Barrett’s esophagus: Review of natural history and comparative efficacy of endoscopic and surgical therapies

Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma (EAC). Progression to cancer typically occurs in a stepwise fashion through worsening dysplasia and ultimately, invasive neoplasia. Established EAC with deep involvement of the esophageal wall and/or metastatic disease is invariably associated with poor long-term survival rates. This guides the rationale of surveillance of Barrett’s in an attempt to treat lesions at an earlier, and potentially curative stage. The last two decades have seen a paradigm shift in management of Barrett’s with rapid expansion in the role of endoscopic eradication therapy (EET) for management of dysplastic and early neoplastic BE, and there have been substantial changes to international consensus guidelines for management of early BE based on evolving evidence. This review aims to assist the physician in the therapeutic decision-making process with patients by comprehensive review and summary of literature surrounding natural history of Barrett’s by histological stage, and the effectiveness of interventions in attenuating the risk posed by its natural history. Key findings were as follows. Non-dysplastic Barrett’s is associated with extremely low risk of progression, and interventions cannot be justified. The annual risk of cancer progression in low grade dysplasia is between 1%-3%; EET can be offered though evidence for its benefit remains confined to highly select settings. High-grade dysplasia progresses to cancer in 5%-10% per year; EET is similarly effective to and less morbid than surgery and should be routinely performed for this indication. Risk of nodal metastases in intramucosal cancer is 2%-4%, which is comparable to operative mortality rate, so EET is usually preferred. Submucosal cancer is associated with nodal metastases in 14%-41% hence surgery remains standard of care, except for select situations.     

Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922.

For a PET agent to be successful as a biomarker in early clinical trials of new anticancer agents, some conditions need to be fulfilled: the selected tracer should show a response that is related to the antitumoral effects, the quantitative value of this response should be interpretable to the antitumoral action, and the timing of the PET scan should be optimized to action of the drug. These conditions are not necessarily known at the start of a drug-development program and need to be explored. We proposed a translational imaging activity in which experiments in spheroids and later in xenografts are coupled to modeling of growth inhibition and to the related changes in the kinetics of PET tracers and other biomarkers. In addition, we demonstrated how this information can be used for planning clinical trials. METHODS: The first part of this concept is illustrated in a spheroid model with BT474 breast cancer cells treated with the heat shock protein 90 (Hsp90) inhibitor NVP-AUY922. The growth-inhibitory effect after a pulse treatment with the drug was measured with digital image analysis to determine effects on volume with high accuracy. The growth-inhibitory effect was described mathematically by a combined E(max) and time course model fitted to the data. The model was then used to simulate a once-per-week treatment; in these experiments the uptake of the PET tracers (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was determined at different doses and different time points. RESULTS: A drug exposure of 2 h followed by washout of the drug from the culture medium generated growth inhibition that was maximal at the earliest time point of 1 d and decreased exponentially with time during 10-12 d. The uptake of (18)F-FDG per viable tumor volume was minimally affected by the treatment, whereas the (18)F-FLT uptake decreased in correlation with the growth inhibition. CONCLUSION: The study suggests a prolonged action of the Hsp90 inhibitor that supports a once-per-week schedule. (18)F-FLT is a suitable tracer for the monitoring of effect, and the (18)F-FLT PET study might be performed within 3 d after dosing.     

Acute Cellular Rejection Predominated by Monocytes Is a Severe Form of Rejection in Human Renal Recipients With or Without Campath-1H (Alemtuzumab) Induction Therapy

Campath-1H has been used successfully for induction and has resulted in a low rate of acute cellular rejection (ACR) in renal transplantation in combination with various postoperative immunosuppression regimens. This study was undertaken to investigate the extent of monocyte involvement in ACR, with or without Campath-1H induction. We found that monocytes represented the majority of inflammatory cells in grades Ib or higher ACR, but not with Ia type of ACR, regardless of the status of Campath-1H induction. Cases of ACR, following Campath-1H induction, appear to demonstrate a 'pure form' of monocytic ACR, whereas monocytes were mixed with many other types of inflammatory cells in the cases of ACR in the absence of Campath-1H induction. In addition with Campath-1H induction, the cases of monocyte-predominant ACR were found to uniformly exhibit a good response to corticosteroid treatment. We conclude that monocyte-predominate ACR may represent a severe form of rejection, with or without Campath-1H treatment.     

Chronic subdural haematoma associated with nontraumatic CSF rhinorrhea: a management challenge.

We report an unusual case of chronic subdural haematoma (CSH) associated with cerebrospinal fluid (CSF) rhinorrhoea emphasizing the importance of managing both conditions simultaneously. A 59- year-old man presented with watery discharge from the right nostril, of 2 months duration. MRI of the brain showed a CSH in the left fronto-parietal region with significant mass effect. There was an arachnoidocoele with a defect in the planum sphenoidale. He first underwent a burr hole evacuation of the CSH following which the CSF rhinorrhea did not subside, even with bed rest. Transnasal endoscopic closure of the CSF dural fistula was done. On the first post-operative day, he was disoriented and a CT scan showed a recollection of the subdural haematoma that required repeat evacuation. The patient was asymptomatic at discharge. To our knowledge this is the first reported case of CSF rhinorrhoea associated with CSH. Simultaneous closure of the CSF dural fistula at the time of evacuation of a coexisting CSH would be the optimal management.     

