Gene expression analysis of diagnostic biopsies predicts pathological response to neoadjuvant chemoradiotherapy of esophageal cancer

OBJECTIVE: This study explored gene expression differences in predicting response to chemoradiotherapy in esophageal cancer. PURPOSE:: A major pathological response to neoadjuvant chemoradiation is observed in about 40% of esophageal cancer patients and is associated with favorable outcomes. However, patients with tumors of similar histology, differentiation, and stage can have vastly different responses to the same neoadjuvant therapy. This dichotomy may be due to differences in the molecular genetic environment of the tumor cells. BACKGROUND DATA: Diagnostic biopsies were obtained from a training cohort of esophageal cancer patients (13), and extracted RNA was hybridized to genome expression microarrays. The resulting gene expression data was verified by qRT-PCR. In a larger, independent validation cohort (27), we examined differential gene expression by qRT-PCR. The ability of differentially-regulated genes to predict response to therapy was assessed in a multivariate leave-one-out cross-validation model. RESULTS: Although 411 genes were differentially expressed between normal and tumor tissue, only 103 genes were altered between responder and non-responder tumor; and 67 genes differentially expressed >2-fold. These included genes previously reported in esophageal cancer and a number of novel genes. In the validation cohort, 8 of 12 selected genes were significantly different between the response groups. In the predictive model, 5 of 8 genes could predict response to therapy with 95% accuracy in a subset (74%) of patients. CONCLUSIONS: This study has identified a gene microarray pattern and a set of genes associated with response to neoadjuvant chemoradiation in esophageal cancer. The potential of these genes as biomarkers of response to treatment warrants further investigation. Copyright © 2009 by Lippincott Williams & Wilkins.

Thymidylate synthase expression and outcome of patients receiving pemetrexed for advanced nonsquamous non-small-cell lung cancer in a prospective blinded assessment phase II clinical trial

INTRODUCTION In retrospective analyses of patients with nonsquamous non-small-cell lung cancer treated with pemetrexed, low thymidylate synthase (TS) expression is associated with better clinical outcomes. This phase II study explored this association prospectively at the protein and mRNA-expression level. METHODS Treatment-naive patients with nonsquamous non-small-cell lung cancer (stage IIIB/IV) had four cycles of first-line chemotherapy with pemetrexed/cisplatin. Nonprogressing patients continued on pemetrexed maintenance until progression or maximum tolerability. TS expression (nucleus/cytoplasm/total) was assessed in diagnostic tissue samples by immunohistochemistry (IHC; H-scores), and quantitative reverse-transcriptase polymerase chain reaction. Cox regression was used to assess the association between H-scores and progression-free/overall survival (PFS/OS) distribution estimated by the Kaplan-Meier method. Maximal χ analysis identified optimal cutpoints between low TS- and high TS-expression groups, yielding maximal associations with PFS/OS. RESULTS The study enrolled 70 patients; of these 43 (61.4%) started maintenance treatment. In 60 patients with valid H-scores, median (m) PFS was 5.5 (95% confidence interval [CI], 3.9-6.9) months, mOS was 9.6 (95% CI, 7.3-15.7) months. Higher nuclear TS expression was significantly associated with shorter PFS and OS (primary analysis IHC, PFS: p < 0.0001; hazard ratio per 1-unit increase: 1.015; 95%CI, 1.008-1.021). At the optimal cutpoint of nuclear H-score (70), mPFS in the low TS- versus high TS-expression groups was 7.1 (5.7-8.3) versus 2.6 (1.3-4.1) months (p = 0.0015; hazard ratio = 0.28; 95%CI, 0.16-0.52; n = 40/20). Trends were similar for cytoplasm H-scores, quantitative reverse-transcriptase polymerase chain reaction and other clinical endpoints (OS, response, and disease control). CONCLUSIONS The primary endpoint was met; low TS expression was associated with longer PFS. Further randomized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts. © 2013 by the International Association for the Study of Lung Cancer.

