Identification of a novel t(7;14) translocation in multiple myeloma resulting in overexpression of EGFR

IGH translocations in myeloma are a primary event and determine the prognostic outcome of a patient. These events are characterized by FISH and classical cytogenetics, but in a small proportion of samples a translocation involving the IGH locus can be detected but the partner chromosome cannot be identified. These cases are usually genetically complex and are the result of cryptic events that cannot be discerned at the resolution of FISH. Here we analyzed a sample with an unidentified translocation partner using a targeted capture and massively parallel sequencing. We identified the partner chromosome as a t(7;14) with the breakpoint upstream of EGFR. This sample over‐expresses the target oncogene, EGFR. This case represents a rare and novel translocation in myeloma, from which a targeted personalized treatment, in the form of EGFR inhibitors, which are commonly used in other cancer types, could be used. © 2013 Wiley Periodicals, Inc.     

Parametrized rectal dose and associations with late toxicity in prostate cancer radiotherapy

Objective:

We investigated possible associations between planned dose–volume parameters and rectal late toxicity in 170 patients having radical prostate cancer radiotherapy.

Methods:

For each patient, the rectum was outlined from anorectal junction to sigmoid colon, and rectal dose was parametrized using dose–volume (DVH), dose–surface (DSH) and dose–line (DLH) histograms. Generation of DLHs differed from previous studies in that the rectal dose was parametrized without first unwrapping onto 2-dimensional dose–surface maps. Patient-reported outcomes were collected using a validated Later Effects in Normal Tissues Subjective, Objective, Management and Analytic questionnaire. Associations between dose and toxicity were assessed using a one-sided Mann–Whitney U test.

Results:

Associations (p < 0.05) were found between equieffective dose (EQD2₃) and late toxicity as follows: overall toxicity with DVH and DSH at 13–24 Gy; proctitis with DVH and DSH at 25–36 Gy and with DVH, DSH and DLH at 61–67 Gy; bowel urgency with DVH and DSH at 10–20 Gy. None of these associations met statistical significance following the application of a Bonferroni correction.

Conclusion:

Independently confirmed associations between rectal dose and late toxicity remain elusive. Future work to increase the accuracy of the knowledge of the rectal dose, either by accounting for interfraction and intrafraction rectal motion or via stabilization of the rectum during treatment, may be necessary to allow for improved dose–toxicity comparisons.

Advances in knowledge:

This study is the first to use parametrized DLHs to study associations with patient-reported toxicity for prostate radiotherapy showing that it is feasible to model rectal dose mapping in three dimensions.     

Analysis of the premalignant stages of Barrett's oesophagus through to adenocarcinoma by comparative genomic hybridization

OBJECTIVES: Barrett's oesophagus is a pre-neoplastic lesion, which develops as a complication of chronic gastro-oesophageal reflux disease and predisposes the patient to oesophageal adenocarcinoma. Our aim was to characterize karyotypic changes that may occur during the progression of Barrett's metaplasia through low-grade dysplasia and high-grade dysplasia to adenocarcinoma. METHODS: The technique of comparative genomic hybridization was used to characterize genome-wide changes in biopsies from patients with low-grade dysplasia, low-grade dysplasia plus high-grade dysplasia, high-grade dysplasia or adenocarcinoma. Both fresh and archival material was examined. RESULTS: Comparative genomic hybridization revealed a large amount of widespread chromosome instability at the high-grade dysplasia stage. No significant chromosome changes were detectable by comparative genomic hybridization in patients with low-grade dysplasia. Karyotypic changes in the adenocarcinoma patients were more specific than those found in the high-grade dysplasia patients. Chromosome 4 was amplified most often in high-grade dysplasia and chromosome 8q was amplified most frequently in the adenocarcinomas. CONCLUSIONS: These data demonstrate that high-grade dysplasia is the stage exhibiting widespread chromosome instability, which is detectable by comparative genomic hybridization. This instability is undetectable in low-grade dysplasia. The chromosome variation seen at high-grade dysplasia may be the source of more specific karyotypes that progress to adenocarcinoma. Importantly, we have identified chromosome 4 amplification as being heavily involved in the initiation of Barrett's progression. Specific chromosome changes (4 and 8q) may represent important regions on which to focus attention in future studies, with a view to identifying diagnostic markers.     

