A new potassium-based intermediate and its role in the desorption properties of the K-Mg-N-H system.

New insights into the reaction pathways of different potassium/magnesium amide-hydride based systems are discussed. In situ SR-PXD experiments were for the first time performed in order to reveal the evolution of the phases connected with the hydrogen releasing processes. Evidence of a new K-N-H intermediate is shown and discussed with particular focus on structural modification. Based on these results, a new reaction mechanism of amide-hydride anionic exchange is proposed.

HIV and hepatitis C virus coinfection in Canada: challenges and opportunities for reducing preventable morbidity and mortality.

OBJECTIVES: Hepatitis C virus (HCV) has emerged as an important health problem in the era of effective HIV treatment. However, very few data exist on the health status and disease burden of HIV/HCV-coinfected Canadians. METHODS: HIV/HCV-coinfected patients were enrolled prospectively in a multicentre cohort from 16 centres across Canada between 2003 and 2010 and followed every 6 months. We determined rates of a first liver fibrosis or endstage liver disease (ESLD) event and all-cause mortality since cohort enrolment and calculated standardized mortality ratios compared with the general Canadian population. RESULTS: A total of 955 participants were enrolled in the study and followed for a median of 1.4 (interquartile range 0.5-2.3) years. Most were male (73%) with a median age of 44.5 years; 13% self-identified as aboriginal. There were high levels of current injecting drug and alcohol use and poverty. Observed event rates [per 100 person-years; 95% confidence interval (CI)] were: significant fibrosis (10.21; 8.49, 12.19), ESLD (3.16; 2.32, 4.20) and death (3.72; 2.86, 4.77). The overall standardized mortality ratio was 17.08 (95% CI 12.83, 21.34); 12.80 (95% CI 9.10, 16.50) for male patients and 28.74 (95% CI 14.66, 42.83) for female patients. The primary causes of death were ESLD (29%) and overdose (24%). CONCLUSIONS: We observed excessive morbidity and mortality in this HIV/HCV-coinfected population in care. Over 50% of observed deaths may have been preventable. Interventions aimed at improving social circumstances, reducing harm from drug and alcohol use and increasing the delivery of HCV treatment in particular will be necessary to reduce adverse health outcomes among HIV/HCV-coinfected persons.

Results from a 1-year, open-label, single arm, multi-center trial evaluating the efficacy and safety of oral Deferasirox in patients diagnosed with low and int-1 risk myelodysplastic syndrome (MDS) and transfusion-dependent iron overload.

The majority of patients with myelodysplastic syndrome (MDS) present with anemia and will become dependent on regular transfusions of packed red blood cells (PRBC) with the risk of iron overload (IOL). Liver iron content best reflects the total body iron content, and measurement of liver iron concentration (LIC) by MRI is a validated tool for detection, but data in MDS is rather limited. Here we present the results of a multi-center trial evaluating the efficacy and safety of deferasirox (DFX) in low and intermediate-1 risk MDS patients with transfusion-dependent IOL. Three patients with transfusion frequency of > 4 units PRBC per month were initially treated with 30 mg/kg/day while in 46 patients with a lower transfusion burden deferasirox was initiated at 20 mg/kg/day, due to patient related reasons one patient received DFX in a dose of 6 mg/kg/day only. LIC was measured by MRI at baseline and end of study using the method by St. Pierre et al. The intention to treat population consisted of 50 MDS patients (28 male; 22 female) with a median age of 69 years who were treated with DFX for a median duration of 354 days. Mean daily dose of DFX was 19 mg/kg/day. Median serum ferritin level (SF) at baseline was 2,447 ng/mL and decreased to 1,685 ng/mL (reduction by 31 %) at end of study (p = 0.01). In 7 (13 %) patients the initially chosen dose had to be increased due to unsatisfactory efficacy of chelation therapy. For 21 patients, LIC measurement by liver MRI was performed at baseline and for 19 of these patients at the end of study: mean LIC decreased significantly from 16,8 mg/g dry tissue weight (± 8.3 mg/g dry tissue weight) at study entry to 10,8 mg/g dry tissue weight (± 10.4 mg/g dry tissue weight) at end of study (p = 0.01). Of all patients exposed to the study drug (n = 54), 28 (52 %) did not complete the 12 month study period most commonly due to AEs in 28 % (n = 15) and abnormal laboratory values in 7 % (n = 4), respectively. The most common adverse events (≥ 10 % of all patients) with suspected drug relationship were diarrhea (n = 25, 46 %), nausea (n = 13, 24 %), upper abdominal pain (n = 8, 15 %), serum creatinine increase (n = 16, 30 %) and rash (n = 5, 9 %). Adverse events making dose adjustments or interruption of study drug necessary occurred in 33 patients (61 %). Hematologic improvement according to IWG criteria (2006) was observed in 6 patients (11 %). Initiation of treatment of IOL with DFX depending on the transfusion burden yields sufficient reduction of excess iron indicated by serum ferritin levels and most importantly by liver MRI. The safety profile of DFX was comparable to previous observations.

