[Regional Deprivation in Germany: Nation-wide Analysis of its Association with Mortality Using the German Index of Multiple Deprivation (GIMD)]. / Regionale Deprivation in Deutschland: Bundesweite Analyse des Zusammenhangs mit Mortalität unter Verwendung des 'German Index of Multiple Deprivation (GIMD)'.

BACKGROUND: Deprivation indices are increasingly being used to assess the effects of contextual factors on health. In Germany, the recently developed 'German Index of Multiple Deprivation (GIMD)' integrates various dimensions of regional deprivation. We aim to assess the validity of the GIMD through a recalculation using more recent rural and urban district level data and by analysing its association with mortality at the national level. METHODS: We calculated a new version of the GIMD based on data from 2007 to 2010 for all 412 rural and urban districts in Germany. Mortality was quantified using indirectly standardised mortality ratios (SMRs). Correlation analyses and Poisson regression analyses were used to assess the association between the GIMD scores and total mortality, as well as premature mortality (< 65 years). RESULTS: Correlation analyses showed a positive association between the GIMD and both total mortality (p<0.001) and premature mortality (p<0.001). In the Poisson regression analyses, rural and urban districts in the quintile with the highest deprivation showed a significantly elevated risk of total mortality (RR: 1.29; 95% CI: 1.28-1.30) as well as premature mortality (RR: 1.50; 95% CI: 1.47-1.53), compared to the districts in the lowest quintile. CONCLUSION: The association between regional deprivation and mortality has already been shown for the federal state of Bavaria. Using more recent data, this relationship could be confirmed here for Germany as a whole. The GIMD has been shown to be able to effectively assess regional deprivation. Concerning public health policy, the significant, positive and stable association between regional deprivation and mortality indicates an increased need for health care provision particularly in the most deprived districts. Further studies should examine, for example, whether and how the allocation of districts to quintiles of regional deprivation changes over time, and how this affects mortality.

Phase I ficlatuzumab monotherapy or with erlotinib for refractory advanced solid tumours and multiple myeloma.

BACKGROUND: Ficlatuzumab, a humanised hepatocyte growth factor (HGF) IgG1κ inhibitory monoclonal antibody, was evaluated for recommended phase II dose (RP2D), safety, pharmacokinetics (PKs), antidrug antibody (ADA), pharmacodynamics (PDs) and antitumour activity as monotherapy or combined with erlotinib. METHODS: Patients with solid tumours received ficlatuzumab 2, 5, 10 or 20 mg kg(-1) intravenously every 2 weeks (q2w). Additional patients were treated at the RP2D erlotinib. RESULTS: Forty-one patients enrolled at doses ⩽20 mg kg(-1). Common adverse events (AEs) included peripheral oedema, fatigue and nausea. Three patients experienced grade ⩾3 treatment-related hyperkalaemia/hypokalaemia, diarrhoea or fatigue. Best overall response (44%) was stable disease (SD); median duration was 5.5 months (0.4-18.7 months). One patient has been on therapy with SD for >4 years. Pharmacokinetics of ficlatuzumab showed low clearance (0.17-0.26 ml h(-1) kg(-1)), a half-life of 6.8-9.4 days and dose-proportional exposure. Ficlatuzumab/erlotinib had no impact on the PK of either agent. No ADAs were detected. Ficlatuzumab increased serum HGF levels. CONCLUSIONS: Recommended phase II dose is 20 mg kg(-1) q2w for ficlatuzumab monotherapy or with erlotinib. Preliminary antitumour activity and manageable AEs were observed. Pharmacokinetics were dose-proportional and consistent with other IgG therapeutics. Ficlatuzumab was not immunogenic, and serum HGF was a potential PD marker.

Phase II clinical trial of arsenic trioxide with liposomal doxorubicin, vincristine, and dexamethasone in newly diagnosed multiple myeloma.

