The prognostic value of serum MMP-7 levels in prostate cancer patients who received docetaxel, abiraterone, or enzalutamide therapy.

OBJECTIVES: The rapidly changing treatment landscape in metastatic castration-resistant prostate cancer (mCRPC) calls for biomarkers to guide treatment decisions. We recently identified MMP-7 as a potential serum marker for the prediction of response and survival in mCRPC patients who received docetaxel (DOC) chemotherapy. Here, we aimed to test this finding in an independent patient cohort and in addition to explore the prognostic potential of serum MMP-7 in abiraterone (ABI) or enzalutamide (ENZA) treated patients. METHODS AND MATERIALS: MMP-7 levels were measured in 836 serum samples from 320 mCRPC patients collected before and during DOC (n = 95), ABI (n = 140), or ENZA (n = 85) treatment by using the ELISA method. Results were correlated with clinical and follow-up data. RESULTS: MMP-7 baseline levels were similar between the 3 treatment groups. In the ABI and ENZA cohorts, baseline MMP-7 levels were lower in patients with prior radical prostatectomy (P = 0.058 and P = 0.041, respectively). Baseline MMP-7 levels above the median were associated with shorter overall survival for the DOC (P = 0.001) and ENZA (P = 0.006) cohorts. Multivariable analyses in the DOC and ENZA cohorts revealed that high pretreatment MMP-7 level is an independent risk factor for patients' survival. In addition, in DOC-treated patients with high baseline MMP-7 level, marker decrease at the third DOC cycle was associated with improved survival. Patients with high baseline MMP-7 levels had better survival when treated with ABI compared to DOC or ENZA. CONCLUSIONS: We confirmed the prognostic value of pretreatment MMP-7 serum level and its changes as independent predictors of survival in DOC-treated mCRPC patients. In addition, high MMP-7 was a negative predictor in ENZA-treated but not in ABI-treated patients. These results warrant further research to confirm the predictive value of serum MMP-7 and to explore the potential mechanistic involvement of MMP-7 in DOC and ENZA resistance of mCRPC patients.

Exhaled nitric oxide and pulmonary complications after paediatric stem cell transplantation.

UNLABELLED: Pulmonary complications are major causes of morbidity and mortality after haematopoietic stem cell transplantation (HSCT). We hypothesise that elevated exhaled nitric oxide (FeNO) levels early after HSCT in children are predictive for pulmonary complications. The present prospective study included 30 children (age, 4-18 years) before HSCT. FeNO levels were evaluated 10 days before transplant, at day 0, day +28 and day +60 after HSCT. During the follow-up period until day +100, pulmonary complications and lung function were assessed. Before HSCT, the mean FeNO levels were comparable in children with or without post-transplant pulmonary complications. However, they differed at day 0 and day +28 with a mean of 7 (±1.95) and 13 (±3.44) ppb at day 0 and a mean of 13 (±3.44) and 14 (±3.57) ppb at day +28, respectively. CONCLUSION: Children with pulmonary complications after day +28 have higher mean FeNO levels 28 days after HSCT than children without later pulmonary complications. Therefore, FeNO could be an important diagnostic tool for hyperinflammatory response in bronchial epithelium after paediatric HSCT.

Non-atopic IgE and eosinophil cationic protein after allogeneic hematopoietic stem cell transplantation in children.

Allogeneic hematopoietic stem cell transplantation (HSCT) in childhood is associated with severe pulmonary complications, but the pathophysiologic mechanisms remain unclear. Our aim was to evaluate the association of total and specific IgE, eosinophil cationic protein (ECP) and eosinophilia in HSCT recipients with pulmonary complications. We prospectively measured total and specific serum IgE, eosinophils, and ECP before and 28, 100, and 180 days after HSCT. We included 30 children (age 2-17 years) undergoing HSCT. Nine patients had a history of previous atopy without being associated with pulmonary complications after HSCT until day +360. Specific IgE levels showed a decline after HSCT, associated with the absence of allergy symptoms, suggesting a reduction of atopy. Elevated total serum IgE levels occurred in seven patients on day +28 after HSCT. This elevation did not coincide with allergy symptoms. ECP showed no correlation with total allergy symptoms, eosinophilia, IgE levels, or pulmonary complications. There was a significant correlation (p = 0.0367) between ECP levels on day +28 and concurrent acute graft-versus-host disease (GvHD). Non-atopic serum ECP and IgE levels are elevated on day +28 after HSCT in children, with ECP showing a potential relation to acute GvHD.

Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD.

