilateral tinnitus, two with bilateral tinnitus. Of the patients with unilateral tinnitus, three had right-sided tinnitus and one had left-sided tinnitus. The average age was 57.3 years (range 43-69). Average tinnitus duration was 5.3 years (range 1-10). The differences in visual analogue scale (VAS) scores before and after the amytal tests were analysed. RESULTS: Amytal injection ipsilateral to the side where the tinnitus was perceived resulted in a maximum of 30% tinnitus suppression, whereas amytal injection contralateral to the tinnitus side yielded a 60-70% tinnitus suppression in three patients with unilateral chronic tinnitus (>4 years). Only pure tone tinnitus was suppressed, white noise was not. Two patients with bilateral tinnitus had no suppression, irrespective of the tinnitus type. A third patient without clinical tinnitus suppression had tinnitus of more recent origin (1.5 years).     

Aging and animal models of systemic insult: trauma, burn, and sepsis

In the acute-care setting, it is widely accepted that elderly patients have increased morbidity and mortality compared with young healthy patients. The reasons for this, however, are largely unknown. Although animal modeling has helped improve treatment strategies for young patients, there are a scarce number of studies attempting to understand the mechanisms of systemic insults such as trauma, burn, and sepsis in aged individuals. This review aims to highlight the relevance of using animals to study the pathogenesis of these insults in the aged and, despite the deficiency of information, to summarize what is currently known in this field.     

Precursor B lymphoblastic leukemia 32 months after local therapy for a primary extramedullary myeloid cell tumor

A primary extramedullary myeloid cell tumor (pEMT) of an inguinal lymph node was completely excised without subsequent anti-tumor therapy in a 6-year-old child. Clinical observation and monitoring of blood and bone marrow (BM) did not reveal any pathologic results before 32 months, when a precursor B lymphoblastic leukemia was diagnosed. Identical T-cell receptor gamma rearrangement in nodal pEMT and in precursor B lymphoblastic leukemia in BM indicates a clonal relationship of these two tumors.     

Phacoemulsification on previously vitrectomized eyes: results of a 10-year-period

PURPOSE: To provide an overview of intraoperative and postoperative complications during phacoemulsification cataract surgery and to evaluate the visual results in patients having pars plana vitrectomy (PPV) with 10 years of follow-up. METHODS: Retrospective evaluation of intraoperative and postoperative complications and postoperative visual results in 134 consecutive patients who underwent phacoemulsification after PPV. Of 11,498 eyes treated with phacoemulsification, 143 (1.2%) had previous PPV during the 10-year period were included in this study. RESULTS: The phacoemulsification procedure seemed to be difficult where there was a deep or fluctuating anterior chamber (93%) and primary posterior capsule opacification (19%). The most frequent intraoperative complications were posterior capsule rupture (9%) and incomplete capsular rhexis (5%). Postoperative intraocular pressure elevation (7%), retinal detachment (6%), and posterior capsule opacification (8%) occurred most frequently during the mean follow-up period of 18.2 months (1.5-110 months). Best-corrected visual acuity (BCVA) increased two or more Snellen E lines in 55% of the cases or became better than or equal to 0.5 in 10% of the cases. CONCLUSIONS: Despite the well-known difficulties encountered in vitrectomized eyes such as zonular damage, increased mobility of the lens-iris diaphragm, and altered intraocular fluid dynamics, phacoemulsification proved to be a safe procedure in the hands of experienced surgeons.     

Non-specific caspase inhibition reduces infarct size and improves post-ischaemic recovery in isolated ischaemic/reperfused rat hearts

Myocardial ischaemia and reperfusion lead to myocardial cell death due, at least in part, to apoptotic mechanisms. Although cysteinyl aspartate-specific proteinase (caspase) activation is a major event and the most-cited culprit in the development of apoptosis, its potential contribution to ischaemic myocardial cell death is largely unknown. To study the role of caspase activation, isolated rat hearts (n=6 per group) were subjected to 30 min coronary artery occlusion followed by 120 min reperfusion. A non-selective [0.1 or 0.5 microM acetyl-Tyr-Val-Ala-Asp chloromethylketone (YVAD-cmk)] or selective caspase inhibitors [0.07 or 0.2 microM acetyl-Asp-Glu-Val-Asp-cmk (Ac-DEVD-cmk, caspase-3 inhibitor); 0.07 or 0.2 microM benzoxycarbonyl-Leu-Glu-OMe-His-Asp(OMe)-fluoromethylketone (z-LEHD-fmk, caspase-9 inhibitor)] were added to the perfusate at the start of reperfusion. Non-selective caspase inhibition with 0.1 or 0.5 microM YVAD-cmk limited infarct size: (21 +/- 4%, P<0.05; 17 +/- 3%, P<0.05, respectively) compared with the ischaemic/reperfused control (32 +/- 5%). In hearts treated with 0.1 or 0.5 microM caspase II non-selective inhibitor, the fraction of terminal-deoxynucleotidyl-transferase deoxyuridine nick end labelling (TUNEL)-positive myocyte nuclei in the infarcted zone was reduced from the ischaemic/reperfused non-treated control of 11.2 +/- 2.1% to 6.2 +/- 1.6% (P<0.05) and 1.2 +/- 0.2% (P<0.05), respectively. The recovery of post-ischaemic cardiac function (coronary flow, aortic flow and left-ventricular developed pressure) improved significantly with the application of the non-selective caspase inhibitor as well. In hearts perfused with specific caspase inhibitors (caspase-3 and caspase-9) there was no significant reduction in the infarct size, no improvement in post-ischaemic cardiac function and no reduction of apoptotic cell death. We conclude that non-specific inhibition of caspases may be therapeutically beneficial in myocardial ischaemia/reperfusion-induced damage, while selective caspase inhibitors may fail to prevent such reperfusion-induced injury in our model system.     

Friction studies of hydrogel contact lenses using AFM: non-crosslinked polymers of low friction at the surface

The surface of soft contact lenses made of crosslinked poly(2-hydroxyethyl methacrylate), pHEMA, has been investigated with atomic force microscopy in contact mode. The friction force and adhesive force measurements were able to differentiate the non-crosslinked pHEMA chains from the surface of the crosslinked pHEMA networks. These non-crosslinked pHEMA chains at the surface were anchored to the crosslinked pHEMA network, most likely by entanglement and their surfaces were about 2–4 nm higher than the surrounding surface in a dehydrated state. In saline solution, the surface friction and adhesive force of the contact lens were significantly reduced compared to those measured for the surface-dehydrated contact lens.