MR Imaging Findings of Iron Overload

Hemochromatosis can be classified as (a) primary, when it originates from a genetic disturbance that promotes the increase of iron absorption, or (b) secondary, when it relates to chronic diseases or to multiple transfusions. The distribution of iron accumulation differs between these two forms; therefore, they can be distinguished by using imaging methods in the majority of cases. Magnetic resonance (MR) imaging is the most sensitive and specific imaging modality in the diagnosis of hemochromatosis. The susceptibility effect caused by the accumulation of iron leads to signal loss in the affected tissues, particularly with the T2*-weighted sequences, which makes the diagnosis of iron overload possible. By using MR imaging techniques, it is possible to estimate the hepatic iron concentration in a noninvasive way, thereby avoiding repeated biopsies. Hemochromatosis can lead to complications, such as a higher frequency of neoplasia, particularly the development of hepatocellular carcinoma. Other neoplasms, such as colorectal tumors, are also associated. Complications related to the treatment of chronic anemia include the appearance of peliosis hepatis and tumors, which can regress after the suspension of treatment with drugs. Knowledge of the disease and of the patterns of iron deposition in patients with iron overload enables not only diagnosis, but also treatment, follow-up, and the detection of possible complications by using imaging methods. (C) RSNA, 2009 . radiographics.rsna.org

Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI With Diffusion-Weighted and FLAIR Imaging

OBJECTIVE. Toxic leukoencephalopathy may present acutely or subacutely with symmetrically reduced diffusion in the periventricular and supraventricular white matter, hereafter referred to as periventricular white matter. This entity may reverse both on imaging and clinically. However, a gathering together of the heterogeneous causes of this disorder as seen on MRI with diffusion-weighted imaging (DWI) and an analysis of their likelihood to reverse has not yet been performed. Our goals were to gather causes of acute or subacute toxic leukoencephalopathy that can present with reduced diffusion of periventricular white matter in order to promote recognition of this entity, to evaluate whether DWI with apparent diffusion coefficient (ADC) values can predict the extent of chronic FLAIR abnormality ( imaging reversibility), and to evaluate whether DWI can predict the clinical outcome ( clinical reversibility). MATERIALS AND METHODS. Two neuroradiologists retrospectively reviewed the MRI examinations of 39 patients with acute symptoms and reduced diffusion of periventricular white matter. The reviewers then scored the extent of abnormality on DWI and FLAIR. ADC ratios of affected white matter versus the unaffected periventricular white matter were obtained. Each patient`s clinical records were reviewed to determine the cause and clinical outcome. Histology findings were available in three patients. Correlations were calculated between the initial MRI markers and both the clinical course and the follow-up extent on FLAIR using Spearman`s correlation coefficient. RESULTS. Of the initial 39 patients, seven were excluded because of a nontoxic cause (hypoxic-ischemic encephalopathy [HIE] or congenital genetic disorders) or because of technical errors. In the remaining 32 patients, no correlation was noted between any of the initial MRI markers (percentage of ADC reduction, DWI extent, or FLAIR extent) with the clinical outcome. Three patients had histologic correlation. However, moderate correlation was seen between the extent of abnormality on initial FLAIR and the extent on follow-up FLAIR (r = 0.441, p = 0.047). Of the 13 patients who underwent repeat MRI at 21 days or longer, the reduced diffusion resolved in all but one. Significant differences were noted between ADC values in affected white matter versus unaffected periventricular white matter on initial (p < 0.0001) but not on follow-up MRI (p = 0.13), and in affected white matter on initial versus follow-up (p = 0.0014) in those individuals who underwent repeat imaging on the same magnet (n = 9), confirming resolution of the DWI abnormalities. CONCLUSION. Acute toxic leukoencephalopathy with reduced diffusion may be clinically reversible and radiologically reversible on DWI, and may also be reversible, but to a lesser degree, on FLAIR MRI. None of the imaging markers measured in this study appears to correlate with clinical outcome, which underscores the necessity for prompt recognition of this entity. Alerting the clinician to this potentially reversible syndrome can facilitate treatment and removal of the offending agent in the early stages.

