German Patient Blood Management Network: effectiveness and safety analysis in 1.2 million patients.

BACKGROUND: Patient Blood Management (PBM) is a patient-centred, systematic, evidence-based approach to improve patient outcomes by managing and preserving a patient's own blood whilst promoting patient safety and empowerment. The effectiveness and safety of PBM over a longer period have not yet been investigated. METHODS: We performed a prospectively designed, multicentre follow-up study with non-inferiority design. Data were retrospectively extracted case-based from electronic hospital information systems. All in-hospital patients (≥18 yr) undergoing surgery and discharged between January 1, 2010 and December 31, 2019 were included in the analysis. The PBM programme focused on three domains: preoperative optimisation of haemoglobin concentrations, blood-sparing techniques, and guideline adherence/standardisation of allogeneic blood product transfusions. The outcomes were utilisation of blood products, composite endpoint of in-hospital mortality and postoperative complications (myocardial infarction/ischaemic stroke/acute renal failure with renal replacement therapy/sepsis/pneumonia), anaemia rate at admission and discharge, and hospital length of stay. RESULTS: A total of 1 201 817 (pre-PBM: n=441 082 vs PBM: n=760 735) patients from 14 (five university/nine non-university) hospitals were analysed. Implementation of PBM resulted in a substantial reduction of red blood cell utilisation. The mean number of red blood cell units transfused per 1000 patients was 547 in the PBM cohort vs 635 in the pre-PBM cohort (relative reduction of 13.9%). The red blood cell transfusion rate was significantly lower (P<0.001) with odds ratio 0.86 (0.85-0.87). The composite endpoint was 5.8% in the PBM vs 5.6% in the pre-PBM cohort. The non-inferiority aim (safety of PBM) was achieved (P<0.001). CONCLUSIONS: Analysis of >1 million surgical patients showed that the non-inferiority condition (safety of Patient Blood Management) was fulfilled, and PBM was superior with respect to red blood cell transfusion. CLINICAL TRIAL REGISTRATION: NCT02147795.

A rare PALB2 germline variant causing G2/M cell cycle arrest is associated with isolated myelosarcoma in infancy.

BACKGROUND: Isolated myelosarcoma of infancy is a rare presentation of acute myelogenous leukaemia (AML). Because of its rarity and early onset in infancy underlying genetic predisposition is potentially relevant in disease initiation. METHODS AND RESULTS: We report an oncologic emergency in an infant with thoracic and intraspinal aleukaemic myeloid sarcoma causing acute myelon compression and lower leg palsy. Whole-exome sequencing of the patient's germline DNA identified a rare PALB2 (OMIM 610355) variant (p.A1079S), which is located in a domain critical for the gene's proper function within the homology-directed repair pathway. In line with potential DNA damage repair defects mediated by the PALB2 deregulation, the patient's fibroblasts showed increased sensitivity towards radiation and DNA intercalating agents. CONCLUSION: Therefore, we suggest PALB2 p.A1079S as a pathogenic variant potentially contributing to the here observed patient phenotype.

Software-based analysis of 1-hour Holter ECG to select for prolonged ECG monitoring after stroke.

