Characteristics and outcome of patients with therapy-related acute promyelocytic leukemia front-line treated with or without arsenic trioxide.

Therapy-related acute promyelocytic leukemia (t-APL) is relatively rare, with limited data on outcome after treatment with arsenic trioxide (ATO) compared to standard intensive chemotherapy (CTX). We evaluated 103 adult t-APL patients undergoing treatment with all-trans retinoic acid (ATRA) alone (n=7) or in combination with ATO (n=24), CTX (n=53), or both (n=19). Complete remissions were achieved after induction therapy in 57% with ATRA, 100% with ATO/ATRA, 78% with CTX/ATRA, and 95% with CTX/ATO/ATRA. Early death rates were 43% for ATRA, 0% for ATO/ATRA, 12% for CTX/ATRA and 5% for CTX/ATO/ATRA. Three patients relapsed, two developed therapy-related acute myeloid leukemia and 13 died in remission including seven patients with recurrence of the prior malignancy. Median follow-up for survival was 3.7 years. None of the patients treated with ATRA alone survived beyond one year. Event-free survival was significantly higher after ATO-based therapy (95%, 95% CI, 82-99%) as compared to CTX/ATRA (78%, 95% CI, 64-87%; P=0.042), if deaths due to recurrence of the prior malignancy were censored. The estimated 2-year overall survival in intensively treated patients was 88% (95% CI, 80-93%) without difference according to treatment (P=0.47). ATO when added to ATRA or CTX/ATRA is feasible and leads to better outcomes as compared to CTX/ATRA in t-APL.

Pretransplant NPM1 MRD levels predict outcome after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia.

The objective was to evaluate the prognostic impact of pre-transplant minimal residual disease (MRD) as determined by real-time quantitative polymerase chain reaction in 67 adult NPM1-mutated acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-eight of the 67 patients had a FLT3-ITD (42%). Median age at transplantation was 54.7 years, median follow-up for survival from time of allografting was 4.9 years. At transplantation, 31 patients were in first, 20 in second complete remission (CR) and 16 had refractory disease (RD). Pre-transplant NPM1 MRD levels were measured in 39 CR patients. Overall survival (OS) for patients transplanted in CR was significantly longer as compared to patients with RD (P=0.004), irrespective of whether the patients were transplanted in first or second CR (P=0.74). There was a highly significant difference in OS after allogeneic HSCT between pre-transplant MRD-positive and MRD-negative patients (estimated 5-year OS rates of 40 vs 89%; P=0.007). Multivariable analyses on time to relapse and OS revealed pre-transplant NPM1 MRD levels >1% as an independent prognostic factor for poor survival after allogeneic HSCT, whereas FLT3-ITD had no impact. Notably, outcome of patients with pre-transplant NPM1 MRD positivity >1% was as poor as that of patients transplanted with RD.

Evaluation of the 'Jumping to conclusions' bias in different subgroups of the at-risk mental state: from cognitive basic symptoms to UHR criteria.

BACKGROUND: Patients with psychosis display the so-called 'Jumping to Conclusions' bias (JTC) - a tendency for hasty decision-making in probabilistic reasoning tasks. So far, only a few studies have evaluated the JTC bias in 'at-risk mental state' (ARMS) patients, specifically in ARMS samples fulfilling 'ultra-high risk' (UHR) criteria, thus not allowing for comparisons between different ARMS subgroups. METHOD: In the framework of the PREVENT (secondary prevention of schizophrenia) study, a JTC task was applied to 188 patients either fulfilling UHR criteria or presenting with cognitive basic symptoms (BS). Similar data were available for 30 healthy control participants matched for age, gender, education and premorbid verbal intelligence. ARMS patients were identified by the Structured Interview for Prodromal Symptoms (SIPS) and the Schizophrenia Proneness Instrument - Adult Version (SPI-A). RESULTS: The mean number of draws to decision (DTD) significantly differed between ARM -subgroups: UHR patients made significantly less draws to make a decision than ARMS patients with only cognitive BS. Furthermore, UHR patients tended to fulfil behavioural criteria for JTC more often than BS patients. In a secondary analysis, ARMS patients were much hastier in their decision-making than controls. In patients, DTD was moderately associated with positive and negative symptoms as well as disorganization and excitement. CONCLUSIONS: Our data indicate an enhanced JTC bias in the UHR group compared to ARMS patients with only cognitive BS. This underscores the importance of reasoning deficits within cognitive theories of the developing psychosis. Interactions with the liability to psychotic transitions and therapeutic interventions should be unravelled in longitudinal studies.

