FLT3-directed UniCAR T-cell therapy of acute myeloid leukaemia.

Adaptor chimeric antigen receptor (CAR) T-cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T-cell therapy in myeloid malignancies. The adaptor CAR T-cell platform 'UniCAR' is currently under early clinical investigation. Recently, the first proof of concept of a well-tolerated, rapidly switchable, CD123-directed UniCAR T-cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti-tumour responses, underlining the need to further design alternative AML-specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS-like tyrosine kinase 3 (FLT3)-directed UniCAR T-cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half-life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3-specific UniCAR T cells for the therapy of AML.

[Weaning in a Pandemic Situation - A Position Paper]. / Weaning in der Situation einer Pandemie ­ Ein Positionspapier.

The logistical and infectious peculiarities and requirements challenge the intensive care treatment teams aiming at a successful liberation of patients from long-term mechanical ventilation. Especially in the pandemic, it is therefore important to use all potentials for weaning and decannulation, respectively, in patients with prolonged weaning.Weaning centers represent units of intensive medical care with a particular specialization in prolonged weaning. They are an integral part of a continuous care concept for these patients. A systematic weaning concept in the pandemic includes structural, personnel, equipment, infectiological and hygienic issues. In addition to the S2k guideline "Prolonged weaning" this position paper hightlights a new classification in prolonged weaning and organizational structures required in the future for the challenging pandemic situation. Category A patients with high weaning potential require a structured respiratory weaning in specialized weaning units, so as to get the greatest possible chance to realize successful weaning. Patients in category B with low or currently nonexistent weaning potential should receive a weaning attempt after an intermediate phase of further stabilization in an out-of-hospital ventilator unit. Category C patients with no weaning potential require a permanent out-of-hospital care, alternatively finishing mechanical ventilation with palliative support.Finally, under perspective in the position paper the following conceivable networks and registers in the future are presented: 1. locally organized regional networks of certified weaning centers, 2. a central, nationwide register of weaning capacities accordingly the already existing DIVI register and 3. registration of patients in difficult or prolonged weaning.

[Nocardiosis as a Differential Diagnosis of Pulmonary Epitheloid Cell Granulomas]. / Nokardiose als Differenzialdiagnose pulmonaler epitheloidzelliger Granulome.

A 47-year-old man presented with fever, weight loss and pulmonary consolidations and cavitation in the x-ray of the thorax. The comprehensive diagnostics resulted pulmonary epitholoid cell granulomas, therefore an immunosuppressive therapy was applied on suspicion of sarcoidosis. Progressivly the pulmonary infiltration increased and cerebral and abdominal abscesses were determined with microbiological detection of Nocardia farcinica. Despite antibiotic therapy, the patient died in a septic shock with multiple organ failure.Nocardiosis is a rare granulomatous bacterial infectious disease. Risk factors include immunosuppression and structural lung diseases. Characteristic is an abscess formation that can occur in any organ, while pulmonary onset is common.The case demonstrates the importance of considering rare differential diagnoses in the detection of pulmonary epithelioid granulomas.

Determinants of diagnostic discordance for non-diabetic hyperglycaemia and Type 2 diabetes using paired glycated haemoglobin measurements in a large English primary care population: cross-sectional study.

AIM: To investigate factors influencing diagnostic discordance for non-diabetic hyperglycaemia and Type 2 diabetes. METHODS: Some 10 000 adults at increased risk of diabetes were screened with HbA1c and fasting plasma glucose (FPG). The 2208 participants with initial HbA1c ≥ 42 mmol/mol (≥ 6.0%) or FPG ≥ 6.1 mmol/l were retested after a median 40 days. We compared the first and second HbA1c results, and consequent diagnoses of non-diabetic hyperglycaemia and Type 2 diabetes, and investigated predictors of discordant diagnoses. RESULTS: Of 1463 participants with non-diabetic hyperglycaemia and 394 with Type 2 diabetes on first testing, 28.4% and 21.1% respectively had discordant diagnoses on repeated testing. Initial diagnosis of non-diabetic hyperglycaemia and/or impaired fasting glucose according to both HbA1c and FPG criteria, or to FPG only, made reclassification as Type 2 diabetes more likely than initial classification according to HbA1c alone. Initial diagnosis of Type 2 diabetes according to both HbA1c and FPG criteria made reclassification much less likely than initial classification according to HbA1c alone. Age, and anthropometric and biological measurements independently but inconsistently predicted discordant diagnoses and changes in HbA1c . CONCLUSIONS: Diagnosis of non-diabetic hyperglycaemia or Type 2 diabetes with a single measurement of HbA1c in a screening programme for entry to diabetes prevention trials is unreliable. Diagnosis of non-diabetic hyperglycaemia and Type 2 diabetes should be confirmed by repeat testing. FPG results could help prioritise retesting. These findings do not apply to people classified as normal on a single test, who were not retested.