Computational fluid dynamic analysis of intracranial aneurysmal bleb formation

Background The management of unruptured aneurysms is controversial with the decision to treat influenced by aneurysm characteristics including size and morphology. Aneurysmal bleb formation is thought to be associated with an increased risk of rupture. Objective To correlate computational fluid dynamic (CFD) indices with bleb formation. Methods Anatomical models were constructed from three-dimensional rotational angiogram (3DRA) data in 27 patients with cerebral aneurysms harbouring single blebs. Additional models representing the aneurysm before bleb formation were constructed by digitally removing the bleb. We characterised haemodynamic features of models both with and without the bleb using CFDs. Flow structure, wall shear stress (WSS), pressure and oscillatory shear index (OSI) were analysed. Results There was a statistically significant association between bleb location at or adjacent to the point of maximal WSS (74.1%, p=0.019), irrespective of rupture status. Aneurysmal blebs were related to the inflow or outflow jet in 88.9% of cases (p<0.001) whilst 11.1% were unrelated. Maximal wall pressure and OSI were not significantly related to bleb location. The bleb region attained a lower WSS following its formation in 96.3% of cases (p<0.001) and was also lower than the average aneurysm WSS in 86% of cases (p<0.001). Conclusion Cerebral aneurysm blebs generally form at or adjacent to the point of maximal WSS and are aligned with major flow structures. Wall pressure and OSI do not contribute to determining bleb location. The measurement of WSS using CFD models may potentially predict bleb formation and thus improve the assessment of rupture risk in unruptured aneurysms.

Radiolabelled somatostatin analogue scintigraphy in oncology

Somatostatin analogue scintigraphy represents a new technique employing radiolabelled peptides to detect specific receptor-bearing lesions. 111Indium diethylenetriaminopentaacetic acid-linked octreotide (111In-DTPA-D-Phe1 octreotide), also known as [111In]pentetreotide or OctreoScan, is now established in the management of patients with neuroendocrine gastrointestinal tract and pancreatic tumours, and has proved effective in localizing disease sites in lung, breast and medullary thyroid carcinomas, lymphomas, meningiomas and others. In these conditions (a) the imaging of all disease sites at a single sitting (in a proportion of patients) thereby making further investigations unnecessary, (b) the localization of otherwise unexpected metastatic deposits and (c) the detection of residual disease not found by other means suggest that [111In]pentetreotide may be a useful adjunct in the diagnostic evaluation of patients with somatostatin receptor-bearing tumours.

The role of inflammation in the pathogenesis of non-small cell lung cancer

The link between chronic immune activation and tumorigenesis is well established. Compelling evidence has accumulated that histologic assessment of infiltration patterns of different host immune response components in non-small cell lung cancer specimens helps identify different prognostic patient subgroups. This review provides an overview of recent insights gained in the understanding of the role played by chronic inflammation in lung carcinogenesis. The usefulness of quantification of different populations of lymphocytes, natural killer cells, macrophages, and mast cells within the tumor microenvironment in non-small cell lung cancer is also discussed. In particular, the importance of assessment of inflammatory cell microlocalization within both the tumor islet and surrounding stromal components is emphasized. Copyright © 2010 by the International Association for the Study of Lung Cancer.

Long-term outcomes following neoadjuvant chemoradiotherapy for esophageal cancer

OBJECTIVE: We present and analyze long-term outcomes following multimodal therapy for esophageal cancer, in particular the relative impact of histomorphologic tumor regression and nodal status. PATIENTS AND METHODS: A total of 243 patients [(adenocarcinoma (n = 170) and squamous cell carcinoma (n = 73)] treated with neoadjuvant chemoradiotherapy in the period 1990 to 2004 were followed prospectively with a median follow-up of 60 months. Pathologic stage and tumor regression grade (TRG) were documented, the site of first failure was recorded, and Kaplan-Meier survival curves were plotted. RESULTS: Thirty patients (12%) did not undergo surgery due to disease progression or deteriorated performance status. Forty-one patients (19%) had a complete pathologic response (pCR), and there were 31(15%) stage I, 69 (32%) stage II, and 72 (34%) stage III cases. The overall median survival was 18 months, and the 5-year survival was 27%. The 5-year survival of patients achieving a pCR was 50% compared with 37% in non-pCR patients who were node-negative (P = 0.86). Histomorphologic tumor regression was not associated with pre-CRT cTN stage but was significantly (P < 0.05) associated with ypN stage. By multivariate analysis, ypN status (P = 0.002) was more predictive of overall survival than TRG (P = 0.06) or ypT stage (P = 0.39). CONCLUSION: Achieving a node-negative status is the major determinant of outcome following neoadjuvant chemoradiotherapy. Histomorphologic tumor regression is less predictive of outcome than pathologic nodal status (ypN), and the need to include a primary site regression score in a new staging classification is unclear. © 2007 Lippincott Williams & Wilkins, Inc.