Individuals with inherited chromosomally integrated human herpes virus 6 (ciHHV-6) have functionally active HHV-6 specific T-cell immunity.

To evaluate the human herpes virus 6 (HHV-6) -specific immune response in individuals with chromosomally integrated HHV-6 (ciHHV-6), we measured HHV-6-antigen-specific cytokine responses (interferon-γ, interleukin-2, tumour necrosis factor-α) in T cells by flow cytometry in 12 and 16 individuals with and without ciHHV-6, respectively. All individuals with ciHHV-6 showed HHV-6-specific T cells with higher frequencies of HHV-6-specific CD8(+) cells (0.03-14.93, median 2.15% of CD8(+) cells) compared with non-ciHHV-6 (0.0-10.67, median 0.36%, p 0.026). The observed increased HHV-6-specific functionally active responses in individuals with ciHHV-6 clearly disprove speculations on immune tolerance in ciHHV-6 and indicate clinical and immunological implications of ciHHV-6.

Magnetic seizure therapy in treatment-resistant depression: clinical, neuropsychological and metabolic effects.

BACKGROUND: Magnetic seizure therapy (MST), despite being in an early phase of clinical research, has been demonstrated to be associated with antidepressant efficacy. However, safety, tolerability and efficacy data in connection with functional brain activity from larger samples are lacking. The aim of this study was to determine clinical and cognitive effects of MST and the influence of MST on regional brain glucose metabolism. METHOD: Twenty-six patients suffering from treatment-resistant depression (TRD) underwent MST. Ten patients underwent a randomized trial and 16 patients an open-label study design. The primary outcome criterion was the severity of depressive symptoms assessed with the Hamilton Depression Rating Scale (HAMD). Depressive symptoms, tolerability and cognitive safety, along with social functioning and quality of life parameters, were assessed using various rating scales. A clinical follow-up visit 6 months following the completion of a course of MST and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans of 12 patients were analysed. RESULTS: A significant response to MST was demonstrated by 69% of the patient sample, with 46% meeting remission criteria. Anxiety ratings were significantly reduced in responders and their quality of life was improved. Half of the responders relapsed within 6 months. No cognitive side-effects were observed. FDG-PET scans showed a metabolic increase in the frontal cortex bilaterally and a decrease in the left striatum. CONCLUSIONS: Robust antidepressant and anti-anxiety efficacy of MST was demonstrated, and found to be associated with localized metabolic changes in brain areas that are strongly implicated in depression. Thus, MST presents an effective, well-tolerated and safe treatment option for patients unable to respond to other forms of therapy for depression.

Differential expression of THELPER 1 cytokines upon antigen stimulation predicts ex vivo proliferative potential and cytokine production of virus-specific T cells following re-stimulation.

INTRODUCTION: Cytomegalovirus (CMV) and human adenovirus (ADV) infections are causes of morbidity after stem cell transplantation. Antigen (Ag)-specific T cells are essential for the control of viral infections. However, in vivo expansion potential of T-cell subpopulations is hardly predictable in humans. Furthermore, ex vivo identification of human T cells with repopulating capacity for adoptive T-cell transfer has been difficult. METHODS: We analyzed Ag-specific T-cell populations, subdivided according to the expression of different THELPER- 1 (Th1) cytokines. Isolation by flow cytometry was based on interferon-gamma (IFN)-γ, interleukin (IL)-2, or tumor necrosis factor-alpha (TNF-α) secretion of T cells after ex vivo stimulation with the Ags hexon (for ADV) and pp65 (for CMV). Isolated T cells were expanded and examined for functional characteristics, expansion/differentiation potential, and naïve, effector memory, central memory, and late effector phenotypes. RESULTS: Isolation based on IFN-γ production provides a T-cell population with a mixture of early, central memory, and effector memory T cells, high expansion potential, and effective cytokine production. Selection of T cells with Ag-specific expression of IL-2 or TNF-α, however, results in a T-cell population with reduced proliferation and lower effector potential after expansion. CONCLUSION: We conclude that the exclusive secretion of IFN-γ in the human antiviral T-cell responses preferentially leads to higher repopulation capacities of antiviral T cells, compared to IL-2 or TNF-α secreting T-cell populations.