Prevalence of diabetic peripheral neuropathy and relation to glycemic control therapies at baseline in the BARI 2D cohort

We evaluated the associations between glycemic therapies and prevalence of diabetic peripheral neuropathy (DPN) at baseline among participants in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial on medical and revascularization therapies for coronary artery disease (CAD) and on insulin-sensitizing vs. insulin-providing treatments for diabetes. A total of 2,368 patients with type 2 diabetes and CAD was evaluated. DPN was defined as clinical examination score > 2 using the Michigan Neuropathy Screening Instrument (MNSI). DPN odds ratios across different groups of glycemic therapy were evaluated by multiple logistic regression adjusted for multiple covariates including age, sex, hemoglobin A1c (HbA1c), and diabetes duration. Fifty-one percent of BARI 2D subjects with valid baseline characteristics and MNSI scores had DPN. After adjusting for all variables, use of insulin was significantly associated with DPN (OR = 1.57, 95% CI: 1.15-2.13). Patients on sulfonylurea (SU) or combination of SU/metformin (Met)/thiazolidinediones (TZD) had marginally higher rates of DPN than the Met/TZD group. This cross-sectional study in a cohort of patients with type 2 diabetes and CAD showed association of insulin use with higher DPN prevalence, independent of disease duration, glycemic control, and other characteristics. The causality between a glycemic control strategy and DPN cannot be evaluated in this cross-sectional study, but continued assessment of DPN and randomized therapies in BARI 2D trial may provide further explanations on the development of DPN.

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

Considering that mycobacterial heat-shock protein 65 (hsp65) gene transfer can elicit a profound antitumoral effect, this study aimed to establish the safety, maximum-tolerated dose (MTD) and preliminary efficacy of DNA-hsp65 immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). For this purpose, 21 patients with unresectable and recurrent HNSCC were studied. Each patient received three ultrasound-guided injections at 21-day intervals of: 150, 600 or 400 mu g of DNA-hsp65. Toxicity was graded according to CTCAE directions. Tumor volume was measured before and after treatment using computed tomography scan. The evaluation included tumor mass variation, delayed-type hypersensitivity response and spontaneous peripheral blood mononuclear cell proliferation before and after treatment. The MTD was 400 mg per dose. DNA-hsp65 immunotherapy was well tolerated with moderate pain, edema and infections as the most frequent adverse effects. None of the patients showed clinical or laboratory alterations compatible with autoimmune reactions. Partial response was observed in 4 out of 14 patients who completed treatment, 2 of which are still alive more than 3 years after the completion of the trial. Therefore, DNA-hsp65 immunotherapy is a feasible and safe approach at the dose of 400 mg per injection in patients with HNSCC refractory to standard treatment. Further studies in a larger number of patients are needed to confirm the efficacy of this novel strategy.

Value of real time three-dimensional echocardiography in patients with hypertrophic cardiomyopathy: Comparison with two-dimensional echocardiography and magnetic resonance imaging

Real time three-dimensional echocardiography (RT3DE) has been demonstrated to be an accurate technique to quantify left ventricular (LV) volumes and function in different patient populations. We sought to determine the value of RT3DE for evaluating patients with hypertrophic cardiomyopathy (HCM), in comparison with cardiac magnetic resonance imaging (MRI). Methods: We studied 20 consecutive patients with HCM who underwent two-dimensional echocardiography (2DE), RT3DE, and MRI. Parameters analyzed by echocardiography and MRI included: wall thickness, LV volumes, ejection fraction (LVEF), mass, geometric index, and dyssynchrony index. Statistical analysis was performed by Lin agreement coefficient, Pearson linear correlation and Bland-Altman model. Results: There was excellent agreement between 2DE and RT3DE (Rc = 0.92), 2DE and MRI (Rc = 0.85), and RT3DE and MRI (Rc = 0.90) for linear measurements. Agreement indexes for LV end-diastolic and end-systolic volumes were Rc = 0.91 and Rc = 0.91 between 2DE and RT3DE, Rc = 0.94 and Rc = 0.95 between RT3DE and MRI, and Rc = 0.89 and Rc = 0.88 between 2DE and MRI, respectively. Satisfactory agreement was observed between 2DE and RT3DE (Rc = 0.75), RT3DE and MRI (Rc = 0.83), and 2DE and MRI (Rc = 0.73) for determining LVEF, with a mild underestimation of LVEF by 2DE, and smaller variability between RT3DE and MRI. Regarding LV mass, excellent agreement was observed between RT3DE and MRI (Rc = 0.96), with bias of -6.3 g (limits of concordance = 42.22 to -54.73 g). Conclusion: In patients with HCM, RT3DE demonstrated superior performance than 2DE for the evaluation of myocardial hypertrophy, LV volumes, LVEF, and LV mass.