Implementation of a successful endovascular surgical program in a non-teaching tertiary-care centre in Ontario.

Endovascular surgical techniques have become an accepted standard of care for high-risk patients with abdominal aortic aneurysms and for certain patients with thoracic aortic pathology and peripheral arterial aneurysms. In Canada, endovascular surgery has been concentrated in tertiary-care academic teaching institutions. As the technology evolves and as expertise advances, the applicability of endovascular techniques will expand. With time, and as the demand for endovascular techniques rises, this expertise will increasingly need to be delivered by dedicated vascular surgical services in nonteaching institutions. The dissemination of endovascular surgical capabilities represent a unique challenge. We report the successful implementation of an endovascular surgical program in a tertiary-care nonteaching institution using a carefully planned preceptorship model. We review our initial 49 cases and discuss 6 factors important to the successful establishment of an endovascular surgical service: education, teamwork, strict selection of patients, use of a single stent-graft manufacturer, industry support and endovascular preceptorship. Our experience may be used as a model by other institutions in Canada.     

Receiver Operating Characteristic (ROC) to Determine Cut-Off Points of Biomarkers in Lung Cancer Patients

The role of biomarkers in disease prognosis continues to be an important investigation in many cancer studies. In order for these biomarkers to have practical application in clinical decision making regarding patient treatment and follow-up, it is common to dichotomize patients into those with low vs. high expression levels. In this study, receiver operating characteristic (ROC) curves, area under the curve (AUC) of the ROC, sensitivity, specificity, as well as likelihood ratios were calculated to determine levels of growth factor biomarkers that best differentiate lung cancer cases versus control subjects. Selected cut-off points for p185^erbB-2 and EGFR membrane appear to have good discriminating power to differentiate control tissues versus uninvolved tissues from patients with lung cancer (AUC = 89% and 90%, respectively); while AUC increased to at least 90% for selected cut-off points for p185^erbB-2 membrane, EGFR membrane, and FASE when comparing between control versus carcinoma tissues from lung cancer cases. Using data from control subjects compared to patients with lung cancer, we presented a simple and intuitive approach to determine dichotomized levels of biomarkers and validated the value of these biomarkers as surrogate endpoints for cancer outcome.     

The role of beta-catenin, TGF beta 3, NGF2, FGF2, IGFR2, and BMP4 in the pathogenesis of mesenteric sclerosis and angiopathy in midgut carcinoids

A subset of midgut carcinoids (MCs) result in mesenteric angiopathy (MA) and bowel infarction as a consequence of vascular compression caused by extensive mesenteric sclerosis (MS). The goal of this study was to determine whether the level of expression of several fibrosing-related growth factors was related to the finding of MA and/or MS in MCs. Eighteen cases of MC, 6 with both extensive MS and MA (group I), 5 with extensive MS only (group II), and 7 with ordinary MS only (group III), were analyzed for immunoexpression of beta-catenin, transforming growth factor-beta 2 (TGF beta 2), nerve growth factor 2 (NGF2), fibroblast growth factor 2 (FGF2), insulin growth factor receptor (IGFR), and bone morphogenic protein 4 (BMP4) in formalin-fixed, paraffin-embedded sections. Standard immunohistochemical technique was used following antigen retrieval. Immunostaining was scored semiquantitively as the product of the percentage and intensity (0 to 2+) of the immunostaining, giving a possible range of 0 to 200. One-way analysis of variance and Mann-Whitney nonparametric analyses were used for statistical analysis. The mean scores of immunoreactivity of each factor in groups I, II, and III were as follows: 135, 174, and 147 for beta-catenin (cytoplasmic reactivity only); 106, 112, and 92 for TGF beta 3; 1.67, 32, and 36 for NGF-2; 2.5, 48, and 55 for FGF-2; 19, 112, and 66 for IGFR2; 140, 45, and 52 for BMP4. There were significant differences in NGF-2 immunoreactivity between groups I and III (P = 0.0023) and in BMP4 immunoreactivity between groups I and II (P = 0.017) and groups I and III (P = 0.022). All MCs expressed high levels of membranous beta-catenin, moderate levels of TGF beta 3 and IGFR2, and low levels of FGF-2, with no significant differences seen among the groups. MCs with prominent MS and MA (group I) expressed significantly higher BMP4 than those in groups II and III, suggesting a potential role of BMP4 in the pathogenesis of MA. The level of NGF-2 expression was significantly lower in group I than in group III, possibly indicating abnormal angiogenesis in the formation of angiopathy.     

Non-isotropic noise correlation in PET data reconstructed by FBP but not by OSEM demonstrated using auto-correlation function

Background  

Positron emission tomography (PET) is a powerful imaging technique with the potential of obtaining functional or biochemical information by measuring distribution and kinetics of radiolabelled molecules in a biological system, both in vitro and in vivo. PET images can be used directly or after kinetic modelling to extract quantitative values of a desired physiological, biochemical or pharmacological entity. Because such images are generally noisy, it is essential to understand how noise affects the derived quantitative values. A pre-requisite for this understanding is that the properties of noise such as variance (magnitude) and texture (correlation) are known.