In patients with multiple myeloma, there is preclinical justification to combine arsenic trioxide (ATO and As(2)O(3)) with DVd (Doxiltrade mark, vincristine, and dexamethasone) for newly diagnosed patients. Eleven patients on this phase II trial received 0.15 mg/kg of ATO for five consecutive days followed by four cycles of DVd plus ATO with the ATO at 0.25mg/kg IV twice per week. The most common grade 3 toxicities were hyperglycemia, hyponatremia, and hypocalcemia. There were four partial and no complete responses. We could not demonstrate that the addition of ATO with this schedule improved the response rate of MM to DVd.

Correction: Pomalidomide, bortezomib, and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

Following the publication of this article, the authors noted that the pomalidomide dose for the additional SC cohort in Fig. 1 was incorrectly listed. The correct dose for pomalidomide in the additional SC cohort should be the maximum tolerated dose of 4 mg/day, not 2 mg/day as listed in the original Fig. 1. The authors apologize for any inconvenience caused.

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche.

Umbilical cord blood transplantation (UCBT) in adults is limited by the small number of primitive hematopoietic stem cells (HSC) in each graft, resulting in delayed engraftment post transplant, and both short- and long-term infectious complications. Initial efforts to expand UCB progenitors ex vivo have resulted in expansion of mature rather than immature HSC, confounded by the inability to accurately and reliably measure long-term reconstituting cells. Ex vivo expansion of UCB HSC has failed to improve engraftment because of resulting defects that promote apoptosis, disrupt marrow homing and initiate cell cycling. Here we discuss the future of ex vivo expansion, which we suggest will include the isolation of immature hematopoietic progenitors on the basis of function rather than surface phenotype and will employ both cytokines and stroma to maintain and expand the stem cell niche. We suggest that ex vivo expansion could be enhanced by manipulating newly discovered signaling pathways (Notch, Wnt, bone morphogenetic protein 4 and Tie2/angiopoietin-1) and intracellular mediators (phosphatase and tensin homolog and glycogen synthase kinase-3) in a manner that promotes HSC expansion with less differentiation. Improved methods for ex vivo expansion will make UCBT available to more patients, decrease engraftment times and allow more rapid immune reconstitution post transplant.

Associations of High-Dose Melphalan Pharmacokinetics and Outcomes in the Setting of a Randomized Cryotherapy Trial.

High-dose melphalan followed by autologous stem cell transplantation remains the standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 h) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate that 2-h is at least as effective as 6-h cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified that fat-free mass, hematocrit, and creatinine clearance were significant covariates, as reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression-free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.

Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1-4 mg days 1-14), bortezomib (1-1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1-8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.

Retrospective utility of bronchoscopy after hematopoietic stem cell transplant.

Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is thought to be the procedure of choice to evaluate pulmonary infiltrates in hematopoietic stem cell transplant (HSCT) recipients. We retrospectively reviewed 91 bronchoscopies performed on 190 in-patient HSCT recipients admitted or treated for pneumonia from January 1994 to December 2004. These yielded a diagnosis 49% of the time with an overall survival of 35 days post-bronchoscopy. We were unable to detect any survival benefit from an addition to the treatment regimen after a positive result from analysis of the BAL fluid or transbronchial biopsy. The most common bacteria isolated was Pseudomonas that was often resistant to the patient's current antibiotics, suggesting that in lieu of this diagnostic procedure, changes to better cover resistant Gram-negative bacteria are reasonable. Although transbronchial biopsies provided an additional diagnosis in one out of 21 biopsies performed, six of the seven complications in our series were directly related to the transbronchial biopsy. With approximately a 50% yield from a bronchoscopy, additional treatment given after only 20% of all bronchoscopies, and no detectable survival benefit with a bronchoscopy that yielded a diagnosis, the utility of a bronchoscopy in this patient population is questioned by these data.

Effect of age on clinical and morphological characteristics in patients with brain arteriovenous malformation.