OBJECTIVE: Identification of ischemic stroke patients at high risk for paroxysmal atrial fibrillation (pAF) during 72 hours Holter ECG might be useful to individualize the allocation of prolonged ECG monitoring times, currently not routinely applied in clinical practice. METHODS: In a prospective multicenter study, the first analysable hour of raw ECG data from prolonged 72 hours Holter ECG monitoring in 1031 patients with acute ischemic stroke/TIA presenting in sinus rhythm was classified by an automated software (AA) into "no risk of AF" or "risk of AF" and compared to clinical variables to predict AF during 72 hours Holter-ECG. RESULTS: pAF was diagnosed in 54 patients (5.2%; mean age: 78 years; female 56%) and was more frequently detected after 72 hours in patients classified by AA as "risk of AF" (n = 21, 17.8%) compared to "no risk of AF" (n = 33, 3.6%). AA-based risk stratification as "risk of AF" remained in the prediction model for pAF detection during 72 hours Holter ECG (OR3.814, 95% CI 2.024-7.816, P < 0.001), in addition to age (OR1.052, 95% CI 1.021-1.084, P = 0.001), NIHSS (OR 1.087, 95% CI 1.023-1.154, P = 0.007) and prior treatment with thrombolysis (OR2.639, 95% CI 1.313-5.306, P = 0.006). Similarly, risk stratification by AA significantly increased the area under the receiver operating characteristic curve (AUC) for prediction of pAF detection compared to a purely clinical risk score (AS5F alone: AUC 0.751; 95% CI 0.724-0.778; AUC for the combination: 0.789, 95% CI 0.763-0.814; difference between the AUC P = 0.022). INTERPRETATION: Automated software-based ECG risk stratification selects patients with high risk of AF during 72 hours Holter ECG and adds predictive value to common clinical risk factors for AF prediction.

Methylation of the Phospholipase A2 Receptor 1 Promoter Region in Childhood B Cell Acute Lymphoblastic Leukaemia.

Acute lymphoblastic leukaemia (ALL) is the most common form of paediatric cancer and epigenetic aberrations are determinants of leukaemogenesis. The aim of this study was to investigate the methylation degree of a distinct phospholipase A2 receptor 1 (PLA2R1) promoter region in paediatric ALL patients and to evaluate its relevance as new biomarker for monitoring treatment response and burden of residual disease. The impact of PLA2R1 re-expression on proliferative parameters was assessed in vitro in Jurkat cells with PLA2R1 naturally silenced by DNA methylation. Genomic DNA was isolated from bone marrow (BM) and peripheral blood (PB) of 44 paediatric ALL patients. PLA2R1 methylation was analysed using digital PCR and compared to 20 healthy controls. Transfected Jurkat cells were investigated using cell growth curve analysis and flow cytometry. PLA2R1 was found hypermethylated in BM and PB from pre-B and common ALL patients, and in patients with the disease relapse. PLA2R1 methylation decreased along with leukaemic blast cell reduction during ALL induction treatment. In vitro analysis revealed an anti-proliferative phenotype associated with PLA2R1 re-expression, suggesting a tumour-suppressive function of PLA2R1. Collected data indicates that PLA2R1 promoter methylation quantitation can be used as biomarker for ALL induction treatment control, risk stratification, and early detection of ALL relapse.

Bleeding signs due to acquired von Willebrand syndrome at diagnosis of chronic myeloid leukaemia in children.

A considerable proportion of patients with chronic myeloid leukaemia (CML) may present at diagnosis with high platelet counts. This may result in thrombosis or bleeding complications due to binding of von Willebrand factor (VWF) multimers to platelets. Paediatric CML is very rare and no systematic investigation on clinical complications of elevated platelets has been reported. Data on platelet count and associated haemostaseological complications were retrospectively analysed in a cohort of 156 children with CML. Fifty-one percent (81/156) patients presented with thrombocytosis (platelet count> 500 × 109 /l), and were extreme (>1 000 × 109 /l) in 23/156 (16%). There were no cases of thrombosis but mild bleeding signs were present in 12% (n = 9) children with thrombocytosis. Bleeding occurred without correlation to elevated platelet counts and was associated with reduced large VWF multimers, indicating a diagnosis of acquired von Willebrand syndrome (AVWS), which resolved after initiation of CML treatment. Patients with paediatric CML frequently exhibit high platelet counts not resulting in thrombosis. In patients with thrombocytosis mild bleeding signs due to a low percentage of large VWF multimers can be demonstrated. AVWS may be underdiagnosed in paediatric CML (Clinical-Trials.gov NCT00445822, 9 March 2007).

Predictors of successful complex catheter ablation for persistent atrial fibrillation despite failure of targeted procedural arrhythmia termination.

