Myofibroblastic tumor of the esophagus - a case report of long-term follow-up and literature review.

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm with intermediate malignant potential. Although most often seen in the lungs, it can occur at multiple anatomical locations, including the gastrointestinal tract. An esophageal lesion is extremely rare, however. IMTs present most commonly in children and young adults. The main therapeutic approach is surgical resection. CASE REPORT: We report on the follow-up of a case in a 13-year-old boy with IMT in the esophagus. He underwent surgical resection in 2013 and is free of disease to date. CONCLUSION: Surgical resection is the most preferred therapy. If the resection is complete, the risk of recurrence is low. Nevertheless, every patient should be carefully followed up after the resection.

Blunt cerebrovascular injuries in the craniofacial fracture population-Are we screening the right patients?

Current knowledge of blunt cerebrovascular injuries (BCVIs) in craniomaxillofacial fracture (CMF) patients is limited. The purpose of this study was to determine the occurrence of BCVIs in patients with all types of CMF. This retrospective study included CMF patients in a level 1 trauma centre during a 3-year period. Patients who were not imaged with computed tomography angiography and patients with mechanisms other than blunt injury were excluded. The primary outcome variable was BCVI. A total of 753 patients were included in the analysis. A BCVI was detected in 4.4% of the patients screened. BCVIs occurred in 8.7% of cranial fracture patients, 7.1% of combined craniofacial fracture patients, and 3.1% of facial fracture patients. The risk of BCVI was significantly increased in patients with isolated cranial fractures (odds ratio (OR) 2.55, 95% confidence interval (CI) 1.18-5.50; P=0.017), those involved in motor vehicle accidents (OR 3.42, 95% CI 1.63-7.17; P=0.001), and those sustaining high-energy injuries (OR 3.17, 95% CI 1.57-6.40; P=0.001). BCVIs in CMF patients are relatively common in high-energy injuries. However, these injuries also occur in minor traumas. Imaging thresholds should be kept low in this patient population when BCVIs are suspected.

Does postoperative orbital volume predict postoperative globe malposition after blow-out fracture reconstruction? A 6-month clinical follow-up study.

PURPOSE: The aim of this study was to investigate the relationship between intraorbital volume change caused by orbital fracture and globe malposition (GMP) in blow-out fracture patients undergoing surgery and to clarify the significance of different radiologically detected predictors associated with GMP. PATIENTS AND METHODS: A 6-month prospective follow-up study of unilateral isolated orbital fractures was designed and implemented. The main outcome variable was GMP (present or absent); the secondary outcome was orientation of GMP (horizontal or vertical). The primary predictor variable was postoperative orbital volume difference determined as the difference between the fractured and non-fractured orbit (measured in milliliter and analyzed in milliliter and percentages). The explanatory variables were gender, age, treatment delay from trauma to surgery, fracture site, horizontal depth of the fracture, fracture area, maximum vertical dislocation of the fracture, and preoperative volume difference. RESULTS: A total of 15 patients fulfilled the inclusion criteria and were followed for 6 months from a larger cohort. GMP was detected in 6/15 patients (40.0%). GMP was more often present in large (≥ 2.5 cm2) fractures (55.6%), in combined orbital fractures (50.0%), and in fractures with preoperative volume difference ≥ 2.5 ml (62.5%) regardless of the postoperative volume correction. Postoperatively, patients with and without GMP displayed overcorrection of orbital volume; 4.15% corresponded to 1.15 ml (with GMP) and 7.6% corresponded to 1.9 ml (without GMP). CONCLUSION: GMP was present in large and combined orbital fractures. Clinically detectable postoperative GMP occurred despite satisfactory orbital reconstruction and overcorrection. Mild GMP, however, is not significant for the patient.

Cardiac remodeling and MMPs on the model of chronic daunorubicin-induced cardiomyopathy in rabbits.