Lifestyle interventions for weight loss in adults with severe obesity: a systematic review.

Severe obesity is an increasingly prevalent condition and is often associated with long-term comorbidities, reduced survival and higher healthcare costs. Non-surgical methods avoid the side effects, complications and costs of surgery, but it is unclear which non-surgical method is most effective. The objective of this article was to systematically review the effectiveness of lifestyle interventions compared to standard or minimal care for weight loss in adults with severe obesity. MEDLINE, EMBASE, CENTRAL, databases of on-going studies, reference lists of any relevant systematic reviews and the Cochrane Library database were searched from inception to February 2016 for relevant randomized controlled trials (RCTs). Inclusion criteria were participants with severe obesity (body mass index [BMI] > 40 kg/m2 or BMI > 35 kg/m2 with comorbidity) and interventions with a minimal duration of 12 weeks that were multi-component combinations of diet, exercise and behavioural therapy. Risk of bias was evaluated using the Cochrane risk of bias criteria. Meta-analysis was not possible because of methodological heterogeneity. Seventeen RCTs met the inclusion criteria. Weight change in kilograms of participants from baseline to follow-up was reported for 14 studies. Participants receiving the lifestyle intervention had a greater decrease in weight than participants in the control group for all studies (1.0-11.5 kg). Lifestyle interventions varied greatly between the studies. Overall lifestyle interventions with combined diet and exercise components achieved the greatest weight loss. Lifestyle interventions for weight loss in adults with severe obesity were found to result in increased weight loss when compared to minimal or standard care, especially those with combined diet and exercise components.

Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts.

The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide 'proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo.

Screening attendance, age group and diabetic retinopathy level at first screen.

AIMS: To report on the relationships between age at diagnosis of diabetes, time from registration with the screening programme to first diabetic eye screening and severity of diabetic retinopathy. METHODS: Data were extracted from four English screening programmes and from the Scottish, Welsh and Northern Irish programmes. Time from diagnosis of diabetes to first screening and age at diagnosis were calculated. RESULTS: Time from registration with the screening programme to first screening episode is strongly related to age at registration. Within 18 months of registration 89% of 3958 young people under 18 years of age and 81% of 391 293 people over 35 years of age were seen. In 19 058 people between 18 and 34 years of age, 80% coverage was not reached until 2 years and 9 months. The time from diagnosis of diabetes to first screening is positively associated with severity of disease (P < 0.0001). CONCLUSIONS: This report is the first that to demonstrate that those in the 18-34 year age group are least likely to attend promptly for screening after registration with a higher risk of referable diabetic retinopathy being present at the time of first screen. Date of diagnosis should be recorded and prodigious efforts made to screen all people promptly after diagnosis. Screening programmes should collect data on those who have not attended within one year of registration.

Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts.

Bispecific antibodies (bsAbs) engaging T cells are emerging as a promising immunotherapeutic tool for the treatment of hematologic malignancies. Because their low molecular mass, bsAbs have short half-lives. To achieve clinical responses, they have to be infused into patients continously, for a long period of time. As a valid alternative we examined the use of mesenchymal stromal cells (MSCs) as autonomous cellular machines for the constant production of a recently described, fully humanized anti-CD33-anti-CD3 bsAb, which is capable of redirecting human T cells against CD33-expressing leukemic cells. The immortalized human MSC line SCP-1 was genetically modified into expressing bsAb at sufficient amounts to redirect T cells efficiently against CD33 presenting target cells, both in vitro and in an immunodeficient mouse model. Moreover, T cells of patients suffering from acute myeloid leukemia (AML) in blast crisis eliminated autologous leukemic cells in the presence of the bsAb secreting MSCs over time. The immune response against AML cells could be enhanced further by providing T cells an additional co-stimulus via the CD137-CD137 ligand axis through CD137L expression on MSCs. This study demonstrates that MSCs have the potential to be used as cellular production machines for bsAb-based tumor immunotherapy in the future.

Economic inequalities in burden of illness, diagnosis and treatment of five long-term conditions in England: panel study.