INTRODUCTION: Procedural atrial fibrillation (AF) termination is considered as a predictor of long-term success after catheter ablation for persistent AF (persAF). However, some patients remain free of arrhythmia recurrences despite failure to achieve AF termination. The objective of this study was to assess long-term outcome and prognostic factors in patients undergoing complex ablation without procedural AF termination. METHODS AND RESULTS: This study comprised 419 patients (63.8 ± 10.2 years, 63.4% male) undergoing complex ablation for persAF. Patients without procedural AF termination (n = 137, 64.2 ± 9.7 years, 63.5% male) were categorized into patients who remained in sinus rhythm (SR) in long-term outcome (SR-group) and patients with recurrence of AF or atrial tachycardia (AT) (AR-group). During a follow-up (FU) of 19.6 ± 14.6 months, the SR-group consisted of 65 (47.5%) and the AR-group of 69 (50.4%) patients. Three patients (2.2%) were lost to FU. Left atrial appendage (LAA) flow velocity and left atrium volume index (LAVI) could be identified as predictors for long-term success. LAA flow velocity and baseline AF cycle length (AFCL) were significantly associated with the type of arrhythmia recurrence (AF vs AT), ie, higher values of both are predictive for AT rather than AF recurrences. Patients with a LAVI < 34.4 mL/m² and significant AFCL increase during the ablation procedure had rather AT than AF recurrences. CONCLUSION: Patients with an arrhythmia-free outcome despite failure of procedural AF termination during complex ablation for persAF are characterized by specific morphological and functional properties that are easy to obtain.

Prevalence of Cardiac Disease in Breast Cancer Patients at Time of Diagnosis Compared to the General Female Population in Germany.

BACKGROUND: Advances in oncological therapy have significantly improved breast cancer survival; therefore comorbid conditions are becoming more relevant. We investigated the prevalence of prior cardiovascular diseases and risk factors in patients with breast cancer compared to those in the general female population in Germany. METHODS: The PASSOS heart study is a retrospective multicenter cohort study on cardiac late effects in breast cancer patients treated between 1998 and 2008. We analyzed the frequencies of cardiac diseases and cardiovascular risk factors in patients from this cohort as documented in anesthesia protocols compared to self-reported frequencies in the general female population in Germany. RESULTS: 3,496 patients aged between 40 and 79 years who underwent breast surgery were considered for analysis. The age-standardized prevalence of cardiac diseases or cardiovascular risk factors was 6.75 versus 7.52% and 69 versus 80.92%, respectively. Coronary heart disease (3.96 vs. 5.18%) and angina pectoris (0.37 vs. 1.03%) prevalence was lower in breast cancer patients, while non-fatal myocardial infarction (2.06 vs. 1.81%) and stroke (2.64 vs. 2.34%) were more frequent (not statistically significant). CONCLUSION: Pre-existing cardiac diseases and cardiovascular risk factors are common in both study populations, being slightly less frequent in the PASSOS cohort. When making therapy decisions, the cardiac risk profile should be carefully monitored and taken into account.

Identification and Quantification of Heterogeneously-methylated DNA Fragments Using Epiallele-sensitive Droplet Digital Polymerase Chain Reaction (EAST-ddPCR).

BACKGROUND/AIM: DNA methylation plays an important role in the initiation and propagation of carcinogenesis; however, the role of heterogeneously methylated epialleles is currently not well studied, also due to the lack of sensitive, unbiased and high throughput methods. Here, a newly developed droplet digital PCR (ddPCR)-based method was evaluated regarding its ability to quantify such heterogeneously methylated epialleles with sufficient analytical sensitivity and specificity. MATERIALS AND METHODS: Genomic DNA from blood leukocytes and bone marrow aspirate of an 8-year old male with B-cell acute lymphoblastic leukemia (B-ALL) and from normal and malignant prostate cell lines were analysed using ddPCR. RESULTS: By using these DNA samples, the specificity of an applied set of fluorescence-labeled probes was demonstrated as a proof of concept. CONCLUSION: All individual heterogeneously-methylated epialleles were quantifiable by a set of fluorescence-labeled probes with complementary sequences to epialleles in a closed-tube and high-throughput manner. The new method named epiallele-sensitive droplet digital PCR (EAST-ddPCR) may give new insights in the generation and regulation of epialleles and may help in finding new biomarkers for the diagnosis of benign und malignant diseases.