Left ventricular aneurysm and congestive heart failure: Value of exercise stress and isosorbide dinitrate in predicting hemodynamic results of aneurysmectomy

In 12 patients with left ventricular aneurysm and chronic congestive heart failure, left ventricular functional reserve was assessed from the hemodynamic response to exercise stress after administration of isosorbide dinitrate. Two to 23 months (mean 8.6 months) after left ventricular aneurysmectomy hemodynamic measurements were made with the patient at rest and during exercise and were analyzed with respect to preoperative data. Left ventricular aneurysmectomy reduced mean left ventricular filling pressure from 25 to 17 mm Hg at rest (p < 0.02) and from 39 to 32 mm Hg during exercise (p < 0.05). There was no significant change in mean stroke volume index at rest or during exercise.Changes in resting and exercise hemodynamic indexes of left ventricular function produced by aneurysmectomy were inversely related to preoperative left ventricular function. Hence, hemodynamic status was less likely to improve In patients with good preoperative left ventricular function. Similarly, resting and exercise values for left ventricular function tended to improve in patients with reduced ejection fraction of the contractile section of the left ventricle. Left ventricular aneurysmectomy was generally effective in reducing left ventricular filling pressure but failed to achieve clinically important improvement in left ventricular performance during exercise. In patients with chronic congestive heart failure, left Ventricular aneurysmectomy should be performed only after careful assessment of preoperative left ventricular functional reserve.     

The Basement Membrane and the Sex Establishment in the Juvenile Hermaphroditism During Gonadal Differentiation of the Gymnocorymbus ternetzi (Teleostei: Characiformes: Characidae)

Although there are several studies on morphogenesis in Teleostei, until now there is no research describing the role of the basement membrane in the establishment of the germinal epithelium during gonadal differentiation in Characiformes. In attempt to study these events that result in the formation of ovarian and testicular structures, gonads of Gymnocorymbus ternetzi were prepared for light microscopy. During gonadal development in G. ternetzi, all individuals first developed ovarian tissue. The undifferentiated gonad was formed by somatic cells (SC) and primordial germ cells (PGCs). After successive mitosis, the PGCs became oogonia, which entered into meiosis originating oocytes. An interstitial tissue developed. In half of the individuals, presumptive female, prefollicle cells synthesized a basement membrane around oocyte forming a follicle. Along the ventral region of the ovary, the tissue invaginated to form the ovigerous lamellae, bordered by the germinal epithelium. Stroma developed and the follicle complexes were formed. The gonadal aromatase was detected in interstitial cells in the early steps of the gonadal differentiation in both sexes. In another half of the individuals, presumptive male, there was no synthesis of basement membrane. The interstitium was invaded by numerous granulocytes. Pre‐Leydig cells proliferated. Apoptotic oocytes were observed and afterward degenerated. Spermatogonia appeared near the degenerating oocytes and associated to SCs, forming testicular tubules. Germinal epithelium developed and the basement membrane was synthesized. Concomitantly, there was decrease of the gonadal aromatase and increase in the 3β‐HSD enzyme expression. Thus, the testis was organized on an ovary previously developed, constituting an indirect gonochoristic differentiation. Anat Rec, 298:1984–2010, 2015. © 2015 Wiley Periodicals, Inc.     

Endothelial injury markers before and after nasal continuous positive airway pressure treatment for obstructive sleep apnoea hypopnoea syndrome

Purpose

The purpose of this study was to evaluate whether serum amyloid A (SAA), C-reactive protein (CRP), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) levels are elevated in obstructive sleep apnoea hypopnoea syndrome (OSAHS), and whether they change following acute- and medium-term CPAP treatment.

Methods

Consecutive subjects (n?=?40) referred to the Sleep Disordered Breathing Unit were included in the research. Sera were sampled in the afternoon prior to an in-hospital limited-channel sleep study and on the next morning. Those diagnosed with OSAHS were commenced on CPAP and had further blood samples collected in the morning after the first night and then after a month of treatment.

Results

We had 20 subjects with moderate/severe OSAHS (mean ± SD), 4 % desaturation rate (4 % DR) 44.3?±?31.4 events/h, and 20 comparator subjects with symptoms but negative sleep studies, 4 % DR 5.6?±?2.9 events/h. There was no difference in the morning and afternoon vascular injury marker levels between the OSAHS and comparator groups. However, CRP (6.52?±?9.53 vs. 5.58?±?8.47, p?=?0.04) and VCAM-1 (366.30?±?90.11 vs. 339.60?±?95.87, p?=?0.02) levels showed significant diurnal variation within the OSAHS group with higher afternoon levels compared to morning measurements. There were no changes in any of the vascular injury marker levels following CPAP.

Conclusions

This study demonstrates that OSAHS leads to endothelial dysfunction as reflected by higher afternoon than morning CRP and VCAM-1 levels. However, despite a good CPAP compliance, a month of treatment does not decrease vascular injury marker levels.