Bilateral bispectral index monitoring during and after electroconvulsive therapy compared with magnetic seizure therapy for treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) is a highly effective and established treatment for depression. Magnetic seizure therapy (MST) has recently been developed and seems equally effective while associated with fewer side-effects. Both require general anaesthesia, which could be quantified using the bispectral index (BIS). We compared ECT and MST with respect to recovery times, left-sided BIS, and left-right differences in BIS. METHODS: In this prospective, observational study, we enrolled 10 successive patients receiving ECT and 10 patients undergoing MST. Anaesthesia was performed with propofol and monitored with a bilateral BIS sensor. The seizure was elicited when the BIS was within a range from 50 to 60. The time to eye opening was measured and bilateral BIS were recorded for 10 min after seizure induction. RESULTS: A comparable anaesthetic depth was observed in the ECT and MST groups at baseline [mean (standard deviation, sd) BIS values of 94.1 (4.1) and 95.5 (3.0), respectively] and before seizure induction [mean (sd) BIS values of 52.3 (9.6) and 55.2 (10.3), respectively]. Post-ictally, MST patients opened their eyes significantly earlier than ECT patients [3.0 (1.0) vs 6.7 (1.3) min, P<0.001]. They showed a significantly higher BIS at 2 min after seizure induction [69.2 (10.1) vs 50.9 (15.9), P=0.003], and this difference was still present at 10 min after seizure induction [BIS 81.5 (6.5) vs 68.0 (16.4), P<0.001]. Significant differences between the left and right BIS were observed in neither the ECT nor the MST group. CONCLUSIONS: At a comparable anaesthetic depth, MST is superior to ECT in terms of post-ictal recovery, which is correctly reflected by higher post-ictal BIS values. Unilateral BIS monitoring is sufficient to monitor anaesthetic depth in ECT and MST patients. TRIAL REGISTRY NUMBER: NCT 01318018.

Perioral gustatory sweating: case report.

OBJECTIVE: Presentation of a case of perioral Frey syndrome. DESIGN: Case report. SUBJECT: A 72-year-old woman with hyperhidrosis around the mouth and chin. RESULTS: This patient suffered from bilateral perioral gustatory sweating following a mandibular osteotomy; such a case has not previously been described. Possible pathophysiological hypotheses are discussed in relation to the anatomy and innervation of the salivary glands. CONCLUSION: Perioral gustatory sweating is a rare complication of osteotomy.

[Brain stimulation procedures. Transcranial magnetic stimulation, magnetic seizure therapy and deep brain stimulation]. / Hirnstimulationsverfahren. Transkranielle Magnetstimulation, Magnetkrampftherapie und tiefe Hirnstimulation.

Brain stimulation methods are promising treatment options in severe treatment-resistant psychiatric disorders. A safe and noninvasive method is transcranial magnetic stimulation, but the clinical application is not clear. Magnetic seizure therapy is a further development of transcranial magnetic stimulation, by which generalized seizures are induced under anaesthesia. Previous results with regard to the antidepressant effects and the fewer cognitive side effects were significant. Deep brain stimulation is an invasive procedure in which electrodes are stereotactically implanted in special brain areas. The effects in severe therapy-resistant obsessive-compulsive disorders and depressions are promising. However, the evaluation of ethical issues remains an important task.

[The development of deep brain stimulation as a putative treatment for resistant psychiatric disorders]. / Die Entwicklung der tiefen Hirnstimulation bei der Behandlung therapieresistenter psychiatrischer Erkrankungen.

Since approximately 10 years investigations have been carried out on the impact of deep brain stimulation (DBS) of treatment-resistant obsessive-compulsive disorders and depression. New fields of application are for Tourette's syndrome, substance abuse, dementia and anxiety. New functional, structural and molecular data have led to a new conceptualization of these disorders as dysfunctions of networks which process motivational and affective stimuli. DBS permits the selective and basically reversible modulation of such networks. So far adverse effects have been graded as marginal. In the field of treatment-resistant obsessive-compulsive disorders and depressive disorders uncontrolled studies have been published with initial satisfactory and concordant indications of the therapeutic effect of DBS in a variety of target areas of the brain. It is most important to provide a consistent interdisciplinary and durable development of concepts for a responsible use of DBS in patients with psychiatric disorders. Only in this way can the potentially most interesting therapeutic development of clinical psychiatry of the last 20 years be continued uninterrupted.