Smartphone and wearable detected atrial arrhythmias in Older Adults: Results of a fully digital European Case finding study.

Aims: Simplified detection of atrial arrhythmias via consumer-electronics would enable earlier therapy in at-risk populations. Whether this is feasible and effective in older populations is not known. Methods and results: The fully remote, investigator-initiated Smartphone and wearable detected atrial arrhythmia in Older Adults Case finding study (Smart in OAC-AFNET 9) digitally enrolled participants ≥65 years without known atrial fibrillation, not receiving oral anticoagulation in Germany, Poland, and Spain for 8 weeks. Participants were invited by media communications and direct contacts. Study procedures adhered to European data protection. Consenting participants received a wristband with a photoplethysmography sensor to be coupled to their smartphone. The primary outcome was the detection of atrial arrhythmias lasting 6 min or longer in the first 4 weeks of monitoring. Eight hundred and eighty-two older persons (age 71 ± 5 years, range 65-90, 500 (57%) women, 414 (47%) hypertension, and 97 (11%) diabetes) recorded signals. Most participants (72%) responded to adverts or word of mouth, leaflets (11%) or general practitioners (9%). Participation was completely remote in 469/882 persons (53%). During the first 4 weeks, participants transmitted PPG signals for 533/696 h (77% of the maximum possible time). Atrial arrhythmias were detected in 44 participants (5%) within 28 days, and in 53 (6%) within 8 weeks. Detection was highest in the first monitoring week [incidence rates: 1st week: 3.4% (95% confidence interval 2.4-4.9); 2nd-4th week: 0.55% (0.33-0.93)]. Conclusion: Remote, digitally supported consumer-electronics-based screening is feasible in older European adults and identifies atrial arrhythmias in 5% of participants within 4 weeks of monitoring (NCT04579159).

Remote Design of a Smartphone and Wearable Detected Atrial Arrhythmia in Older Adults Case Finding Study: Smart in OAC - AFNET 9.

Introduction: Screening for atrial fibrillation and timely initiation of oral anticoagulation, rhythm management, and treatment of concomitant cardiovascular conditions can improve outcomes in high-risk populations. Whether wearables can facilitate screening in older adults is not known. Methods and Analyses: The multicenter, international, investigator-initiated, single-arm case-finding Smartphone and wearable detected atrial arrhythmia in older adults case finding study (Smart in OAC - AFNET 9) evaluates the diagnostic yield of a validated, cloud-based analysis algorithm detecting atrial arrhythmias via a signal acquired by a smartphone-coupled wristband monitoring system in older adults. Unselected participants aged ≥65 years without known atrial fibrillation and not receiving oral anticoagulation are enrolled in three European countries. Participants undergo continuous pulse monitoring using a wristband with a photo plethysmography (PPG) sensor and a telecare analytic service. Participants with PPG-detected atrial arrhythmias will be offered ECG loop monitoring. The study has a virtual design with digital consent and teleconsultations, whilst including hybrid solutions. Primary outcome is the proportion of older adults with newly detected atrial arrhythmias (NCT04579159). Discussion: Smart in OAC - AFNET 9 will provide information on wearable-based screening for PPG-detected atrial arrhythmias in Europe and provide an estimate of the prevalence of atrial arrhythmias in an unselected population of older adults.

Lacking CD56 expression in a relapsing cutaneous blastic plasmacytoid dendritic cell neoplasm after allogeneic bone marrow transplantation: FISH analysis revealed loss of 11q.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare entity characterized by a CD4+/CD56+/CD123+ immunophenotype and a fatal clinical course. The average survival of 12-14 months may be prolonged by allogeneic bone marrow transplantation (BMT). OBJECTIVES: We report about a male patient who suffered from BPDCN with a typical histology and co-expression of CD4/CD123 and a CD56 expression by 80% of the tumour cells. The cutaneous tumour relapse after chemotherapy and allogeneic BMT was completely negative for CD56. METHODS: We performed interphase fluorescence in situ hybridization (FISH) analysis of tumour tissue, asserved before and after BMT, using specific probes for chromosome 11, which encompass the CD56 gene region. RESULTS: The tumour cells revealed a partial loss of 11q as well as a monosomy of chromosome 11. CONCLUSION: This case demonstrates for the first time that loss of CD56 expression can also occur as a secondary event after chemotherapy and BMT. In our case, DNA loss of 11q23 could be responsible for the negativity of 20% of tumour cells as observed before chemotherapy. However, the complete loss of CD56 expression in the relapsed tumour cannot be explained by the loss of 11q23 alone. Additional factors such as chemotherapy-induced mutations might also have contributed.

Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification-an approach to classification of patients with t-MDS.

In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p < 0.001). The results regarding carefully reviewed cytogenetic data, classifications, and prognostic scores confirmed that t-MDS are similarly heterogeneous as p-MDS and therefore deserve the same careful differentiation regarding risk. As reference, these results were compared with 4593 primary MDS (p-MDS) patients represented in the International Working Group for Prognosis in MDS database (IWG-PM). Although a less favorable clinical outcome occurred in each t-MDS subset compared with p-MDS subgroups, FAB and WHO-classification, IPSS-R, and WPSS-R separated t-MDS patients into differing risk groups effectively, indicating that all established risk factors for p-MDS maintained relevance in t-MDS, with cytogenetic features having enhanced predictive power. These data strongly argue to classify t-MDS as a separate entity distinct from other WHO-classified t-myeloid neoplasms, which would enhance treatment decisions and facilitate the inclusion of t-MDS patients into clinical studies.

Prognostic impact of age and gender in 897 untreated patients with primary myelodysplastic syndromes.

BACKGROUND: The International Prognostic Scoring System (IPSS) is the golden standard to assess prognosis in myelodysplastic syndromes (MDS). The aim of this analysis was to study age and gender as interacting variables for individualized prognostication. PATIENTS AND METHODS: In all, 897 patients with primary MDS treated with supportive care only were examined in a retrospective multicenter study. A Cox model was developed to determine the prognostic impact of age and gender on survival and to examine their modulating influence on IPSS results. Based on main effects and interactions of these variables, we established an individualized age- and gender-adapted scoring system to improve prognostication in MDS. RESULTS: While the risk of a patient in the IPSS is best represented by the values 0 (low), +1 (intermediate-1), +2 (intermediate-2), and +3 (high), these values were found to vary between -1.9 and +3.5 in the same patients when including age and gender. Whereas in low-risk MDS, male patients were found to have a less favorable survival, a particularly high risk (+3.5) was found in younger (< or = 66 years) high-risk female patients. CONCLUSION: The inclusion of age and gender and their respective interactions contribute to improved and individualized prognostication in MDS.

Delivery of carboplatin by carbon-based nanocontainers mediates increased cancer cell death.

Since the activity of several conventional anticancer drugs is restricted by resistance mechanisms and dose-limiting side-effects, the design of nanocarriers seems to be an efficient and promising approach for drug delivery. Their chemical and mechanical stability and their possible multifunctionality render tubular nanomaterials, such as carbon nanotubes (CNTs) and carbon nanofibres (CNFs), promising delivery agents for anticancer drugs. The goal of the present study was to investigate CNTs and CNFs in order to deliver carboplatin in vitro. No significant intrinsic toxicity of unloaded materials was found, confirming their biocompatibility. Carboplatin was loaded onto CNTs and CNFs, revealing a loading yield of 0.20 mg (CNT-CP) and 0.13 mg (CNF-CP) platinum per milligram of material. The platinum release depended on the carrier material. Whereas CNF-CP marginally released the drug, CNT-CP functioned as a drug depot, constantly releasing up to 68% within 14 days. The cytotoxicity of CNT-CP and CNF-CP in urological tumour cell lines was dependent on the drug release. CNT-CP was identified to be more effective than CNF-CP concerning the impairment of proliferation and clonogenic survival of tumour cells. Moreover, carboplatin, which was delivered by CNT-CP, exhibited a higher anticancer activity than free carboplatin.

Papular exanthem discloses acute myeloid leukaemia: interphase fluorescence in situ hybridization revealed deletion of p53 and gain at 8q22/8q24/Tel8q without trisomy 8.

We describe a 79-year-old patient who presented with fatigue, weight loss, pancytopenia and a papular exanthem. Previous attempts to taking bone-marrow biopsies had resulted in a 'dry tap', with no material collected, suggesting idiopathic myelofibrosis. Histological examination of skin biopsies showed dermal infiltration of monocytoid cells, resulting in a diagnosis of acute myeloid leukaemia (French-American-British M5 morphology) with leukaemia cutis (LC). Numerous abnormalities of chromosome 8 (trisomy or tetrasomy) have been identified in association with LC. We performed fluorescent in situ analysis on cutaneous tissue using directly labelled probes for various gene loci often involved in patients with AML; these tests showed deletion of p53 and excluded trisomy 8. However, application of probes for AML/ETO, MYC and telomere 8q revealed a gain at 8q22/8q24/8q telomere in a significant number of infiltrating cells. We hypothesize that a partial gain at 8q rather than trisomy of the whole chromosome 8 exhibits an association with LC in AML.