Repeatability and comparison of peripheral eye lengths with two instruments

Purpose: To assess intrasessional and intersessional repeatability of two commercial partial coherence interferometry instruments for measuring peripheral eye lengths and to investigate the agreement between the two instruments. Methods: Central and peripheral eye lengths were determined with the IOLMaster (Carl-Zeiss Meditec AG, Jena, Germany) and the Lenstar (Haag Streit, Bern, Switzerland) in seven adults. Measurements were performed out to 35° and 30° from fixation for horizontal and vertical visual fields, respectively, in 5° intervals. An external fixation target at optical infinity was used. At least four measurements were taken at each location for each instrument, and measurements were taken at two sessions. Results: The mean intrasessional SDs for the IOLMaster along both the horizontal and vertical visual fields were 0.04 ± 0.04 mm; corresponding results for the Lenstar were 0.02 ± 0.02 mm along both fields. The intersessional SDs for the IOLMaster for the horizontal and vertical visual fields were ±0.11 and ±0.08 mm, respectively; corresponding limits for the Lenstar were ±0.05 and ±0.04 mm. The intrasessional and intersessional variability increased away from fixation. The mean differences between the two instruments were 0.01 ± 0.07 mm and 0.02 ± 0.07 mm in the horizontal and vertical visual fields, but the lengths with the Lenstar became greater than those with the IOLMaster as axial length increased (rate of approximately 0.016 mm/mm). Conclusions: Both the IOLMaster and the Lenstar demonstrated good intrasessional and intersessional repeatability for peripheral eye length measurements, with the Lenstar showing better repeatability. The Lenstar would be expected to give a slightly greater range of eye lengths than the IOLMaster across the visual field.

Influence of stop position on spectacle magnification

Purpose To develop and use equations of spectacle magnification when the limiting stop is either the entrance pupil of the eye or an artificial pupil in front of a lens. Methods Spectacle magnification was determined for ophthalmic lenses in air and for water environments. The reference was the retinal image for an uncorrected eye in air with a natural pupil. Results When an artificial pupil is placed in front of lenses, spectacle magnification is hardly affected by lens power, unlike the usual situation where the natural pupil is used. The water environment provides interesting influences in which spectacle magnification is highly sensitive to the distance between the cornea and eye entrance pupil. In water, retinal images are approximately 18% bigger than in air. Wearing air-filled goggles in water increases retinal image size by about 13% compared with that when they are not worn. Conclusions The equations extend earlier understanding of spectacle magnification and should be useful for those wishing to determine magnification of ophthalmic lens systems when artificial pupils and environments such as water are used.

Power profiles of multifocal contact lenses and their interpretation

Purpose Many contact lens (CL) manufacturers produce simultaneous-image lenses in which power varies either smoothly or discontinuously with zonal radius. We present in vitro measurements of some recent CLs and discuss how power profiles might be approximated in terms of nominal distance corrections, near additions, and on-eye visual performance. Methods Fully hydrated soft, simultaneous-image CLs from four manufacturers (Air Optix AQUA, Alcon; PureVision multifocal, Bausch & Lomb; Acuvue OASYS for Presbyopia, Vistakon; Biofinity multifocal- ‘‘D’’ design, Cooper Vision) were measured with a Phase focus Lens Profiler (Phase Focus Ltd., Sheffield,UK) in a wet cell and powerswere corrected to powers in air. All lenses had zero labeled power for distance. Results Sagittal power profiles revealed that the ‘‘low’’ add PureVision and Air Optix lenses exhibit smooth (parabolic) profiles, corresponding to negative spherical aberration. The ‘‘mid’’ and ‘‘high’’ add PureVision and Air Optix lenses have biaspheric designs, leading to different rates of power change for the central and peripheral portions. All OASYS lenses display a series of concentric zones, separated by abrupt discontinuities; individual profiles can be constrained between two parabolically decreasing curves, each giving a valid description of the power changes over alternate annular zones. Biofinity lenses have constant power over the central circular region of radius 1.5 mm, followed by an annular zone where the power increases approximately linearly, the gradient increasing with the add power, and finally an outer zone showing a slow, linear increase in power with a gradient being almost independent of the add power. Conclusions The variation in power across the simultaneous-image lenses produces enhanced depth of focus. The throughfocusnature of the image, which influences the ‘‘best focus’’ (distance correction) and the reading addition, will vary with several factors, including lens centration, the wearer’s pupil diameter, and ocular aberrations, particularly spherical aberration; visual performance with some designs may show greater sensitivity to these factors.

Maternal exposure to heatwave and preterm birth in Brisbane, Australia

Objective To quantify the short-term effects of maternal exposure to heatwave on preterm birth. Design An ecological study. Setting: A population-based study in Brisbane, Australia. Population All pregnant women who had a spontaneous singleton live birth in Brisbane between November and March in 2000–2010 were studied. Methods Daily data on pregnancy outcomes, meteorological factors, and ambient air pollutants were obtained. The Cox proportional hazards regression model with time-dependent variables was used to examine the short-term impact of heatwave on preterm birth. A series of cut-off temperatures and durations were used to define heatwave. Multivariable analyses were also performed to adjust for socio-economic factors, demographic factors, meteorological factors, and ambient air pollutants. Main outcome measure Spontaneous preterm births. Results The adjusted hazard ratios (HRs) ranged from 1.13 (95% CI 1.03–1.24) to 2.00 (95% CI 1.37–2.91) by using different heatwave definitions, after controlling for demographic, socio-economic, and meteorological factors, and air pollutants. Conclusions Heatwave was significantly associated with preterm birth: the associations were robust to the definitions of heatwave. The threshold temperatures, instead of duration, could be more likely to influence the evaluation of birth-related heatwaves. The findings of this study may have significant public health implications as climate change progresses.