Duodenocolonic Fistula As A Rare Complication of Intestinal Burkitt Lymphoma in a Three-Year-Old Boy.

BACKGROUND: Burkitt lymphoma (BL) in children often presents with abdominal localization. Intestinal perforations have been described mainly during treatment. We report on a three-year-old patient with abdominal BL who was diagnosed with a duodenocolonic fistula. CASE REPORT: A three-year-old boy presented with diarrhea, crampy abdominal pain, and a four-week history of loss of appetite and weight. Ultrasound and MRI detected a colonic tumor forming a duodenocolonic fistula which was verified by gastroduodenoscopy. A surgical biopsy revealed BL. The stage III BL with low LDH was treated with four courses of BFM-type short-pulse chemotherapy. After two courses of chemotherapy the patient developed a mechanic ileus. A segmental resection of a short segment of the colon at the right flexure carrying the residual tumor mass with cicatricial stenosis and fistula followed by colonic end to end anastomosis and covering of the fistula by omentum major were carried out without complication. 15 days after surgery, two additional courses of chemotherapy could be administrated and the boy is in ongoing remission and free of any symptoms with a follow-up interval of 18 months. CONCLUSIONS: Duodeonocolonic fistula at presentation in a child with abdominal BL is extremely rare. Delayed surgery after size of the tumor bulk has been reduced by chemotherapy might represent a risk adapted approach. However, due to limited experience with duodenocolonic fistulas even in larger pediatric lymphoma trials any decision has to be based on the problems to be faced in individual cases.

Treatment of high-grade osteoblastic osteosarcoma of the humerus in a 5-year-old boy with cystic fibrosis: A case report.

Antineoplastic treatment of osteoblastic osteosarcoma in a patient with cystic fibrosis (CF) may harbor a high risk of neutropenia-associated complications, and, to the best of our knowledge, has not been previously reported. Diagnosis of CF was confirmed in a 6-week-old boy following pathological newborn screening. The patient had a stable course of CF under standardized continuous therapy. At the age of 5 years, osteosarcoma of the left proximal humerus was diagnosed without evidence of metastases. Neoadjuvant chemotherapy, including doxorubicin, cisplatin and methotrexate, was administered for 10 weeks. The patient tolerated this therapy relatively well, with a continuous antibiotic prophylaxis of cefuroxime without experiencing major complications; in particular, no pulmonary exacerbations were observed as a consequence of immunosuppression or mucosal toxicity. The tumor responded well, and amputation of the limb was avoided via the use of 'clavicle per humerus' osteosynthesis. Postoperatively, compartmental syndrome occurred, requiring management by fasciotomy. Adjuvant chemotherapy was applied thereafter again, without major toxicity that would have required dose reduction. Under intensive physiotherapy, the mobility of the left arm and hand was deemed to be satisfactory. The coincidence of CF with osteosarcoma is extremely rare, and, to the best of our knowledge, has not been previously described. Under antibiotic prophylaxis, antineoplastic treatment was possible without major complications during neutropenia.

Quantitative Subsurface Atomic Structure Fingerprint for 2D Materials and Heterostructures by First-Principles-Calibrated Contact-Resonance Atomic Force Microscopy.

Interfaces and subsurface layers are critical for the performance of devices made of 2D materials and heterostructures. Facile, nondestructive, and quantitative ways to characterize the structure of atomically thin, layered materials are thus essential to ensure control of the resultant properties. Here, we show that contact-resonance atomic force microscopy-which is exquisitely sensitive to stiffness changes that arise from even a single atomic layer of a van der Waals-adhered material-is a powerful experimental tool to address this challenge. A combined density functional theory and continuum modeling approach is introduced that yields sub-surface-sensitive, nanomechanical fingerprints associated with specific, well-defined structure models of individual surface domains. Where such models are known, this information can be correlated with experimentally obtained contact-resonance frequency maps to reveal the (sub)surface structure of different domains on the sample.