Randomized phase-II trial evaluating induction therapy with idarubicin and etoposide plus sequential or concurrent azacitidine and maintenance therapy with azacitidine.

The aim of this randomized phase-II study was to evaluate the effect of substituting cytarabine by azacitidine in intensive induction therapy of patients with acute myeloid leukemia (AML). Patients were randomized to four induction schedules for two cycles: STANDARD (idarubicin, cytarabine, etoposide); and azacitidine given prior (PRIOR), concurrently (CONCURRENT), or after (AFTER) therapy with idarubicin and etoposide. Consolidation therapy consisted of allogeneic hematopoietic-cell transplantation or three courses of high-dose cytarabine followed by 2-year maintenance therapy with azacitidine in the azacitidine-arms. AML with CBFB-MYH11, RUNX1-RUNX1T1, mutated NPM1, and FLT3-ITD were excluded and accrued to genotype-specific trials. The primary end point was response to induction therapy. The statistical design was based on an optimal two-stage design applied for each arm separately. During the first stage, 104 patients (median age 62.6, range 18-82 years) were randomized; the study arms PRIOR and CONCURRENT were terminated early due to inefficacy. After randomization of 268 patients, all azacitidine-containing arms showed inferior response rates compared to STANDARD. Event-free and overall survival were significantly inferior in the azacitidine-containing arms compared to the standard arm (p < 0.001 and p = 0.03, respectively). The data from this trial do not support the substitution of cytarabine by azacitidine in intensive induction therapy.

FRMD3, a novel putative tumour suppressor in NSCLC.

Lung cancer including non-small cell lung carcinoma (NSCLC) represents a leading cause of cancer death in Western countries. Yet, understanding its pathobiology to improve early diagnosis and therapeutic strategies is still a major challenge of today's biomedical research. We analyzed a set of differentially regulated genes that were identified in skin cancer by a comprehensive microarray study, for their expression in NSCLC. We found that ferm domain containing protein 3 (FRMD3), a member of the protein 4.1 superfamily, is expressed in normal lung tissue but silenced in 54 out of 58 independent primary NSCLC tumours compared to patient-matched normal lung tissue. FRMD3 overexpression in different epithelial cell lines resulted in a decreased clonogenicity as measured by colony formation assay. Although cell attachment capabilities and cell proliferation rate remained unchanged, this phenotype was most likely owing to induced apoptosis. Our data identify FRMD3 as a novel putative tumour suppressor gene suggesting an important role in the origin and progression of lung cancer.

The IPSS-R has prognostic impact in untreated patients with MDS del(5q).

The IPSS-R proved to be a powerful tool for the assessment of prognosis in MDS patients. We aimed at a validation of the IPSS-R for patients with MDS harboring deletion (5q) isolated or accompanied by additional aberrations. The study was based on 444 MDS patients from MDS centers in Europe. 67% of the patients were female, median age was 69 years. 43.5% had MDS del(5q), 5.9% were diagnosed with RCUD, 2.0% RARS, 18.4% RCMD, 14.6% RAEB-I and 15.5% RAEB-II. According to the IPSS-R, there were 9.9% very low, 39.6% low, 16.6% intermediate, 12.8% high, 20.9% very high risk patients. For very low risk patients survival was 7.5 years, low 9.0 years, intermediate 6.5 years, high 1.5 years and very high 0.7 years (p < 0.001). For low and intermediate risk, the probability of AML evolution was significantly different (p = 0.03) as well as for high versus very high risk groups (p = 0.002). The IPSS-R proved to be an appropriate prognostic tool for MDS with del(5q).

[Robot-assisted surgery - Progress or expensive toy? : Matched-pair comparative analysis of robot-assisted cholecystectomy vs. laparoscopic cholecystectomy]. / Roboterassistierte Chirurgie ­ Fortschritt oder teures Spielzeug? : Matched-Pair-Vergleichsanalyse der roboterassistierten Cholezystektomie vs. der laparoskopischen Cholezystektomie.