Effects of immunosuppressants on hepatocyte cell mitosis during liver regeneration in growing animal models of partial hepatectomy

Objective. We sought to evaluate the effects of immunosuppressant drugs (corticosteroid, cyclosporine [CsA], and tacrolimus [Tac]) on liver regeneration in growing animals submitted to 70% hepatectomy. Materials and Methods. Newborn and weaning rats were submitted to 70% hepatectomy receiving separately methylprednisolone, CsA, or Tac. All animals were sacrificed 24 hours after the procedure. The remnant liver lobes were subjected to histomorphometric analyses with determination of hepatocyte mitotic index. Results., Administration of immunosuppressants did not change the mitotic index of the regenerating liver in newborn animals. In weaning rats, methylprednisolone reduced the mitotic index (P = .01) and Tac caused a greater increase in this rate (P = .001). CsA had no effect on mitotic index. The number of hepatocyte mitoses in newborn animal livers was greater than that in weaning animal livers (P = .001). Conclusion. In situations in which intense, fast processes of liver regeneration are crucial, the advantages of the use of Tac must be considered, such as in pediatric transplant patients.

Diagnostic Performance of Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320-MDCT: The CT Angiography and Perfusion Methods of the CORE320 Multicenter Multinational Diagnostic Study

OBJECTIVE. Coronary MDCT angiography has been shown to be an accurate noninvasive tool for the diagnosis of obstructive coronary artery disease (CAD). Its sensitivity and negative predictive value for diagnosing percentage of stenosis are unsurpassed compared with those of other noninvasive testing methods. However, in its current form, it provides no information regarding the physiologic impact of CAD and is a poor predictor of myocardial ischemia. CORE320 is a multicenter multinational diagnostic study with the primary objective to evaluate the diagnostic accuracy of 320-MDCT for detecting coronary artery luminal stenosis and corresponding myocardial perfusion deficits in patients with suspected CAD compared with the reference standard of conventional coronary angiography and SPECT myocardial perfusion imaging. CONCLUSION. We aim to describe the CT acquisition, reconstruction, and analysis methods of the CORE320 study.

Management of Neuroendocrine Tumors: A Meeting of Experts from Latin America

A panel of experts from Latin America convened in Brazil, in May of 2007, for consensus recommendations regarding the management of neuroendocrine tumors ( NETs) of the gastrointestinal tract and pancreas. The recently introduced World Health Organization classification of NETs represents a step forward, but the former classification of carcinoids into foregut, midgut and hindgut is still likely to be useful in the near future. Macroscopic description of the tumor should be followed by light microscopic examination and immunohistochemical staining, whereas other techniques might not be widely available in Latin America. Surgery remains the mainstay of treatment for patients with potentially curable tumors, and adequate selection is paramount in order to optimize treatment results. Regarding systemic therapy, patients with well-differentiated tumors or islet-cell carcinomas may be categorized as having indolent disease, while patients with poorly differentiated, anaplastic, and small-cell carcinomas, or with atypical carcinoids, may be approached initially as having aggressive disease. Somatostatin analogues play a cytostatic role in indolent tumors, and chemotherapy may play a role against other, more aggressive NETs. Obviously, there is an urgent need for novel therapies that are effective against NETs. Copyright (C) 2008 S. Karger AG, Basel

Magnetic resonance imaging of idiopathic carpal tunnel syndrome: Correlation with clinical findings and electrophysiological investigation