This consensus statement established under the auspices of the German working group on BM and blood stem cell transplantation (DAG-KBT), the German Society of Hematology and Oncology (DGHO), the Austrian Stem Cell Transplant Working Group, the Swiss Blood Stem Cell Transplantation Group (SBST) and the German-Austrian Pediatric Working Group on SCT (Päd-Ag-KBT) summarizes current evidence for diagnosis, immunosuppressive and supportive therapy to provide practical guidelines for the care and treatment of patients with pulmonary manifestations of chronic GVHD (cGVHD). Pulmonary cGVHD can present with obstructive and/or restrictive changes. Disease severity ranges from subclinical pulmonary function test (PFT) impairment to respiratory insufficiency with bronchiolitis obliterans being the only pulmonary complication currently considered diagnostic of cGVHD. Early diagnosis may improve clinical outcome, and regular post-transplant follow-up PFTs are recommended. Diagnostic work-up includes high-resolution computed tomography, bronchoalveolar lavage and histology. Topical treatment is based on inhalative steroids plus beta-agonists. Early addition of azithromycin is suggested. Systemic first-line treatment consists of corticosteroids plus, if any, continuation of other immunosuppressive therapy. Second-line therapy and beyond includes extracorporeal photopheresis, mammalian target of rapamycin inhibitors, mycophenolate, etanercept, imatinib and TLI, but efficacy is limited. Clinical trials are urgently needed to improve understanding and treatment of this deleterious complication.

[History of atrial fibrillation]. / Zur Geschichte des Vorhofflimmerns.

The authors review the history of atrial fibrillation, the most frequent clinically observed cardiac arrhythmia. A French "clinicopathologist", Jean Baptist de Sénac (1693-1770), was the first who assumed a correlation between "rebellious palpitation" and a stenosis of the mitral valve. From an analysis of simultaneously recorded arterial and venous pressure curves, the Scottish Sir James Mackenzie (1853-1925) demonstrated that a presystolic a wave cannot be seen on the jugular phlebogram during "pulsus irregularis perpetuus". The first human ECG depicting atrial fibrillation was published by Willem Einthoven (1860-1927) in 1906. The proof of a direct connection between absolute arrhythmia and auricular fibrillation was established by two Viennese physicians, Rothberger and Winterberg. The major discoveries relating to the pathomechanism and the clinical features of atrial fibrillation in the 20(th) century stemmed from the scientific activities of Karel Frederik Wenckebach, Sir Thomas Lewis, Gordon Moe, and Maurits Allessie.

[Antireflux procedures at our unit (1990-1999)]. / Refluxgátló mútétek klinikánk gyakorlatában (1990-1999).

UNLABELLED: A retrospective analysis was carried out to evaluate the changing attitude of antireflux surgical practice of the authors. Between 1990 and 1994 24 antireflux procedures were performed. Laparoscopic antireflux surgery was introduced in 1995. Since then 41 laparoscopic and 23 open repairs have been performed. Indication for surgery was always based on thorough preoperative examination protocol including functional tests of the esophagus. Each patients had undergone endoscopic and X-ray examinations. The patients are under continuous follow-up surveillance. During the postoperative follow-up studies more than 2/3 of the patients (61 patients) agreed to carry out the functional tests postoperatively. RESULTS: The demographic data of patients of the two study periods proved to be comparable. The length of history was 10.5 years in the first group, while it was 8.9 years in the second group. In both groups the surgical repair caused significant reflux control confirmed by decrease of reflux index and number of reflux episodes furthermore by increase of resting lower esophageal sphincter pressure. Actually 4 recurrences are known in the first group and 2 in the second group. One of the 4 recurrences observed in the first period was treated by redo surgery. The patients having recurrences in the second period can easily be managed by medical therapy. There was no mortality and severe morbidity during the study periods. Few patients reported mild temporary dysphagia. CONCLUSIONS: In a given proportion of reflux patients the individually planned and perfectly performed antireflux surgery offers an acceptable definitive treatment option. The availability of endoscopic surgery enhances this trend, which can be seen all over the world. An increase can be seen in the number of procedures: nearly three times more patients were operated on during the second period. The early clinical results of laparoscopic antireflux procedures are good enough. Good long-term results can be expected if we accept and apply the basic technical principles determined during the open surgery era.

[Scientometric and publication malpractices. The appearance of globalization in biomedical publishing]. / Scientometriás és publikációs praktikák. A globalizáció megjelenése az orvosi publicisztikában.