The matrix metalloproteinases (MMPs) play a key role during cardiac remodeling. The aim of the study was to investigate the changes in collagenous proteins and MMPs in the model of non-ischemic, anthracycline-induced chronic cardiomyopathy in rabbits using both biochemical and histological approaches. The study was carried out in three groups of Chinchilla male rabbits: 1) daunorubicin (3 mg/kg, once weekly for 10 weeks), 2) control (saline in the same schedule), 3) daunorubicin with the cardioprotectant dexrazoxane (60 mg/kg, before each daunorubicin). Morphological changes in the myocardium of daunorubicin-treated animals were characterized by focal myocardial interstitial fibrosis of different intensity. The subsequent proliferation of the fibrotic tissue was marked by an increased content of both collagen types I and III, which resulted in their typical coexpression in the majority of bundles of fibers forming either smaller or larger scars. Biochemical analysis showed a significantly increased concentration of hydroxyproline, mainly in the pepsin-insoluble fraction of collagenous proteins, in the daunorubicin-treated group (1.42+/-0.12 mg/g) as compared with the control (1.03+/-0.04 mg/g) and dexrazoxane (1.07+/-0.07 mg/g) groups. Dexrazoxane co-administration remarkably reduced the cardiotoxic effects of daunorubicin to the extent comparable with the controls in all evaluated parameters. Using zymography, it was possible to detect only a gelatinolytic band corresponding to MMP-2 (MMP-9 activity was not detectable). However, no significant changes in MMP-2 activity were determined between individual groups. Immunohistochemical analysis revealed increased MMP-2 expression in both cardiomyocytes and fibroblasts. Thus, this study has revealed specific alterations in the collagen network in chronic anthracycline cardiotoxicity in relationship to the expression and activity of major MMPs.

Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death.

BACKGROUND: Dexrazoxane (DEX, ICRF-187) is the only clinically approved cardioprotectant against anthracycline cardiotoxicity. It has been traditionally postulated to undergo hydrolysis to iron-chelating agent ADR-925 and to prevent anthracycline-induced oxidative stress, progressive cardiomyocyte degeneration and subsequent non-programmed cell death. However, the additional capability of DEX to protect cardiomyocytes from apoptosis has remained unsubstantiated under clinically relevant in vivo conditions. METHODS: Chronic anthracycline cardiotoxicity was induced in rabbits by repeated daunorubicin (DAU) administrations (3 mg kg(-1) weekly for 10 weeks). Cardiomyocyte apoptosis was evaluated using TUNEL (terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling) assay and activities of caspases 3/7, 8, 9 and 12. Lipoperoxidation was assayed using HPLC determination of myocardial malondialdehyde and 4-hydroxynonenal immunodetection. RESULTS: Dexrazoxane (60 mg kg(-1)) co-treatment was capable of overcoming DAU-induced mortality, left ventricular dysfunction, profound structural damage of the myocardium and release of cardiac troponin T and I to circulation. Moreover, for the first time, it has been shown that DEX affords significant and nearly complete cardioprotection against anthracycline-induced apoptosis in vivo and effectively suppresses the complex apoptotic signalling triggered by DAU. In individual animals, the severity of apoptotic parameters significantly correlated with cardiac function. However, this effective cardioprotection occurred without a significant decrease in anthracycline-induced lipoperoxidation. CONCLUSION: This study identifies inhibition of apoptosis as an important target for effective cardioprotection against chronic anthracycline cardiotoxicity and suggests that lipoperoxidation-independent mechanisms are involved in the cardioprotective action of DEX.

Anthracycline toxicity to cardiomyocytes or cancer cells is differently affected by iron chelation with salicylaldehyde isonicotinoyl hydrazone.

BACKGROUND AND PURPOSE: The clinical utility of anthracycline antineoplastic drugs is limited by the risk of cardiotoxicity, which has been traditionally attributed to iron-mediated production of reactive oxygen species (ROS). EXPERIMENTAL APPROACH: The aims of this study were to examine the strongly lipophilic iron chelator, salicylaldehyde isonicotinoyl hydrazone (SIH), for its ability to protect rat isolated cardiomyocytes against the toxicity of daunorubicin (DAU) and to investigate the effects of SIH on DAU-induced inhibition of proliferation in a leukaemic cell line. Cell toxicity was measured by release of lactate dehydrogenase and staining with Hoechst 33342 or propidium iodide and lipid peroxidation by malonaldehyde formation. KEY RESULTS: SIH fully protected cardiomyocytes against model oxidative injury induced by hydrogen peroxide exposure. SIH also significantly but only partially and with no apparent dose-dependency, reduced DAU-induced cardiomyocyte death. However, the observed protection was not accompanied by decreased lipid peroxidation. In the HL-60 acute promyelocytic leukaemia cell line, SIH did not blunt the antiproliferative efficacy of DAU. Instead, at concentrations that reduced DAU toxicity to cardiomyocytes, SIH enhanced the tumoricidal action of DAU. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that iron is most likely involved in anthracycline cardiotoxicity and that iron chelation has protective potential, but apparently through mechanism(s) other than by inhibition of ROS-induced injury. In addition to cardioprotection, iron chelation may have considerable potential to improve the therapeutic action of anthracyclines by enhancing their anticancer efficiency and this potential warrants further investigation.