[CD80-modified tumor cell lines: implications for cell-based vaccinations in breast cancer patients]. / Eine CD80-modifizierte Tumorzelllinie als therapeutische Vakzine beim Mammakarzinom--Vakzinedesign und Studienkonzeption.

A number of genetic alterations are required for malignant transformation. However, these mutations provide the source for tumor-associated antigens which can be recognized by cellular effectors of the immune system. Recent advances in tumor immunology - such as the improved understanding of antigen presentation as well as T cell activation - have opened new perspectives for cancer immunotherapy. The advantage of using tumor cell based vaccines is that these comprise the complete antigen pool of an individual tumor for activating polyclonal immune responses. However, the induction of antigen-specific immune responses is impaired by the fact that T cell activation is depending on additional nonspecific costimulatory signals provided by the antigen-presenting cell. The majority of solid human tumors does not express costimulatory molecules and is unable to deliver all signals required for T cell activation. In contrast, tumors often induce immunologic tolerance. Therefore, the introduction of genes encoding costimulatory molecules such as CD80 or cytokines is aimed at conferring the immunostimulatory potential of tumor cells. We have undertaken efforts at endowing a breast carcinoma cell line expressing at least seven known tumor associated antigens with immunostimulatory competence by CD80 gene transfer. In preclinical studies this cell line was demonstrated to induce specific immune responses. We designed a phase I/II trial to administer the CD80-modified cell line to patients with metastatic breast cancer to determine the toxicities of the vaccination protocol and nature of the vaccine-induced immune response.

A MAGE-A1 HLA-A A*0201 epitope identified by mass spectrometry.

Peptides presented by HLA-A*0201 molecules on the surface of the human breast carcinoma cell line KS24.22 after IFN-gamma induction were analyzed by the "Predict-Calibrate-Detect" approach, which combines epitope prediction and high-performance liquid chromatography mass spectrometry. One of the predicted epitopes, MAGE-A1(278-286) (KVLEYVIKV), was found to be presented by HLA-A*0201, with an estimated copy number of 18 molecules/cell. HLA-A*0201 transgenic mice (HHD mice) were used to generate CTL lines that stained positive with an HLA-A*0201 tetramer folded around the KVLEYVIKV peptide and killed peptide-loaded mouse target cells expressing HLA-A*0201. IFN-gamma-treated or -nontreated HLA-A*0201 expressing HeLa cells transiently transfected with a plasmid expressing the MAGE-A1 gene stimulated in vitro cytokine production by the CTL lines. Moreover, IFN-gamma-treated KS24.22 cells, but not IFN-gamma-treated HLA-A*0201(+) MAGE-A1(-) cells or IFN-gamma-treated HLA-A*0201(-) MAGE-A1(+) cells, were killed by these CTLS: Thus, the combination of HLA epitope prediction, peptide analysis, and immunological methods is a powerful approach for the identification of tumor-associated epitopes.

Intermittent output failure of a VVI device due to the disintegration of the generator.

The metal case and the header of a Biovallees Coralite 247 pacemaker fell apart in a patient resulting in syncope due to myopotential inhibition. Upon recalling our patients with that type of device, we found a similar technological failure in 11 of 16 of them. This finding warrants a consideration for recalling that Biovallees device.

Chemical cardioversion of atrial fibrillation or flutter with ibutilide in patients receiving amiodarone therapy.

BACKGROUND: Ibutilide is a class III drug that is used for the cardioversion of atrial arrhythmias, but it can cause torsade de pointes. Amiodarone also prolongs the QT interval but rarely causes torsade de pointes. There are no studies in which the concomitant use of the 2 agents was examined. The purpose of the present study was to assess the efficacy and safety of cardioversion with combination therapy in patients with atrial fibrillation or flutter. METHODS AND RESULTS: The study included 70 patients who were treated with long-term oral amiodarone and were referred for elective cardioversion of atrial fibrillation (57 of 70, 81%) or flutter (13 of 70, 19%). Patients were taking amiodarone (153+/-259 days, mean+/-SD) and were administered 2 mg intravenous ibutilide. Left ventricular ejection fraction was measured with echocardiography. The QT intervals were measured on 12-lead ECG. Fifty-five patients (79%) had structural heart disease. Patients were in arrhythmia for 196+/-508 days before cardioversion, with a left ventricular ejection fraction of 50+/-11%. In patients with atrial fibrillation, 22 (39%) of 57 and 7 (54%) of 13 patients with flutter converted within 30 minutes of infusion. Thirty-nine patients who did not convert after ibutilide were treated with electrical cardioversion, and 35 (90%) of 39 patients were successfully converted. The QT intervals were further prolonged after ibutilide for the group from 371+/-61 to 479+/-92 ms (P:<0.001). There was 1 episode of nonsustained torsade de pointes (1 of 70, 1.4%) after ibutilide. CONCLUSIONS: The use of ibutilide converted 54% of patients with atrial flutter and 39% of patients with atrial fibrillation who were treated with long-term amiodarone. Despite QT-interval prolongation after ibutilide, only 1 episode of torsade de pointes occurred. Our observations suggest that combination therapy may be a useful cardioversion method for chronic atrial fibrillation or flutter.