AIM AND METHODS: By means of a matched-pair analysis comparing data obtained from laparoscopic cholecystectomy (LC) and robot-assisted laparoscopic cholecystectomy (RAC), the value of both methods as well as the advantages and disadvantages of both approaches were elucidated. The consideration was carried out by evaluation of postoperative surgical results, a cost analysis and a subjective survey of the patients using a questionnaire. Thus, from the 35 consecutive RAC, 35 (parallel) retrospectively matched pairs were established. RESULTS: Postoperative surgical results did not show any significant differences between LC and RAC. In the individual assessment by each patient, there were also no significant differences; however, there was a tendency towards the assessment of the RAC to be slightly worse. A striking difference was found with respect to the cost analysis at the time of surgery. CONCLUSION: The RAC operation alone is significantly more expensive compared to LC with respect to maintenance and acquisition costs. In addition, RAC can at present not be completely reimbursed under the current German diagnosis-related system. The postulated advantages of RAC comprise mainly the precise preparation within narrow confinements and the favorable ergonomic handling for the surgeon. The basic prerequisites are control of the costs and a reasonable reflection in the current reimbursement system.

Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia.

Prognostic predictions in B-cell chronic lymphocytic leukemia (B-CLL) at early clinical stage are based on biological disease parameters, such as ZAP-70 and CD38 protein levels, genomic aberrations as well as immunoglobulin variable heavy chain gene (IgV(H)) mutation status. In the current study, ZAP-70 and CD38 expressions were examined by flow cytometry in 252 patients with B-CLL. Cytoplasmic ZAP-70 expression in more than 20% (ZAP-70(+)) and surface CD38 expression on more than 30% (CD38(+)) of B-CLL cells were associated with an unfavorable clinical course. The levels of ZAP-70 and CD38 did not change over time in the majority of patients where sequential samples were available for analysis. Combined analysis of ZAP-70 and CD38 yielded discordant results in 73 patients (29.0%), whereas 120 patients (47.6%) were concordantly negative and 59 patients (23.4%) were concordantly positive for ZAP-70 and CD38 expression. Median treatment-free survival times in patients whose leukemic cells were ZAP-70(+)CD38(+) was 30 months as compared to 130 months in patients with a ZAP-70(-)CD38(-) status. In patients with discordant ZAP-70/CD38 results, the median treatment-free survival time was 43 months. Thus, ZAP-70 and CD38 expression analyses provided complementary prognostic information identifying three patient subgroups with good, intermediate and poor prognosis. Over-representation of high-risk genomic aberrations such as 17p deletion or 11q deletion and distribution of the IgV(H) mutation status in B-CLL discordant for ZAP-70/CD38 pointed toward a distinct biologic background of the observed disease subgroups. This finding was also supported by microarray-based gene expression profiling in a subset of 35 patients. The expression of 37 genes differed significantly between the three groups defined by their expression of ZAP-70 and CD38, including genes that are involved in regulation of cell survival and chemotherapy resistance.

Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS).

The international prognostic scoring system (IPSS) is considered the gold standard for risk assessment in primary myelodysplastic syndromes (MDS). This score includes several prognostic factors except serum lactate dehydrogenase (LDH). We evaluated the prognostic power of LDH as an additional variable in IPSS-based risk assessment. For this purpose, a total of 892 patients with primary MDS registered by the Austrian-German cooperative MDS study group was analyzed retrospectively. Multivariate analysis confirmed the value of established parameters such as medullary blasts, karyotype and peripheral cell counts and showed that elevated LDH was associated with decreased overall survival (P<0.00005) and increased risk of AML development (P<0.00005), independent of the system used to classify MDS (FAB or WHO). Moreover, elevated LDH was found to be a significant predictor of poor survival within each IPSS risk group and within each FAB group except RAEB-T. To exploit these results for refined prognostication, each IPSS risk group was split into two separate categories (A=normal LDH vs B=elevated LDH). Using this LDH-assisted approach, it was possible to identify MDS patients with unfavorable prognosis within the low and intermediate IPSS risk groups. We propose that the IPSS+LDH score should improve clinical decision-making and facilitate proper risk stratification in clinical trials.

Effect of side-chain asymmetry on the intermolecular structure and order-disorder transition in alkyl-substituted polyfluorenes.

We study relations among the side-chain asymmetry, structure, and order-disorder transition (ODT) in hairy-rod-type poly(9,9-dihexylfluorene) (PF6) with two identical side chains and atactic poly(9-octyl-9-methyl-fluorene) (PF1-8) with two different side chains per repeat. PF6 and PF1-8 organize into alternating side-chain and backbone layers that transform into an isotropic phase at T^{ODT}(PF6) and T_{bi}^{ODT}(PF1-8). We interpret polymers in terms of monodisperse and bidisperse brushes and predict scenarios T^{ODT}