Evaluation of ECG time intervals in a rabbit model of anthracycline-induced cardiomyopathy: a useful tool for assessment of cardioprotective agents.

The aim of this study was to analyze the ECG time intervals in the course of the development of chronic anthracycline cardiomyopathy in rabbits. Furthermore, this approach was employed to study the effects of a model cardioprotective drug (dexrazoxane) and two novel iron chelating compounds--salicylaldehyde isonicotinoyl hydrazone (SIH) and pyridoxal 2-chlorobenzoyl hydrazone (o-108). Repeated daunorubicin administration induced a significant and progressive prolongation of the QRS complex commencing with the eighth week of administration. At the end of the study, we identified a significant correlation between QRS duration and the contractility index dP/dt(max) (r = -0.81; P<0.001) as well as with the plasma concentrations of cardiac troponin T (r = 0.78; P<0.001). In contrast, no alterations in ECG time intervals were revealed in the groups co-treated with either dexrazoxane or both novel cardioprotective drugs (SIH, o-108). Hence, in this study, the QRS duration is for the first time shown as a parameter suitable for the non-invasive evaluation of the anthracycline cardiotoxicity and cardioprotective effects of both well established and investigated drugs. Moreover, our results strongly suggest that novel iron chelators (SIH and o-108) merit further study as promising cardioprotective drugs against anthracycline cardiotoxicity.

Early detection of anthracycline cardiotoxicity in a rabbit model: left ventricle filling pattern versus troponin T determination.

Anthracycline cardiotoxicity represents a serious risk of anticancer chemotherapy. The aim of the present pilot study was to compare the potential of both the left ventricular (LV) filling pattern evaluation and cardiac troponin T (cTnT) plasma levels determination for the early detection of daunorubicin-induced cardiotoxicity in rabbits. The echocardiographic measurements of transmitral LV inflow as well as cTnT determinations were performed weekly for 10 weeks in daunorubicin (3 mg/kg weekly) and control groups (n=5, each). Surprisingly, no significant changes in LV-filling pattern were observed through the study, most likely due to the xylazine-containing anesthesia, necessary for appropriate resolving of the E and A waves. In contrast to the echographic measurement, the dP/dt(min) index obtained invasively at the end of the study revealed a significant impairment in LV relaxation, which was further supported by observed disturbances in myocardial collagen content and calcium homeostasis. However, at the same time cTnT plasma levels were progressively rising in the daunorubicin-treated animals from the fifth week (0.024+/-0.008 microg/l) until the end of the experiment (0.186+/-0.055 microg/l). Therefore, in contrast to complicated non-invasive evaluation of diastolic function, cTnT is shown to be an early and sensitive marker of anthracycline-induced cardiotoxicity in the rabbit model.

Safety and tolerability of repeated administration of pyridoxal 2-chlorobenzoyl hydrazone in rabbits.

Recently, pyridoxal 2-chlorobenzoyl hydrazone (o-108) has been identified as an effective iron chelator [Link et al., Blood 2003; 101: 4172-79]. Since chronic treatment would be necessary in its potential indications, in the present study, the safety and tolerability of this agent after repeated administration was determined. Three doses of o-108 (25, 50, 100 mg/kg, in 10% Cremophor EL) were administered intraperitoneally, once weekly, for 10 weeks to three groups (n=5 each) of Chinchilla male rabbits. The effects on biochemical, haematological and cardiovascular parameters were examined during the experiment; histopathological examination was performed at the end of the experiment. Results were compared with control (saline 2 mL/kg, n=11) and vehicle groups (10% Cremophor EL, 2 mL/kg, n=12). No premature deaths occurred; the well-being of animals was evidenced by their body weight gain, although lower gain was observed with the highest dose (100 mg/kg). Significant elevations of cardiac troponin T plasma concentrations were observed with the highest dose of o-108, but no abnormalities were found in the cardiovascular function and only minor and inconsistent changes in haematological and biochemical parameters were observed. Histopathological examinations of selected organs revealed only weak and reversible changes through all studied groups. Thus, the data from this study suggest that o-108 remains a promising drug from the standpoint of the possibility of its repeated administration and warrants further investigation.

Study of daunorubicin cardiotoxicity prevention with pyridoxal isonicotinoyl hydrazone in rabbits.