[Human fascioliasis symptoms. A case report with review of the literature]. / Das Krankheitsbild der humanen Fasciolose. Ein Fallbericht mit Literaturübersicht.

We present the case of a 17 years old man with fasciola hepatica infection. After initial therapy with Praziquantel and Metronidazole abdominal pain as well as eosinophilia persisted. The diagnosis was made by ERC and examination of the bile, where typical ovulas were found. An analysis of faeces and the serology (ELISA, IFAT) were not diagnosticated. After papillotomy, extraction of the parasites and therapy with Triclabendazole the patient became asymptomatic, the serology turned to negative and the haematology was normalised.

Potential interaction between ritonavir and carbamazepine.

Ritonavir (RTV), a protease inhibitor, and carbamazepine (CBZ), an anticonvulsant, were administered concurrently to a patient who had human immunodeficiency virus infection and epilepsy. The combination resulted in elevated serum concentrations of CBZ, with accompanying vomiting, vertigo, and transient liver dysfunction. After discontinuing RTV and reducing the dosage of CBZ, the serum concentration of CBZ returned to the optimal range, symptoms subsided, and liver function returned to baseline. Carbamazepine is metabolized in the liver to a large extent by the cytochrome P450 (CYP) system, especially CYP3A4, 2C8, and 1A2, whereas RTV is metabolized primarily by CYP3A and is a potent inhibitor of this enzyme. Careful clinical monitoring may help prevent adverse drug interactions when these drugs are administered concurrently.

Angiographic results after minimally invasive coronary bypass grafting using the minimally invasive direct coronary bypass grafting (MIDCAB) approach.

OBJECTIVE: The aim of the study was to evaluate the early and mid-term angiographic results after minimally invasive coronary bypass grafting using an 'off-pump' technique via a lateral minithoracotomy. METHODS: In 221 out of 271 patients (81.5%) who underwent minimally invasive direct coronary bypass grafting (MIDCAB) the quality of the internal thoracic artery (ITA)-graft and the anastomosis was evaluated by conventional coronary angiography between the 2nd and 6th postoperative day (POD). A subgroup of 130 patients (47.9%) of the initial cohort were repeatedly controlled by angiography 6 months later. RESULTS: The early postoperatively patency rate of the grafts was (96.8%). Moderate anastomotic stenosis between 50 and 75% was found in 13/221 (5.8%) patients, whereas severe stenosis of more than 75% was seen in 10/221 (4.5%) and occlusion of the graft in 3/221 (1.3%) patients. A stress-ECG was performed in patients with a severe stenosis to provoke ST-segment changes or clinical findings of myocardial ischemia. A positive stress test was found in 4/221 patients (1,8%). Early re-intervention was required in 7/221 (3.1%) patients. After 6 months, angiographic follow-up revealed a patency rate of (95.4%). Of 130 patients 5 (3.8%) presented with moderate anastomotic stenosis, whereas 3/130 (2.0%) patients showed a severe stenosis with one patient (0.7%) having myocardial ischemia during stress test. Occlusion of the graft was seen in 3/130 patients (2.3%). During follow-up, 4/130 (3.0%) patients underwent re-intervention. A comparison between early postoperative and 6-months angiogram revealed a decrease or a disappearance of the severity of the stenosis in 4/15 patients (26.6%). CONCLUSION: Since stenosis of the anastomosis may occur after minimally invasive, beating heart coronary bypass grafting, postoperative angiography should be performed to provide quality control and to guide appropriate further treatment. The latter is necessary if the stenosis is accompanied by reduced run-off and evidence of myocardial ischemia during stress test. An improvement of early stenosis at the anastomosis may be expected in more than 25%.