BACKGROUND AND PURPOSE: The goal of this work was to determine the effect of age at initial presentation on clinical and morphological characteristics in patients with brain arteriovenous malformation (AVM). METHODS: The 542 consecutive patients from the prospective Columbia AVM database (mean+/-SD age, 34+/-15 years) were analyzed. Univariate statistical models were used to test the effect of age at initial presentation on clinical (AVM hemorrhage, seizures, headaches, neurological deficit, other/asymptomatic) and morphological (AVM size, venous drainage pattern, AVM brain location, concurrent arterial aneurysms) characteristics. RESULTS: Hemorrhage was the presenting symptom in 46% (n=247); 29% (n=155) presented with seizures, 13% (n=71) with headaches, 7% (n=36) with a neurological deficit, and 6% (n=33) without AVM-related symptoms. Increasing age correlated positively with intracranial hemorrhage (P=0.001), focal neurological deficits (P=0.007), infratentorial AVMs (P<0.001), and concurrent arterial aneurysms (P<0.001); an inverse correlation was found with seizures (P<0.001), AVM size (P=0.001), and lobar (P<0.001), deep (P=0.008), and borderzone (P=0.014) location. No age differences were found for sex, headache, asymptomatic presentation, and venous drainage pattern. CONCLUSIONS: Our data suggest a significant interaction of patient age and clinical and morphological AVM features and argue against uniform AVM characteristics across different age classes at initial presentation. In particular, AVM patients diagnosed at a higher age show a higher fraction of AVM hemorrhage and are more likely to harbor additional risk factors such as concurrent arterial aneurysms and small AVM diameter. Longitudinal population-based AVM data are necessary to confirm these findings.

Determinants of neurological outcome after surgery for brain arteriovenous malformation.

BACKGROUND AND PURPOSE: We sought to define determinants of neurological deficit after surgery for brain arteriovenous malformation (AVM). METHODS: One hundred twenty-four prospective patients (48% women, mean age 33 years) underwent microsurgical brain AVM resection. Patients were examined by 3 study neurologists immediately before surgery, postoperatively in-hospital, by in-person long-term follow-up, and with a structured telephone follow-up. They were classified according to the 5-point Spetzler-Martin grading system, with its 3 elements: size, venous drainage pattern, and location. The functional neurological status was classified with the modified Rankin scale. Multivariate logistic regression models were applied to test the effect of patient age, gender, and the 3 Spetzler-Martin elements on early and long-term postoperative neurological complications. RESULTS: Twelve patients (10%) were classified as Spetzler-Martin grade 1; 36 (29%) as grade 2; 47 (38%) as grade 3; 26 (21%) as grade 4; and 3 (2%) as grade 5. Postoperatively, in-hospital, 51 patients (41%) showed new neurological deficits (15% disabling [ie, Rankin scale score >2] and 26% nondisabling [ie, Rankin 1 or 2]). At long-term follow-up (mean follow-up time 12 months), 47 patients (38%) revealed surgery-related neurological deficits (6% disabling; 32% nondisabling). The rate of neurological complications increased by Spetzler-Martin grade. Female gender, AVM size, and deep venous drainage were significantly associated with neurological deficits at in-hospital and long-term evaluation. For patient age and AVM location, no significant association was found. CONCLUSIONS: The findings suggest that female gender, AVM size, and AVM drainage into the deep venous system may be determinants of neurological deficit after microsurgical AVM resection.

Interrater agreement for high grade carotid artery stenosis measurement and treatment decision.

OBJECTIVES: Randomized trials in North America (NASCET, ACAS) and Europe (ECST) have shown a beneficial effect of endarterectomy for patients with high grade carotid artery stenosis. The results of the NASCET and the ECST further suggest that the effect of endarterectomy differed by degree of stenosis, supporting the importance of stenosis measurement as a factor in the decision process regarding surgery. We investigated the interrater agreement for carotid artery stenosis measurements and treatment decision in a post hoc study on patients undergoing carotid surgery. METHODS: In a one-year series, 45 consecutive patients underwent preoperative conventional cerebral angiography followed by endarterectomy. Using a magnifying eyepiece and applying the two different measurement criteria of the randomized trials, angiograms were re-evaluated post hoc by three masked raters. Intra-class correlation coefficients (ICCs) with one-sided 95% confidence intervals (CIs) were calculated for the estimation of interrater agreement for degree of stenosis. Conger s kappa (k) statistics were used for the estimation of interrater agreement for a dichotomized stenosis evaluation, i.e. therapeutic decision on surgery (cut-off point for symptomatic stenosis: 70%, cut-off point for asymptomatic stenosis: 60%). RESULTS: ICCs were.74 (CI.63) for NASCET/ACAS criteria and.72 (CI. 59) for ECST criteria. k values were.55 (CI.42) for NASCET/ACAS criteria and.57 (CI.44) for ECST criteria. Disagreement for a therapeutic decision was seen in 6 of 23 symptomatic patients by NASCET criteria, in 2 of 23 symptomatic patients by ECST and in 4 of 22 asymptomatic patients by ACAS criteria. CONCLUSIONS: Overall, the interrater agreement for stenosis measurements was good. Agreement for therapeutic decisions on carotid surgery, however, was less strong. These findings suggest that accurate stenosis measurement may not suffice for reliable treatment decisions in patients with high grade carotid artery stenosis.