OBJECTIVE: We compared the distribution by wealth of self-reported illness burden (estimated from validated scales, biomarker and reported symptoms) for angina, cataract, depression, diabetes and osteoarthritis, with the distribution of self-reported medical diagnosis and treatment. We aimed to determine if the greater illness burden borne by poorer participants was matched by appropriately higher levels of diagnosis and treatment. DESIGN: The English Longitudinal Study of Ageing, a panel study of 12,765 participants aged 50 years and older in four waves from 2004 to 2011, selected using a stratified random sample of households in England. Distribution of illness burden, diagnosis and treatment by wealth was estimated using regression analysis. OUTCOME MEASURES: The main outcome measures were ORs for the illness burden, diagnosis and treatment, respectively, adjusted for age, sex and wealth. We estimated the illness burden for angina with the Rose Angina scale, diabetes with fasting glycosylated haemoglobin, depression with the Centre for Epidemiologic Studies Depression Scale, osteoarthritis with self-reported pain and disability and cataract with self-reported poor vision. Medical diagnoses were self-reported for all conditions. Treatment was defined as ß-blocker prescription for angina, surgery for osteoarthritis and cataract, and receipt of predefined effective interventions for diabetes and depression. RESULTS: Compared with the wealthiest, the least wealthy participant had substantially higher odds for illness burden from any of the five conditions at all four time points, with ORs ranging from 4.2 (95% CI 2.6 to 6.8) for diabetes to 15.1 (11.4 to 20.0) for osteoarthritis. The ORs for diagnosis and treatment were smaller in all five conditions, and ranged from 0.9 (0.5 to 1.4) for diabetes treatment to 4.5 (3.3 to 6.0) for angina diagnosis. CONCLUSIONS: The substantially higher illness burden in less wealthy participants was not matched by appropriately higher levels of diagnosis and treatment.

Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia.

Owing to the more recent positive results with the anti-CD33 immunotoxin gemtuzumab ozogamicin, therapy against acute myeloid leukemias (AMLs) targeting CD33 holds many promises. Here, CD33 and CD123 expression on AML blasts was studied by flow cytometry in a cohort of 319 patients with detailed information on French-American-British/World Health Organization (FAB/WHO) classification, cytogenetics and molecular aberrations. AMLs of 87.8% express CD33 and would therefore be targetable with anti-CD33 therapies. Additionally, 9.4% of AMLs express CD123 without concomitant CD33 expression. Thus, nearly all AMLs could be either targeted via CD33 or CD123. Simultaneous presence of both antigens was observed in 69.5% of patients. Most importantly, even AMLs with adverse cytogenetics express CD33 and CD123 levels comparable to those with favorable and intermediate subtypes. Some patient groups with unfavorable alterations, such as FMS-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations, high FLT3-ITD mutant/wild-type ratios and monosomy 5 are even characterized by high expression of CD33 and CD123. In addition, blasts of patients with mutant nucleophosmin (NPM1) revealed significantly higher CD33 and CD123 expression pointing toward the possibility of minimal residual disease-guided interventions in mutated NPM1-positive AMLs. These results stimulate the development of novel concepts to redirect immune effector cells toward CD33- and CD123-expressing blasts using bi-specific antibodies or engineered T cells expressing chimeric antigen receptors.

Temporary hemiepiphysiodesis of the distal medial femur: MPFL in danger.

INTRODUCTION: Temporary hemiepiphysiodesis (TH) with plate fixation is a well-accepted and common treatment for correcting leg malalignment in skeletally immature patients. The purpose of this study was to investigate any soft tissue damage caused during TH at the distal medial femur with a plate and two screws. We hypothesized that correct plate placement can affect the integrity of the medial stabilizing structures of the knee, especially the medial patellofemoral ligament (MPFL), the medial collateral ligament (MCL) or result in arthrotomy of the knee joint itself. MATERIALS AND METHODS: In eight cadaveric knees of five adult humans a TH was performed with a plate and two cancellous screws at the distal medial femur using a standardized surgical technique. Subsequently the medial capsular and ligamentous structures were systematically exposed and assessed. Capsular and synovial tissue was also inspected for impingement by the plate or screws. RESULTS: In all knees the MPFL was present. In two specimens the MPFL was intact and the plate was lying over the dorsal part of the MPFL close to the MCL. The MPFL was completely cut in two cases in the central part of the ligament. In four cases the MPFL was partially dissected or perforated by a screw and fixed to the femur by the plate. The MCL was intact and not impinged by the implant in any case. In total four of eight knees the capsule was transected or perforated by a screw or by a part of the plate, resulting in intraarticular implant placement. CONCLUSIONS: Standard plate placement during TH on the distal medial femur frequently leads to damage to the MPFL, impingement of the MPFL, the capsular and synovial tissues or exposure of the knee joint.

Costimulation improves the killing capability of T cells redirected to tumor cells expressing low levels of CD33: description of a novel modular targeting system.