Risk of cardiotoxicity is the most serious drawback of the clinical usefulness of anthracycline antineoplastic antibiotics, which however, remain among the most powerful and widely employed anticancer drugs. In this study we have used daunorubicin-induced cardiomyopathy in rabbits as a model to investigate possible cardioprotective effects of pyridoxal isonicotinoyl hydrazone (PIH)-a principal representative of a novel group of aroylhydrazone iron chelators. Three groups of animals were used: a control group (n=11; i.v. saline), daunorubicin-treated animals (n=11; 3mg/kg, i.v.), and animals pretreated with PIH (n=9, 25 mg/kg, i.p.) 60 min before daunorubicin administration. All substances were administered once weekly for 10 weeks. Repeated administration of daunorubicin caused premature death in four animals and induced conspicuous histopathological changes in the myocardium, progressive and significant impairment of systolic heart function (a decrease in left ventricular dP/dt(max), ejection fraction, an increase in the pre-ejection period/left ventricular ejection time index), and a gradual increase in cardiac troponin T plasma concentrations. On the contrary, all the PIH-treated animals have survived all daunorubicin applications. Furthermore, in this group, the daunorubicin-induced cardiac changes were in most functional, biochemical as well as morphological parameters less pronounced than in the group receiving daunorubicin alone. Hence, PIH and other aroylhydrazones merit further investigation as potentially protective agents against anthracycline-induced cardiotoxicity.

Essay in the classification of morning and evening types of activity in the light of the daily course of autonomically influenced body functions.

The present study is an attempt for an objective classification of types of activity by determining the daily periodicity of autonomically influenced body functions. On the basis of a questionnaire, the 23 probands of the test group were classified into morning types (7), evening types (11) and indifferent types (5). Then, for a period of 12h from 07(00) to 18(00), 17 different autonomically influenced parameters were recorded and their mean daily courses calculated separately for the probands of the morning and of the evening type. A comparison of the synchronous values showed that the greatest differences occur between the types at 10(00) and 17(00). At these times of the day, a multidimensional variance and discrimination analysis was carried out which resulted in a very good discrimination of the probands at 10(00) and in a satisfactory one at 17(00). At the same time, an evaluation of the individual parameters recorded was carried out according to their informative value. The most important parameters proved to be the vibration threshold, the R wave height, T wave height, peak time of the pupillogram and d.c. resistance of the skin. On the basis of these results, the classification of 10 probands of an independent test group was effected by a discrimination analysis. In 7 cases this resulted in an agreement with the classification according to the questionnaire.

Binding and metabolism of 5alpha-androstane-3alpha, 17 beta-diol and of 5alpha-androstane-3beta, 17 beta-diol in the prostate, seminal vesicles and plasma of male rats: studies in vivo and in vitro.

Binding of 5alpha-androstane-3alpha, 17 beta-diol (3alpha-diol) and 5alpha-androstane-3beta,-17 beta-diol (3beta-diol) in vivo and in vitro to the 100 000 g cytosol fraction of the rat prostate and seminal vesicles as well as to plasma was studied by agargel electrophoresis and sucrose density gradient ultracentrifugation and the results compared with the corresponding findings for 5alpha-dihydrotestosterone (5alpha-DHT). The metabolism of 3alpha-diol and 3beta-diol was also investigated by thin-layer chromatography. The following results were obtained: (1) A specific binding of 3alpha-diol and 3beta-diol by the cytosols could not be demonstrated in vitro, while 5alpha-DHT was specifically bound. (2) In plasma, 3alpha-diol was extensively bound, 3beta-diol less extensively bound, while 5alpha-DHT remained unbound. (3) After intravenous injection of 3alpha-diol, specifically bound radioactivity, increasing within 30 min, was found in the prostate cytosol, while after 3beta-diol injection no binding occurred. (4) Parallel to the increased binding, the total radioactivity in the prostate accumulated within 30 min after 3alpha-diol injection, the uptake being 5-3 times higher than in skeletal muscle. However after 3beta-diol injection, total radioactivity decreased in the prostate within 30 min, the uptake being only 1-5 times higher than in skeletal muscle. (5) One minute after injection of 3alpha-diol, 53% of the extracted radioactivity in the prostate had been converted to 5alpha-DHT, this increased within 30 min to 81%. Thirty minutes after the injection of 3beta-diol, about 32% of the extracted radioactivity in the prostate had been converted to 5alpha-DHT. (6) From the in-vivo and in-vitro experiments it was concluded that 3alpha-diol exerts its biological effects mainly by its conversion into 5alpha-DHT.