Zigarettenrauchen als Risikofaktor hochgradiger Stenosen der Arteria carotis.

BACKGROUND: We investigated the association of cigarette smoking with high-grade carotid artery stenosis in patients with ischemic stroke and transient ischemic attacks. METHODS: Prospectively collected data from 404 patients with focal brain ischemia were used for a cross-sectional study estimating the association between cigarette smoking and high-grade carotid artery stenosis (diagnosed by Doppler-ultrasound and defined as a luminal narrowing of > or = 70%). Cerebral ischemia patients with normal sonographic findings served as a comparison group. Multivariate logistic regression models were used for statistical tests to determine the association between smoking and high-grade carotid stenosis. Age, gender, hypertension, diabetes mellitus, hypercholesterolemia and co-existing heart disease (myocardial infarction, angina, heart failure) were considered potential confounders. RESULTS: High-grade carotid stenoses were found in 25% (n = 101) of the patients; 39% (n = 156) were classified as smokers. Smoking (odds ratio 3.6, 95% confidence interval [CI] 2.2 to 5.8), hypercholesterolemia (odds ratio 1.8; CI 1.1 to 2.8) and preexisting heart disease (odds ratio 1.7; CI 1.1 to 2.7) were significantly associated with carotid stenosis > or = 70%. The impact of smoking augmented with increasing degree of stenosis (odds ratio for stenoses > or = 80%: 4.3, CI 2.3 to 7.7), whereas the association with hypercholesterolemia, and co-existing heart disease decreased in strength for stenoses greater than 80%. Hypertension and diabetes mellitus were not found to be significantly with high-grade carotid artery stenoses. CONCLUSION: Smoking is an independent determinant of severe carotid artery stenosis in patients with focal cerebral ischemia.

The hematopoietic stem cell transplant comorbidity index can predict for 30-day readmission following autologous stem cell transplant for lymphoma and multiple myeloma.

Patients who undergo autologous stem cell transplant (ASCT) for hematologic malignancies frequently have multiple comorbidities. The hematopoietic cell transplantation comorbidity index (HCT-CI), a transplant-specific modification of the Charlson comorbidity index, can predict risk of readmission following allogeneic stem cell transplant. Its utility in the autologous setting is unknown. We evaluated 620 patients who underwent ASCT at the Ohio State University from 2007 to 2012 for lymphoma or multiple myeloma (MM) to identify factors associated with readmission. Univariable and multivariable logistic regression were used to estimate the odds of readmission within 30 days of discharge following ASCT. A Cox proportional hazards model was used to evaluate OS. Sixty-four patients were readmitted within 30 days; the most common indications were fever and prolonged gastrointestinal toxicity. MM compared with lymphoma (odds ratio (OR) 1.89, 95% confidence interval (95% CI): 1.06-3.38, P=0.03), HCT-CI⩾3 (OR 1.74, 95% CI: 1.03-2.96, P=0.04) and length of hospitalization ⩾28 days (OR 3.14, 95% CI: 1.26-7.83, P=0.01) remained significantly associated with 30-day readmission in a multivariable model. While the model had excellent fit (P>0.75), its ability to predict individual patients who would be readmitted was less than acceptable (receiver-operator curve=0.64, 95% CI: 0.57-0.71). In a multivariable proportional hazards model, 30-day readmission (hazards ratio (HR) 1.81, 95% CI: 1.04-3.18, P=0.04), length of hospitalization ⩾28 days (HR 4.93, 95% CI: 2.65-9.18, P<0.001) and chemorefractory disease (HR 3.08, 95% CI: 1.74-5.43, P<0.001) were independently associated with inferior OS, but HCT-CI was not. Evaluation of other assessment tools may allow better prediction of outcomes following ASCT.

CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma.

Multiple myeloma (MM) is an incurable hematological malignancy. Chimeric antigen receptor (CAR)-expressing T cells have been demonstrated successfully in the clinic to treat B-lymphoid malignancies. However, the potential utility of antigen-specific CAR-engineered natural-killer (NK) cells to treat MM has not been explored. In this study, we determined whether CS1, a surface protein that is highly expressed on MM cells, can be targeted by CAR NK cells to treat MM. We successfully generated a viral construct of a CS1-specific CAR and expressed it in human NK cells. In vitro, CS1-CAR NK cells displayed enhanced MM cytolysis and interferon-γ (IFN-γ) production, and showed a specific CS1-dependent recognition of MM cells. Ex vivo, CS1-CAR NK cells also showed similarly enhanced activities when responding to primary MM tumor cells. More importantly, in an aggressive orthotopic MM xenograft mouse model, adoptive transfer of NK-92 cells expressing CS1-CAR efficiently suppressed the growth of human IM9 MM cells and also significantly prolonged mouse survival. Thus, CS1 represents a viable target for CAR-expressing immune cells, and autologous or allogeneic transplantation of CS1-specific CAR NK cells may be a promising strategy to treat MM.

Size-based speciation of natural colloidal particles by flow field flow fractionation, inductively coupled plasma-mass spectroscopy, and transmission electron microscopy/X-ray energy dispersive spectroscopy: colloids-trace element interaction.

Flow field flow fractionation (FIFFF), inductively coupled plasma-mass spectroscopy (ICP-MS), and transmission electron microscopy (TEM) coupled to X-ray energy dispersive spectrometry (X-EDS) are used in series for the first time to characterize colloids. Results demonstrate the utility of FIFFF-ICP-MS-TEM/X-EDS to relate physical properties (size) of colloids to their chemical properties (chemical composition, surface chemical composition, and colloids-trace elements association). Results suggest that the major part of natural organic matter (NOM) is concentrated in the fraction < 0.01 microm (C2). Aluminum, iron, and manganese are the main colloidal components in the fraction 0.01-0.45 microm (C1). Aluminum occurs as aluminum oxides or aluminosilicates in the whole size range, while iron and manganese occur as individual oxyhydroxides in the size range < 0.20 microm. Within the C2 fraction, Al, Mn, Cu, and Ni elements are complexed to NOM (e.g., humic substances). Iron is complexed to NOM in some samples and probably free in other samples. Lead is totally free in all samples. Within the C1 fraction, Cu and Pb are mostly associated to Fe and Mn oxyhydroxides. Consequently, NOM with Fe and Mn oxyhydroxides are the main colloidal carriers of trace elements in the Loire watershed system.

The development of communicative competence of securely and insecurely attached children in interactions with their mothers.

Coordinated interpersonal timing in preverbal mother-child interactions is assumed to be one fundamental feature of interpersonal relatedness and the basis for parent-child bonding. The ubiquity of and early evidence for this phenomenon in ontogeny hint at its biological "prewiredness" and relevance for development. The quality of interpersonal timing in early preverbal parent-child interactions was hypothesized (and partially shown) to predict quality of attachment, level of cognitive functioning, and patterns of language acquisition. The aim of this study was to investigate the assumption of a facilitating effect of adequate interpersonal coordination (measured by quality of attachment) on the development of verbal communicative competence in children during the first stages of language development. On the basis of longitudinal data for 25 mother-child dyads, videotaped when the children were 17, 23, 30, and 36 months old in a free play and a short separation situation, it was investigated whether securely and insecurely attached children differ with respect to the amount of verbal contributions, their realization as alternating or simultaneous utterances, and the duration of intra-turn and inter-turn pauses. The results show that attachment was related to children's use of communicative competence especially in stressful situations, its development being paced by the age or maturation of the child.