Objective: To compare clinical evaluation, electrophysiological investigation and magnetic resonance findings in assessing the severity of idiopathic carpal tunnel syndrome. Patients and methods: Seventy-four patients with idiopathic carpal tunnel syndrome were prospectively recruited. Clinical evaluation included symptoms severity score and two-point discrimination, sensory and motor nerve conduction velocities were determined by electroneuromyography and imaging parameters were obtained after wrist magnetic resonance. The Wilcoxon test was used to define the differences between measurements of median nerve area. The Pearson and Spearman correlation tests were used to determine the relationships between all the measured parameters. Results: Cross-sectional area of median nerve was smaller at hamate level than at radio-ulnar joint and pisiform levels (p < 0.001). With exception of median nerve area at hamate level, there was a lower degree of correlation between MRI parameters and findings obtained by clinical assessments and electrophysiological measurements. The median nerve area at hamate level correlated negatively with duration of symptoms, two-point discrimination, symptoms severity score and positively with sensory nerve conduction velocity (P < 0.01). Conclusion: In patients with idiopathic carpal tunnel syndrome, median nerve area measured by wrist magnetic resonance at hamate level may be considered as a valuable indicator to grading the severity of disease. (c) 2007 Elsevier B.V. All rights reserved.

Immunohistochemical analysis of p53, APE1, hMSH2 and ERCC1 proteins in actinic cheilitis and lip squamous cell carcinoma

Aims: This study has compared the tissue expression of the p53 tumour suppressor protein and DNA repair proteins APE1, hMSH2 and ERCC1 in normal, dysplastic and malignant lip epithelium. Methods and results: Morphological analysis and immunohistochemistry were performed on archived specimens of normal lip mucosa (n = 15), actinic cheilitis (AC) (n = 30), and lip squamous cell carcinoma (LSCC) (n = 27). AC samples were classified morphologically according to the severity of epithelial dysplasia and risk of malignant transformation. LSCC samples were morphologically staged according to WHO and invasive front grading (IFG) criteria. Differences between groups and morphological stages were determined by bivariate statistical analysis. Progressive increases in the percentage of epithelial cells expressing p53 and APE1 were associated with increases in morphological malignancy from normal lip mucosa to LSCC. There was also a significant reduction in epithelial cells expressing hMSH2 and ERCC1 proteins in the AC and LSCC groups. A higher percentage of malignant cells expressing APE1 was found in samples with an aggressive morphological IFG grade. Conclusions: Our data showed that epithelial cells from premalignant to malignant lip disease exhibited changes in the expression of p53, APE1, hMSH2 and ERCC1 proteins; these molecular change might contribute to lip carcinogenesis.

Bariatric Surgery Reverses Natural Killer (NK) Cell Activity and NK-Related Cytokine Synthesis Impairment Induced by Morbid Obesity

Background Obesity is related to a higher rate of infections and some types of cancer. Here we analyzed the impact of obesity and weight loss induced by Roux-en-Y gastric bypass (RYGB) on immunological parameters, i.e., cytokine productions and natural killer cell function. Methods We analyzed 28 morbidly obese patients before and 6 months after RYGB. Biochemical parameters were analyzed in plasma. The percent of natural killer (NK) cells, their cytotoxicity, and the production of cytokines by peripheral blood mononuclear cells were analyzed. The percent of NK cells was determined by flow cytometry and cytokine production determined by enzyme-linked immunosorbent assay. NK cytotoxicity was determined by the lactate dehydrogenase release assay. Results The weight loss 6 months following surgery was 35.3 +/- 4.5 kg. RYGB also improves biochemical parameters. No significant difference was found in the percent of NK cells after surgery. We found an increase in the production of interferon-gamma, interleukin (IL)-12 and IL-18, but not in IL-2, 6 months after RYGB. Cytotoxic activity of NK cells was significantly enhanced 6 months after RYGB [17.1 +/- 14.7% before RYGB vs 51.8 +/- 11.3% at 6 months after, at 40: 1 effector to target cell ratio; p<0.001]. We observed significant post-surgical improvement in the cytotoxic activity curve in 22 out of 28 patients (78.6%), irrespective of the target to effector cell ratio. Conclusions The weight loss induced by RYGB modifies the production of cytokines related with NK cell function and improves its activity.