Attention is drawn to publication and scientometric malpractices utilized by biomedical authors who do not adhere to the accepted ethical norms. The difference between duplicate/redundant and bilingual publications is defined. In the course of discussion of the manipulations that may be observed in the field of scientometry, it is pointed out that abstract of congress lectures/posters can not be taken into consideration for scientometric purposes even if such abstracts are published in journals with impact factors. A further behavioral form is likewise regarded as unacceptable from the aspect of publication ethics: when a physician who has participated in a multicentre, randomized clinical trial receives recognition (in an appendix or in an acknowledgement of an article) as having contributed data, but assesses this appreciation as co-authorship and thereby attempts to augment the value of his or her publication activity. The effects of globalization on biomedical publication activity are considered, and evidence is provided that the rapidly spreading electronic publication for a give rise to new types of ethical dilemmas. It is recommended that, in the current age of Anglo-American globalization, greater emphasis should be placed on the development of medical publication in the mother tongue (Hungarian).

[Scientometrics and publishing in Hungarian medical science. Ethical and technical issues]. / A scientometria és a hazai szakirodalmi tevékenység. Etikai és technikai kérdések.

The authors present an account of the main ethical and technical aspects relating to the measurement of medical publication activities and the compilation of publications lists. It is demonstrated that the Anglo-American scientometric system (Institute for Scientific Information, USA) is currently gaining stable ground in Hungary. At the same time, however, there continues to be a place for a national publication index used to assess Hungarian-language publication activity, for the two systems conveniently supplement one another. The criterion system of medical publishing established by the International Committee of Medical Journal Editors (ICMJE) is described in detail, and is recommended for wide-ranging application in Hungary.

Gallbladder hypomotility in diabetic polyneuropathy.

This study was performed to evaluate the gallbladder motility in long-standing diabetes mellitus. The gallbladder function of diabetic patients was measured by means of quantitative hepatobiliary scintigraphy, and the severity of the associated autonomic and sensory polyneuropathy was determined. The presence of a marked gallbladder hypomotility was established, and a positive correlation was observed between the severity of the autonomic disturbance and the contractile disorder. This study underlines the important role of the neuropathy in the development of gallbladder hypomotility accompanying long-term diabetes mellitus.

[Electrocardiographic Osborn wave in hypothermia]. / Elektrokardiográfiás Osborn-hullám hypothermiában.

The authors report the first Hungarian case of electrocardiographic Osborn wave with accidental hypothermia (core temperature 32 degrees C). The cellular and ionic mechanisms of the development of J-wave-elevation and the cardiac electrophysiological and ECG changes caused by hypothermia are briefly reviewed. An account is presented of those conditions in which, in a few or in all ECG leads, an Osborn wave or distinct J-point-elevation may be observed.

Effect of GLG-V-13, a class III antiarrhythmic agent, on potassium currents in rabbit ventricular myocytes.

The effects of a new Class III antiarrhythmic drug, GLG-V-13, on the 4-aminopyridine sensitive transient outward current, on the inward rectifier potassium current, on the ATP sensitive potassium current and on the rapid and slow components of the delayed rectifier potassium current were studied in single rabbit ventricular myocytes using the whole-cell voltage-clamp technique. GLG-V-13 blocked the rapid component of the delayed rectifier potassium current in a dose-dependent manner, with an estimated EC50 value of 0.36 microM. At high concentration, the slow component of the delayed rectifier potassium current was also depressed by the drug (40% effect at 10 microM concentration). The transient outward current, the inward rectifier potassium current and the ATP sensitive potassium current were not influenced by GLG-V-13, even at 10 microM concentration. Thus, GLG-V-13 blocks predominantly the rapid component of the delayed rectifier potassium current which may play a significant role in the prolongation of repolarization by the drug in ventricular tissue.

Hexamethylene bisacetamide (HMBA) increases thyroglobulin levels in porcine thyroid cells without increasing cyclic-AMP.

The polar planar compound hexamethylene bisacetamide (HMBA) is an inducer of terminal differentiation which has been extensively studied in the murine erythroleukemia cells (MELC). We have tested this compound in normal porcine thyroid cells in primary culture where it either activates or inhibits the major tissue specific functions of these cells: it induces the reorganization of cells into follicles, prevents the loss of thyrotropin sensitivity in monolayer cells, activates cell growth but inhibits their iodide metabolism. In this paper, we demonstrate that HMBA acts on the total thyroglobulin levels measured in cell layers plus media. This specific marker of thyroid tissue is increased by HMBA both in kinetics and in concentration-response experiments. HMBA per se does not increase the total cyclic AMP measured either during the first hours after stimulation or in the following days when compared to controls. As expected, cyclic AMP in the same experiment increased rapidly within minutes after the cells were challenged by TSH (positive control). Altogether, the results show that the drug HMBA mimics thyrotropin effects on thyroglobulin levels measured in porcine thyroid cells in culture. This modulation cannot be explained by an increase in cyclic AMP, indicating that despite similarities between TSH and HMBA effects, the mechanism of the mode of action of these two molecules is very different.