Owing to their clinical success, there is growing interest in novel bispecific antibodies (bsAbs) for retargeting of T cells to tumor cells including for the treatment of acute myeloid leukemia (AML). One potential target for retargeting of T cells to AML blasts is the surface molecule CD33. Here we describe a novel modular targeting platform that consists of a universal effector module (EM) and individual target modules (TMs). Both modules can form an immune complex via a peptide epitope. The resulting targeting complex can functionally replace a conventional bsAb. By fusion of a costimulatory domain (for example, the extracellular CD137 ligand domain) to the TM, the targeting complex can even provide a costimulatory signal to the redirected T cells at their side of interaction with the tumor cell. Furthermore, we observed that an efficient killing of tumor cells expressing low levels of the tumor target CD33 becomes critical at low effector-to-target cell ratios but can be improved by costimulation via CD137 using our novel targeting system.

Smoking behaviour, former quit attempts and intention to quit in urban adolescents and young adults: a five-year longitudinal study.

OBJECTIVES: To examine smoking behaviour, former quit attempts and intention to quit among Swiss adolescents and young adults over five year's time. STUDY DESIGN: five-year longitudinal study (2003, 2005 and 2008) based on a random urban community sample (N = 1345 complete cases). METHODS: Data were collected by computer-assisted telephone interviews with adolescents (16-17) and young adults (18-24). Main outcome measures included self-reported smoking behaviour, former quit attempts, smoking cessation methods and current intentions to quit smoking. RESULTS: Adolescents were more often non-smokers and less often daily smokers when compared to young adults at baseline (χ(2)(4) = 28.68, P < .001). Their smoking behaviour increased significantly from baseline to follow-up (T = 1445.50, r = .20, P < .001) in contrast to the stable smoking behaviour in young adults (χ(2)(2) = .12, n.s.). In longitudinal analyses young adults were also more stable in their smoking status at the later measurement points. In comparison adolescents changed their smoking status more often being non-smokers at baseline and smokers later on. Independently of the age group, the majority of smokers already had previously attempted to quit (65%) or intended to give up smoking at some point (72%). However only 17% were motivated to make the quit attempt within the next 6 months. Self-quitting was the preferred method, and 25% of the self-quitters had been successful. CONCLUSION: This study illustrates that different developments in smoking behaviour exist in adolescents and young adults. Our study reveals that a majority of smokers are willing to quit but often fail. Furthermore, the data indicates that for adolescents the focus should lie on primary prevention.

Preeclampsia: mediadores moleculares del daño placentario / Preeclampsia: molecular mediators of placental damage

La preeclampsia se constituye como una de las complicaciones más serias del embarazo y una causa importante de mortalidad materna y perinatal. Pese a ser una de las patologías del embarazo más estudiadas, muchas dudas e incertidumbre rondan aún acerca de su mecanismo fisiopatológico. En esta revisión se intenta hacer un análisis sobre las nuevas teorías acerca de la fisiopatología de la preeclampsia, dando énfasis en las distintas moléculas que transfieren el daño placentario hacia el territorio sistémico.

Preeclampsia is one of the most serious gestational disease which causes maternal and perinatal mortality. In spite of being one of the most studied pathologies of the pregnancy there are many concerns around its physiopathology. In this review we attempt to analyze the new preeclampsia physiopathology theories, giving emphasis in the different molecules that transfer the placental damage towards the systemic territory.

Trends in yield and effects of screening intervals during 17 years of a large UK community-based diabetic retinopathy screening programme.

AIMS: To describe changes in risk profiles and yield in a screening programme and to investigate relationships between retinopathy prevalence, screening interval and risk factors. METHODS: We analysed a population of predominantly Type 2 diabetic patients, managed in general practice, and screened between 1990 and 2006, with up to 17 years' follow-up and up to 14 screening episodes each. We investigated associations between referable or sight-threatening diabetic retinopathy (STDR), screening interval and frequency of repeated screening, whilst adjusting for age, duration and treatment of diabetes, hypertension treatment and period. RESULTS: Of 63 622 screening episodes among 20 788 people, 16 094 (25%) identified any retinopathy, 3136 (4.9%) identified referable retinopathy and 384 (0.60%) identified STDR. The prevalence of screening-detected STDR decreased by 91%, from 1.7% in 1991-1993 to 0.16% in 2006. The prevalence of referable retinopathy increased from 2.0% in 1991-1993 to 6.7% in 1998-2001, then decreased to 4.7% in 2006. Compared with screening intervals of 12-18 months, screening intervals of 19-24 months were not associated with increased risk of referable retinopathy [adjusted odds ratio 0.93, 94% confidence interval (CI) 0.82-1.05], but screening intervals of more than 24 months were associated with increased risk (odds ratio 1.56, 95% CI 1.41-1.75). Screening intervals of < 12 months were associated with high risks of referable retinopathy and STDR. CONCLUSIONS: Over time the risk of late diagnosis of STDR decreased, possibly attributable to earlier diagnosis of less severe retinopathy, decreasing risk factors and systematic screening. Screening intervals of up to 24 months should be considered for lower risk patients.