What is the evidence to guide best practice for the management of older people with cognitive impairment presenting to emergency departments? A systematic review

The aim of this study was to conduct a systematic literature review of research-based studies to identify practices designed to meet the specific care needs of older cognitively impaired patients in emergency departments (ED). A systematic literature review of studies was completed using PRIMSA methodology. The search criteria included articles from both emergency and acute care settings. A total of 944 articles were screened, and a total of 43 articles were identified as eligible. The review found a number of intervention studies to improve quality of care for older persons with cognitive impairment carried out or commenced in emergency settings, including interventions to improve cognitive impairment recognition (n = 9) and clinical approaches to reduce falls (n = 1) and both delirium incidence and prevalence (n = 2). Relevant studies carried out in acute care settings regarding cognitive impairment recognition (n = 4) and primary and secondary prevention of delirium (n = 18) and intervention studies that reduced the prescription of deliriogenic drugs (n = 1), reduced behavioral symptoms and discomfort (n = 7), and improved nutritional intake (n = 1) in hospitalized older persons with dementia were also identified. There is limited research available that reports interventions that improve the quality of care of older ED patients with cognitive impairment. Although this review found evidence obtained from the acute care setting, additional research is needed to identify whether these interventions are beneficial in fast-paced emergency settings.

Screening for risk of later mental health problems : a longitudinal study

Purpose: This is one of the first studies to report that the Achenbach internalising scales were much more effective at identifying those with current comorbid depression and anxiety, rather than individual mood disorder. Introduction: The Achenbach behaviour checklists (YSR,YASR) are widely used, low cost screening tools used to assess problem behaviour. Several studies report good association between the checklists and psychiatric diagnoses; although with varying degrees of agreement. Most are cross-sectional studies involving adolescents referred to mental health services; few are in large community-based studies. This study examined the usefulness of the Achenbach internalising scales in the primary screening (both predictive and concurrent)for depression and anxiety. Methods: The sample was 2400 young adults from an Australian population-based prospective birth cohort study. The association between the empirical anxiety and depression scales were individually assessed against DSM-IV depression and anxiety diagnoses. Odds ratios and diagnostic efficiency tests report the findings. Results: Adolescents with internalising symptoms were twice (OR 2.3, 95%CI 1.7 to 3.1) as likely to be diagnosed with later DSM-IV depression. YASR internalising scale predicted DSM-IV mood disorders (depression OR = 6.9, 95% CI 5.0–9.5; anxiety OR = 5.1, 95% CI 3.8–6.7) in the previous 12 months. The internalising scales were much more effective at identifying those with comorbid depression and anxiety. Conclusions: Adolescence and early adulthood are key risk periods for the onset of anxiety and depression. This study found that young people with internalising behaviour problems were more likely to have comorbid depression and anxiety DSM-IV disorder.

A threshold analysis of dengue transmission in terms of weather variables and imported dengue cases in Australia

Dengue virus (DENV) transmission in Australia is driven by weather factors and imported dengue fever (DF) cases. However, uncertainty remains regarding the threshold effects of high-order interactions among weather factors and imported DF cases and the impact of these factors on autochthonous DF. A time-series regression tree model was used to assess the threshold effects of natural temporal variations of weekly weather factors and weekly imported DF cases in relation to incidence of weekly autochthonous DF from 1 January 2000 to 31 December 2009 in Townsville and Cairns, Australia. In Cairns, mean weekly autochthonous DF incidence increased 16.3-fold when the 3-week lagged moving average maximum temperature was <32 °C, the 4-week lagged moving average minimum temperature was ≥24 °C and the sum of imported DF cases in the previous 2 weeks was >0. When the 3-week lagged moving average maximum temperature was ≥32 °C and the other two conditions mentioned above remained the same, mean weekly autochthonous DF incidence only increased 4.6-fold. In Townsville, the mean weekly incidence of autochthonous DF increased 10-fold when 3-week lagged moving average rainfall was ≥27 mm, but it only increased 1.8-fold when rainfall was <27 mm during January to June. Thus, we found different responses of autochthonous DF incidence to weather factors and imported DF cases in Townsville and Cairns. Imported DF cases may also trigger and enhance local outbreaks under favorable climate conditions.