Gastric teratoma in a 6-month-old boy.

Gastric teratomas are very rare embryonal neoplasms, accounting for 2.6% of all perinatal diagnosed germ cell tumours. About 85% are well-differentiated mature lesions and about 15% are immature tumours with the potential of malignant transformation. The recommended therapy for gastric teratomas is surgical excision. We present the case of a 6-month-old boy with an incidentally detected epigastric mass. The histological examination revealed a mature gastric teratoma. The diagnostic imaging, therapy and postoperative follow-up are discussed.

Proposal for a precision measurement of |Vub|.

A new method for a precision measurement of the Cabibbo-Kobayashi-Maskawa matrix element |V(ub)| is discussed, which combines good theoretical control with high efficiency and a powerful discrimination against charm background. The resulting combined theoretical uncertainty on |V(ub)| is estimated to be 10%.

Renormalization-group evolution of the B-meson light-cone distribution amplitude.

An integro-differential equation governing the evolution of the leading-order B-meson light-cone distribution amplitude is derived. The anomalous dimension in this equation contains a logarithm of the renormalization scale, whose coefficient is identified with the cusp anomalous dimension of Wilson loops. The exact solution of the evolution equation is obtained, from which the asymptotic behavior of the distribution amplitude is derived. These results can be used to resum Sudakov logarithms entering the hard-scattering kernels in QCD factorization theorems for exclusive B decays.

Hydrolytically activated etoposide prodrugs inhibit MDR-1 function and eradicate established MDR-1 multidrug-resistant T-cell leukemia.

Effective therapy of high-risk leukemia with established cytotoxic drugs may be limited by poor antitumor efficacy, systemic toxicity, and the induction of drug resistance. Here, we provide the first evidence that hydrolytically activated prodrugs may overcome these problems. For this purpose, VP16 was functionally blocked by hydrolytically cleavable carbonate linkers with unique characteristics to generate 2 novel prodrugs of VP16. First, we established a more than 3-log higher efficacy of the 2 prodrugs compared with VP16 on a panel of naturally drug-resistant tumor cell lines. Second, the prodrugs did overcome VP16-induced multidrug resistance-1 gene (MDR-1)-mediated multidrug resistance in vitro in a newly established VP16-resistant T-cell leukemia cell line MOVP-3 by functionally blocking MDR-1-mediated efflux. Third, in vivo studies showed a maximum tolerated dose of ProVP16-II (> 45mg/kg), which was at least 3-fold higher than that of VP16 (15 mg/kg). Finally, tests of ProVP16-II in a multidrug-resistant xenograft model of T-cell leukemia expressing MDR-1 indicated that only the mice treated with this prodrug revealed a complete and long-lasting regression of established, drug-resistant leukemia. In summary, the hydrolytically activated etoposide prodrugs proved effective against multidrug-resistant T-cell leukemia in vitro and in vivo and provide proof of concept for a highly promising new strategy for the treatment of MDR-1 drug-resistant malignancies.

Temperature dependence of light absorption in water at holmium and thulium laser wavelengths.

A simple experimental setup is described that facilitates accurate measurements of the temperature-dependent water absorption coefficient in the mid-infrared spectral region. With this setup, the absorption of holmium and thulium laser radiation in water was quantified to a precision of 0.5%. In the 20-100 degrees C temperature range, a linear decrease of the absorption coefficient with temperature is observed. The slope coefficients amount to -0.104 +/- 0.001 and -0.259 +/- 0.003 l/(K cm) for 2090-nm holmium and 2014-nm thulium radiation, respectively. At both wavelengths, this bleaching reduces the absorption coefficients of water at 100 degrees C by one third when compared with room temperature. A numerical simulation shows that the variable absorption has a noticeable influence on peak temperatures in laser heating of water.