[Cardiac electrophysiological effect and clinical use of adenosine]. / Az adenozin szív-elektrofiziológiai hatásai és klinikai alkalmazása.

A review is provided of the present state of knowledge relating to the cardiac electrophysiological effects of adenosine at ion channel and clinical levels. It is emphasized that intravenous adenosine is highly effective in terminating sinus node, atrioventricular (AV) nodal and AV-reciprocating reentrant tachycardias. In the course of an account of the antiarrhythmic indications of adenosine therapy, the main aspects of the diagnostic use of the nucleoside are briefly discussed. It is pointed out that adenosine treatment may possibly be accompanied by the occurrence of atrial and ventricular proarrhythmias, for at pharmacological dose of 6-12 mg this endogenous cardioprotective and antiarrhythmic agent is not devoid of side-effects.

[The principles of pharmacotherapy for arrhythmia at the turn of the millenium]. / Az antiarrhythmiás farmakoterápia alapelvei az ezredfordulón.

A review is presented at the main causes of the change in paradigm that has occurred in the past 10 years in antiarrhythmic pharmacotherapy. The new attitude is ascribed to (1) the advances made in the application of non-pharmacological therapeutic modalities (radiofrequency catheter ablation, implantable antiarrhythmic devices), (2) the modification of therapeutic practice in response to the results of large-scale prospective randomized clinical trials, and (3) the proper recognition and appropriate appreciation of the frequently life-threatening proarrhythmic action of antiarrhythmic drugs. The current state of knowledge is discussed as concerns the anti- and proarrhythmic effects of the drugs available at present, and also their safe clinical use.

Hexamethylenebisacetamide modulation of thyroglobulin and protein levels in thyroid cells is not mediated by phosphatidylinositol-3-kinase: a study with wortmannin.

Hexamethylenebisacetamide (HMBA) induces in murine erythroleukemia cells (MELC) the commitment to terminal differentiation leading to globin gene expression. In the thyroid, HMBA acts as a growth factor and also as a differentiating agent. In the present paper, we studied the effect of HMBA on the very specific thyroid marker thyroglobulin (Tg) in two different thyroid cell systems, i.e., porcine cells in primary culture and ovine cells in long term culture. Using wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase, we investigated whether this enzyme is involved in HMBA mode of action. We found that HMBA is a positive modulator of Tg production in porcine cells, but a negative effector in the OVNIS cell line. As all HMBA effects studied in the present paper, i.e., Tg production and total protein levels, are not inhibited by wortmannin, we suggest the non-involvement of phosphatidylinositol-3-kinase in HMBA mode of action.

DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) increases iodide trapping, inhibits thyroperoxidase and antagonizes the TSH-induced apical iodide efflux in porcine thyroid cells.

4,4'-Di-isothiocyanatostilbene-2,2'-disulfonic acid (DIDS), an inhibitor of several anionic channels and transporters including the band 3 protein of the red blood cell membrane was tested on iodide metabolism in cultured porcine thyroid cells. We used three experimental cell culture models: (i) forskolin-stimulated correctly inside-in polarized follicle-associated thyroid cells cultured onto plastic support (ii) suspensions of isolated cells derived from such cultures (iii) polarized monolayers in bicameral chambers. DIDS was observed to increase free-iodide trapping in all conditions. Organification of iodide by follicle-associated cell cultures incubated for 6 h decreased as a function of DIDS concentration with an IC50 of 5 x 10(-5) M. This block in organification is accounted for a block in thyroperoxidase activity as in vitro both purified lactoperoxidase and purified porcine thyroperoxidase were inhibited by DIDS with a similar dose-dependency the IC50 being also of 5 x 10(-5) M. Both control and DIDS-treated cells in suspension, actively trapped iodide and reached a steady concentration in about 50 min; however the plateau was 4.4-fold higher in (10(-3) M) DIDS-treated cells. Acute TSH-stimulation at this plateau of 125I-preloaded cells in suspension in the presence of 2 mM methimazole (MMI) induced a fast release of iodide from these cells as expected (first step of the TSH-biphasic effect). This TSH-induced iodide efflux was however completely inhibited by DIDS (10(-3) M). Furthermore, addition of DIDS to the apical compartment of TSH-prestimulated cell monolayers in bicameral chambers resulted in an increase in intracellular-iodide concentration and in an inhibition of iodide efflux into the apical medium. Taken together, the present results demonstrate that DIDS mainly interacts with two main components of the thyroid apical cell membrane: thyroperoxidase and a cAMP-sensitive iodide channel.