Loss of heterozygosity of the APC gene in oral squamous cell carcinoma

The aim of this study was to investigate loss of heterozygosity (LOH) of the APC tumor suppressor gene loci, using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) in 40 cases of oral squamous cell carcinoma (OSCC). Observed informativity was 72.5% for APC exon 11 and 82.5% for APC exon 15. LOH at APC exon 11 was observed in 2 (6.9%) of 29 informative cases, and no LOH was observed for APC exon 15. Our results suggest that inactivation of the APC gene plays a minor role in the carcinogenesis of OSCC. (C) 2008 Elsevier GmbH. All rights reserved.

ERCC1 protein, mRNA expression and T19007C polymorphism as prognostic markers in head and neck squamous cell carcinoma patients treated with surgery and adjuvant cisplatin-based chemoradiation

Adjuvant cisplatin-based chemoradiation improves survival in HNSCC patients presenting with risk features. ERCC1 (excision repair cross-complementation group 1) is associated with resistance to chemo- and radiation therapy and may have a prognostic value in HNSCC patients. Here we studied ERCC1 expression and the polymorphism T19007C as prognostic markers in these patients. This is a retrospective and translational analysis, where ERCC1 protein expression was evaluated by immunohistochemistry, using an H-score, and mRNA expression was determined by RT-PCR. T 19007C genotypes were detected by PCR-RFLP carried out using DNA template extracted from normal lymph nodes. A high H-score was seen in 32 patients (54%), who presented better 5-year overall survival (5-y OS: 50% vs. 18%, HR 0.43, p=0.026). Fifteen out of 45 patients (33%), with high mRNA expression, presented better 5-year overall survival (OS) (86% vs. 30%, HR 0.26, p=0.052). No OS difference was detected among T 19007C genotypes. High H-score and mRNA expression remained significant as favorable prognostic factors in a multivariate analysis. Collectively, our results suggest that high ERCC1 expression seems to be associated with better OS rates in HNSCC patients submitted to adjuvant cisplatin-based chemoradiation.

In situ hybridization detection of homeobox genes reveals distinct expression patterns in oral squamous cell carcinomas

Aims: To analyse the expression of three homeobox genes (HOXA7, PITX1 and PRRX1) in oral squanous cell carcinomas (OSCC) and the relationship of such expression to certain distinct histopathological features of OSCC and in comparison to adjacent non-neoplastic epithelium (NT). Methods and results: Digoxigenin-labelled riboprobes that are specific for each homeobox gene were generated and in situ hybridization was carried out on frozen sections. In NT samples, HOXA7 and PITX1 transcripts were found more frequently in all epithelial layers, while PRRX1 was expressed in the basal layer. With OSCC samples, expression of the three genes was associated with all histological features. However, the HOXA7 and PITX1 signals were more intense in sheets and nests and PRRX1 in small nests and isolated cells. Conclusion: HOXA7, PIXT1 and PRRX1 homeobox genes have different patterns of expression in OSCC depending on its histological features.

Negative Pressure Therapy for Complex Wounds in Patients with Sickle-Cell Disease: A Case Study

Sickle-cell disease is the most prevalent genetic disease in the Brazilian population. Lower limb ulcers are the most frequent cutaneous complications, affecting 8% to 10% of the patients. These ulcers are usually deep and may take many years to heal. Evidence about the effectiveness of systemic or topical treatment of these wounds is limited, apart from stabilization of the anemia. A 28-year old woman with sickle-cell disease was admitted for treatment of three deep chronic lower leg ulcers. All wounds had tendon exposure and contained firmly adherent fibrin slough. Following surgical debridement and before grafting, the wounds were managed with three different dressings: a rayon and normal saline solution dressing, a calcium alginate dressing covered with gauze, and negative pressure therapy. All three wounds healed successfully and their grafts showed complete integration; only the rayon-dressed wound required a second debridement. The alginate and rayon-dressed wounds recurred after 9 months and required additional skin grafts. Helpful research on managing ulcers in patients with sickle-cell disease is minimal, but the results of this case study suggest that topical treatment modalities may affect outcomes. Research to explore the safety and effectiveness of NPT in patients with sickle-cell wounds is warranted.